PAIR_ID	Mechanism_description
PAIR0038529	"ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs"
PAIR0038530	"This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance."
PAIR0038531	"This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance."
PAIR0038532	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0038533	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0038534	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038535	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038536	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038537	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038538	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038539	"We found that histone Kla-induced BCAM was overexpressed in OSCC, and a high BCAM level was related to a lower immune cell score and inhibition of immune response. On the other hand, BCAM induced EMT and angiogenesis, leading to OSCC malignant progression via activating the Notch signaling pathway. However, the difference of the BCAM function in Pan-cancers might be attributed to tumor heterogeneity. Taken together, BCAM played a vital role in OSCC chemotherapy resistance and prognosis and contributed to inhibition of the immune process, suggesting that it might be a novel therapeutic target for OSCC. "
PAIR0038540	"This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 5-FU chemoresistance in CRC cells. "
PAIR0038541	"This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 6-FU chemoresistance in CRC cells. "
PAIR0038542	"This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 5-FU chemoresistance in CRC cells. "
PAIR0038543	"This study has demonstrated that overexpression of ALDOB in CRC cells promotes lactagenesis by regulating PDK1 activation. The secreted lactate is then transported to neighboring cells and converted to pyruvate by lactate-induced LDHB, enhancing the ability of OXPHOS in terms of basal respiration and acting as a repressor of CEACAM6 expression. Consequently, ALDOB/lactate-mediated expression of CEACAM6 promotes cell proliferation and 6-FU chemoresistance in CRC cells. "
PAIR0038544	"Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells. "
PAIR0038545	"Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells. "
PAIR0038546	Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
PAIR0038547	TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
PAIR0038548	TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
PAIR0038549	"Metabolic pressures like glutamine deficiency lead to the emergence of an aggressive and poor prognostic reverse Warburg phenotype in PDAC. As the major fuel of this phenotype, lactate taken up by MCT1 maintains cellular redox homeostasis and thereby cell viability during critical shortages of glutamine supply. This also manifests in resistance against inhibitors of glutamine metabolism, thus limiting their usage in the clinic. "
PAIR0038550	"Metabolic pressures like glutamine deficiency lead to the emergence of an aggressive and poor prognostic reverse Warburg phenotype in PDAC. As the major fuel of this phenotype, lactate taken up by MCT1 maintains cellular redox homeostasis and thereby cell viability during critical shortages of glutamine supply. This also manifests in resistance against inhibitors of glutamine metabolism, thus limiting their usage in the clinic. "
PAIR0038551	.
PAIR0038552	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038553	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038554	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038555	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038556	"Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment."
PAIR0038557	"Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment."
PAIR0038558	"In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment."
PAIR0038559	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0038560	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0038561	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0038562	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0038563	"Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1alpha/signal transducer and activator of transcription-4 pathway"
PAIR0038564	Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
PAIR0038565	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K504."
PAIR0038566	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038567	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038568	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038569	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038570	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038571	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC7."
PAIR0038572	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC8."
PAIR0038573	"Recently, the dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 displayed efficacy in different brain cancer animal models"
PAIR0038574	"Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC."
PAIR0038575	"Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC."
PAIR0038576	"Functional experiments using both transgenic mouse models and human cancer-derived models confirmed the critical tumor-suppressive role of OTUB2 in ovarian cancer. Intriguingly, we identified sorting nexin 29 pseudogene 2 (SNX29P2), an ill-defined protein with biased expression in ovarian tissue, as a bona fide substrate of OTUB2. The deubiquitination and stabilization of SNX29P2 by OTUB2 promotes the interaction between the E3 ligase VHL and HIF-1alpha and results in HIF-1alpha degradation, consequently inhibiting the expression of CA9. Activation of CA9 restores OTUB2-mediated inhibition of glycolysis and tumor growth; thus, CA9 inhibitors might be a promising strategy for ovarian cancer treatment."
PAIR0038577	"we demonstrated that FSP3 downregulation suppressed numerous potential axis pathways leading to decreased migration, invasion, colony, and sphere formation."
PAIR0038578	.
PAIR0038579	.
PAIR0038580	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038581	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038582	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038583	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038584	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038585	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038586	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038587	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038588	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038589	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038590	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038591	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038592	"The main study findings were validated in an independent cohort of HER2+ BC patients enrolled in the randomized, phase II trial NeoSphere. Our results consistently indicate a negative predictive role of a metabolic gene, namely CD36, which is not a classical downstream effector of the HER2 pathway, in HER2+ BC patients receiving trastuzumab-based neoadjuvant therapy."
PAIR0038593	"We established cisplatin-resistant ESCA cell line (EC109 CDDP Res) and detected that PVT1 and glutamine metabolism were remarkedly elevated in CDDP-resistant esophageal cancer cells. Bioinformatical analysis and luciferase assay illustrated that PVT1 sponged miR-181a-5p to form a ceRNA network, resulting in the downregulation of miR-181a-5p expression in ESCA cells. Glutaminase (GLS), which is a key enzyme in the glutamine metabolism, was identified and validated as a direct target of miR-181-5p in ESCA cells. Inhibiting glutamine metabolism effectively re-sensitized CDDP-resistant cells."
PAIR0038594	"The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients"
PAIR0038595	"The analysis of differentially expressed proteins exhibited the deregulation of energetic metabolism and mitochondrial pathways. A down-regulation of carbohydrate metabolism and up-regulation of mitochondria organization proteins, the tricarboxylic acid cycle, and oxidative phosphorylation, were observed in nRSs. Of note, Complex I-related proteins were increased in this condition and the inhibition by metformin highlighted that their activity is necessary for nRS survival. Furthermore, a correlation analysis showed that overexpression of Complex I proteins NDUFA10 and NDUFS2 was associated with high clinical risk and worse survival for HER2+ BC patients"
PAIR0038596	"Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. "
PAIR0038597	" SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. "
PAIR0038598	" SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. "
PAIR0038599	"Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition. "
PAIR0038600	"Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect."
PAIR0038601	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0038602	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0038603	"Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARalpha mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARalpha and downstream p-AKT/p-GSK-3beta/beta-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRalpha to the lncRNA UCA1 promoter. "
PAIR0038604	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT1B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038605	"MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions."
PAIR0038606	Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.
PAIR0038607	These results provided new evidence that miR-18a-5p may suppress the Warburg effect by targeting HIF-1alpha.Cells transfected with miR-18a-5p mimics were more sensitive to Adriamycin (AMD) compared with AMD group.
PAIR0038608	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038609	Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3.
PAIR0038610	"In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals."
PAIR0038611	This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS. 
PAIR0038612	"Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level. "
PAIR0038613	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038614	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT2B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038615	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT3B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038616	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT4B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038617	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT5B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038618	"Moreover, enrichment of oxidative phosphorylation (OXPHOS)-associated genes was a common property shared by PDAC cell lines, and patient clinical samples coupled with low DCK expression was also demonstrated, which implicates DCK in cancer metabolism. In this article, we reveal that the expression of most genes encoding mitochondrial complexes is remarkably upregulated in PDAC patients with low DCK expression. The DCK-knockout (DCK KO) CFPAC-1 PDAC cell line model reiterated this observation."
PAIR0038619	"Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. "
PAIR0038620	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038621	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038622	"Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an increased IC50 value of gemcitabine, and a higher abundance of tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, we found that increased C-C motif chemokine ligand 2 (CCL2) release mediated by TGM2 contributes to macrophage infiltration into the tumor microenvironment."
PAIR0038623	"Therefore, in the present study, we set out to reprocess and reanalyze the PDAC PDX gene expression data produced by Yang et al. (referred to as the Yang dataset hereafter) using our validated pipeline to identify markers of intrinsic and acquired resistance to gemcitabine. The association between presence of pathogenic TP53 mutations and gemcitabine response was also examined."
PAIR0038624	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038625	"In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of Pancreatic Cancercells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT6B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma."
PAIR0038626	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038627	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038628	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038629	"Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect."
PAIR0038630	"PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [39]."
PAIR0038631	"PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [40]."
PAIR0038632	"FASN, as a representative gene, was further verified as a promoting factor for gemcitabine resistance in vitro and in vivo. Previous researches have proven that the effect of a FASN inhibitor (TVB-3166) on carcinogenic signals and gene expression enhances the antitumor efficacy of various xenograft tumor models [37]. Our study further demonstrated that TVB-3166 can reverse gemcitabine resistance."
PAIR0038633	"PHGDH is a key enzyme in serine synthesis and is involved in the synthesis of NADPH and glycine. Activation of serine biosynthesis contributes to cancer cell proliferation, and overexpression of PHGDH has been observed in various cancers [21, 32, 33, 34, 35]. Glycine is necessary for the synthesis of glutathione, which is essential for tumorigenesis [36]. Previous studies have reported that NCT503, a small molecule PHGDH inhibitor, impairs the synthesis of glucose-derived serine and induces apoptosis in BC, thereby suppressing tumor growth [37]. High PHGDH expression is a poor prognostic factor for BC [37]. High PHGDH expression has also been reported as a poor prognostic factor in patients with advanced or recurrent non-small cell lung cancer treated with anti-PD-1/PD-L1 antibodies, which would suggest that PHGDH inhibitors have potential clinical application [38]."
PAIR0038634	"After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance."
PAIR0038635	"After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance."
PAIR0038636	"Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway."
PAIR0038637	"We observed that high Dicer levels in pancreatic ductal adenocarcinoma cells were positively correlated with advanced Pancreatic Cancerand acquired resistance to GEM. Metabolomic analysis indicated that PANC-1 GR cells rapidly utilised glutamine as their major fuel and increased levels of glutaminase (GLS): glutamine synthetase (GLUL) ratio which is related to high Dicer expression. In addition, we found that phosphomimetic Dicer S1016E but not phosphomutant Dicer S1016A facilitated miRNA maturation, causing an imbalance in GLS and GLUL and resulting in an increased response to GLS inhibitors."
PAIR0038638	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0038639	"Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC."
PAIR0038640	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0038641	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-10p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038642	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-11p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038643	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-9p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038644	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. "
PAIR0038645	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-6p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038646	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-7p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038647	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-12p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038648	"Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-8p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism."
PAIR0038649	"Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. "
PAIR0038650	"First, an analysis of ABCB6 expression in human NSCLCs was found to be associated with poor prognosis and gemcitabine resistance in a hypoxia-inducible factor (HIF)-1-dependent manner. Further experiments showed that activation of HIF-1alpha/ABCB6 signaling led to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased catalase levels diminished the effective levels of reactive oxygen species, thereby promoting gemcitabine-based resistance. In a mouse NSCLC model, inhibition of HIF-1alpha or ABCB6, in combination with gemcitabine, strongly restrained tumor proliferation, increased tumor cell apoptosis, and prolonged animal survival. "
PAIR0038651	"Using complementary approaches in multiple models, including a MYC-amplified patient-derived cell line and xenograft (LUAD-0006), we established that MYC overexpression induces broad ROS1-TKI resistance. Pharmacologic inhibition of ROS1 combined with MYC knockdown were essential to completely suppress LUAD-0006 cell proliferation compared with either treatment alone. We interrogated cellular signaling in ROS1-TKI-resistant LUAD-0006 and discovered significant differential regulation of targets associated with cell cycle, apoptosis, and mitochondrial function."
PAIR0038652	"Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs' characteristics that can be inhibited by cerulenin."
PAIR0038653	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0038654	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0038655	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038656	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038657	"Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis."
PAIR0038658	"Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1alpha), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells."
PAIR0038659	Upregulation of HIF-1alpha in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of beta-catenin in the nucleus. Both HIF-1alpha gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.
PAIR0038660	"Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1alpha), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells."
PAIR0038661	"Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition. "
PAIR0038662	"In accordance with these findings, we demonstrated that DDX5 bound to PHGDH mRNA and stimulated its expression by suppressing mRNA degradation in colorectal cancer."
PAIR0038663	"Mechanistically, we report that intracellular lipid accumulation results in lipid peroxidation (LPO) overload, whereas mitochondrial DHODH deficiency weakens the ferroptosis defense system. The combination of these factors makes 5-FU-resistant CRC cells susceptible to ferroptosis. Moreover, mitochondrial DHODH redistribution to the cytosol increases intracellular pyrimidine pools, thereby impeding the effectiveness of 5-FU through molecular competition. "
PAIR0038664	"In the TME of CRC-PC, tumor cells outcompete adipocytes for Gln, leading to Gln deficiency. We show that this change in the TME induces GS upregulation in adipocytes, increasing the production of Gln, which promotes resistance of tumor cells to 5FU chemotherapy, a process mediated by mTOR activation. We also show that abnormal methionine metabolism in adipocytes may lead to altered H3k4me2 expression, which contributes to GS upregulation and chemoresistance to 5FU"
PAIR0038665	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 10-FU metabolite concentrations"
PAIR0038666	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 11-FU metabolite concentrations"
PAIR0038667	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 12-FU metabolite concentrations"
PAIR0038668	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 5-FU metabolite concentrations"
PAIR0038669	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 6-FU metabolite concentrations"
PAIR0038670	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 7-FU metabolite concentrations"
PAIR0038671	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 8-FU metabolite concentrations"
PAIR0038672	"Specifically, we elucidated the mechanism underlying 5-FU resistance in CRC cells, whereby the cytosolic DHODH-mediated pathway enhanced intracellular pyrimidine pools, reducing 9-FU metabolite concentrations"
PAIR0038673	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038674	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038675	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038676	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038677	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038678	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038679	"Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and beta5-integrin expression in GemR pancreatic and lung cancer cells as well as stable beta5-integrin-expressing cells."
PAIR0038680	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038681	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038682	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038683	"ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration."
PAIR0038684	"ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration."
PAIR0038685	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0038686	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038687	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038688	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0038689	"We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells."
PAIR0038690	"We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells."
PAIR0038691	"Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC."
PAIR0038692	"Our results revealed that FASN predominates under sensitive conditions, crucially contributing to aerobic respiration. However, its activity diminishes in advanced stages and in tamoxifen-resistant conditions. Conversely, the progressive upregulation of LDHA and the prevalence of anaerobic respiration emerged as metabolic signatures associated with the acquisition of tamoxifen resistance. Subsequently, we delineated the functional roles and metabolic adaptability in response to the inhibition of FASN and LDHA using cellular models representative of tamoxifen-resistant BC."
PAIR0038693	"Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease."
PAIR0038694	"Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival"
PAIR0038695	"Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival"
PAIR0038696	"Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival"
PAIR0038697	"Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO3a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production."
PAIR0038698	"Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO4a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production."
PAIR0038699	"Here, we report, for the first time, an additional mechanism through which an active FoxO3a can counteract Tam resistance in BCCs. Our data demonstrate how FoxO5a can affect multiple biochemical pathways of BC cell metabolism, spanning from the impairment of glucose breakdown, mitochondrial functionality and NADPH production to the induction of ROS production."
PAIR0038700	"Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1alpha/signal transducer and activator of transcription-3 pathway"
PAIR0038701	"Here, we characterized sodium/glucose cotransporter 1 (SGLT1) overexpression drives the highly glycolytic phenotype of tamoxifen-resistant breast cancer cells where enhanced lactic acid secretion promotes M2-like TAM polarization via the hypoxia-inducible factor-1alpha/signal transducer and activator of transcription-4 pathway"
PAIR0038702	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0038703	"Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition."
PAIR0038704	"Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway."
PAIR0038705	"In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals."
PAIR0038706	"In this study, we found that there was a pronounced upregulation of ROCK2 in AML cells. Suppressing ROCK2 significantly boosts the effectiveness of drugs in both AML cell lines and primary AML specimens while causing a substantial decrease in the activation of MAPK and PI3K/AKT pathways."
PAIR0038707	"CA13is involved in cellular pH regulation, carbon dioxide transport, and cell homeostasis. Abnormalities in these processes can affect the tumor microenvironment, influencing cancer cell survival, proliferation, and resistance to therapy"
PAIR0038708	"Mechanistic analysis indicated that the mRNA stability, rather than ERRalpha transcription was markedly increased in chemoresistant OS cells. Therefore, it was hypothesized that the 3'-untranslated region of ERRalpha mRNA was methylated by N6-methyladenine, which could further recruit insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress mRNA decay and increase mRNA stability. IGF2BP1 knockdown downregulated ERRalpha and reversed the metabolic alteration of resistant OS cells. Additionally, the oncogenic effect of the IGF2BP1/ERRalpha axis on Dox-resistant OS cells was verified by in vitro and in vivo experiments. Clinical analysis also revealed that the expression levels of IGF2BP1 and ERRalpha were associated with the clinical progression of OS."
PAIR0038709	"The physical association of TG2 with the cytoskeletal component vimentin appeared pivotal both in drug-treated MCF-7 and in MDA-MB-231 cells and seemed to be independent of the catalytic activity of TG2. NC9 altered the subcellular distribution of TG2 and, consequently, the co-localization of TG2 with vimentin. Furthermore, NC9 induced a nuclear accumulation of TG2 as a prelude to TG2-dependent gene expression modifications. Since enzyme activity can affect both motility and nuclear functions, targeting of this protein could represent a method to improve therapeutic interventions in breast tumors, particularly those to control progression and to limit drug resistance."
PAIR0038710	"In conclusion, we have identified a mechanistic chain initiated by NEK10 that regulates de novo purine synthesis through C-MYC, contributing to the development of chemotherapy resistance."
PAIR0038711	"In conclusion, we have identified a mechanistic chain initiated by NEK6 that regulates de novo purine synthesis through C-MYC, contributing to the development of chemotherapy resistance."
PAIR0038712	"In conclusion, we have identified a mechanistic chain initiated by NEK7 that regulates de novo purine synthesis through C-MYC, contributing to the development of chemotherapy resistance."
PAIR0038713	"In conclusion, we have identified a mechanistic chain initiated by NEK8 that regulates de novo purine synthesis through C-MYC, contributing to the development of chemotherapy resistance."
PAIR0038714	"In conclusion, we have identified a mechanistic chain initiated by NEK9 that regulates de novo purine synthesis through C-MYC, contributing to the development of chemotherapy resistance."
PAIR0038715	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0038716	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0038717	"Our study found significant correlations between ROMO1 and NE-related gene upregulation in PCa after ADT, which may have been caused by the nuclear translocation of PKLR and its interaction with the MYCN/MAX complex to promote ROMO1 and NE marker expression. Importantly, we found that this interaction decreased after treatment with a putative MYCN inhibitor. These data suggest that PKLR may also act as a transcription cofactor of MYCN, in addition to acting as a kinase, similar to PKM2, which acts as a transcription cofactor to activate hypoxia-inducible factor-1A (HIF1A) to promote castration resistance [22]. "
PAIR0038718	"Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate."
PAIR0038719	"Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate."
PAIR0038720	"Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-kappaB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment."
PAIR0038721	"The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy."
PAIR0038722	"Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-kappaB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo."
PAIR0038723	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX10 expression."
PAIR0038724	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX11 expression."
PAIR0038725	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX12 expression."
PAIR0038726	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX13 expression."
PAIR0038727	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX9 expression."
PAIR0038728	"The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance."
PAIR0038729	"The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes.In vitroexperiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance."
PAIR0038730	The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. 
PAIR0038731	The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. 
PAIR0038732	"Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate."
PAIR0038733	"Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate."
PAIR0038734	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER4-positive BC.
PAIR0038735	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER5-positive BC.
PAIR0038736	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038737	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038738	"The overexpression of EGR1 in ibrutinib-resistant cells is likely to result from the transcription factor TCF4-mediated EGR1 transcription and EGR1 self-regulation. Genetic and pharmacological inhibition of EGR1 restores the sensitivity of the resistant cells to ibrutinib, suggesting a role EGR1 plays in ibrutinib resistance. The underlying mechanism is that EGR1 mediates metabolic reprogramming to mitochondrial OXPHOS by transcriptional activation of PDP1, which increases ATP production."
PAIR0038739	We provide evidence that DNMT3A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.
PAIR0038740	We provide evidence that DNMT4A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.
PAIR0038741	We provide evidence that DNMT5A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.
PAIR0038742	We provide evidence that DNMT6A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.
PAIR0038743	We provide evidence that DNMT7A contributes to ibrutinib resistance in MCL by increasing mitochondrial biogenesis and OXPHOS. Recent clinical studies demonstrated the potential of BTKis as a first-line treatment option for MCL.
PAIR0038744	"Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition."
PAIR0038745	"Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition."
PAIR0038746	"Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition."
PAIR0038747	"PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC11 cells, and the YAP expression was inhibited by pitavastatin administration."
PAIR0038748	"PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. "
PAIR0038749	"It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT1 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD"
PAIR0038750	"It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT2 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD"
PAIR0038751	"It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT3 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD"
PAIR0038752	"It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT4 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD"
PAIR0038753	"It is confirmed that purine metabolism catalyzed by HPRT1 promotes the proliferation of EGFR-mutant LUAD in vitro and in vivo. Furthermore, the study of the mechanism shows that HIF-1alpha transcriptionally regulates HPRT1 to accelerate purine nucleotides synthesis to promote cell proliferation and tumorigenesis. Finally, inhibition of HPRT5 coupled with EGFR-TKIs significantly inhibits the tumor growth of EGFR-mutant LUAD"
PAIR0038754	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis in NSCLC."
PAIR0038755	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B3 axis in NSCLC."
PAIR0038756	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis in NSCLC."
PAIR0038757	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B3 axis in NSCLC."
PAIR0038758	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038759	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038760	"In addition, the lncRNA PXN-AS1 was found to mediate GS expression and disorder cell cycle in CML IR cells via mTOR signaling pathway. PXN-AS1 regulated GS expression by binding to miR-635. Additionally, knockdown of PXN-AS1 attenuated BCR::ABL1-independent Imatinib resistance in CML cells via PXN-AS1/miR-635/GS/Gln/mTOR signaling pathway."
PAIR0038761	"Here, we demonstrate that TXNIP expression was decreased in response to the activated BCR-ABL signaling, which is associated with a previously unappreciated mechanism that involves in c-Myc/Miz-1/P300 complex. Restoration of TXNIP expression sensitizes CML cells to imatinib treatment, potentially through the blockage of glucose metabolism. In particular, TXNIP suppressed glycolytic enzyme expressions through Fbw7-dependent c-Myc degradation. BCR-ABL suppression of TXNIP provided a novel survival pathway for CML transformation."
PAIR0038762	"Here, we demonstrate that TXNIP expression was decreased in response to the activated BCR-ABL signaling, which is associated with a previously unappreciated mechanism that involves in c-Myc/Miz-1/P300 complex. Restoration of TXNIP expression sensitizes CML cells to imatinib treatment, potentially through the blockage of glucose metabolism. In particular, TXNIP suppressed glycolytic enzyme expressions through Fbw7-dependent c-Myc degradation. BCR-ABL suppression of TXNIP provided a novel survival pathway for CML transformation."
PAIR0038763	Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.
PAIR0038764	Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer.
PAIR0038765	Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer.
PAIR0038766	Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer.
PAIR0038767	Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer.
PAIR0038768	"Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models."
PAIR0038769	"Furthermore, we identified E3-ubiquitin ligase NEDD4L as a major regulator of GPX4 stability. Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4."
PAIR0038770	"Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase?1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC"
PAIR0038771	"ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach."
PAIR0038772	"Lactylation is upregulated in recurrent glioblastoma (GBM) tissues and temozolomide (TMZ)-resistant cells, mainly concentrated in histone H3K9. H3K9 lactylation activates LUC7L2 transcription. LUC7L2 mediates MLH1 intron 7 retention to reduce MLH1 expression, thereby inhibit mismatch repair (MMR), ultimately leading to TMZ resistance."
PAIR0038773	"Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM."
PAIR0038774	"DSCR3 is upregulated in MGMT-deficient GBM cells during TMZ treatment. Both DSCR3 and SLC38A1 were highly expressed in recurrent GBM patients. Silencing DSCR3 or SLC38A1 expression can increase TMZ sensitivity in MGMT-deficient GBM cells. Combination of proteomics and in vitro experiments show that DSCR3 directly binds internalized SLC38A1 to mediate its sorting into recycling pathway, which maintains the abundance on plasma membrane and enhances uptake of glutamine in MGMT-deficient GBM cells."
PAIR0038775	Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
PAIR0038776	Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
PAIR0038777	Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
PAIR0038778	Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
PAIR0038779	"ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs"
PAIR0038780	"ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs"
PAIR0038781	"In summary, this study investigated the important role of 6PGD in promoting TNBC progression and attenuating chemotherapy response efficacy of chemotherapy-resistant cells. Inhibition of 6PGD and epirubicin exerted synergistic effects on resistant cells, effectively increasing the sensitivity of resistant cells to chemotherapeutic agents through metabolic remodeling. Therefore, 6PGD might be a potential and important metabolic target in clinical applications such as reversing chemotherapy resistance in TNBC and tumor therapies."
PAIR0038782	"Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARalpha mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARalpha and downstream p-AKT/p-GSK-3beta/beta-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRalpha to the lncRNA UCA1 promoter. "
PAIR0038783	"Our findings demonstrate that lncRNA UCA1 positively regulates the expression of CD36 and FATP, which are known to stimulate fatty acid uptake."
PAIR0038784	"Our findings demonstrate that lncRNA UCA1 positively regulates the expression of CD36 and FATP, which are known to stimulate fatty acid uptake."
PAIR0038785	"Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPARalpha mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPARalpha and downstream p-AKT/p-GSK-3beta/beta-catenin signaling. Furthermore, mixed free fatty acids upregulated lncRNA UCA1 expression by promoting recruitment of the transcription factor RXRalpha to the lncRNA UCA1 promoter. "
PAIR0038786	"In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-alpha-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs."
PAIR0038787	"In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-alpha-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs."
PAIR0038788	"In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-alpha-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs."
PAIR0038789	"In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-alpha-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs."
PAIR0038790	"PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT1A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression."
PAIR0038791	"PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT2A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression."
PAIR0038792	"PC knockdown significantly inhibited PDAC progression. Lactate content, SUVmax, and ECAR significantly decreased after PC knockdown. Peroxisome proliferator-activated receptor gamma coactivator-one alpha (PGC-1alpha) was upregulated after PC knockdown; and PGC1a expression promoted AMPK phosphorylation to activate mitochondrial metabolism. Metformin significantly inhibited mitochondrial respiration after PC knockdown, further activated AMPK and downstream carnitine palmitoyltransferase 1A (CPT3A)-regulated fatty acid oxidation (FAO), and inhibited PDAC cells progression."
PAIR0038793	"Our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC."
PAIR0038794	"Our results reveal that PDT resistance implies, at least partially, a metabolic reprogramming towards aerobic glycolysis that is prevented by metformin treatment. Therefore, metformin may constitute an excellent adjuvant for PDT in sSCC."
PAIR0038795	"Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level. "
PAIR0038796	"Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing nonsmall cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment."
PAIR0038797	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0038798	"The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy."
PAIR0038799	"The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy."
PAIR0038800	"The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy."
PAIR0038801	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0038802	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0038803	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER6-positive BC.
PAIR0038804	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER7-positive BC.
PAIR0038805	"Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer."
PAIR0038806	"Immunoblotting showed the upregulation of Bcl-2 phosphorylation and a decrease in Mcl-1 expression in SKOV3-TR via the cotreatment of paclitaxel with PF-4708671 and V-9302. Collectively, this study demonstrates that the inhibition of glutamine uptake can resensitize SKOV3-TR to paclitaxel and represents a promising therapeutic target for overcoming paclitaxel resistance in ovarian cancer."
PAIR0038807	Warburg effect activated HIF1-alpha-mediated signaling-induced autophagic pathway may have an important role in paclitaxel chemoresistance.
PAIR0038808	Our evidence revealed that Icariin-Curcumol attenuated DTX resistance through modulation of the PI3K-Akt pathway and the Warburg effect and that Icariin-Curcumol and DTX have synergistic effects.
PAIR0038809	"FOXG1 exhibited high expression in PCa tissues and cell lines. Knockdown of FOXG1 inhibited the proliferation, migration, and invasion of PCa cells, while FOXG1 overexpression had the opposite effect and promoted OXPHOS levels. The addition of an OXPHOS inhibitor prevented this outcome. Finally, SSd was shown to suppress FOXG1 expression and reverse docetaxel resistance in PCa cells through the OXPHOS pathway."
PAIR0038810	Our evidence revealed that Icariin-Curcumol attenuated DTX resistance through modulation of the PI3K-Akt pathway and the Warburg effect and that Icariin-Curcumol and DTX have synergistic effects.
PAIR0038811	"Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism."
PAIR0038812	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492."
PAIR0038813	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K493."
PAIR0038814	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K494."
PAIR0038815	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K495."
PAIR0038816	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K496."
PAIR0038817	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K497."
PAIR0038818	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K498."
PAIR0038819	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K499."
PAIR0038820	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0038821	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K500."
PAIR0038822	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K501."
PAIR0038823	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K502."
PAIR0038824	"Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K503."
PAIR0038825	"Pharmacological and genetic interference with GLUD1 in vitro significantly reversed drug resistance and decreased cell migration and invasion capability. Lastly, the successful application of R162, a selective GLUD1 inhibitor, to overcome both acquired resistance and EMT-induced metastasis in vivo, identified GLUD1 as a promising and druggable therapeutic target for malignant progression of NSCLC. Collectively, our study offers a potential strategy for NSCLC therapy, especially for drug-resistant patients with highly expressed GLUD1."
PAIR0038826	This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS. 
PAIR0038827	"SLC1A3 had the highest mRNA expression level in PC-9/OsmR2 compared to PC-9 cells by microarray analysis and SLC1A3 was increased by flow cytometry. In PC-9/OsmR2 cells, osimertinib sensitivity was significantly increased in combination with siSLC1A3. Because SLC1A3 functions in glutamic acid transport, osimertinib with a glutaminase inhibitor (CB-839) or an SLC1A3 inhibitor (TFB-TBOA) increased the sensitivity. "
PAIR0038828	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA5-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038829	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA6-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038830	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA7-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038831	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA8-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038832	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA9-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038833	"Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy."
PAIR0038834	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B4 axis in NSCLC."
PAIR0038835	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B5 axis in NSCLC."
PAIR0038836	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B4 axis in NSCLC."
PAIR0038837	"Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B5 axis in NSCLC."
PAIR0038838	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038839	"We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. "
PAIR0038840	"Here, we identified PKCalpha as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA sequencing of t(4;14) multiple myeloma cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCalpha, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCalpha in a PI3K/Akt-dependent manner. Loss of PKCalpha displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. In addition, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production."
PAIR0038841	"Mechanistically, silencing of SLC25A17 and SLC27A6 led to the downregulation of FASN and ACC and their downstream metabolic products including triglycerides and lactic acid with a decrease in cell proliferation and migration in C4-2B enzalutamide resistant cells (Figures 5 and 6). Suppression of SLC25A17 and SLC27A6 delays cell cycle progression with the reduction in the protein expression of CyclinD1 and CDK6 in enzalutamide resistant cells (Figures 4 and 5)."
PAIR0038842	"Mechanistically, silencing of SLC25A17 and SLC27A6 led to the downregulation of FASN and ACC and their downstream metabolic products including triglycerides and lactic acid with a decrease in cell proliferation and migration in C4-2B enzalutamide resistant cells (Figures 5 and 6). Suppression of SLC25A17 and SLC27A6 delays cell cycle progression with the reduction in the protein expression of CyclinD1 and CDK6 in enzalutamide resistant cells (Figures 4 and 5)."
PAIR0038843	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-11B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038844	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038845	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-16B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038846	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-7B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038847	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-12B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038848	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-3B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038849	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-18B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038850	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-9B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038851	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-17B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038852	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-8B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038853	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-13B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038854	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-4B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038855	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-14B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038856	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-5B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038857	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-15B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038858	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-6B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038859	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-10B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038860	We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-19B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation
PAIR0038861	"Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. "
PAIR0038862	"Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. "
PAIR0038863	"In this study, we demonstrate, for the first time, that MPC was significantly expressed at low levels in NEPC cells and that its downregulation contributed to NED and enzalutamide resistance. Moreover, MPC overexpression increased enzalutamide sensitivity and reversed NED in adenocarcinoma prostate cancer. These effects were likely mediated through the EMT induced by nuclear PKM2 translocation, which is controlled by acetyl-CoA, a product of pyruvate catabolism."
PAIR0038864	"Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. "
PAIR0038865	"Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. "
PAIR0038866	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-10p overexpression results in suppressing nuclear translocation of"
PAIR0038867	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-5p overexpression results in suppressing nuclear translocation of"
PAIR0038868	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-6p overexpression results in suppressing nuclear translocation of"
PAIR0038869	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-7p overexpression results in suppressing nuclear translocation of"
PAIR0038870	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-8p overexpression results in suppressing nuclear translocation of"
PAIR0038871	"On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-9p overexpression results in suppressing nuclear translocation of"
PAIR0038872	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM2 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038873	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM3 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038874	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM4 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038875	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM5 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038876	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM6 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038877	"Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM7 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease."
PAIR0038878	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038879	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038880	"Shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. "
PAIR0038881	"Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT5 increased the susceptibility of sunitinib-resistant cells."
PAIR0038882	"Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC2 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC."
PAIR0038883	"Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC4 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC."
PAIR0038884	"Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. "
PAIR0038885	"Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC1 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC."
PAIR0038886	"Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC3 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC."
PAIR0038887	"Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT1 increased the susceptibility of sunitinib-resistant cells."
PAIR0038888	"Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT2 increased the susceptibility of sunitinib-resistant cells."
PAIR0038889	"Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT3 increased the susceptibility of sunitinib-resistant cells."
PAIR0038890	"Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT4 increased the susceptibility of sunitinib-resistant cells."
PAIR0038891	"In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 2a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)"
PAIR0038892	"In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 3a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)"
PAIR0038893	"Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC5 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC."
PAIR0038894	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB3 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038895	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB4 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038896	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB5 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038897	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB6 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038898	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB7 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038899	"In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB8 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression."
PAIR0038900	"Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. "
PAIR0038901	"Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC. "
PAIR0038902	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO2was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0038903	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO3was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0038904	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO4was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0038905	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO5was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0038906	"This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress."
PAIR0038907	"Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism."
PAIR0038908	"We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis."
PAIR0038909	"We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis."
PAIR0038910	"We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis."
PAIR0038911	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS10 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0038912	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS6 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0038913	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS7 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0038914	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS8 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0038915	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS9 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0038916	"Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis."
PAIR0038917	"Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis."
PAIR0038918	"The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma."
PAIR0038919	"The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma."
PAIR0038920	"The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma."
PAIR0038921	"Immunohistochemical analysis revealed that higher PDK1 expression is associated with a poor prognosis in OSCC. The immunoprecipitation assay indicated PDK1/CD47 binding. PDK1 ligation significantly impaired OSCC orosphere formation and downregulated Sox2, Oct4, and CD133 expression. The combination of BX795 and cisplatin markedly reduced in OSCC cell's epithelial-mesenchymal transition, implying its synergistic effect. p-PDK1, CD47, Akt, PFKP, PDK3 and LDHA protein expression were significantly reduced, with the strongest inhibition in the combination group. Chemo/radiotherapy together with abrogation of PDK1 inhibits the oncogenic (Akt/CD47) and glycolytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming."
PAIR0038922	"The results revealed that miR?106b?3p levels were upregulated, whereas TMG3 levels were downregulated in ESCC tissues. Dual?luciferase reporter assays confirmed that miR?106b?3p negatively regulated TGM3 expression by binding to its 3'UTR sequence. It was also shown that inhibition of miR?106b?3p could enhance the anti?proliferative effects, while promoting the apoptotic effects of cisplatin in the KYSE30 cell line by targeting TGM3. In conclusion, the present study demonstrated that downregulation of miR?106b?3p may increase the sensitivity of KYSE30 cell to cisplatin by targeting TGM3."
PAIR0038923	"The results revealed that miR?106b?3p levels were upregulated, whereas TMG3 levels were downregulated in ESCC tissues. Dual?luciferase reporter assays confirmed that miR?106b?3p negatively regulated TGM3 expression by binding to its 3'UTR sequence. It was also shown that inhibition of miR?106b?3p could enhance the anti?proliferative effects, while promoting the apoptotic effects of cisplatin in the KYSE30 cell line by targeting TGM3. In conclusion, the present study demonstrated that downregulation of miR?106b?3p may increase the sensitivity of KYSE30 cell to cisplatin by targeting TGM3."
PAIR0038924	Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.
PAIR0038925	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC3."
PAIR0038926	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC4."
PAIR0038927	"Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1alpha (HIF-1alpha), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. "
PAIR0038928	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC5."
PAIR0038929	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC6."
PAIR0038930	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC1."
PAIR0038931	"Taken together, in the present study, HKDC1 was showed to modulate gastric cancer metastasis and to play a pivotal role in gastric cancer chemoresistance by remodeling lipid metabolism. Our results strongly indicate that the newly identified HKDC1/G3BP1-PRKDC axis is a potential therapeutic target in GC and that specific small molecule inhibitors of PRKDC can be used to treat GC patients with high expression levels of HKDC2."
PAIR0038932	"Using a microRNA (miRNA) microArray assay, miR-137, a tumor suppressor in colon cancer, was significantly induced by curcumin treatments in CRC cells. Bioinformatics analysis and a luciferase assay illustrated miR-137 directly targeted the 3' UTR of GLS mRNA. Rescue experiments demonstrated that miR-137-induced cisplatin sensitization was through targeting of GLS. Finally, curcumin treatment overcame cisplatin resistance through miR-137-mediated glutamine inhibition."
PAIR0038933	"Overexpression of YTHDF1 decreased the cisplatin sensitivity of colon cancer cells. From the established cisplatin-resistant CRC cell line (LoVo CDDP R), we detected that YTHDF1 was significantly upregulated in cisplatin-resistant CRC cells. Intriguingly, RNA sequencing (RNA-seq) results revealed that glutamine metabolism enzymes were clearly upregulated in LoVo CDDP R cells. Glutamine uptake, that is, glutaminase (GLS) activity, was upregulated in LoVo CDDP R cells. Furthermore, bioinformatics analysis indicated that the 3' UTR of GLS1 contained a putative binding motif of YTHDF1, and an interaction was further validated by a protein-RNA interaction assay (RNA immunoprecipitation [RIP])."
PAIR0038934	Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11-RAD50-NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks.It promotes DNA-damaging treatment resistance via HR repair.
PAIR0038935	The molecular mechanisms on how PRMT6 linked cell metabolism to tumor growth were also explored by regulating the enzyme activity of 6PGD/ENO1 mediated by asymmetric arginine demethylation modification.
PAIR0038936	"The present study demonstrated that ADM can induce cisplatin chemoresistance in human ovarian epithelial carcinoma cells through reprogramming of glucose metabolism via upregulation of PKM2 and subsequently contribute to cancer prevention and therapy. This conclusion is supported by the following observations: (1) ADM expression was upregulated in cisplatin-resistant EOC cells; (2) ADM attenuated cisplatin-inhibited cell survival and cisplatin-induced apoptosis in sensitive EOC cells; (3) knockdown of ADM enhanced cisplatin chemosensitivity of cisplatin-resistant EOC cells; (4) ADM enhanced glycolysis in cisplatin-sensitive EOC cells; (5) knockdown of ADM significantly inhibited glycolysis in cisplatin-resistant EOC cells; and (6) ADM significantly upregulated PKM2 protein level, the key enzyme during glycolysis. "
PAIR0038937	"The present study demonstrated that ADM can induce cisplatin chemoresistance in human ovarian epithelial carcinoma cells through reprogramming of glucose metabolism via upregulation of PKM2 and subsequently contribute to cancer prevention and therapy. This conclusion is supported by the following observations: (1)ADMexpression was upregulated in cisplatin-resistant EOC cells; (2) ADM attenuated cisplatin-inhibited cell survival and cisplatin-induced apoptosis in sensitive EOC cells; (3) knockdown of ADM enhanced cisplatin chemosensitivity of cisplatin-resistant EOC cells; (4) ADM enhanced glycolysis in cisplatin-sensitive EOC cells; (5) knockdown of ADM significantly inhibited glycolysis in cisplatin-resistant EOC cells; and (6) ADM significantly upregulated PKM2 protein level, the key enzyme during glycolysis."
PAIR0038938	"Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2."
PAIR0038939	"Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues."
PAIR0038940	"Our data demonstrated that BAG5 knockdown was implicated in metabolic reprogramming and maintenance of cancer stem cell (CSC)-like features of ovarian cancer cells via regulation of Rictor and subsequent mTORC2 signaling pathway. In addition, the current study demonstrated that Bcl6 upregulation was responsible for repression of BAG5 transactivation via recruitment on the BAG5 promoter in cisplatin-resistant ovarian cancer. The current study also demonstrated reverse correlations between BAG5 and Bcl6, BAG5 and Rictor in ovarian serous adenocarcinoma tissues."
PAIR0038941	"Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival."
PAIR0038942	"Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP2 inversely correlates with stage and grade and directly correlates with survival."
PAIR0038943	"Thus, this study aimed to elucidate the underlying mechanisms by which ovarian cancer cells acquire CDDP resistance."
PAIR0038944	"Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK3."
PAIR0038945	"High expression of ERRalpha, triggered by the hypoxic microenvironment, enhances cell resistance to pyroptosis by direct target binding to the promoter of NLRP3 with the sequence 3'-ACAACTTGAACACGGAAACG-5', inhibiting the downstream pyroptosis signaling pathway. Moreover, overexpression of ERRalpha participates in the malignant progression of EC through the reprogramming of glycolysis, accompanied by increased extracellular acidification rate, which leads to the resistance of EC cells to pyroptosis and cisplatin chemotherapy (Fig. 7)."
PAIR0038946	"High expression of ERRalpha, triggered by the hypoxic microenvironment, enhances cell resistance to pyroptosis by direct target binding to the promoter of NLRP3 with the sequence 3'-ACAACTTGAACACGGAAACG-5', inhibiting the downstream pyroptosis signaling pathway. Moreover, overexpression of ERRalpha participates in the malignant progression of EC through the reprogramming of glycolysis, accompanied by increased extracellular acidification rate, which leads to the resistance of EC cells to pyroptosis and cisplatin chemotherapy (Fig. 7)."
PAIR0038947	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0038948	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0038949	"Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 46]."
PAIR0038950	"Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 47]."
PAIR0038951	"Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa."
PAIR0038952	"Acetyl-CoA is then carboxylated into malonyl-CoA via acetyl-CoA carboxylase, and malonyl-CoA is then converted to the 16-carbon-long fatty acid palmitic acid by the enzyme FASN. Enzymes involved in fatty acid synthesis are highly expressed in many types of cancer, and their pharmacological inhibition has been shown to exert anticancer activity [43]. ATP citrate lyase and FASN upregulation has been shown in colorectal, gastric, liver, and lung cancer, and their overexpression has been significantly associated with poor survival in lung cancer patients [44, 45]."
PAIR0038953	"After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance."
PAIR0038954	"After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFbeta1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFbeta1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance."
PAIR0038955	"Furthermore, analyses of the DEMRGs in METArisk phenotypes suggested PYGL, the key biomarker in glycogen degradation, was strongly potential to guide the development and drug resistance of HNSCC by the PYGL/GSH/ROS/p53 pathway, thereby setting the foundation for new clinical therapies of HNSCC in the future"
PAIR0038956	"Furthermore, analyses of the DEMRGs in METArisk phenotypes suggested PYGL, the key biomarker in glycogen degradation, was strongly potential to guide the development and drug resistance of HNSCC by the PYGL/GSH/ROS/p54 pathway, thereby setting the foundation for new clinical therapies of HNSCC in the future"
PAIR0038957	"we demonstrated that FSP1 downregulation suppressed numerous potential axis pathways leading to decreased migration, invasion, colony, and sphere formation. "
PAIR0038958	"we demonstrated that FSP2 downregulation suppressed numerous potential axis pathways leading to decreased migration, invasion, colony, and sphere formation."
PAIR0038959	"Furthermore, analyses of the DEMRGs in METArisk phenotypes suggested PYGL, the key biomarker in glycogen degradation, was strongly potential to guide the development and drug resistance of HNSCC by the PYGL/GSH/ROS/p55 pathway, thereby setting the foundation for new clinical therapies of HNSCC in the future"
PAIR0038960	"PDK1 inhibition by siRNA or DCA significantly suppressed the growth of ESCC cells. miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and DDP synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress partly through the suppression of Keap1/Nrf2 signaling pathway."
PAIR0038961	"Consistently, PTBP1 promotes glutamine uptake and the glutamine metabolism key enzyme, glutaminase (GLS) expression. Bioinformatics analysis predicted that the 3'-UTR of GLS mRNA contained PTBP1 binding motifs which were further validated by RNA immunoprecipitation and RNA pull-down assays. PTBP1 associated with GLS 3'-UTR to stabilize GLS mRNA in HCC cells. Finally, we demonstrated that the PTBP1-promoted CDDP resistance of HCC cells was through modulating the GLS-glutamine metabolism axis."
PAIR0038962	"Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase?1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC"
PAIR0038963	"Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis."
PAIR0038964	"Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis."
PAIR0038965	"Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells. "
PAIR0038966	"The observed elevation in GLS1 expression, which is important in glutaminolysis, and intracellular glutamine and glutamate levels in SCK-R cells, revealed that glutaminolysis was associated with metabolic reprogramming represented by cisplatin resistance in SCK-R cells. Indeed, treatment with CB-839 led to reduced L1CAM, AXL, and ZEB2 expression. Combination treatment with DRB18 and CB-839 reduced SCK-R cell proliferation. Based on these results, we speculate that inhibiting glucose and glutamine metabolism re-sensitized SCK-R cells to cisplatin."
PAIR0038967	"Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells. "
PAIR0038968	"Our research unequivocally underscores the critical role of MAL2 as an oncogenic promoter in ICC. Upon exposure to EGF, MAL2 exhibits its ability to retain EGFR on the cell surface, thwarting the endocytosis process. This action consecutively triggers the PI3K/AKT/SREBP-1 signaling cascade, inciting an increase in lipid deposition within ICC cells. "
PAIR0038969	"Herein, we found that the abnormal IGF1R pathway is a potential target for OSCC therapy. Under low-oxygen conditions, IGF1R induces DDP resistance by enhancing ASS1 and PYCR1 expression to promote arginine and proline metabolism. Combining the IGF1R inhibitor linsitinib and DDP led to synergistic effects on inhibiting cell proliferation in vitro and in vivo."
PAIR0038970	"We demonstrated that SREBP-1 and SCAP are highly expressed in NSCLC and are positively correlated with the aggressive phenotypes of NSCLC cells. In addition, downregulation of the expression of tumor-suppressing hsa-miR-497-5p, which predictively targets SREBP-1, was observed. We also demonstrated that SREBP-1/SCAP/FASN lipogenic signaling plays a key role in CSCs-like and chemoresistant NSCLC phenotypes, especially because the fatostatin or shRNA targeting of SREBP-1 significantly suppressed the viability, cisplatin resistance, and cancer stemness of NSCLC cells and because treatment induced the expression of hsa-miR-497."
PAIR0038971	"We demonstrated that SREBP-1 and SCAP are highly expressed in NSCLC and are positively correlated with the aggressive phenotypes of NSCLC cells. In addition, downregulation of the expression of tumor-suppressing hsa-miR-497-5p, which predictively targets SREBP-1, was observed. We also demonstrated that SREBP-1/SCAP/FASN lipogenic signaling plays a key role in CSCs-like and chemoresistant NSCLC phenotypes, especially because the fatostatin or shRNA targeting of SREBP-1 significantly suppressed the viability, cisplatin resistance, and cancer stemness of NSCLC cells and because treatment induced the expression of hsa-miR-497."
PAIR0038972	"The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance."
PAIR0038973	"The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance."
PAIR0038974	"In cisplatin-resistant MB cell line, DAOY Cis R, NEAT1 expression, and glutamine metabolism were remarkably upregulated in cisplatin-resistant cells. Under low glutamine supply, cisplatin-resistant cells displayed increased cisplatin sensitivity. Bioinformatical analysis and luciferase assay uncovered that NEAT1 functions as a ceRNA of miR-23a-3p to downregulate its expressions in MB cells. Moreover, miR-23a-3p was apparently downregulated in MB patient tissues and cisplatin resistant MB cells. We identified GLS (glutaminase), a glutamine metabolism enzyme, was directly targeted by miR-23a-3p in MB cells. "
PAIR0038975	"In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl5 signaling pathway."
PAIR0038976	"In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment."
PAIR0038977	"Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib."
PAIR0038978	"In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl2 signaling pathway. "
PAIR0038979	"In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl3 signaling pathway."
PAIR0038980	"In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl4 signaling pathway."
PAIR0038981	"MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions."
PAIR0038982	"Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC."
PAIR0038983	"NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results."
PAIR0038984	"NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results."
PAIR0038985	"Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib."
PAIR0038986	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0038987	"NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results."
PAIR0038988	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0038989	"Here, we confirmed the synergic effect of antimiR-494/sorafenib treatment and demonstrated for the first time that, together with AKT pathway repression, G6pc targeting mediates miR-494-induced sorafenib resistance in HCC cells. In line, the oncomiR-21 triggered sorafenib resistance in HCC cells by PTEN direct targeting or by regulating the nuclear localization of the long non-coding RNA SNHG1 [63]."
PAIR0038990	"Here, we confirmed the synergic effect of antimiR-494/sorafenib treatment and demonstrated for the first time that, together with AKT pathway repression, G6pc targeting mediates miR-494-induced sorafenib resistance in HCC cells. In line, the oncomiR-21 triggered sorafenib resistance in HCC cells by PTEN direct targeting or by regulating the nuclear localization of the long non-coding RNA SNHG1 [63]."
PAIR0038991	Our findings suggest that glycolysis promotes sorafenib resistance through maintaining AMPK activation.
PAIR0038992	"Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib."
PAIR0038993	"Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC."
PAIR0038994	"MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions."
PAIR0038995	"Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib."
PAIR0038996	"In this study, we found that HBXIP suppresses ferroptosis by inducing abnormal free FA accumulation and blocks the anti-cancer activity of sorafenib in HCC cells. Mechanistic investigation revealed that HBXIP acts as a coactivator to induce SCD expression via coactivating transcription factor ZNF263, leading to upregulation of FA biosynthesis. Overexpression of HBXIP prevents ferroptosis and reduces the anti-tumor effect of sorafenib in vivo and in vitro. "
PAIR0038997	"In this study, we found that HBXIP suppresses ferroptosis by inducing abnormal free FA accumulation and blocks the anti-cancer activity of sorafenib in HCC cells. Mechanistic investigation revealed that HBXIP acts as a coactivator to induce SCD expression via coactivating transcription factor ZNF263, leading to upregulation of FA biosynthesis. Overexpression of HBXIP prevents ferroptosis and reduces the anti-tumor effect of sorafenib in vivo and in vitro. "
PAIR0038998	"In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment."
PAIR0038999	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039000	Our findings suggest that glycolysis promotes sorafenib resistance through maintaining AMPK activation.
PAIR0039001	"ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo."
PAIR0039002	"ACTR promotes glycolysis through upregulation of glucose uptake, ATP and lactate production, and reduction of the extracellular acidification and the oxygen consumption rates. Glycolysis regulated by ACTR is vital for the susceptibility of HCC to sorafenib in vitro and in vivo."
PAIR0039003	"In the KIRC tissues, a high expression of PGK1 is often accompanied with an increase of glycolysis-related enzymes and CXCR4. PGK1 exhibits pro-tumorigenic properties in vitro and in a xenograft tumor model by accelerating glycolysis and inducing CXCR4-mediated phosphorylation of AKT and ERK. Moreover, PGK1 promotes sorafenib resistance via increasing CXCR4-mediated ERK phosphorylation. "
PAIR0039004	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0039005	"Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize gamma-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. "
PAIR0039006	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0039007	"Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer."
PAIR0039008	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0039009	"Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer."
PAIR0039010	"Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis."
PAIR0039011	"our findings revealed that oxaliplatin impressed a specific lipid profile signature and lipid transcriptional reprogramming in HT29 cells, which provides new insights into biomarker discovery and pathways for overcoming drug resistance and adverse reactions."
PAIR0039012	"Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis."
PAIR0039013	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0039014	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0039015	"Glucomet-PDACs are more resistant to chemotherapy than lipomet-PDACs, and patients with glucomet-PDAC have a worse prognosis. Integrated analyses reveal that the GLUT1/aldolase B (ALDOB)/glucose-6-phosphate dehydrogenase (G6PD) axis induces chemotherapy resistance by remodeling glucose metabolism in glucomet-PDAC. Increased glycolytic flux, G6PD activity, and pyrimidine biosynthesis are identified in glucomet-PDAC with high GLUT1 and low ALDOB expression, and these phenotypes could be reversed by inhibiting GLUT1 expression or by increasing ALDOB expression."
PAIR0039016	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0039017	The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin.
PAIR0039018	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0039019	"Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance."
PAIR0039020	"he results of the present study suggested that there may be a new mechanism of action for the antitumor effects of pemetrexed, namely, LCN2-mediated modulation of N-cadherin expression."
PAIR0039021	"The mechanistic analysis demonstrated that FAM83B impedes the translocation of calbindin 2 (CALB2) from the cytoplasm to the mitochondria, resulting in the inhibition of apoptosis and the promotion of mitochondrial activity. Consequently, this ultimately confers resistance to chemotherapy in LUAD. Furthermore, the administration of metformin, which blocks mitochondrial oxidative phosphorylation (OXPHOS), can restore sensitivity to drug resistance in LUAD. Taken together, these findings provide substantial evidence supporting the notion that FAM83B enhances chemotherapy resistance in LUAD through the upregulation of mitochondrial metabolism and the inhibition of apoptosis."
PAIR0039022	"Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle."
PAIR0039023	"Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle."
PAIR0039024	"Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings."
PAIR0039025	Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
PAIR0039026	Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.
PAIR0039027	"We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression"
PAIR0039028	"We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab-induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression"
PAIR0039029	"The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-gamma-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo."
PAIR0039030	"Restoration of SLC25A21 expression abrogates KRAS-mutation-mediated resistance to cetuximab in CRC. KRAS mutation, which results in hyperactive PI3K/AKT and RAF/ERK signaling (26), is responsible for resistance to anti-EGFR antibody therapy (27)."
PAIR0039031	"Restoration of SLC25A21 expression abrogates KRAS-mutation-mediated resistance to cetuximab in CRC. KRAS mutation, which results in hyperactive PI3K/AKT and RAF/ERK signaling (26), is responsible for resistance to anti-EGFR antibody therapy (27). "
PAIR0039032	"Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARalpha in 3D spheroids and tumor xenografts in mice. Importantly, the PPARalpha-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. "
PAIR0039033	"Here we report that cetuximab-resistant HNSCC cells display a peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated lipid metabolism reprogramming, with increased fatty acid uptake and oxidation capacities, while glycolysis is not modified. This metabolic shift makes cetuximab-resistant HNSCC cells particularly sensitive to a pharmacological inhibition of either carnitine palmitoyltransferase 1A (CPT1A) or PPARalpha in 3D spheroids and tumor xenografts in mice. Importantly, the PPARalpha-related gene signature, in human clinical datasets, correlates with lower response to anti-EGFR therapy and poor survival in HNSCC patients, thereby validating its clinical relevance. "
PAIR0039034	TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.
PAIR0039035	"By developing l-Asparaginase-resistant Pancreatic Cancercells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation."
PAIR0039036	"Taken together, these findings demonstrate that GATA6 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer."
PAIR0039037	"Taken together, these findings demonstrate that GATA7 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer."
PAIR0039038	"Taken together, these findings demonstrate that GATA8 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer."
PAIR0039039	"Taken together, these findings demonstrate that GATA9 is involved in metabolism reprogramming which might contribute to trastuzumab resistance in gastric cancer."
PAIR0039040	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC.
PAIR0039041	ur findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER3-positive BC.
PAIR0039042	"Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. "
PAIR0039043	"Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. "
PAIR0039044	"Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. "
PAIR0039045	"Overexpression of MACC1-induced trastuzumab resistance, enhanced the Warburg effect, and activated the PI3K/AKT signaling pathway, while downregulation of MACC1 presented the opposite effects. "
PAIR0039046	"Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment."
PAIR0039047	"Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3'UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer."
PAIR0039048	"Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3'UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer."
PAIR0039049	"Inhibition of glutaminolysis significantly reduced the cFLIP level, leading to TRAIL-mediated formation of death-inducing signaling complexes. Overexpression of cFLIP dramatically rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Alpha-Ketoglutarate (aKG) supplementation significantly reversed the decrease in the cFLIP level induced by glutaminolysis inhibition and rescued PDAC cells from TRAIL/Gln deprivation-induced apoptosis. Knockdown of glutamic-oxaloacetic transaminase 2, which facilitates the conversion of oxaloacetate and glutamate into aspartate and aKG, decreased aKG production and the cFLIP level and activated TRAIL-induced apoptosis."
PAIR0039050	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039051	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039052	"Of note, our transcriptome analyses showed that, in HCC cell competition scenario, lenvatinib-resistant cells captured the increased glycolysis activity but the attenuated oxidative phosphorylation level as well as decreased mitochondria mass; however, lenvatinib-sensitive cells obtain opposite metabolic features."
PAIR0039053	"Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells. "
PAIR0039054	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039055	"Of note, our transcriptome analyses showed that, in HCC cell competition scenario, lenvatinib-resistant cells captured the increased glycolysis activity but the attenuated oxidative phosphorylation level as well as decreased mitochondria mass; however, lenvatinib-sensitive cells obtain opposite metabolic features."
PAIR0039056	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039057	"This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance."
PAIR0039058	"Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells. "
PAIR0039059	"This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance."
PAIR0039060	"Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells. "
PAIR0039061	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
PAIR0039062	"Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity."
PAIR0039063	"Here, we found that high levels of ENO2 expression and ENO2-related neuroendocrine differentiation were associated with resistance to antiangiogenic therapy in CRC. Notably, the ENO2-derived PEP was responsible for ENO2-mediated resistance to antiangiogenic therapy in CRC, and PEP enhanced beta-catenin Lys49 acetylation by selectively inhibiting histone deacetylase 1 (HDAC1) activity. "
PAIR0039064	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
PAIR0039065	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
PAIR0039066	Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
PAIR0039067	"In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide."
PAIR0039068	"DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839."
PAIR0039069	"PKMYT1 was aberrantly high-expressed in TNBC and was related to an unfavorable prognosis. Furthermore, PKMYT1 activated the TNF/TRAF1/AKT signaling pathway, thereby upregulating the expression of enzymes involved in SREBF2-mediated cholesterol synthesis. Notably, knockdown of PKMYT1 significantly suppressed the feedback upregulation of the statin-mediated cholesterol synthesis pathway, and PKMYT1 knockdown increased the drug sensitivity of ATV in TNBC cells."
PAIR0039070	"Our study shows that the long-term treatment of androgen-sensitive prostate cancer cells with the antiandrogen 2-hydroxy-flutamide leads to the development of a quiescent state with stem cell-like characteristics, enabling survival in a low metabolic state and conferring drug resistance. In this context, there is a reduction in the de novo biosynthesis of phosphatidylcholine and the activation of epigenetic reprogramming."
PAIR0039071	"Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2alpha/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells."
PAIR0039072	This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER- breast cancer cells.
PAIR0039073	"We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition."
PAIR0039074	"PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL."
PAIR0039075	"We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation."
PAIR0039076	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039077	"Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC."
PAIR0039078	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039079	" In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes. "
PAIR0039080	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039081	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [21]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039082	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [22]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039083	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [23]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039084	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [24]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039085	"Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2alpha pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. "
PAIR0039086	"PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL."
PAIR0039087	"Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. "
PAIR0039088	"Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism."
PAIR0039089	"Like dipyridamole (41, 57), caffeine can block statin-induced feedback activation of SREBP2 and mevalonate pathway enzymes. Our data suggest that this action of caffeine depends on its activity as an antagonist of adenosine receptors (43, 59, 62), as evidenced by the findings that supplemental adenosine can abrogate the ability of caffeine to block statin-induced feedback activation SREBP2 and mevalonate pathway enzymes and to enhance the antigrowth effect of simvastatin."
PAIR0039090	"Our data are consistent with a recent study in liver cancer cell lines showing that statin represses FOXM1 expression by blocking geranylgeranylation of RhoA, Rac1 or Cdc42 proteins (46). Together, these findings suggest a molecular mechanism for the long-observed connection between the mevalonate pathway and cell-cycle progression (47). "
PAIR0039091	"Furthermore, we observed that gain-of-function of isocitrate dehydrogenase 2 (IDH2) induced reductive glutamine metabolism to stabilize Hif-1alpha expression and consequently stimulate aerobic glycolysis and PPP bypass in gemcitabine-resistant UC cells. Interestingly, IDH2-mediated metabolic reprogramming also caused cross resistance to CDDP, by elevating the antioxidant defense via increased NADPH and glutathione production. Downregulation or pharmacological suppression of IDH2 restored chemosensitivity. "
PAIR0039092	"Therefore, our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells. Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen."
PAIR0039093	"Therefore, our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells. Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen."
PAIR0039094	Our evidence revealed that Icariin-Curcumol attenuated DTX resistance through modulation of the PI3K-Akt pathway and the Warburg effect and that Icariin-Curcumol and DTX have synergistic effects.
PAIR0039095	"Metabolic pressures like glutamine deficiency lead to the emergence of an aggressive and poor prognostic reverse Warburg phenotype in PDAC. As the major fuel of this phenotype, lactate taken up by MCT1 maintains cellular redox homeostasis and thereby cell viability during critical shortages of glutamine supply. This also manifests in resistance against inhibitors of glutamine metabolism, thus limiting their usage in the clinic. "
PAIR0039096	"Metabolic pressures like glutamine deficiency lead to the emergence of an aggressive and poor prognostic reverse Warburg phenotype in PDAC. As the major fuel of this phenotype, lactate taken up by MCT1 maintains cellular redox homeostasis and thereby cell viability during critical shortages of glutamine supply. This also manifests in resistance against inhibitors of glutamine metabolism, thus limiting their usage in the clinic. "
PAIR0039097	"Similarly, miR-125b mimic decreased the glycolysis [(25.28±9.51) mpH/min] in HCT-8-7T cells as compared with that [(54.38±12.70)mpH/min,P=0.003] in HCT-8-7T cells transfected with control. Meanwhile, in comparison with control transfected HCT-8-7T cells, miR-125b mimic also significantly led to an increase in the levels of p53 and beta-catenin, in parallel with a decrease in the levels of PFK1 and HK1 in HCT-8-7T cells"
PAIR0039098	"The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo."
PAIR0039099	"The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo."
PAIR0039100	the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers
PAIR0039101	the mechanism of action of HA344 provides potential therapeutic avenues for patients with CMM and a broad range of different cancers
PAIR0039102	"we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75)."
PAIR0039103	"we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75)."
PAIR0039104	"In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell. "
PAIR0039105	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0039106	The main reason was that FpSA promoted cancer cells to switch from fatty acid metabolism to glycolysis and alleviate resistance to cisplatin.
PAIR0039107	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO6was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0039108	"CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO7was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells."
PAIR0039109	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS1 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0039110	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS2 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0039111	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS3 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0039112	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS4 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0039113	"Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS5 is mainly involved in cytidine metabolism and nucleic acids metabolism."
PAIR0039114	"CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis."
PAIR0039115	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [25]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039116	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [26]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039117	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [27]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039118	"Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [28]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways."
PAIR0039119	"PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC12 cells, and the YAP expression was inhibited by pitavastatin administration."
PAIR0039120	"PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC10 cells, and the YAP expression was inhibited by pitavastatin administration."
PAIR0039121	"Adding to this, our research shows that METTL1-modified m7G tRNA increases translation of enzymes associated with the respiratory chain, boosting OXPHOS capacity in anlotinib-resistant cells. This highlights the potential of epigenetic interventions in overcoming TKI resistance."
PAIR0039122	"Adding to this, our research shows that METTL1-modified m8G tRNA increases translation of enzymes associated with the respiratory chain, boosting OXPHOS capacity in anlotinib-resistant cells. This highlights the potential of epigenetic interventions in overcoming TKI resistance."
PAIR0039123	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039124	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039125	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039126	"Lastly,NF1deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis."
PAIR0039127	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX4 expression."
PAIR0039128	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX5 expression."
PAIR0039129	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX6 expression."
PAIR0039130	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX7 expression."
PAIR0039131	"In this study, we find that TGFB1 levels are elevated in relapsed or refractory AML patients and in drug-resistant cell lines, and can induce chemoresistance by stimulating the activation of the TGFB signaling pathway via an autocrine/paracrine manner. This process may be achieved through metabolic reprogramming induced by TGFB1-triggered SOX8 expression."
PAIR0039132	"Because these data indicate that GART is highly expressed in ERalpha-positive IDCs, which are poorly differentiated and metastatic, and that this metabolic protein could play a role in the development of Tam resistance, GART could be considered also a target in BC cell lines resistant to ET. "
PAIR0039133	"Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A."
PAIR0039134	"Our data are consistent with a recent study in liver cancer cell lines showing that statin represses FOXM1 expression by blocking geranylgeranylation of RhoA, Rac1 or Cdc42 proteins (46). Together, these findings suggest a molecular mechanism for the long-observed connection between the mevalonate pathway and cell-cycle progression (47). "
PAIR0039135	"Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2alpha pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. "
PAIR0039136	The molecular mechanisms on how PRMT6 linked cell metabolism to tumor growth were also explored by regulating the enzyme activity of 6PGD/ENO1 mediated by asymmetric arginine demethylation modification.
PAIR0039137	"PDK1 inhibition by siRNA or DCA significantly suppressed the growth of ESCC cells. miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and DDP synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress partly through the suppression of Keap1/Nrf2 signaling pathway."
PAIR0039138	"Immunohistochemical analysis revealed that higher PDK1 expression is associated with a poor prognosis in OSCC. The immunoprecipitation assay indicated PDK1/CD47 binding. PDK1 ligation significantly impaired OSCC orosphere formation and downregulated Sox2, Oct4, and CD133 expression. The combination of BX795 and cisplatin markedly reduced in OSCC cell's epithelial-mesenchymal transition, implying its synergistic effect. p-PDK1, CD47, Akt, PFKP, PDK3 and LDHA protein expression were significantly reduced, with the strongest inhibition in the combination group. Chemo/radiotherapy together with abrogation of PDK1 inhibits the oncogenic (Akt/CD47) and glycolytic (LDHA/PFKP/PDK3) signaling and, enhanced or sensitizes OSCC to the anticancer drug effect through inducing apoptosis and DNA damage together with metabolic reprogramming."
PAIR0039139	"Mechanistically, we demonstrated that Trp metabolite kynurenine (Kyn) promoted the upregulation and nuclear translocation of transcription factor aryl hydrocarbon receptor (AhR). Subsequently, AhR collaborated with NF-kappaB to facilitate the activation of c-Myc. In turn, c-Myc promoted the up-regulation of ATP-binding cassette (ABC) transporters and Trp transporters, thereby contributing to chemoresistance and strengthened Trp metabolism in prostatic cancer. Interrupt of Trp/TDO2/Kyn/AhR/c-Myc loop with c-Myc inhibitor Mycro-3 efficiently suppressed the chemoresistance and improved the outcome of chemotherapy, which described a new strategy in clinical prostatic cancer treatment."
PAIR0039140	"These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo."
PAIR0039141	"These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo."
PAIR0039142	"The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-gamma-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo."
PAIR0039143	" SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. "
PAIR0039144	"The expression of SIRT3 improves mitochondrial function and biogenesis. Furthermore, the anti-proliferative effects of SIRT3 and RSV are increased in ccRCC through metabolic reprogramming. "
PAIR0039145	"ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration."
PAIR0039146	"ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration."
PAIR0039147	"Further in vitro and in vivo studies were implemented using Fatty Acid Synthase (FASN), a representative gene, which promotes gemcitabine resistance, and its inhibitor (TVB-3166) that can reverse this resistance effect."
PAIR0039148	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0039149	"Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. "
PAIR0039150	" Accordingly, downmodulation of ACOX1 (a rate-limiting pFAO enzyme overexpressed in CLL cells) was enough to shift the CLL cells' metabolism from lipids to a carbon- and amino-acid-based phenotype. Complete blockade of ACOX1 resulted in lipid droplet accumulation and caspase-dependent death in CLL cells, including those from individuals with poor cytogenetic and clinical prognostic factors."
PAIR0039151	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0039152	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0039153	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0039154	"Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis."
PAIR0039155	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0039156	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0039157	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0039158	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0039159	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0039160	"SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity. "
PAIR0040000	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040001	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040002	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040003	"Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166."
PAIR0040004	"In the present study, we identified apigenin as an effective compound for ameliorating ER stress and insulin resistance. It attenuated ER stress-induced cell death and hepatic insulin resistance and improved abnormal glucose tolerance in a db/db diabetic model. The molecular mechanism of apigenin involved direct binding to beta-tubulin and improving tubulin stability, thereby recovering insulin resistance and developing diabetes."
PAIR0040005	"In the present study, we identified apigenin as an effective compound for ameliorating ER stress and insulin resistance. It attenuated ER stress-induced cell death and hepatic insulin resistance and improved abnormal glucose tolerance in a db/db diabetic model. The molecular mechanism of apigenin involved direct binding to beta-tubulin and improving tubulin stability, thereby recovering insulin resistance and developing diabetes."
PAIR0040006	"Mutations L393S, L393F, F397L, and F397I of the SQLE gene were associated with terbinafine resistance. Resistance to itraconazole could not be explained by mutations in the ERG11B gene."
PAIR0040007	"A key cofactor of several enzymes implicated in DNA synthesis, repair, and methylation, folate has been shown to be required for normal cell growth and replication and is the basis for cancer chemotherapy using antifolates. gamma-Glutamyl hydrolase (GGH) catalyzes the removal of gamma-polyglutamate tails of folylpoly-/antifolylpoly-gamma-glutamates to facilitate their export out of the cell, thereby maintaining metabolic homeostasis of folates or pharmacological efficacy of antifolates. However, the factors that control or modulate GGH function are not well understood. In this study, we show that intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide (GGH?deltaN) confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. In addition, ALL cells harboring GGH?deltaN show high susceptibility to the change in folates, and glycosylation is not responsible for these phenotypes elicited by GGH?deltaN. Mechanistically, the loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition. "
PAIR0040008	"The objective of the present research was to explore the potential of let-7a-3p when used in combination with carmustine in human glioblastoma cancer cells. Based on previous studies, the expression of let-7a is downregulated in the U87MG cell line. Let-7a-3p transfected into U87MG glioblastoma cells. Cell viability of the cells was assessed by MTT assay. The apoptotic induction in U87MG cancerous cells was determined through the utilization of DAPI and Annexin V/PI staining techniques. Moreover, the induction of autophagy and cell cycle arrest was evaluated by flow cytometry. Furthermore, cell migration was evaluated by the wound healing assay while colony formation assay was conducted to evaluate colony formation. Also, the expression of the relevant genes was evaluated using qRT-PCR. Transfection of let-7a-3p mimic in U87MG cells increased the expression of the miRNA and also increased the sensitivity of U87MG cells to carmustine."
PAIR0040009	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp3c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040010	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp6c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040011	"Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy."
PAIR0040012	"LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations."
PAIR0040013	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040014	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040015	Similar Genomic Alterations but Distinctive Expression of Influx/Efflux Transporters Between Chemoresistant and Parental Cells
PAIR0040016	"In conclusion, we reveals a novel regulator PPP1CA driving abiraterone resistance. The natural product nodularin-R ameliorates abiraterone resistance by inhibiting PPP1CA. The combination of nodularin-R and abiraterone exerts synergistic anti-CRPC effects."
PAIR0040017	"Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible."
PAIR0040018	"The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. "
PAIR0040019	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040020	"For QN, resistance mapped to a dominant chromosome 7 peak centered 295 kb downstream of pfcrt, with pfcrt showing a smaller peak. We identified the drug/metabolite transporter 1 (DMT1) as the top chromosome 7 candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoform in vitro. Gene editing confirmed an additional role for mutant PfCRT in mediating QN resistance. "
PAIR0040021	"Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible."
PAIR0040022	"The experiments carried out to evaluate?T pallidum?resistance to macrolides showed that azithromycin was effective against?T pallidum?strains that did not have either of the 23S rRNA gene mutations (A2058G or A2059G) conferring resistance to macrolides, remained ineffective for two strains (SS14 and UW330B) carrying either one of the aforementioned mutations."
PAIR0040023	"The experiments carried out to evaluate?T pallidum?resistance to macrolides showed that azithromycin was effective against?T pallidum?strains that did not have either of the 23S rRNA gene mutations (A2058G or A2059G) conferring resistance to macrolides, remained ineffective for two strains (SS14 and UW330B) carrying either one of the aforementioned mutations."
PAIR0040024	"Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future."
PAIR0040025	"Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. "
PAIR0040026	"Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. "
PAIR0040027	"Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation."
PAIR0040028	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040029	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040030	"Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future."
PAIR0040031	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040032	"Overall, we presented the first evidence that STAMBP expression is increased in PC-resistant tissues and is linked to the prognosis of patients with PC. We further showed that STAMBP leads to chemotherapy resistance in PC by increasing PDK1-mediated aerobic glycolysis. Our findings additionally demonstrated that STAMBP promotes the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1, which is achieved by binding directly to E2F1 and suppressing its degradation and ubiquitination . Importantly, entrectinib-mediated targeting of STAMBP enhanced the chemosensitivity of PC cells remarkably. Based on these findings, STAMBP was concluded to act against chemoresistance in PC by enhancing aerobic glycolysis mediated by E2F1/PDK1. Therefore, targeting the STAMBP/E2F1/PDK1 axis may be a promising therapeutic strategy for PC."
PAIR0040033	"Overall, we presented the first evidence that STAMBP expression is increased in PC-resistant tissues and is linked to the prognosis of patients with PC. We further showed that STAMBP leads to chemotherapy resistance in PC by increasing PDK1-mediated aerobic glycolysis. Our findings additionally demonstrated that STAMBP promotes the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1, which is achieved by binding directly to E2F1 and suppressing its degradation and ubiquitination . Importantly, entrectinib-mediated targeting of STAMBP enhanced the chemosensitivity of PC cells remarkably. Based on these findings, STAMBP was concluded to act against chemoresistance in PC by enhancing aerobic glycolysis mediated by E2F1/PDK1. Therefore, targeting the STAMBP/E2F1/PDK1 axis may be a promising therapeutic strategy for PC."
PAIR0040034	"The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. EGFR is a potential target molecule for reducing Gem resistance and enhancing its anti-tumor effects in patients with CCA."
PAIR0040035	" Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion."
PAIR0040036	" Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion."
PAIR0040037	" Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion."
PAIR0040038	" Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1alpha expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion."
PAIR0040039	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040040	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040041	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040042	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040043	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040044	SHC1 phosphorylation was increased in CR mice
PAIR0040045	AXL phosphorylation was increased in CR mice
PAIR0040046	"Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166."
PAIR0040047	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040048	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040049	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040050	"Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future."
PAIR0040051	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040052	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040053	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040054	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040055	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040056	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040057	"The PI3K/Akt/mTOR signaling pathway was activated in drug-resistant GC cells and tumor tissues of patients refractory to 5-FU chemotherapy, as evidenced by high PI3K, Akt, and mTOR levels in MKN-45/R, MKN-74/R, and GC tissues resistant to 5-FU. Silencing of the PI3K/Akt/mTOR signaling pathway suppressed the 5-FU resistance of GC cells."
PAIR0040058	"BATF2 was confirmed as a tumor suppressor in gastric cancer through scRNA-seq analysis. Elevated BATF2 expression correlated with improved outcomes from postoperative chemotherapy in GC patients and increased sensitivity to 5-Fu. BATF2 enhanced 5-Fu responsiveness by inhibiting the ABCG2 drug transporter and promoting PTEN stability, which suppressed AKT phosphorylation. This led to reduced nuclear beta-catenin levels and decreased expression of stem cell markers CD44, SOX2, and NANOG, ultimately reducing chemoresistance and stem-like properties in GC cells. BATF2 plays a pivotal role in regulating stem-like characteristics and chemoresistance in gastric cancer through the BATF2/PTEN/AKT/ABCG2 pathway."
PAIR0040059	"The expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells."
PAIR0040060	"The expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells."
PAIR0040061	"The expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells."
PAIR0040062	"The expression of Hedgehog pathway-relevant proteins (PTCH1, PTCH2, GLI1, and SHH) was increased in drug-resistant HCT116/5-FU cells, and Rg3 and 5-FU co-treatment downregulated the expression of PTCH1, PTCH2, GLI1, and SHH proteins in HCT116/5-FU cells."
PAIR0040063	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040064	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040065	"We evaluated the effect of?FOXK2?knockdown in combination with conventional chemotherapeutic agents in BC cells.?FOXK2?knockdown significantly enhanced the cytotoxic effect of?doxorubicin, 5-fluorouracil, and?etoposide?in MDA-MB-231?cells and MDA-MB-361?cells. These results show that inhibiting FOXK2 sensitizes FOXK2-overexpressing BC cells to conventional chemotherapeutic agents."
PAIR0040066	"We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer."
PAIR0040067	"We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer."
PAIR0040068	"We discovered FGD5-AS1 and the RNA methylation reader protein, YTHDF2, were positively associated with 5-Fu resistance in cervical cancer. A positive correlation between FGD5-AS1 and YTHDF2 was found in cervical tumor tissues. Expressions of FGD5-AS1 and YTHDF2 were significantly upregulated in the established 5-Fu resistant cervical cancer cells. MiRNA-microArray analysis screened that FGD5-AS1 downregulated miR-130a-3p expression in cervical cancer cells. Subsequently, we demonstrated FGD5-AS1 acted as a ceRNA by sponging miR-130a-3p, which targeted the 3'UTR of YTHDF2 mRNA. Rescue experiments validated overexpression of FGD5-AS1 increased 5-Fu resistance in cervical cancer cells, which was reversed by miR-130a-3p overexpression. Finally, combining FGD5-AS1 silencing with 5-Fu treatments resulted in a synergistic inhibitory effect (CI < 1) on the viability of cervical cancer cells. This study reveals a FGD5-AS1-miR-130a-3p-YTHDF2 axis that could be a promising therapeutic target for overcoming 5-Fu resistance in cervical cancer."
PAIR0040069	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040070	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040071	EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
PAIR0040072	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040073	"Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?"
PAIR0040074	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040075	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040076	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040077	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040078	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040079	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040080	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040081	"Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies."
PAIR0040082	"Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies."
PAIR0040083	"Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies."
PAIR0040084	"Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies."
PAIR0040085	"Our data suggest that irinotecan upregulates various oncogenes, proliferative pathways, and metastatic markers, which may compromise its efficacy. SN38 induces p53-independent CDKIs and regulates cancer cell growth. OPN silencing regulates the SN38-mediated increase in PD-L1. Inhibition of non-canonical NF-kappaB signaling by QNZ results in the regulation of SN38-induced survivin and ISG15 (Figure 7). The targeting of OPN, PD-L1, ISG15, and NF-kappaB pathways may elevate irinotecan potency and lead to its combination with immunomodulatory therapies for CRC prognostic strategies."
PAIR0040086	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040087	"S. maltophilia?JUNP350 was found to encode a novel 6'-N-aminoglycoside acetyltransferase, AAC(6')-Iap, consisting of 155 amino acids with 85.0% identity to AAC(6')-Iz.?E. coli?transformants expressing?aac(6')-Iap?were less susceptible to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin and tobramycin. The recombinant AAC(6')-Iap protein acetylated all aminoglycosides tested, except for apramycin and paromomycin."
PAIR0040088	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040089	"We discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110alpha protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110alpha inhibitor A66."
PAIR0040090	"Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model."
PAIR0040091	"Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. "
PAIR0040092	"Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. "
PAIR0040093	"Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation."
PAIR0040094	"Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation."
PAIR0040095	"We demonstrate that long-term sorafenib or quizartinib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates beta-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit beta-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3beta (GSK3beta) pathway."
PAIR0040096	"Aberrant Met amplification and HGF-Met signaling pathway activation have been proven to be the main mechanism of acquired resistance of EGFR inhibition by small molecules, such as erlotinib and gefitinib."
PAIR0040097	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040098	EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
PAIR0040099	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040100	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040101	"We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML."
PAIR0040102	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040103	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040104	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040105	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040106	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040107	"ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells."
PAIR0040108	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040109	"The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway."
PAIR0040110	"The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway."
PAIR0040111	"The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway."
PAIR0040112	We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
PAIR0040113	"We evaluated the effect of?FOXK2?knockdown in combination with conventional chemotherapeutic agents in BC cells.?FOXK2?knockdown significantly enhanced the cytotoxic effect of?doxorubicin, 5-fluorouracil, and?etoposide?in MDA-MB-231?cells and MDA-MB-361?cells. These results show that inhibiting FOXK2 sensitizes FOXK2-overexpressing BC cells to conventional chemotherapeutic agents."
PAIR0040114	"7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells."
PAIR0040115	"The ABC transporters are responsible for the efflux of a wide range of chemotherapeutics across the plasma membrane, leading to lower intracellular drug levels and treatment resistance."
PAIR0040116	Induction of DNA double-strand breaks and chromatin damage through histone eviction;Less affected by ABCG2-mediated drug export.
PAIR0040117	CISD2 may play a role in promoting tumor cell proliferation and drug resistance through ferroptosis and ferritinophagy. CISD2 expression levels were higher in HBL-1/DOX cells compared to HBL-1 cells.
PAIR0040118	"The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression."
PAIR0040119	"OE-IDH2 in AML cells, enhances resistance to the Ara-C, promotes cell proliferation and glycolysis, and inhibits apoptosis. KD-IDH2 exhibits opposite effects. Both IDH2 mutations and OE-IDH2 produce similar effects on these cellular processes. The increase in glycolysis levels following IDH2 mutation may contribute to the reduced efficacy of Enasidenib in inhibiting the proliferation of IDH-mutant AML cells. Transcriptome sequencing results indicate an enrichment of the PI3K/Akt signaling pathway in IDH2-mutant AML cells. BEZ235 significantly inhibits the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), mTOR, glycolytic metabolism, and Ara-C resistance both in vitro and in vivo. Overexpression and mutation of IDH2 coordinate with the Warburg effect through the PI3K/Akt/mTOR pathway to promote Ara-C resistance in AML."
PAIR0040120	"The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting."
PAIR0040121	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients."
PAIR0040122	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine."
PAIR0040123	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine."
PAIR0040124	"HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines."
PAIR0040125	"HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines."
PAIR0040126	"HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines."
PAIR0040127	"HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines."
PAIR0040128	"Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?"
PAIR0040129	"Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of alphaPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with alphaPD-1 did not improve the outcome."
PAIR0040130	"The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. "
PAIR0040131	"A novel aminoglycoside resistance gene, designated aph(3')-Ie, which confers resistance to ribostamycin, kanamycin, sisomicin and paromomycin, was identified in the chromosome of the animal bacterium Citrobacter gillenii DW61, which exhibited a multidrug resistance phenotype. APH(3')-Ie showed the highest amino acid identity of 74.90% with the functionally characterized enzyme APH(3')-Ia. Enzyme kinetics analysis demonstrated that it had phosphorylation activity toward four aminoglycoside substrates, exhibiting the highest affinity (K m, 4.22 &plusmn; 0.88 uM) and the highest catalytic efficiency [k cat/K m, (32.27 &plusmn; 8.14) x 104] for ribomycin. Similar to the other APH(3') proteins, APH(3')-Ie contained all the conserved functional sites of the APH family. The aph(3')-Ie homologous genes were present in C. gillenii isolates from different sources, including some of clinical significance."
PAIR0040132	"The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells."
PAIR0040133	"Induction of transcription factor FoxO1 during ibrutinib therapy upregulates Rictor, an mTORC2 assembly protein, leading to phosphorylation of Akt, an essential molecule supporting CLL cell survival"
PAIR0040134	"Induction of transcription factor FoxO1 during ibrutinib therapy upregulates Rictor, an mTORC2 assembly protein, leading to phosphorylation of Akt, an essential molecule supporting CLL cell survival"
PAIR0040135	"Clinically, most ibrutinib-resistant patients (~80%) harbor a C481S mutation in the BTK protein, blocking ibrutinib from covalently binding to BTK, and/or a gain of function mutation in PLCgamma2, activating downstream BCR signaling independent of BTK inhibition. Resistance is also mediated through alternative survival pathways, such as the activation of PI3K/AKT/ERK signaling ."
PAIR0040136	"Fluconazole susceptibility testing of 34 urinary Candida isolates indicated that 76.5% were FLC-R, with a higher prevalence of resistance recorded in non-albicans Candida spp. (88.9%) than in Candida albicans (62.5%). The calculated Spearman's correlation coefficients implied significant positive correlations between fluconazole minimum inhibitory concentrations and both biofilm formation and phospholipase production. Real-time PCR results revealed that most FLC-R isolates (60%) significantly overexpressed at least one efflux pump gene, while 42.3% significantly upregulated the ERG11 gene. The most prevalent mutation detected upon ERG11 sequencing was G464S, which is conclusively linked to fluconazole resistance. "
PAIR0040137	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040138	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040139	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040140	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040141	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040142	"The FLCR rate was 26.7% (91/341), out of which 75.8% (69/91) harboured the?ERG11Y132F?mutation. Patients infected with FLCR isolates had a higher mortality rate compared to their susceptible counterparts (49% for FLCR vs. 42% for susceptible). ECR rate was 2.1% (7/341) and isolates carried?FKS1F652L/R658G/W1370R?mutations. Concerningly, four ECR isolates were MDR. FLCR isolates grouped in distinct clusters without evidence of inter-hospital transmission, whereas large clusters containing susceptible isolates from all centres were noted."
PAIR0040143	KBV20 cells were highly resistant to Vincristine
PAIR0040144	KBV20 cells were highly resistant to Vincristine
PAIR0040145	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040146	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040147	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040148	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040149	"The current study aims to understand the resistance of Bifidobacterium adolescentis to different anti-tubercular drugs (first-line oral tuberculosis drugs). The bacteria were grown with anti-tubercular drugs such as isoniazid, pyrazinamide, and streptomycin to better understand the resistance phenomena. It was found that even at tenfold higher concentrations, growth rates remained unchanged. In addition, a small number of bacteria were found to aggregate strongly, a property that protects against the toxicity of the drug. Further FE-SEM (Field Emission Scanning Electron Microscopy) analysis revealed that some bacteria became excessively long, elongated, and protruded on the surface. Size scattering analysis confirmed the presence of bifidobacteria in the size range of 1.0-100 um. After whole genome sequence analysis, certain mutations were found in the relevant gene. In vitro, foam formation and growth in the presence of H2O2 and HPLC (High Performance Liquid Chromatography) studies provide additional evidence for the presence of catalase. According to RAST (Rapid Annotation Using Subsystems Technology) annotation and CARD (Comprehensive Antibiotic Resistance Database analysis), there were not many components in the genome that were resistant to antibiotics. Whole genome sequence (WGS) analysis does not show the presence of bacteriocins and antibiotic resistance genes, but few hypothetical proteins were observed. 3D structure and docking studies suggest their interaction with specific ligands."
PAIR0040150	"Aberrant Met amplification and HGF-Met signaling pathway activation have been proven to be the main mechanism of acquired resistance of EGFR inhibition by small molecules, such as erlotinib and gefitinib."
PAIR0040151	"Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of beta-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, beta-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib."
PAIR0040152	"Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of beta-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, beta-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib."
PAIR0040153	"In our study, we first illustrated the role of TS-mediated thymidylate nucleotide biosynthesis in the development of gefitinib resistance. We demonstrated that NSCLC patients with higher expression of TS gene have shorter PFS during EGFR-TKI treatment. Furthermore, we found TS is upregulated in NSCLC patients resistant to gefitinib and in PC9/GR cells which are tolerant of gefitinib. Knockdown of TS-induced apoptosis and diminished survival of gefitinib-resistant NSCLC."
PAIR0040154	"In our study, we first illustrated the role of TS-mediated thymidylate nucleotide biosynthesis in the development of gefitinib resistance. We demonstrated that NSCLC patients with higher expression of TS gene have shorter PFS during EGFR-TKI treatment. Furthermore, we found TS is upregulated in NSCLC patients resistant to gefitinib and in PC9/GR cells which are tolerant of gefitinib. Knockdown of TS-induced apoptosis and diminished survival of gefitinib-resistant NSCLC."
PAIR0040155	"Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment."
PAIR0040156	EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
PAIR0040157	"Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway."
PAIR0040158	"Our results suggested that PD-L1 might play a role in promoting autophagy and inhibiting apoptosis, which was responsible for the generation of primary resistance to EGFR-TKIs, and the combination therapy exerted a synergistic antitumor effect by inhibiting the activation of the MAPK/ERK signaling pathway."
PAIR0040159	"We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway)."
PAIR0040160	"We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway)."
PAIR0040161	"We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway)."
PAIR0040162	"Overexpression of ABCG2 on the membrane surface of CML cells contributes to decreased TKI efficacy. This study demonstrates for the first time that the concomitant use of febuxostat enhances the efficacy of dasatinib in patients with CML. This is at least, in part, by the inhibition of ABCG2-mediated dasatinib excretion from CML cells."
PAIR0040163	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040164	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040165	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040166	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040167	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040168	"M. arginini?and?M. salivarium, promoted the initiation of EMT and simultaneous suppression of the p53 tumor suppressor in A549 lung cancer cells. This led to an increase of cancer cell motility, resistance to the antitumor drug etoposide concomitantly with decreased autophagy."
PAIR0040169	"M. arginini?and?M. salivarium, promoted the initiation of EMT and simultaneous suppression of the p53 tumor suppressor in A549 lung cancer cells. This led to an increase of cancer cell motility, resistance to the antitumor drug etoposide concomitantly with decreased autophagy."
PAIR0040170	"We evaluated the effect of?FOXK2?knockdown in combination with conventional chemotherapeutic agents in BC cells.?FOXK2?knockdown significantly enhanced the cytotoxic effect of?doxorubicin, 5-fluorouracil, and?etoposide?in MDA-MB-231?cells and MDA-MB-361?cells. These results show that inhibiting FOXK2 sensitizes FOXK2-overexpressing BC cells to conventional chemotherapeutic agents."
PAIR0040171	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040172	"We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1."
PAIR0040173	"We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1."
PAIR0040174	We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
PAIR0040175	"Repression of ANP32E increases the responsiveness of EC to PTX, and the concurrent use of erastin with PTX enhances their anti-cancer effectiveness. These findings provide support for the efficacy of inducing ferroptosis as a potential therapeutic approach to enhance the cytotoxic effects of PTX. ANP32E regulates EC progression and ferroptosis through the p53/SLC7A11 axis, offering a potential molecular target for overcoming PTX resistance in EC treatment."
PAIR0040176	"Repression of ANP32E increases the responsiveness of EC to PTX, and the concurrent use of erastin with PTX enhances their anti-cancer effectiveness. These findings provide support for the efficacy of inducing ferroptosis as a potential therapeutic approach to enhance the cytotoxic effects of PTX. ANP32E regulates EC progression and ferroptosis through the p53/SLC7A11 axis, offering a potential molecular target for overcoming PTX resistance in EC treatment."
PAIR0040177	"Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels."
PAIR0040178	"ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes."
PAIR0040179	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040180	"In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level."
PAIR0040181	"The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice."
PAIR0040182	"In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level."
PAIR0040183	"The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice."
PAIR0040184	"In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level."
PAIR0040185	"The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice."
PAIR0040186	"The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice."
PAIR0040187	"Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model."
PAIR0040188	"We demonstrated that RHAMM immensely contributes to breast cancer chemoresistance by several mechanisms: promoting proliferation and migration, enrichment of breast cancer stemness, and induction of EMT. Also, we found that RHAMM served as a potent prognostic factor in breast cancer patients, especially in those who received chemotherapy."
PAIR0040189	"7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells."
PAIR0040190	"In this study, we demonstrated that lncRNA UCA1 inhibits epirubicin-induced cell apoptosis by supporting abnormal lipid metabolism in bladder cancer cells. Mechanistically, lncRNA UCA1 promotes lipid accumulation in vitro and in vivo by upregulating PPAR mRNA and protein expression, which is mediated by miR-30a-3p. Knockdown of lncRNA UCA1 increased epirubicin-induced apoptosis via miR-30a-3p/PPAR and downstream p-AKT/p-GSK-3beta/beta-catenin signaling."
PAIR0040191	"Severe infection with multidrug-resistant Enterobacterales caused by the plasmid-induced colistin resistance gene MCR-1 is a serious public health challenge. In this case, it is necessary and pressing to find a treatment to overcome antibiotic resistance. Here, we investigated the synergistic effect and mechanism of loperamide combined with colistin against MCR-1-positive pathogens. We evaluated the combined effect of loperamide and colistin using the checkerboard method and the time-kill experiment. The results showed that loperamide could enhance the bactericidal ability of colistin, and this combination regimen could completely kill the tested bacteria within 4 h. Subsequently, spectrofluorimetric methods were used to explore the mechanism of loperamide combined with colistin. The results indicated that the mode of action of loperamide combined with colistin was found to involve mechanical disruption of the membrane. Furthermore, molecular simulation and microscale thermophoresis results revealed that loperamide reduced the impact of MCR-1 protein by directly binding to its active site. In addition, the combined regimen of loperamide and colistin effectively reduced the bacterial load in the thighs of mice while increasing the protection rate by 70%. In short, as a potential lead compound, loperamide can enhance the killing effect of colistin on pathogenic Enterobacterales carrying MCR-1 by causing membrane damage and inhibiting MCR-1 protein activity."
PAIR0040192	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040193	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040194	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040195	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040196	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040197	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040198	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040199	"Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6' position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2'-N-acetyltransferase type Ia [AAC(2')-Ia], which reduces the antibiotic's potency. Silver acetate is a potent inhibitor of AAC(2')-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2')-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells."
PAIR0040200	"We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML."
PAIR0040201	"We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML."
PAIR0040202	"We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML."
PAIR0040203	"We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML."
PAIR0040204	"We found that dasatinib-resistant K562/DR and KU812/DR cells did not harbour a BCR::ABL1 mutation but had elevated expression and/or activation of MOS, TPL2 and ERK1/2. In addition, MOS siRNA, TPL2 siRNA and trametinib resensitized dasatinib-resistant cells to dasatinib. Moreover, expression levels of MOS in dasatinib non-responder patients with CML were higher than those in dasatinib responders, and the expression of TPL2 tended to increase in dasatinib non-responder patients compared with that in responder patients. Our results indicate that activation of ERK1/2 by elevated MOS and TPL2 expression is involved in dasatinib resistance, and inhibition of these proteins overcomes dasatinib resistance. Therefore, MOS, TPL2 and ERK1/2 inhibitors may be therapeutically useful for treating BCR::ABL1-independent dasatinib-resistant CML."
PAIR0040205	"Overexpression of ABCG2 on the membrane surface of CML cells contributes to decreased TKI efficacy. This study demonstrates for the first time that the concomitant use of febuxostat enhances the efficacy of dasatinib in patients with CML. This is at least, in part, by the inhibition of ABCG2-mediated dasatinib excretion from CML cells."
PAIR0040206	"We found that, the?rv2820c?K114N mutation was highly enriched in CAP-resistant?Mtb?clinical isolates, especially in those isolates with the known CAP resistance conferring mutation?rrs?A1401G, implying the association of this mutation with the antimycobacterial efficacy of CAP. Subsequently, over-expressing the?rv2820c?K114N mutant was shown to increase the tolerance to CAP in?Ms, implying that the?rv2820c?K114N mutation might also confer tolerance to CAP in?Mtb?and be considered as a potential molecular marker for CAP tolerance in?Mtb?clinical isolates."
PAIR0040207	"Our findings highlight that attenuated ROS accelerates IL-2R translation and therefore brings about aberrant expression of IL-2R protein, leading to overactivation of JAK/STAT, AKT/mTOR and MAPK signaling events, which explains SAHA resistance to CTCL cells. Moreover, cantharidin could overcome SAHA resistance to CTCL by blocking IL-2R-related signaling via ROS dependent manner."
PAIR0040208	"Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future."
PAIR0040209	"CCK-8 assays demonstrated that HCC cells carrying the?XIRP2?mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the?XIRP2?wildtype. The?XIRP2?mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of?XIRP2?resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the?XIRP2?mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin."
PAIR0040210	"Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166."
PAIR0040211	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040212	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040213	"The overexpression of many interferon-stimulated genes (ISGs) in cells infected with the isoniazid-resistant strain, compared to the rifampin-resistant and the drug-sensitive strains. "
PAIR0040214	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040215	"All these findings indicate that the absence of the STPK could increase sulfur metabolism and GSH levels, and decrease the NADPH oxidase activity and NADP+/NADPH ratio, which promotes the antioxidant capacity of B. melitensis."
PAIR0040216	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040217	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040218	"People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the absence of resistance mutations in integrase. To elucidate INSTI resistance mechanisms, we propagated HIV-1 in the presence of escalating concentrations of the INSTI dolutegravir. HIV-1 became resistant to dolutegravir by sequentially acquiring mutations in the envelope glycoprotein (Env) and the nucleocapsid protein. The selected Env mutations enhance the ability of the virus to spread via cell-cell transfer, thereby increasing the multiplicity of infection (MOI)."
PAIR0040219	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040220	Elevated expression of IGFBP-3 is associated with fulvestrant resistance in MCF-7 cells. MCF-7FulR cells expressed significantly higher levels of IGFBP-3 transcript and protein compared to parental cells.
PAIR0040221	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040222	"In a model of AI-resistant breast cancer without ESR1 mutations, LAS alone or combined with PAL inhibited the growth of primary tumors more effectively than FUL. In addition, the LAS/PAL combination significantly reduced bone metastases. These results suggest that LAS alone or in combination with a CDK4/6i may be a promising therapy for patients with AI-resistant breast cancer, independent of ESR1 mutations. These results also suggest that LAS might be effective in tumors that express low levels of ERalpha."
PAIR0040223	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040224	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040225	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040226	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040227	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040228	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040229	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040230	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040231	"In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R."
PAIR0040232	"MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. "
PAIR0040233	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040234	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040235	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040236	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040237	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040238	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040239	"The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when?tcaA?was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when?tcaA?was deleted, all selected strains were more susceptible to beta-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when?tcaA?was deleted.?tcaA?knockout caused ""log-like"" abnormal division of MRSA, and?tcaA?deficiency mediated low expression of?mecA, ponA, and?murA2. tcaA is a potential resistance breaker target for beta-lactams, including ceftobiprole, in MRSA."
PAIR0040240	"The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when?tcaA?was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when?tcaA?was deleted, all selected strains were more susceptible to beta-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when?tcaA?was deleted.?tcaA?knockout caused ""log-like"" abnormal division of MRSA, and?tcaA?deficiency mediated low expression of?mecA, ponA, and?murA2. tcaA is a potential resistance breaker target for beta-lactams, including ceftobiprole, in MRSA."
PAIR0040241	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040242	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040243	"The current study aims to understand the resistance of Bifidobacterium adolescentis to different anti-tubercular drugs (first-line oral tuberculosis drugs). The bacteria were grown with anti-tubercular drugs such as isoniazid, pyrazinamide, and streptomycin to better understand the resistance phenomena. It was found that even at tenfold higher concentrations, growth rates remained unchanged. In addition, a small number of bacteria were found to aggregate strongly, a property that protects against the toxicity of the drug. Further FE-SEM (Field Emission Scanning Electron Microscopy) analysis revealed that some bacteria became excessively long, elongated, and protruded on the surface. Size scattering analysis confirmed the presence of bifidobacteria in the size range of 1.0-100 um. After whole genome sequence analysis, certain mutations were found in the relevant gene. In vitro, foam formation and growth in the presence of H2O2 and HPLC (High Performance Liquid Chromatography) studies provide additional evidence for the presence of catalase. According to RAST (Rapid Annotation Using Subsystems Technology) annotation and CARD (Comprehensive Antibiotic Resistance Database analysis), there were not many components in the genome that were resistant to antibiotics. Whole genome sequence (WGS) analysis does not show the presence of bacteriocins and antibiotic resistance genes, but few hypothetical proteins were observed. 3D structure and docking studies suggest their interaction with specific ligands."
PAIR0040244	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040245	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040246	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040247	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040248	"Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells."
PAIR0040249	"Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells."
PAIR0040250	"Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells."
PAIR0040251	"Docetaxel-resistant cells exhibited down-regulated DYRK2 and up-regulated Twist1 expression. DYRK2 overexpression reversed drug resistance, decreased migration, and attenuated Twist1 and GST-pi expression. DYRK2 was found to suppress Twist1 expression through ubiquitination, supported by decreased Twist1 phosphorylation and increased ubiquitination after DYRK2 overexpression. Twist1 overexpression counteracted DYRK2-induced drug sensitivity enhancement, promoting GST-pi expression, EMT, migration, and proliferation. Twist1 was shown to bind to the GSTP1 promoter, enhancing its transcription. In vivo experiments confirmed DYRK2's ability to suppress chemoresistance in breast cancer cells."
PAIR0040252	"Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance."
PAIR0040253	"This research demonstrated that ANGPTL4 is primarily expressed in CAFs and that ANGPTL4 can bind to IQGAP1 on the PCa cell membrane, activating the Raf-MEK-ERK-PGC1 pathway. This process promotes mitochondrial biogenesis and OXPHOS function, ultimately leading to growth and chemoresistance in PCa. "
PAIR0040254	"This research demonstrated that ANGPTL4 is primarily expressed in CAFs and that ANGPTL4 can bind to IQGAP1 on the PCa cell membrane, activating the Raf-MEK-ERK-PGC1 pathway. This process promotes mitochondrial biogenesis and OXPHOS function, ultimately leading to growth and chemoresistance in PCa. "
PAIR0040255	"The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib,?PLK1?mRNA levels were negatively correlated with progression free survival of patients (R= -0.62,?P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further?in vitro?experiments showed that IC50?of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells."
PAIR0040256	"Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment."
PAIR0040257	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040258	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040259	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040260	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040261	"Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment."
PAIR0040262	EGFR-TKI Rechallenge With Another TKI may be a useful treatment option after first-line osimertinib.
PAIR0040263	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040264	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040265	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040266	"Here, we identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated double-stranded RNA (dsRNA)-sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation, and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy."
PAIR0040267	"In this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM."
PAIR0040268	SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response
PAIR0040269	"In this study, we demonstrated the absence of A1518/1519 methylation in the 16S rRNA of a Pseudomonas aeruginosa ksgA mutant. Biolog phenotypic microarrays were used to screen the phenotypes of the ksgA mutant against various antimicrobial agents. The loss of ksgA led to increased sensitivity to menadione, a superoxide generator, which was, at least in part, attributed to decreased in a superoxide dismutase (SOD) activity. Interestingly, the decrease in SOD activity in the ksgA mutant was linked to a decrease in the SodM protein levels, but not the sodM mRNA levels. Furthermore, the ksgA mutant strain exhibited sensitivity to hygromycin B and tylosin antibiotics. The tylosin-sensitive phenotype was correlated with decreased transcriptional levels of tufA, tufB, and tsf, which encode elongation factors. Additionally, the ksgA mutant showed resistance to kasugamycin. Collectively, these findings highlight the role of KsgA in oxidative stress responses and antibiotic sensitivity in P. aeruginosa."
PAIR0040270	"This study investigated the role of Eps8 in prostate cancer. The LNCaP cell line and enzalutamide-resistant LNCaP (LNCaP Enz-R) cell lines were utilized for the investigation. Overexpression of Eps8 was observed in the LNCaP Enz-R cells. Transfecting pCMV-EPS8 also increased the levels of epithelial-to-mesenchymal transition (EMT), cell proliferation, and cell viability in both cell lines. Conversely, knockdown of Eps8 expression decreased the levels of EMT, cell proliferation, and cell viability in both cell lines. Furthermore, EPS8-induced EMT activation could be reversed by suppressing the Ras/JAK/PI3K signaling pathway. In vivo animal study also confirmed the crucial role of Eps8 expression in prostate cancer progression."
PAIR0040271	"It is demonstrated that under ENZ treatment, osteoblasts in the bone microenvironment secrete increased levels of extracellular matrix protein 1 (ECM1), which affects surrounding prostate cancer cells, promoting tumor cell proliferation and anti-androgen resistance. Mechanistically, ECM1 interacts with the enolase 1 (ENO1) receptor on the prostate cancer cell membrane, leading to its phosphorylation at the Y189 site. This event further recruits adapter proteins including growth factor receptor-bound protein 2 (GRB2) and son of sevenless homolog 1 (SOS1), which activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway to induce anti-androgen resistance. Furthermore, inhibiting ECM1 or utilizing the ENO1-targeting inhibitor phosphonoacetohydroxamate (PhAH) significantly restores tumor cell sensitivity to ENZ. Taken together, a potential mechanism is identified through which osteoblast-derived ECM1 drives resistance in bone metastatic prostate cancer under ENZ treatment."
PAIR0040272	"CAFs significantly promoted cell growth and enzalutamide resistance of PC3-EnzR and DU145-EnzR cells through substantial increased secretion of NRG1 by CAFs. Co-culturing enzalutamide-resistant prostate cancer cells (PC3-EnzR and DU145-EnzR) with CAFs further enhanced enzalutamide resistance, as evidenced by elevated IC50 values. Inhibition of NRG1 in CAFs attenuated their impact on enzalutamide resistance, providing insight into the role of NRG1 in mediating the crosstalk between CAFs and prostate cancer in the context of enzalutamide resistance. This study elucidates the pivotal role of CAF-secreted NRG1 in promoting enzalutamide resistance in prostate cancer, providing valuable insights for developing targeted therapeutic strategies to overcome resistance in advanced prostate cancer."
PAIR0040273	"Transient downregulation of HMMR using SMARTpool siRNA (siHMMR) markedly inhibited cell proliferation and induced apoptosis compared to control siRNA (siCON) in enzalutamide-sensitive LNCaP and enzalutamide-resistant MR49F cells. Additionally, siHMMR suppressed the colony-forming abilities of both LNCaP and MR49F cells, indicative of reduced survival ability."
PAIR0040274	"Our study revealed the release time and anticancer potential of Shk on the SCC9 and H357 oral cancer cell lines. We investigated the antiproliferative, antimigratory, cell cycle arresting and apoptosis promoting activity of Shk in oral cancer cells by performing MTT and morphological assay, colony, and tumor sphere formation assay, AO/EtBr and DAPI staining, Annexin V-FITC/PI staining, assay for reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) measurement, comet assay, qRT-PCR, and western blot analysis. We also checked the interaction of DNA and Shk by docking and CD spectroscopy and EtBr displacement assay. As a result, we found that Shk reduced the viability, proliferation, and tumorigenicity of SCC9 and H357 cells in a time and concentration-dependent manner. We obtained half-maximal inhibitory concentration (IC50) at 0.5 uM for SCC9 and 1.25 uM for H357. It promotes apoptosis via overexpressing proapoptotic Bax and caspase 3 via enhancing ROS that leads to MMP depletion and DNA damage and arrests cells at the G2/M & G2/S phase. The antimigratory activity of Shk was performed by analyzing the expression of markers of epithelial-mesenchymal transition like E-cadherin, ZO-1, N-cadherin, and vimentin. These overall results recommended that Shk shows potent anticancer activity against oral cancer cell lines in both in vitro and ex vivo conditions. So, it could be an excellent agent for the treatment of oral cancer."
PAIR0040275	"Our study revealed the release time and anticancer potential of Shk on the SCC9 and H357 oral cancer cell lines. We investigated the antiproliferative, antimigratory, cell cycle arresting and apoptosis promoting activity of Shk in oral cancer cells by performing MTT and morphological assay, colony, and tumor sphere formation assay, AO/EtBr and DAPI staining, Annexin V-FITC/PI staining, assay for reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) measurement, comet assay, qRT-PCR, and western blot analysis. We also checked the interaction of DNA and Shk by docking and CD spectroscopy and EtBr displacement assay. As a result, we found that Shk reduced the viability, proliferation, and tumorigenicity of SCC9 and H357 cells in a time and concentration-dependent manner. We obtained half-maximal inhibitory concentration (IC50) at 0.5 uM for SCC9 and 1.25 uM for H357. It promotes apoptosis via overexpressing proapoptotic Bax and caspase 3 via enhancing ROS that leads to MMP depletion and DNA damage and arrests cells at the G2/M & G2/S phase. The antimigratory activity of Shk was performed by analyzing the expression of markers of epithelial-mesenchymal transition like E-cadherin, ZO-1, N-cadherin, and vimentin. These overall results recommended that Shk shows potent anticancer activity against oral cancer cell lines in both in vitro and ex vivo conditions. So, it could be an excellent agent for the treatment of oral cancer."
PAIR0040276	Hsa_circ_0072732 was highly expressed in RCC cells. The silence of Hsa_circ_0072732 could increase RCC sensitivity to sunitinib. Hsa_circ_0072732 contributed to sunitinib chemoresistance by impairing ferroptosis. Hsa_circ_0072732 exerts its function mainly by acting as sponges for miR-548b-3p and regulating the expression SLC7A11. 
PAIR0040277	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040278	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040279	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp2c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040280	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp5c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040281	The most prevalent mutation was?pfk13?Arg622Ile
PAIR0040282	distorts the ribosome decoding center
PAIR0040283	"Loss of UBC7 reduces tolerance to multiple transition metals, which oxidatively damage a range of biological macromolecules, including proteins, and genotoxic agents."
PAIR0040284	SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response
PAIR0040285	"In this study, we demonstrated the absence of A1518/1519 methylation in the 16S rRNA of a Pseudomonas aeruginosa ksgA mutant. Biolog phenotypic microarrays were used to screen the phenotypes of the ksgA mutant against various antimicrobial agents. The loss of ksgA led to increased sensitivity to menadione, a superoxide generator, which was, at least in part, attributed to decreased in a superoxide dismutase (SOD) activity. Interestingly, the decrease in SOD activity in the ksgA mutant was linked to a decrease in the SodM protein levels, but not the sodM mRNA levels. Furthermore, the ksgA mutant strain exhibited sensitivity to hygromycin B and tylosin antibiotics. The tylosin-sensitive phenotype was correlated with decreased transcriptional levels of tufA, tufB, and tsf, which encode elongation factors. Additionally, the ksgA mutant showed resistance to kasugamycin. Collectively, these findings highlight the role of KsgA in oxidative stress responses and antibiotic sensitivity in P. aeruginosa."
PAIR0040286	"Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM."
PAIR0040287	"Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM."
PAIR0040288	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040289	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040290	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040291	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040292	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040293	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040294	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040295	"In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma."
PAIR0040296	"In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level."
PAIR0040297	"In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level."
PAIR0040298	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040299	"DTP cells evade ALK-TKI-induced ROS-mediated cell death through GPX4 activity. From these data showing elevated levels of ROS that arise through decreased levels of various antioxidant factors and decreased GSH synthesis, it might be expected that ROS-mediated cell death should occur in alectinib-induced DTP cells. However, DTP cells concurrently upregulated GPX4 protein, suggesting that ALK1903 DTP cells are able to evade ROS-mediated cell death by reducing ROS level in a GPX4-dependent manner."
PAIR0040300	"DTP cells evade ALK-TKI-induced ROS-mediated cell death through GPX4 activity. From these data showing elevated levels of ROS that arise through decreased levels of various antioxidant factors and decreased GSH synthesis, it might be expected that ROS-mediated cell death should occur in alectinib-induced DTP cells. However, DTP cells concurrently upregulated GPX4 protein, suggesting that ALK1903 DTP cells are able to evade ROS-mediated cell death by reducing ROS level in a GPX4-dependent manner."
PAIR0040301	"DTP cells evade ALK-TKI-induced ROS-mediated cell death through GPX4 activity. From these data showing elevated levels of ROS that arise through decreased levels of various antioxidant factors and decreased GSH synthesis, it might be expected that ROS-mediated cell death should occur in alectinib-induced DTP cells. However, DTP cells concurrently upregulated GPX4 protein, suggesting that ALK1903 DTP cells are able to evade ROS-mediated cell death by reducing ROS level in a GPX4-dependent manner."
PAIR0040302	DTP cells evade ALK-TKI-induced cell death through activation of EGFR and HER3 signaling. 
PAIR0040303	SHC1 phosphorylation was increased in CR mice
PAIR0040304	AXL phosphorylation was increased in CR mice
PAIR0040305	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040306	"The overexpression of BECN1 and TXNDC17 reduced NB sensitivity to cisplatin (DDP), etoposide (VP16), and cyclophosphamide (CTX). Autophagy mediated by BECN1 was regulated by TXNDC17, and this process was involved in the resistance to DDP, VP16, and CTX in NB. Suberoylanilide hydroxamic acid (SAHA) can enhance the sensitivity and apoptosis of NB cells to chemotherapeutics by inhibiting TXNDC17, ultimately decreasing autophagy-mediated chemoresistance."
PAIR0040307	"Based on the findings, the high?CSRP1?groups of patients in the TCGA datasets showed higher sensitivity to 5-fluorouracil, gemcitabine, rapamycin, and cisplatin and lower sensitivity to fludarabine. CSRP1 may serve as a potential prognostic marker and a therapeutic target for AML in the future."
PAIR0040308	We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.
PAIR0040309	"We consistently observed an increase in the expression of Mcl-1 in cells exposed to both short and long-term treatment with cisplatin, a drug commonly used in esophageal cancer therapy. Functional analysis showed that Mcl-1 regulates esophageal cancer cell response to cisplatin treatment. Notably, this upregulation of Mcl-1 was not dependent on eukaryotic initiation factor 4E (eIF4E). Instead, it was associated with increased stability due to the activation of Akt. Capivasertib, a potent pan-Akt kinase drug, significantly decreased Mcl-1 level via inhibiting Akt signaling pathway in chemo-resistant cells. In addition, capivasertib not only decreased the viability of chemo-resistant esophageal cancer cells but also synergistically enhanced the effects of cisplatin."
PAIR0040310	This research revealed that beta-elemene could relieve DDP resistance and inhibit tumor growth of GC via suppressing intracellular and exosome-METTL3 expression in and from DDP-resistance GC cells
PAIR0040311	"In the established cisplatin resistant cell line, NORAD was upregulated and miR-106a-5p was downregulated. Furthermore, we disclosed miR-106a-5p directly targeted 3'UTR of CCND1, which is an important cell cycle regulator and is frequently overexpressed in human cancers. Rescue experiments showed restoration of CCND1 in miR-106a-5p-overexpressing CRC cells successfully recovered cisplatin resistance. Finally, restoration of miR-106a-5p in NORAD-overexpressing CRC cells re-sensitized cisplatin resistance by targeting CCND1. Summarily, this study uncovered a NORAD-promoted cisplatin resistance through modulating the miR-106a-5p-CCND1 axis."
PAIR0040312	"In the established cisplatin resistant cell line, NORAD was upregulated and miR-106a-5p was downregulated. Furthermore, we disclosed miR-106a-5p directly targeted 3'UTR of CCND1, which is an important cell cycle regulator and is frequently overexpressed in human cancers. Rescue experiments showed restoration of CCND1 in miR-106a-5p-overexpressing CRC cells successfully recovered cisplatin resistance. Finally, restoration of miR-106a-5p in NORAD-overexpressing CRC cells re-sensitized cisplatin resistance by targeting CCND1. Summarily, this study uncovered a NORAD-promoted cisplatin resistance through modulating the miR-106a-5p-CCND1 axis."
PAIR0040313	"As western blotting revealed, A2780/DDP cells exhibited lower p62 protein level and higher LC3 II/I ratio than parental A2780 cells, indicating that autophagy was enhanced in DDP-resistant OC cells"
PAIR0040314	"As western blotting revealed, A2780/DDP cells exhibited lower p62 protein level and higher LC3 II/I ratio than parental A2780 cells, indicating that autophagy was enhanced in DDP-resistant OC cells"
PAIR0040315	"Our findings demonstrate a significant reduction in O-GlcNAc glycosylation of SRSF2 at Ser101 in cisplatin-resistant cells, suggesting that O-GlcNAc modification may regulate cisplatin resistance through alternative splicing of AUF1 to generate p45 or p37 isoforms mediated by SRSF2. The current study demonstrated that phosphorylation of hnRNPA1 at S95 site was significantly increased in cisplatin-resistant ovarian cancer. In addition, phosphorylation at Ser95 regulated recruitment of hnRNPA1 to AUF1 pre-mRNA to compete with SRSR2. Therefore, the phosphorylation of hnRNPA1 mediated by DNA-PK and O-GlcNAc glycosylation of SRSF2 might potentially regulate the alternative splicing of AUF1 and contribute to cisplatin resistance in ovarian cancer."
PAIR0040316	"Our findings demonstrate a significant reduction in O-GlcNAc glycosylation of SRSF2 at Ser101 in cisplatin-resistant cells, suggesting that O-GlcNAc modification may regulate cisplatin resistance through alternative splicing of AUF1 to generate p45 or p37 isoforms mediated by SRSF2. The current study demonstrated that phosphorylation of hnRNPA1 at S95 site was significantly increased in cisplatin-resistant ovarian cancer. In addition, phosphorylation at Ser95 regulated recruitment of hnRNPA1 to AUF1 pre-mRNA to compete with SRSR2. Therefore, the phosphorylation of hnRNPA1 mediated by DNA-PK and O-GlcNAc glycosylation of SRSF2 might potentially regulate the alternative splicing of AUF1 and contribute to cisplatin resistance in ovarian cancer."
PAIR0040317	"p37 isoform was implicated in the cancer stem cell-like features of ovarian cancer, as knockdown of AUF1 decreased some cancer stem cell like features, including colony formation, spheroid formation, in vivo tumorigenesis, as well as CD133 expression, in cisplatin-resistant ovarian cancer cells. Importantly, restoration of the p37 isoform enhanced cancer stem cell-like characteristics in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Consequently, the differential expression of distinct AUF1 isoforms within diverse cellular contexts may underlie its dualistic impact as either a ""promoter"" or a ""suppressor"" in cancer. Targeted inhibition of the p37 isoform could potentially offer a viable therapeutic approach for ovarian cancer patients exhibiting elevated AUF1 expression."
PAIR0040318	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells. "
PAIR0040319	.
PAIR0040320	.
PAIR0040321	.
PAIR0040322	.
PAIR0040323	"Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in?vitro and in?vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed."
PAIR0040324	"Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in?vitro and in?vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed."
PAIR0040325	"Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in?vitro and in?vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed."
PAIR0040326	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040327	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040328	"Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1alpha (HIF1alpha) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized?HIF1alpha?expression.?PHGDH?downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1alpha expression."
PAIR0040329	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040330	"The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of?SLC30A10?resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of?SLC30A3?resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets."
PAIR0040331	"The cell growth rate, mitochondrial activity, zinc accumulation, and sensitivity to the drugs cetuximab and cisplatin were investigated in functional tests. Overexpression or depletion of SLC30A or SLC39A family genes resulted in the deep reshaping of intracellular signaling and provoked hyperactivation of mitochondrial respiration. Variation in the expression of the SLC30A/SLC39A genes did not increase the sensitivity to cetuximab but significantly altered the sensitivity to cisplatin: overexpression of?SLC30A10?resulted in an ~2.7-4 times increased IC50 of cisplatin, and overexpression of?SLC30A3?resulted in an ~3.3 times decreased IC50 of cisplatin. The SLC30A/SLC39A genes should be considered as potential cancer drug resistance biomarkers and putative therapeutic targets."
PAIR0040332	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040333	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040334	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040335	"The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway."
PAIR0040336	"The expression of Pgp and the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line were both higher than those in RAJI cell line. NVP-BEZ235 downregulated the phosphorylation levels of AKT and mTOR in RAJI/DOX cell line. NVP-BEZ235 inhibited the proliferation of RAJI/DOX cell line, and the effect was obvious when it was cooperated with doxorubicin. The constitutive activation of PI3K/AKT/mTOR pathway of RAJI/DOX cell line was more serious than RAJI cell line. NVP-BEZ235 reversed doxorubicin resistance of RAJI/DOX cell line by inhibiting the PI3K/AKT/mTOR signal pathway."
PAIR0040337	"Western blotting and qRT-PCR were employed to examine alterations in signaling pathways, with an animal model providing additional validation. Our results show a marked increase in the IC50 of NVP-BEZ235 in resistant cell lines compared to their parental counterparts. A significant revelation was the role of LncRNA-CHKB-AS1 in mediating drug resistance. We observed dysregulated expression of CHKB-AS1 in both clinical samples of clear cell renal cell carcinoma (ccRCC) and cell lines. In vivo experiments further substantiated our findings, showing that CHKB-AS1 overexpression significantly enhanced tumor growth and resistance to NVP-BEZ235 in a subcutaneous tumorigenesis model, as evidenced by increased tumor volume and weight, whereas CHKB-AS1 knockdown led to a marked reduction in these parameters. Critically, CHKB-AS1 was identified to interact with MAP4, a key regulator in the phosphorylation of the PI3k/Akt/mTOR pathway."
PAIR0040338	"Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance."
PAIR0040339	"Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance."
PAIR0040340	"Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance."
PAIR0040341	"Sorafenib-resistant MOLM-13/sor cells have increased protein levels of FLT3 and Axl signaling pathways. These results suggest that activated FLT3-ITD signaling, Axl signaling, and protein translation contribute to sorafenib resistance."
PAIR0040342	"Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC."
PAIR0040343	"The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. "
PAIR0040344	"Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers."
PAIR0040345	"Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers."
PAIR0040346	"Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers."
PAIR0040347	"Although secondary?PIK3CA?mutations were previously reported to increase sensitivity to PI3Kalpha inhibitors, we identified emergent secondary resistance mutations in?PIK3CA?that alter the inhibitor binding pocket. Some mutations had differential effects on PI3Kalpha-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Kalpha-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in?PIK3CA-mutated cancers."
PAIR0040348	"In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect."
PAIR0040349	"In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect."
PAIR0040350	"We demonstrate that Alpelisib, Copanlisib and AZD8186 but not Idelalisib enhance radio- and radiochemosensitivity in the majority of HNSCC cell models (= responders) in a manner independent of PIK3CA mutation status. However, Alpelisib promotes MAPK signaling in non-responders compared to responders without profound impact on Akt, NFkappaB, TGFbeta, JAK/STAT signaling and DNA repair. Bioinformatic analyses identified unique gene mutations associated with extracellular matrix to be more frequent in non-responder cell models than in responders. Finally, we demonstrate that targeting of the cell adhesion molecule beta1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel beta1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors."
PAIR0040351	"In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect."
PAIR0040352	"In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect."
PAIR0040353	"In terms of PI3K/Akt pathway activity, Alpelisib treatment reduced phosphorylation of Akt (Ser473), GSK3beta (Ser9) and 4E-BP1 (Ser65) to a similar extent in responder and non-responder cell models (Fig. 2A, B and S2). Likewise, Akt activity was not significantly modified upon Alpelisib exposure (Fig. 2C). Taken together, our data show that inhibition of PI3Kalpha kinase causes varying degrees of radiochemosensitization in different HNSCC models and without an obvious mutational biomarker to predict drug effect."
PAIR0040354	"HIV subtype C is known to harbor mutations at critical positions of HIV aspartic protease compared to HIV subtype B, which affects the binding affinity. Recently, a novel double-insertion mutation at codon 38 (L38HL) was characterized in HIV subtype C protease, whose effects on the interaction with protease inhibitors are hitherto unknown. In this study, the potential of L38HL double-insertion in HIV subtype C protease to induce a drug resistance phenotype towards the protease inhibitor, Saquinavir (SQV), was probed using various computational techniques, such as molecular dynamics simulations, binding free energy calculations, local conformational changes and principal component analysis. The results indicate that the L38HL mutation exhibits an increase in flexibility at the hinge and flap regions with a decrease in the binding affinity of SQV in comparison with wild-type HIV protease C. Further, we observed a wide opening at the binding site in the L38HL variant due to an alteration in flap dynamics, leading to a decrease in interactions with the binding site of the mutant protease. It is supported by an altered direction of motion of flap residues in the L38HL variant compared with the wild-type. These results provide deep insights into understanding the potential drug resistance phenotype in infected individuals."
PAIR0040355	"JQ1, I-BET151, or BRD4 silencing all downregulated Met and inhibited both NSCLC cell viability in vitro and tumor growth in vivo."
PAIR0040356	"Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible."
PAIR0040357	"We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1."
PAIR0040358	"We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1."
PAIR0040359	"Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels."
PAIR0040360	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7027 re-sensitised resistant cells. "
PAIR0040361	"The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells."
PAIR0040362	"A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells."
PAIR0040363	"A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells."
PAIR0040364	"CCK-8 assays demonstrated that HCC cells carrying the?XIRP2?mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the?XIRP2?wildtype. The?XIRP2?mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of?XIRP2?resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the?XIRP2?mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin."
PAIR0040365	"To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity."
PAIR0040366	"To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity."
PAIR0040367	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040368	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040369	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040370	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040371	"Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible."
PAIR0040372	"Metal homeostasis is maintained by the uptake, storage and efflux of metal ions that are necessary for the survival of the bacterium. Homeostasis is mostly regulated by a group of transporters categorized as ABC transporters and P-type ATPases. On the other hand, efflux pumps often play a role in drug-metal cross-resistance. Here, with the help of antibiotic sensitivity, antibiotic/dye accumulation and semi-quantitative biofilm formation assessments we report the ability of Rv3270, a P-type ATPase known for its role in combating Mn2+ and Zn2+ metal ion toxicity in Mycobacterium tuberculosis, in influencing the extrusion of multiple structurally unrelated drugs and enhancing the biofilm formation of Escherichia coli and Mycobacterium smegmatis. Overexpression of Rv3270 increased the tolerance of host cells to norfloxacin, ofloxacin, sparfloxacin, ampicillin, oxacillin, amikacin and isoniazid. A significantly lower accumulation of norfloxacin, ethidium bromide, bocillin FL and levofloxacin in cells harbouring Rv3270 as compared to host cells indicated its role in enhancing efflux activity. Although over-expression of Rv3270 did not alter the susceptibility levels of levofloxacin, rifampicin and apramycin, the presence of a sub-inhibitory concentration of Zn2+ resulted in low-level tolerance towards these drugs. Of note, the expression of Rv3270 enhanced the biofilm-forming ability of the host cells strengthening its role in antimicrobial resistance. Therefore, the study indicated that the over-expression of Rv3270 enhances the drug efflux activity of the micro-organism where zinc might facilitate drug-metal cross-resistance for some antibiotics."
PAIR0040373	"Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166."
PAIR0040374	"the acquisition of drug resistance by 4T1 cells was accompanied by an increase in the constitutive activity of interferon type I and NF-kappaB pathways and an elevated expression of LINE-1 elements, which are known to induce inflammatory responses via their products of reverse transcription. Treatment with NRTI reduced NF-kappaB activity and reverted drug resistance. Furthermore, the inducible expression of LINE-1 stimulated inflammatory response and increased the frequency of drug-resistant variants in a tumor cell population. "
PAIR0040375	This research revealed that beta-elemene could relieve DDP resistance and inhibit tumor growth of GC via suppressing intracellular and exosome-METTL3 expression in and from DDP-resistance GC cells
PAIR0040376	"Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of beta-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, beta-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib."
PAIR0040377	"Bendamustine-resistant leukemia cells exhibited a decreased RNA expression level for Polo-like kinase-1 (PLK-1). Notably, after treatment with the demethylating agent 5-aza-2'-deoxycytidine, PLK-1 gene expression surged significantly, enhancing bendamustine's cytotoxicity in the resistant leukemia cells. However, MDR1 expression, as determined by flow cytometry, remained consistent between parental and bendamustine-resistant leukemia cells."
PAIR0040378	"Olaparib-resistant BRCA1m OvCa cells show greater sensitivity to niraparib and rucaparib relative to other PARPis. Niraparib and rucaparib demonstrated greater cytotoxicity and reduced RF speed compared to the other three PARPis, likely due to the higher levels of SSB induction. "
PAIR0040379	"Rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. The SLC7A11/GSH/GPX4 signal transduction axis is the core pathway of ferroptosis, and SLC7A11 plays a major transport function in the cystine/glutamate anti-transporter (Xc-system). The extracellular cysteine is imported into the cell through the XC- system and then converted to cysteine to synthesize GSH. GPX4 uses reduced GSH as a cofactor to detoxify lipid peroxides into lipid alcohols, thereby preventing ferroptosis induced in cells."
PAIR0040380	"By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients."
PAIR0040381	"By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients."
PAIR0040382	"By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients."
PAIR0040383	"By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients."
PAIR0040384	"By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients."
PAIR0040385	"To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity."
PAIR0040386	"The effect of miR-770-5p on the EGFR/HER2/IGF1R crosstalk signaling. In general, tumorigenesis of breast cancer is assumed to be associated with the PI3K and MAPK pathways and signaling these pathway complex has critical roles in cell proliferation in HER2 amplified cells. Trastuzumab can block this signaling, either by inhibiting the activity of EGFR and HER2 kinases directly or through HER2 binding at the cell surface. miR-770-5p can reduce dissociation of receptor crosstalk signaling, which increases its activity."
PAIR0040387	"Our results show that calycosin inhibits the proliferation and migration abilities of CL1-0 GEMR cells, and that these effects might be through the LDOC1/GNL3L/NFkappaB pathway. These findings improve our understanding of the anti-tumor activity and potential mechanisms of calycosin in gemcitabine-resistant lung cancer cells, and offer valuable support for the clinical application of calycosin in treating gemcitabine-resistant lung cancer."
PAIR0040388	"Our results show that calycosin inhibits the proliferation and migration abilities of CL1-0 GEMR cells, and that these effects might be through the LDOC1/GNL3L/NFkappaB pathway. These findings improve our understanding of the anti-tumor activity and potential mechanisms of calycosin in gemcitabine-resistant lung cancer cells, and offer valuable support for the clinical application of calycosin in treating gemcitabine-resistant lung cancer."
PAIR0040389	"Our results show that calycosin inhibits the proliferation and migration abilities of CL1-0 GEMR cells, and that these effects might be through the LDOC1/GNL3L/NFkappaB pathway. These findings improve our understanding of the anti-tumor activity and potential mechanisms of calycosin in gemcitabine-resistant lung cancer cells, and offer valuable support for the clinical application of calycosin in treating gemcitabine-resistant lung cancer."
PAIR0040390	"Our results show that calycosin inhibits the proliferation and migration abilities of CL1-0 GEMR cells, and that these effects might be through the LDOC1/GNL3L/NFkappaB pathway. These findings improve our understanding of the anti-tumor activity and potential mechanisms of calycosin in gemcitabine-resistant lung cancer cells, and offer valuable support for the clinical application of calycosin in treating gemcitabine-resistant lung cancer."
PAIR0040391	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040392	"Compared with vector control,?E. coli?expressing AAC(6')-Iap showed decreased susceptibilities to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin, and tobramycin. Thin-layer chromatography (TLC) analysis revealed that all the aminoglycosides tested, except for apramycin and paromomycin, were acetylated by AAC(6')-Iap. These results indicated that?aac(6')-Iap?is a functional acetyltransferase that modifies the 6'-NH2?position of aminoglycosides and is involved in aminoglycoside resistance."
PAIR0040393	"In this study, we demonstrated the absence of A1518/1519 methylation in the 16S rRNA of a Pseudomonas aeruginosa ksgA mutant. Biolog phenotypic microarrays were used to screen the phenotypes of the ksgA mutant against various antimicrobial agents. The loss of ksgA led to increased sensitivity to menadione, a superoxide generator, which was, at least in part, attributed to decreased in a superoxide dismutase (SOD) activity. Interestingly, the decrease in SOD activity in the ksgA mutant was linked to a decrease in the SodM protein levels, but not the sodM mRNA levels. Furthermore, the ksgA mutant strain exhibited sensitivity to hygromycin B and tylosin antibiotics. The tylosin-sensitive phenotype was correlated with decreased transcriptional levels of tufA, tufB, and tsf, which encode elongation factors. Additionally, the ksgA mutant showed resistance to kasugamycin. Collectively, these findings highlight the role of KsgA in oxidative stress responses and antibiotic sensitivity in P. aeruginosa."
PAIR0040394	"Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper-activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of?CDK2,?CDK4, and?CCNE1. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR-dependent manner, whilst co-treatment with the AR antagonist bicalutamide recovered its therapeutic effect both?in vitro?and?in vivo. Thus, for BQ-overexpressing breast cancer, targeting AR can combat anastrozole resistance."
PAIR0040395	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040396	"Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties."
PAIR0040397	"This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance."
PAIR0040398	"This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance."
PAIR0040399	"This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance."
PAIR0040400	"This study was comprised of 20 RAIR and 14 non-radioiodine refractory (non-RAIR) thyroid cancer patients. Liquid chromatography-mass spectrometry was used to identify differences in the serum metabolites of RAIR and non-RAIR patients. In addition, chemical assays were performed to determine the effects of the differential metabolites on iodine uptake. Metabolic pathway enrichment analysis of the differential metabolites revealed significant differences in the phenylalanine and tyrosine metabolic pathways. Notably, quinate and shikimic acid, metabolites of the tyrosine pathway, were significantly increased in the RAIR group. In contrast, the phenylalanine pathway metabolites, hippuric acid and 2-phenylacetamide, were markedly decreased in the RAIR group. Thyroid peroxidase plays an important role in catalyzing the iodination of tyrosine residues, while the ionic state of iodine promotes the iodination reaction. Quinate, shikimic acid, hippuric acid, and 2-phenylacetamide were found to be involved in the iodination of tyrosine, which is a key step in thyroid hormone synthesis. Specifically, quinate and shikimic acid were found to inhibit iodination, while hippuric acid and 2-phenylacetamide promoted iodination. Abnormalities in phenylalanine and tyrosine metabolic pathways are closely associated with iodine resistance. Tyrosine is required for thyroid hormone synthesis and could be a potential cause of iodine resistance."
PAIR0040401	"Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited the serine/threonine kinases, JNK and ERK, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where the single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer."
PAIR0040402	"We observed elevated levels of NAALADL2-AS2 in DLBCL tissues. We discovered that NAALADL2-AS2 functions as ceRNA to inhibit expression of miR-34a, miR-125a, whereas overexpression of NAALADL2-AS2 indirectly upregulates expression of BCL-2. Interfering with NAALADL2-AS2 promoted apoptosis in DLBCL cells, resulting in approximately a 40% increase in sensitivity to doxorubicin and rituximab. In vivo experiments further confirmed that targeting NAALADL2-AS2 effectively suppressed tumor growth, leading to upregulation of miR-34a and miR-125a, downregulation of BCL-2, and enhanced apoptosis in DLBCL cells, which significantly improved their sensitivity to doxorubicin and rituximab by approximately 50%. "
PAIR0040403	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040404	"The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells."
PAIR0040405	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040406	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040407	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040408	"Monoclonal antibodies targeting the Spike protein of SARS-CoV-2 are effective against COVID-19 and might mitigate future pandemics. However, their efficacy is challenged by the emergence of antibody-resistant virus variants."
PAIR0040409	We report the case of an allogeneic stem cell transplant recipient with nosocomial acquisition of SARS-CoV-2 infection who received antispike neutralizing monoclonal antibody bamlanivimab 2 days after diagnosis of SARS-CoV-2 infection but progressed to severe COVID-19 pneumonia and died with the selection of E484K/Q resistance mutations to bamlanivimab.
PAIR0040410	"Monoclonal antibodies targeting the Spike protein of SARS-CoV-2 are effective against COVID-19 and might mitigate future pandemics. However, their efficacy is challenged by the emergence of antibody-resistant virus variants."
PAIR0040411	"Monoclonal antibodies targeting the Spike protein of SARS-CoV-2 are effective against COVID-19 and might mitigate future pandemics. However, their efficacy is challenged by the emergence of antibody-resistant virus variants."
PAIR0040412	"Remdesivir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics."
PAIR0040413	"Monoclonal antibodies targeting the Spike protein of SARS-CoV-2 are effective against COVID-19 and might mitigate future pandemics. However, their efficacy is challenged by the emergence of antibody-resistant virus variants."
PAIR0040414	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040415	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040416	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040417	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040418	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040419	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040420	"Multiple mechanisms drive CD22 antigen escape, including epitope loss (protein truncation and destabilization) and epitope alteration.Hypermutation caused by error-prone DNA damage repair may serve as a driver of CD22 mutation and escape."
PAIR0040421	"To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity."
PAIR0040422	"Daclatasvir (DCV) and ledipasvir (LDV) could be effective drugs for Src-associated cancers.DCV and LDV are widely used direct-action antivirals with low toxicity.DCV and LDV selectively affect a Src oncogenic pathway without the inherent toxicity of classical Src inhibitors.DCV and LDV inhibit the formation of a Src-EphA2 complex, specifically blocking the Src-EphA2-Akt oncogenic pathway."
PAIR0040423	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040424	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040425	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040426	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040427	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040428	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040429	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040430	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2002H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040431	"Daclatasvir (DCV) and ledipasvir (LDV) could be effective drugs for Src-associated cancers.DCV and LDV are widely used direct-action antivirals with low toxicity.DCV and LDV selectively affect a Src oncogenic pathway without the inherent toxicity of classical Src inhibitors.DCV and LDV inhibit the formation of a Src-EphA2 complex, specifically blocking the Src-EphA2-Akt oncogenic pathway."
PAIR0040432	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040433	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040434	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040435	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040436	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040437	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040438	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040439	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040440	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040441	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040442	"We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir."
PAIR0040443	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040444	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040445	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040446	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040447	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040448	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040449	"It was found that ivermectin effectively suppressed the expression of autophagy and transport proteins in K562/FLM cells, reduced the activity of the aforementioned phosphoproteins, and promoted apoptotic cell death. The significant effects of ivermectin might offer a novel therapeutic strategy to overcome flumatinib resistance and optimize the treatment outcomes of CML."
PAIR0040450	"Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV."
PAIR0040451	"Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV."
PAIR0040452	"Binding free energies calculated by MM-GBSA method suggest that the decrease in binding enthalpy and the increase in binding entropy induced by mutations V32I, I50V and I84V are responsible for drug resistance of the mutated PRs on APV. The energetic contributions of separate residues on binding of APV to the PR show that V32I, I50V and I84V highly disturb the interactions of two flaps with APV and mostly drive the decrease in binding ability of APV to the PR. Thus, the conformational changes of two flaps in the PR caused by V32I, I50V and I84V play key roles in drug resistance of three mutated PR towards APV."
PAIR0040453	"AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas.?Antioxid. Redox Signal."
PAIR0040454	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040455	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2003H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040456	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040457	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040458	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040459	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040460	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2007H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040461	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040462	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2008H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040463	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040464	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2006H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040465	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040466	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040467	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040468	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040469	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040470	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2004H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040471	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040472	"Key results: Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo.Conclusion and implications: AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC."
PAIR0040473	"To overcome chemotherapy resistance, novel strategies sensitizing cancer cells to chemotherapy are required. Here, we screen the lysyl-oxidase (LOX) family to clarify its contribution to chemotherapy resistance in liver cancer. LOXL3 depletion significantly sensitizes liver cancer cells to Oxaliplatin by inducing ferroptosis. Chemotherapy-activated EGFR signaling drives LOXL3 to interact with TOM20, causing it to be hijacked into mitochondria, where LOXL3 lysyl-oxidase activity is reinforced by phosphorylation at S704. Metabolic adenylate kinase 2 (AK2) directly phosphorylates LOXL3-S704. Phosphorylated LOXL3-S704 targets dihydroorotate dehydrogenase (DHODH) and stabilizes it by preventing its ubiquitin-mediated proteasomal degradation. K344-deubiquitinated DHODH accumulates in mitochondria, in turn inhibiting chemotherapy-induced mitochondrial ferroptosis. CRISPR-Cas9-mediated site-mutation of mouse LOXL3-S704 to D704 causes a reduction in lipid peroxidation. Using an advanced liver cancer mouse model, we further reveal that low-dose Oxaliplatin in combination with the DHODH-inhibitor Leflunomide effectively inhibit liver cancer progression by inducing ferroptosis, with increased chemotherapy sensitivity and decreased chemotherapy toxicity."
PAIR0040474	"Key results: Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo.Conclusion and implications: AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC."
PAIR0040475	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040476	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040477	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040478	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040479	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040480	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles."
PAIR0040481	SHC1 phosphorylation was increased in CR mice
PAIR0040482	AXL phosphorylation was increased in CR mice
PAIR0040483	"MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. "
PAIR0040484	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040485	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040486	Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy.
PAIR0040487	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040488	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040489	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040490	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040491	"Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin. "
PAIR0040492	"Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin. "
PAIR0040493	"Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin. "
PAIR0040494	"Overexpression of PIK3CD-S splice variant in PCa confers AA PCa resistance to PI3Kdelta inhibitor, such as Idelalisib. We also uncovered that the synthesis of aberrant PIK3CD-S splice variant is likely mediated by the splicing factor SRSF2, and inhibition of SRSF2 by SRPK1/2 inhibitor SRPIN340 significantly sensitizes AA PCa to Idelalisib."
PAIR0040495	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040496	"The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations"
PAIR0040497	"Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast?Candida albicans. Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene?CDR1. Hyperactive forms of both Tac1 and Znc1 also cause overexpression of?RTA3, which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane.?RTA3?expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and?rta3delta mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on?RTA3?whereas?CDR1?was dispensable. Intriguingly, the induction of?RTA3?expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent?RTA3?upregulation by fluphenazine. In line with this observation,?znc1delta mutants were hypersensitive to miltefosine, whereas?tac1delta mutants showed wild-type tolerance. Forced expression of?RTA3?reverted the hypersensitivity of?znc1delta mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate?RTA3?in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced?RTA3?expression that is important for wild-type miltefosine tolerance."
PAIR0040498	"Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast?Candida albicans. Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene?CDR1. Hyperactive forms of both Tac1 and Znc1 also cause overexpression of?RTA3, which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane.?RTA3?expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and?rta3delta mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on?RTA3?whereas?CDR1?was dispensable. Intriguingly, the induction of?RTA3?expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent?RTA3?upregulation by fluphenazine. In line with this observation,?znc1delta mutants were hypersensitive to miltefosine, whereas?tac1delta mutants showed wild-type tolerance. Forced expression of?RTA3?reverted the hypersensitivity of?znc1delta mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate?RTA3?in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced?RTA3?expression that is important for wild-type miltefosine tolerance."
PAIR0040499	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040500	"MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. "
PAIR0040501	"In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance."
PAIR0040502	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040503	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040504	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040505	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040506	"The current study aims to understand the resistance of Bifidobacterium adolescentis to different anti-tubercular drugs (first-line oral tuberculosis drugs). The bacteria were grown with anti-tubercular drugs such as isoniazid, pyrazinamide, and streptomycin to better understand the resistance phenomena. It was found that even at tenfold higher concentrations, growth rates remained unchanged. In addition, a small number of bacteria were found to aggregate strongly, a property that protects against the toxicity of the drug. Further FE-SEM (Field Emission Scanning Electron Microscopy) analysis revealed that some bacteria became excessively long, elongated, and protruded on the surface. Size scattering analysis confirmed the presence of bifidobacteria in the size range of 1.0-100 um. After whole genome sequence analysis, certain mutations were found in the relevant gene. In vitro, foam formation and growth in the presence of H2O2 and HPLC (High Performance Liquid Chromatography) studies provide additional evidence for the presence of catalase. According to RAST (Rapid Annotation Using Subsystems Technology) annotation and CARD (Comprehensive Antibiotic Resistance Database analysis), there were not many components in the genome that were resistant to antibiotics. Whole genome sequence (WGS) analysis does not show the presence of bacteriocins and antibiotic resistance genes, but few hypothetical proteins were observed. 3D structure and docking studies suggest their interaction with specific ligands."
PAIR0040507	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040508	"In the present study, the clinical importance of the HGF/MET pathway was analyzed using bioinformatics. By establishing TMZ?resistant cell lines, the impact of combined treatment with lidocaine and TMZ was investigated. Additionally, the effects of lidocaine on cellular function were also examined and confirmed using knockdown techniques. The current findings revealed that the HGF/MET pathway played a key role in brain cancer, and its activation in GBM was associated with increased malignancy and poorer patient outcomes. Elevated HGF levels and activation of its receptor were found to be associated with TMZ resistance in GBM cells. Lidocaine effectively suppressed the HGF/MET pathway, thereby restoring TMZ sensitivity in TMZ?resistant cells. Furthermore, lidocaine also inhibited cell migration. Overall, these results indicated that inhibiting the HGF/MET pathway using lidocaine can enhance the sensitivity of GBM cells to TMZ and reduce cell migration, providing a potential basis for developing novel therapeutic strategies for GBM."
PAIR0040509	"IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.The PI3K/Akt/mTOR signaling pathway acts as the mediator of IDE in alleviating DR.IDE treatment suppressed the activation of the PI3K/Akt/mTOR signaling pathway, and PI3K signaling repressed the protective role of IDE in DR, explaining the IDE-suppressed autophagy in DR."
PAIR0040510	"IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.The PI3K/Akt/mTOR signaling pathway acts as the mediator of IDE in alleviating DR.IDE treatment suppressed the activation of the PI3K/Akt/mTOR signaling pathway, and PI3K signaling repressed the protective role of IDE in DR, explaining the IDE-suppressed autophagy in DR."
PAIR0040511	"IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.The PI3K/Akt/mTOR signaling pathway acts as the mediator of IDE in alleviating DR.IDE treatment suppressed the activation of the PI3K/Akt/mTOR signaling pathway, and PI3K signaling repressed the protective role of IDE in DR, explaining the IDE-suppressed autophagy in DR."
PAIR0040512	"IDE regulated the autophagy of retina cells to alleviate diabetic retinopathy via regulating the PI3K signaling pathway.The PI3K/Akt/mTOR signaling pathway acts as the mediator of IDE in alleviating DR.IDE treatment suppressed the activation of the PI3K/Akt/mTOR signaling pathway, and PI3K signaling repressed the protective role of IDE in DR, explaining the IDE-suppressed autophagy in DR."
PAIR0040513	IDB had successful control over drug resistance in the rotenone corneal kindled model by bypassing blocked complex I. IDB has a good safety profile and can be considered an adjuvant along with standard antiseizure drugs in drug-resistant patients.
PAIR0040514	IDB had successful control over drug resistance in the rotenone corneal kindled model by bypassing blocked complex I. IDB has a good safety profile and can be considered an adjuvant along with standard antiseizure drugs in drug-resistant patients.
PAIR0040515	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040516	"Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties."
PAIR0040517	"Our findings highlight that attenuated ROS accelerates IL-2R translation and therefore brings about aberrant expression of IL-2R protein, leading to overactivation of JAK/STAT, AKT/mTOR and MAPK signaling events, which explains SAHA resistance to CTCL cells. Moreover, cantharidin could overcome SAHA resistance to CTCL by blocking IL-2R-related signaling via ROS dependent manner."
PAIR0040518	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040519	"Lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings."
PAIR0040520	"Therefore, the drug sensitivity of DOC and lovastatin in human lung cancer cells was evaluated. We found that H1355 (mutant TP53-E285K), CL1 (mutant TP53-R248W), and H1299 (TP53-null) human non-small cell lung cancer cells were more sensitive to lovastatin than A549 and H460 cells expressing wild-type TP53. Conversely, A549 and H460 cells showed higher sensitivity to DOC than H1299 and CL1 cells, as demonstrated by the MTT assay. When endogenous TP53 activity was inhibited by pifithrin-alpha in A549 and H460 cells, lovastatin sensitivities significantly increased, and cancer cell viabilities markedly reduced. These results indicate that TP53 status is associated with the anti-cancer effect of statins in human lung cancer cells. Mutated or null TP53 status is correlated with higher statin sensitivity. Furthermore, DOC-resistant H1299 (H1299/D8) cells showed significant sensitivity to lovastatin treatment compared to DOC-resistant A549 (A549/D16) cells, indicating a potential application of statins/chemotherapy combination therapy to control wild-type and abnormal TP53-containing human lung tumors."
PAIR0040521	"In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development."
PAIR0040522	"In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development."
PAIR0040523	"Mutations associated with nitroimidazole resistance were identified by whole-genome sequencing of spontaneous resistant mutants, suggesting a mechanism for reductive activation of the nitroimidazole prodrug by a predicted NAD(P)H-dependent flavin mononucleotide (FMN) oxidoreductase.Mutant MtzR(A) contained two mutations: (i) a 92-bp deletion encompassing bp 439245 to 439346 and (ii) a single base change at bp 481520 (see below). The 92-bp deletion predicts the replacement of the last 6 amino acids of MG343 (annotated as a conserved hypothetical protein) with 21 missense amino acids and deletes 70?bp upstream of MG_342 . Translation of MG342 may be affected in this mutant as the MG343 C terminus now overlaps the native start codon of MG_342; a second ATG located 30?bp downstream may function as an alternative start codon. In addition, deletion of 92 bp in this mutant could affect transcription of MG_342 by removing a potential promoter sequence in the MG_343-MG_342 intergenic region.Mutants MtzR(E) and TdzR(A) both have a single A-to-G mutation at bp 439235 which changes the MG_342 start codon from ATG to ACG on the coding strand. Again, the ATG located 30?bp downstream may serve as the translational start codon for MG342 in these mutants."
PAIR0040524	"Recombinant KBL-1 protein had hydrolytic activities against all the beta-lactams tested, except for aztreonam (Table?3). Recombinant KBL-1 efficiently hydrolyzed the penicillins, including ampicillin, amoxicillin, penicillin G, and piperacillin with?kcat/km?values of 0.422 to 1.166."
PAIR0040525	"Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol."
PAIR0040526	"Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol."
PAIR0040527	"Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol."
PAIR0040528	"Arbidol is a broad-spectrum antiviral that binds to and prevents the fusion-associated conformational changes in the trimeric influenza A virus (IAV) hemagglutinin (HA). The rate-limiting step during the HA-mediated membrane fusion is the release of the hydrophobic fusion peptides from a conserved pocket on HA. Here, we investigated how destabilizing or stabilizing mutations in or near the fusion peptide affect viral sensitivity to Arbidol. The degree of sensitivity was proportional to the extent of fusion-peptide stability on the prefusion HA: stabilized mutants were more sensitive, and destabilized ones were resistant to Arbidol."
PAIR0040529	"Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas."
PAIR0040530	"Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas."
PAIR0040531	"Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas."
PAIR0040532	"Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas."
PAIR0040533	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040534	"The expression of?cyp51A?mRNA was induced by the addition of the azole antifungal drug efinaconazole, whereas no such induction was detected for?cyp51B, suggesting that Cyp51A functions as an azole-responsive Cyp51 isozyme. To explore the contribution of Cyp51A to susceptibility to azole drugs, the neomycin phosphotransferase (nptII) gene cassette was inserted into the?cyp51A?3'-untranslated region of deltaku80?to destabilize the mRNA of?cyp51A. In this mutant, the induction of?cyp51A?mRNA expression by efinaconazole was diminished. The minimum inhibitory concentration for several azole drugs of this strain was reduced, suggesting that dermatophyte Cyp51A contributes to the tolerance for azole drugs."
PAIR0040535	SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response
PAIR0040536	"Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels."
PAIR0040537	"Mechanistic insights revealed sitagliptin's ability to modulate the seizure grade and first myoclonic jerk latency via oxidative stress markers, like reduced glutathione and glutathione peroxidase emphasizing its antioxidative role in epilepsy. Additionally, it demonstrated anti-inflammatory effects by significantly reducing proinflammatory markers interleukin-1beta and interleukin-6. The modulation of key genes of the long-term potentiation pathway, particularly protein kinase C-gamma and metabotropic glutamate receptor 5, was evident through mRNA expression levels. Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-gamma."
PAIR0040538	"Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK, rpoC, glpK, MPN449, and in one of the hsdS (MPN365) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible."
PAIR0040539	"Out of total 112 mycobacterial positive cultures, five?M. bovis?were isolated and underwent WGS. All sequenced strains belonged to?Mycobacterium tuberculosis var bovis, spoligotype BOV_1; BOV_11. Resistance gene mutations were determined in 100% of strains to pyrazinamide (pncA?and?rpsA), isoniazid (KatG?and?ahpC), ethambutol (embB,?embC,?embR?and?ubiA), streptomycin (rpsl) and fluoroquinolones (gyrA?and?gyrB). Rifampin (rpoB?and?rpoC) and delamanid (fbiC) resistance genes were found in 80% of strains. The major represented virulence classes were the secretion system, cell surface components and regulation system."
PAIR0040540	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040541	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040542	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040543	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040544	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040545	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040546	Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.
PAIR0040547	"Olaparib-resistant BRCA1m OvCa cells show greater sensitivity to niraparib and rucaparib relative to other PARPis. Niraparib and rucaparib demonstrated greater cytotoxicity and reduced RF speed compared to the other three PARPis, likely due to the higher levels of SSB induction. "
PAIR0040548	"We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance."
PAIR0040549	"We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance."
PAIR0040550	"Here, we show that a?PPP3CB?transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of?PPP3CB?by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment."
PAIR0040551	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040552	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040553	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040554	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040555	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040556	"Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity."
PAIR0040557	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040558	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040559	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites."
PAIR0040560	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites."
PAIR0040561	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites."
PAIR0040562	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites."
PAIR0040563	"In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. These results suggest that fedratinib might be effective in the suppression of ATP site mutations generated by ruxolitinib due to its ability to bind additional substrate binding sites."
PAIR0040564	"The expression of far upstream element-binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin-induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation-seq and RNA-seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin."
PAIR0040565	"Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC."
PAIR0040566	"Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC."
PAIR0040567	"Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors."
PAIR0040568	"Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors."
PAIR0040569	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040570	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040571	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040572	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040573	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040574	.
PAIR0040575	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040576	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132."
PAIR0040577	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG134."
PAIR0040578	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG133."
PAIR0040579	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG135."
PAIR0040580	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG136."
PAIR0040581	"In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG137."
PAIR0040582	Venetoclax resistance can be driven by the upregulation of other anti-apoptotic BCL2 family members such as BCL-xL and MCL1 by NF-kappaB activation.
PAIR0040583	Down-Regulation of Onc-p53 Increases BIM Expression and Sensitizes to Venetoclax in SCLC-P Cells. Down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells
PAIR0040584	Down-Regulation of Onc-p53 Increases BIM Expression and Sensitizes to Venetoclax in SCLC-P Cells. Down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells
PAIR0040585	"Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option."
PAIR0040586	"Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option."
PAIR0040587	"Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option."
PAIR0040588	"Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option."
PAIR0040589	"Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option."
PAIR0040590	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040591	"Considering the fact that for many tumour cells, inhibition of CDK4/6 can induce cellular quiescence or senescence, we evaluated whether CDK4 expression was affected by copanlisib alone or in combination with palbociclib. Copanlisib was selected as it was more effective than other PI3K inhibitors on its own. While the cells did not react to palbociclib by reducing the expression of CDK4, copanlisib lead to dose-dependent downregulation in CDK4 expression, especially when combined with palbociclib (Additional file 1: Fig. S8). Moreover, the cells did not express p-Akt following treatment with copanlisib (Additional file 1: Fig. S9)."
PAIR0040592	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y191L caused high-level resistance, in agreement with the predictions."
PAIR0040593	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y193L caused high-level resistance, in agreement with the predictions."
PAIR0040594	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y192L caused high-level resistance, in agreement with the predictions."
PAIR0040595	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions."
PAIR0040596	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y189L caused high-level resistance, in agreement with the predictions."
PAIR0040597	"This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y190L caused high-level resistance, in agreement with the predictions."
PAIR0040598	"In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment."
PAIR0040599	Abatacept-resistant memory Th17 cells exhibit genes for aldehyde dehydrogenases. Memory-phenotype pTh17 cells exhibit a unique metabolic pathway that may involve ALDH for both survival and function.
PAIR0040600	"The PI3K/Akt/mTOR pathway is involved in the regulation of cancer cell survival, proliferation, growth, and metabolism. In most prostate cancer cell lines, the PIP3 phosphatase PTEN, which antagonizes this pathway, is mutated and therefore the PI3K/Akt/mTOR pathway is activated. To examine the functioning of this pathway, we determined the expressions and phosphorylation levels of Akt and mTOR via Western blot. As shown in, in the drug-resistant LN-FLU cells, both the phosphorylation levels and overall expressions of Akt and mTOR were decreased when compared to the LNCaP cells. The results in the LN-FLU cells were similar to those observed in the androgen-resistant PC3 cells, which were used as a positive control. The decrease in Akt and mTOR signaling suggests a proliferative arrest of the drug-resistant LN-FLU cells."
PAIR0040601	"To obtain molecular evidence of the acquired resistance of the LN-FLU cells, we checked the expressions of significant proteins involved in prostate cell growth. As shown in, the LN-FLU cells showed less expression of the androgen receptor (AR) compared with the parental LNCaP cells, further confirming the androgen refractory state of the cells."
PAIR0040602	"The PI3K/Akt/mTOR pathway is involved in the regulation of cancer cell survival, proliferation, growth, and metabolism. In most prostate cancer cell lines, the PIP3 phosphatase PTEN, which antagonizes this pathway, is mutated and therefore the PI3K/Akt/mTOR pathway is activated. To examine the functioning of this pathway, we determined the expressions and phosphorylation levels of Akt and mTOR via Western blot. As shown in, in the drug-resistant LN-FLU cells, both the phosphorylation levels and overall expressions of Akt and mTOR were decreased when compared to the LNCaP cells. The results in the LN-FLU cells were similar to those observed in the androgen-resistant PC3 cells, which were used as a positive control. The decrease in Akt and mTOR signaling suggests a proliferative arrest of the drug-resistant LN-FLU cells."
PAIR0040603	"ABCB1A, a well-known multidrug-resistant protein that expels drugs outside the cell, thereby promoting drug resistance, was increased in the LN-FLU cells"
PAIR0040604	"This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the beta-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade."
PAIR0040605	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine."
PAIR0040606	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients."
PAIR0040607	"DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis.DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress.Using PCR arrays we observed an upregulation of of several DDR genes (CDKN1A, GADD45A, GADD45G, EXO1, and PPP1R15A) in KASUMI-1 and MV4-11 cell lines that survived following treatment with Idarubicin and Cytarabine."
PAIR0040608	Induction of DNA double-strand breaks and chromatin damage through histone eviction;Less affected by ABCG2-mediated drug export.
PAIR0040609	Induction of DNA double-strand breaks and chromatin damage through histone eviction.
PAIR0040610	"In this study, we firstly identified the Thr167 and Ser175 residues in the activation loop of S. suis STK (ssSTK) as the kinase autophosphorylation sites. Phenotyping results demonstrated that the autophosphorylation deficient strain resembled the stk deletion strain showing essentiality for bacterial growth in minimal medium, abnormal morphology, and decreased virulence when compared with the wild-type S. suis SC19 strain. Based on these findings, we established an ssSTK inhibitor screening approach by measuring the growth of S. suis in a minimal medium and testing the autophosphorylation inhibition by measuring the consumption of ATP in an enzymatic reaction by ssSTK. A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29. These inhibitors showed antimicrobial activity in vitro. Moreover, by using Galleria mellonella larvae infection assay, compound APY29 displayed in vivo efficacy against S. suis infection. Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds."
PAIR0040611	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040612	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040613	"The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment."
PAIR0040614	"The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment."
PAIR0040615	Perifosine increased cytotoxicity in P-gp-overexpressing drug-resistant KBV20C cancer cells
PAIR0040616	Perifosine increased cytotoxicity in P-gp-overexpressing drug-resistant KBV20C cancer cells
PAIR0040617	Perifosine afforded highly selective sensitization effects only in drug-resistant MCF-8/ADR cancer cells
PAIR0040618	Perifosine afforded highly selective sensitization effects only in drug-resistant MCF-7/ADR cancer cells
PAIR0040619	"Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse."
PAIR0040620	"In this study, we firstly identified the Thr167 and Ser175 residues in the activation loop of S. suis STK (ssSTK) as the kinase autophosphorylation sites. Phenotyping results demonstrated that the autophosphorylation deficient strain resembled the stk deletion strain showing essentiality for bacterial growth in minimal medium, abnormal morphology, and decreased virulence when compared with the wild-type S. suis SC19 strain. Based on these findings, we established an ssSTK inhibitor screening approach by measuring the growth of S. suis in a minimal medium and testing the autophosphorylation inhibition by measuring the consumption of ATP in an enzymatic reaction by ssSTK. A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29. These inhibitors showed antimicrobial activity in vitro. Moreover, by using Galleria mellonella larvae infection assay, compound APY29 displayed in vivo efficacy against S. suis infection. Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds."
PAIR0040621	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040622	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040623	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040624	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040625	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040626	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040627	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040628	"These results indicate that these mutants are dependent on the HSP90 for their folding. To know that downregulation of JAK2 protein leads to the decrease of cell proliferation, we performed biochemical analysis on these mutant JAK2 cells and found that ruxolitinib-resistant variants are sensitive towards 17-AAG and treatment of the cells with 17-AAG leads to the downregulation of JAK2 protein and decrease of STAT5 activation. This study shows that HSP90 inhibitors are potent against ruxolitinib-resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors."
PAIR0040629	Tanespimycin and Coumermycin A1 was attained by MDR1 efflux pump overexpression. 
PAIR0040630	"Chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90 overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90 overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone."
PAIR0040631	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040632	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040633	"The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in?BRAF?L525R cells but not in?BRAF?V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in?BRAF?L525R cells but not in?BRAF?V600E cells or selumetinib-resistant?BRAF?L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance."
PAIR0040634	"ACOX1 and ITGA2 were identified as risk biomarkers associated with 5-FU-resistance. We developed a risk signature, consisting of ACOX1 and ITGA2, that was able to distinguish well between 5-FU-resistance and 5-FU-sensitive. The single-cell sequencing data showed that ITGA2 was mainly enriched in malignant cells. ITGA2 was negatively correlated with IC50 values of most small molecule inhibitors, of which selumetinib had the highest negative correlation. Finally, knocking down ITGA2 can make 5-FU-resistant CRC cells sensitive to 5-FU and combining with selumetinib can improve the therapeutic effect of 5-FU resistant cells."
PAIR0040635	"MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK-733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. "
PAIR0040636	"The expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression. EGFR overexpression promotes acquired resistance to regorafenib through RAS/RAF/ERK bypass activation in HCC."
PAIR0040637	"The expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression."
PAIR0040638	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040639	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040640	"Olaparib-resistant BRCA1m OvCa cells show greater sensitivity to niraparib and rucaparib relative to other PARPis. Niraparib and rucaparib demonstrated greater cytotoxicity and reduced RF speed compared to the other three PARPis, likely due to the higher levels of SSB induction. "
PAIR0040641	"We consistently observed an increase in the expression of Mcl-1 in cells exposed to both short and long-term treatment with cisplatin, a drug commonly used in esophageal cancer therapy. Functional analysis showed that Mcl-1 regulates esophageal cancer cell response to cisplatin treatment. Notably, this upregulation of Mcl-1 was not dependent on eukaryotic initiation factor 4E (eIF4E). Instead, it was associated with increased stability due to the activation of Akt. Capivasertib, a potent pan-Akt kinase drug, significantly decreased Mcl-1 level via inhibiting Akt signaling pathway in chemo-resistant cells. In addition, capivasertib not only decreased the viability of chemo-resistant esophageal cancer cells but also synergistically enhanced the effects of cisplatin."
PAIR0040642	"AZD5363 markedly increased apoptosis only in drug-sensitive MCF-7 cells, whereas the same dose of AZD5363 afforded similar levels of apoptosis in resistant MCF-7/ADR"
PAIR0040643	"AZD5363 markedly increased apoptosis only in drug-sensitive MCF-7 cells, whereas the same dose of AZD5363 afforded similar levels of apoptosis in resistant MCF-7/ADR"
PAIR0040644	"This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the beta-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade."
PAIR0040645	"We discover, via bioinformatics analysis and clinical samples, that N6 adenine-specific DNA methyltransferase 1 (N6AMT1) is highly expressed in luminal breast cancer but downregulated in tamoxifen-resistant (TamR) BC cells. ChIP-qPCR and luciferase reporter assays showed that FOXA1 binds to the N6AMT1 promoter and enhances its transcription. In TamR models, FOXA1 and N6AMT1 are downregulated, increasing p110alpha protein levels (but not mRNA), phospho-AKT levels, and tamoxifen resistance. In vivo, N6AMT1 overexpression enhanced tamoxifen sensitivity, while knockdown reduced it; this sensitivity could be restored with the p110alpha inhibitor A66."
PAIR0040646	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040647	DNA toposomerase 2 (TOP2A) is a ribozyme that controls the topological state of DNA. It is very important for the correct division of ion chromosomes during mitosis and meiosis. The up-regulation of TOP2A expression is related to the shortening of survival time and chemoresistance. 
PAIR0040648	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040649	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040650	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040651	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040652	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040653	"Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins."
PAIR0040654	"Results: Immunohistochemical data demonstrated that levels of CDC25B differed by ~2- to 5-fold in cell lines and PDX models used. In vitro data showed that the level of CDC25B paralleled sensitivity to JQ1. Similarly, in vivo data showed that tumors with high-level CDC25B were more sensitive to JQ1 than tumors with lower CDC25B. The combination of JQ1 + a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells. Conclusion: The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type."
PAIR0040655	"JQ1, I-BET151, or BRD4 silencing all downregulated Met and inhibited both NSCLC cell viability in vitro and tumor growth in vivo.The inhibitory influences of JQ1 on the activity of PI3K/Akt and ERK pathways and cell growth were countervailed by HGF."
PAIR0040656	"Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from?Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and?Artemisia argyi?emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer.?"
PAIR0040657	"In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells."
PAIR0040658	Mutant strains edited for?TgPRP4K significantly decreased sensitivity to altiratinib
PAIR0040659	Mutant strains edited for?TgPRP4K significantly decreased sensitivity to altiratinib
PAIR0040660	Mutant strains edited for?TgPRP4K significantly decreased sensitivity to altiratinib
PAIR0040661	Mutant strains edited for?TgPRP4K significantly decreased sensitivity to altiratinib
PAIR0040662	Mutant strains edited for?TgPRP4K significantly decreased sensitivity to altiratinib
PAIR0040663	"We identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid?FGF2?secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation."
PAIR0040664	"Increased levels of the USP5 protein and decreased ubiquitination in ripretinib-resistant GISTs are detected.TRIM21 governs USP5 expression via ubiquitination, and USP5 regulates MDH2 expression through deubiquitination, consequently fostering ripretinib resistance in GIST."
PAIR0040665	"Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model."
PAIR0040666	"LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations."
PAIR0040667	"This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells."
PAIR0040668	"Colon cancer, thyroid cancer, and melanoma are common malignant tumors that seriously threaten human health globally. The B-Raf proto-oncogene, serine/threonine kinase (BRAF)(V600E) mutation is an important driver gene mutation in these cancer types. In this study, we identified that collagen triple helix repeat containing 1 (CTHRC1) expression was associated with the BRAF(V600E) mutation in colon cancer, thyroid cancer, and melanoma. A high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. "
PAIR0040669	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040670	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040671	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040672	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040673	"Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1."
PAIR0040674	"Olaparib-resistant BRCA1m OvCa cells show greater sensitivity to niraparib and rucaparib relative to other PARPis. Niraparib and rucaparib demonstrated greater cytotoxicity and reduced RF speed compared to the other three PARPis, likely due to the higher levels of SSB induction. "
PAIR0040675	Suppression of MAPK signaling pathway activity by BI-847325 treatment could significantly decrease the expression of?MDR1?and?MRP1?genes in C643 and SW1736 ATC cell lines. BI-847325 decreased multidrug resistance through downregulation of MDR1 and MRP1.
PAIR0040676	Suppression of MAPK signaling pathway activity by BI-847325 treatment could significantly decrease the expression of?MDR1?and?MRP1?genes in C643 and SW1736 ATC cell lines. BI-847325 decreased multidrug resistance through downregulation of MDR1 and MRP1.
PAIR0040677	"The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in?BRAF?L525R cells but not in?BRAF?V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in?BRAF?L525R cells but not in?BRAF?V600E cells or selumetinib-resistant?BRAF?L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance."
PAIR0040678	"In the current study, we explore how PIM kinase correlates with the MRP1 drug efflux pump. We demonstrate that PIM kinase inhibition modulates the function of MRP1 mediated efflux of doxorubicin in neuroblastoma.?"
PAIR0040679	"In summary, BRAFi/MEKi combinations inhibit proliferation and induce apoptosis in sensitive, but not in BRAFi/MEKi-resistant cells in 2D and 3D cell culture models. This effect may be partially caused by an upregulation of pERK and downregulation of mitochondrial apoptotic proteins in the resistant cells."
PAIR0040680	"Altogether, BRAFi/MEKi induce immune stimulatory molecules and APM components in sensitive NRAS-mutant melanoma cells, while the expression of these molecules is reversed in the resistant NRAS-mutant melanoma cells."
PAIR0040681	"In summary, BRAFi/MEKi combinations inhibit proliferation and induce apoptosis in sensitive, but not in BRAFi/MEKi-resistant cells in 2D and 3D cell culture models. This effect may be partially caused by an upregulation of pERK and downregulation of mitochondrial apoptotic proteins in the resistant cells."
PAIR0040682	"Altogether, BRAFi/MEKi induce immune stimulatory molecules and APM components in sensitive NRAS-mutant melanoma cells, while the expression of these molecules is reversed in the resistant NRAS-mutant melanoma cells."
PAIR0040683	"ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells."
PAIR0040684	"ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells."
PAIR0040685	"ABC transporters and CYP1A1 protein level was also upregulated in resistant cells. Moreover, the elevated levels of ABCA1, ABCC2 and ABCG2 were here shown for the first time in BRAFi/MEKi resistant cells."
PAIR0040686	"Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time."
PAIR0040687	"Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time."
PAIR0040688	"Obtained resistant melanoma cells exhibit increased activation of signaling pathways, including JNK, which raised activation in resistant to BRAFi/MEKi melanoma cells is demonstrated here for the first time."
PAIR0040689	"The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 ug/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation."
PAIR0040690	"The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 ug/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation."
PAIR0040691	"In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy-related markers autophagy-related gene 5 (ATG5), autophagy-related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK-promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the beta2-adrenergic receptor (beta2AR)-Akt axis. Finally, we proved that NNK intervention could not only activate beta2AR, but also increase its expression, making beta2AR and Akt form a feedback loop. Overall, these findings show that the NNK-induced beta2AR-Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells."
PAIR0040692	"In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy-related markers autophagy-related gene 5 (ATG5), autophagy-related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK-promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the beta2-adrenergic receptor (beta2AR)-Akt axis. Finally, we proved that NNK intervention could not only activate beta2AR, but also increase its expression, making beta2AR and Akt form a feedback loop. Overall, these findings show that the NNK-induced beta2AR-Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells."
PAIR0040693	"In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy-related markers autophagy-related gene 5 (ATG5), autophagy-related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK-promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the beta2-adrenergic receptor (beta2AR)-Akt axis. Finally, we proved that NNK intervention could not only activate beta2AR, but also increase its expression, making beta2AR and Akt form a feedback loop. Overall, these findings show that the NNK-induced beta2AR-Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells."
PAIR0040694	"Here, we found that ISL inhibited the viability and colony formation of OSCC, and promoted their apoptosis. The immunoblotting data showed that ISL treatment significantly decreased survivin expression. Mechanistically, ISL suppressed survivin phosphorylation on Thr34 by deregulating Akt-Wee1-CDK1 signaling, which facilitated survivin for ubiquitination degradation. ISL inhibited CAL27 tumor growth and decreased p-Akt and survivin expression in vivo. Meanwhile, survivin overexpression caused cisplatin resistance of OSCC cells. ISL alone or combined with cisplatin overcame chemoresistance in OSCC cells. Overall, our results revealed that ISL exerted potent inhibitory effects via inducing Akt-dependent survivin ubiquitination in OSCC cells."
PAIR0040695	"The extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1alpha axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy."
PAIR0040696	"This study demonstrated the finding of a natural product, formononetin, which is a potent inhibitor of human P-gp via uncompetitive inhibition and ATPase stimulation. Formononetin resensitized MDR cancer cells to chemotherapeutic drugs."
PAIR0040697	"This study demonstrated the finding of a natural product, formononetin, which is a potent inhibitor of human P-gp via uncompetitive inhibition and ATPase stimulation. Formononetin resensitized MDR cancer cells to chemotherapeutic drugs."
PAIR0040698	"The results showed that Huaier can regulate autophagy, inhibit the Wnt/-catenin signalling pathway and reverse the drug resistance of OXA-resistant CRC cells."
PAIR0040699	"Repression of ANP32E increases the responsiveness of EC to PTX, and the concurrent use of erastin with PTX enhances their anti-cancer effectiveness. These findings provide support for the efficacy of inducing ferroptosis as a potential therapeutic approach to enhance the cytotoxic effects of PTX. ANP32E regulates EC progression and ferroptosis through the p53/SLC7A11 axis, offering a potential molecular target for overcoming PTX resistance in EC treatment."
PAIR0040700	"A decrease in cell proliferation was observed in HBL-1/DOX cells transfected with shCISD2 and treated with 10 µM Erastin, compared to the inhibition of shCISD2 in HBL-1/DOX cells . Additionally, increases in iron , MDA , and ROS generation were induced by Erastin , while decreases in GSH and MMPs were also observed. Treatment of HBL-1/DOX cells with a combination of Erastin and shCISD2 resulted in a decrease in CISD2, p62, FTH1, and GPX4 levels, along with an increase in BECN1 and NCOA4. These findings suggest that inhibiting CISD2 can enhance the effects of Erastin by promoting increased ferroptosis and ferritinophagy, thereby contributing to the cell death of HBL-1/DOX cells."
PAIR0040701	"ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes."
PAIR0040702	"ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes."
PAIR0040703	"In treating thyroid cancer cells with vemurafenib, we have detected reactivation of the MAPK/ERK signaling pathway as a result of the release of multiple receptor tyrosine kinases (RTKs) from the negative feedback of ERK phosphorylation. SHP2 is an important target protein downstream of the RTK signaling pathway. Decreasing it through SHP2 knockdown or the use of an inhibitor of SHP2 (SHP099) was found to significantly increase the early sensitivity and reverse the late resistance to vemurafenib in BRAFV600E mutant thyroid cancer cells.Blocking SHP2 reverses the reactivation of the MAPK/ERK signaling pathway caused by the activation of RTKs and improves the sensitivity of thyroid cancer to vemurafenib."
PAIR0040704	"Acquired resistance to?vemurafenib?(PLX4032) is a thorny issue in BRAFV600E?mutant?melanoma?therapy. Ferroptotic?programmed cell death?is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive?oxylipin?metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced?lipid?ROS?accumulation and triggered?ferroptotic cell death?in PLX4032 sensitive (A375) and resistant (A375-R) BRAFV600E?melanoma cells by reprogramming?glutathione?and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET."
PAIR0040705	"The PLK1 inhibitors GSK 461364 and BI 2536 had synergistic effect with osimertinib. Compared with osimertinib-sensitive cells, PLK1 regulatory pathway and cell cycle pathway were significantly activated in osimertinib-resistant cells. In NSCLC patients with epidermal growth factor receptor mutations treated with osimertinib,?PLK1?mRNA levels were negatively correlated with progression free survival of patients (R= -0.62,?P<0.05), indicating that excessive activation of PLK1 in NSCLC cells may cause cell resistant to osimertinib. Further?in vitro?experiments showed that IC50?of PLK1 inhibitors BI 6727 and GSK 461364 in osimertinib-resistant cells were lower than those in sensitive ones. Compared with the mono treatment of osimertinib, PLK1 inhibitors combined with osimertinib behaved significantly stronger effect on the proliferation of osimertinib-resistant cells."
PAIR0040706	"Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts."
PAIR0040707	"Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts."
PAIR0040708	DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
PAIR0040709	DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
PAIR0040710	"Moreover, we showed that TNF-alpha amplified by type I IFN signals exacerbated the SARS-CoV-2 infection by stimulating CXCL1 production from macrophages and neutrophil recruitment into the lung tissue. Finally, we showed that intravenous administration to mice or hamsters with TNF protease inhibitor 2 alleviated the severity of SARS-CoV-2 and influenza virus infection. Our results uncover an unexpected mechanism by which type I interferon-mediated TNF-alpha signaling exacerbates the disease severity and will aid in the development of novel therapeutic strategies to treat respiratory virus infection and associated diseases such as influenza and COVID-19."
PAIR0040711	SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response
PAIR0040712	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040713	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040714	SCFM increases Scedosporium/Lomentospora azole tolerance.Azole resistance is partially due to the efflux pump activity.SCFM leads to decrease in sterol membrane content and increase in membrane fluidity.Scedosporium/Lomentospora species undergo cellular adaptations in SCFM that favours their growth in face of the challenges imposed by azole antifungals.
PAIR0040715	"This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance."
PAIR0040716	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040717	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040718	"7928 genes were identified as genes related to tumor progression and metastasis. Of these, 7 genes were found to be associated with PCa prognosis. The scRNA-seq and TCGA data showed that the expression of LDHA was higher in tumors and associated with poor prognosis of PCa. In addition, upregulation of LDHA in PCa cells induces osteoclast differentiation. Additionally, high LDHA expression was associated with resistance to Epirubicin, Elliptinium acetate, and doxorubicin. Cellular experiments demonstrated that LDHA knockdown inhibited doxorubicin resistance in PCa cells."
PAIR0040719	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040720	"These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment."
PAIR0040721	"The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment."
PAIR0040722	"The?protein expression?of the?enhancer of zeste homolog 2?(EZH2),?histone methyltransferase?and its target?histone H3?trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2?siRNA?and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2?siRNA?and DZNep significantly reduced the?cell viability?after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a?histone methyltransferase?EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of?histone methylation?induced under hypoxic?tumor microenvironment."
PAIR0040723	"USC cells stably expressing p.R183W A showed increased resistance to clofarabine treatment in vitro and, corroborated by decreased clofarabine-induced apoptosis, G1 phase arrest, DNA-damage (gammaH2AX) and activation of ATM and Chk1/2 kinases."
PAIR0040724	"USC cells stably expressing p.R183W A showed increased resistance to clofarabine treatment in vitro and, corroborated by decreased clofarabine-induced apoptosis, G1 phase arrest, DNA-damage (gammaH2AX) and activation of ATM and Chk1/2 kinases."
PAIR0040725	"In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-kappaB/HIF-1alpha signaling pathway, thereby attenuating DRE."
PAIR0040726	"The results of the present work are the first to reveal the effects of an inhibitor of dihydrofolate reductase (DHFR), pralatrexate, on the sensitivity of HCC cells to molecularly targeted agents examined using multiple assays. In HCC cells, knockdown of DHFR or treatment with pralatrexate enhanced the sensitivity of HCC cells to molecularly targeted agents, such as sorafenib, regorafenib, lenvatinib, cabozantinib, or anlotinib. Mechanically, pralatrexate decreased the methylation rates of miRNA-34a's promoter region to enhance the expression of miRNA-34a. Treatment with pralatrexate inhibited the expression of Notch and its downstream factors by enhancing the expression of miRNA-34a in HCC cells. In clinical specimens, the expression of miRNA-34a was negatively correlated with DHFR expression, while DHFR expression was positively correlated with the Notch intracellular domain (NICD) and downstream factors of the Notch pathway. The expression of miRNA-34a was negatively correlated with DHFR expression, while the methylation rates of miRNA-34a's promoter were positively related to DHFR. The effect of pralatrexate on the metabolic profile of HCC cells is very different from that of small molecule inhibitors related to glycolipid metabolism. Therefore, pralatrexate upregulates the sensitivity of HCC cells to molecularly targeted drugs. These results expand our understanding of folate metabolism and HCC and can help provide more options for HCC treatment."
PAIR0040727	"The expression of?cyp51A?mRNA was induced by the addition of the azole antifungal drug efinaconazole, whereas no such induction was detected for?cyp51B, suggesting that Cyp51A functions as an azole-responsive Cyp51 isozyme. To explore the contribution of Cyp51A to susceptibility to azole drugs, the neomycin phosphotransferase (nptII) gene cassette was inserted into the?cyp51A?3'-untranslated region of deltaku80?to destabilize the mRNA of?cyp51A. In this mutant, the induction of?cyp51A?mRNA expression by efinaconazole was diminished. The minimum inhibitory concentration for several azole drugs of this strain was reduced, suggesting that dermatophyte Cyp51A contributes to the tolerance for azole drugs."
PAIR0040728	"SRPIN340 treatment could inhibit the synthesis of PIK3CD-S variant through blocking the exon 20 skipping in PIK3CD pre-mRNA, thereby enriching the PIK3CD-L (which is sensitive to Idelalisib treatment) in these cancer cells."
PAIR0040729	"HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs."
PAIR0040730	"HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs."
PAIR0040731	"Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies."
PAIR0040732	"Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies."
PAIR0040733	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040734	"Chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90 overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90 overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone."
PAIR0040735	"The results of drug sensitivity of risk genes showed that the high expression of HIST1H1E made tumor cells resistant to trametinib, selumetinib, RDEA119, Docetaxel and 17-AAG. The high expression of UBE2C makes tumor cells resistant to masitinib. The low expression of ERO1B makes the EC more sensitive to FK866"
PAIR0040736	"This study demonstrated that TRIM21 has a function in promoting K27-polyubiquitination and subsequent phosphorylation of ERK1/2, leading to cell proliferation and resistance to drugs. Fimepinostat and Quisinostat, were able to reduce TRIM21 protein, inhibit cell proliferation, and increase drug sensitivity."
PAIR0040737	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040738	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp4c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040739	"Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the beta-lactam-resistant strain?Corynebacterium jeikeium?K411. In this study, we show that?pbp2c, one of these six genes, is present in resistant strains of?Corynebacteriaceae?but absent from sensitive strains. The molecular study of the?pbp2c?locus from?C. jeikeium?and its heterologous expression in?Corynebacterium glutamicum?allowed us to show that Pbp2c confers high levels of beta-lactam resistance to the host and is under the control of a beta-lactam-induced regulatory system encoded by two adjacent genes,?jk0410?and?jk0411. The detection of this inducible resistance may require up to 48?h of incubation, particularly in?Corynebacterium amycolatum. Finally, the Pbp7c-expressing strains studied were resistant to all the beta-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole."
PAIR0040740	KBV20 cells were highly resistant to GSK690693
PAIR0040741	"GSK690693 markedly increased cytotoxicity in drug-sensitive MCF-7 cancer cells, although it failed to increase cytotoxicity in drug-resistant MCF-8/ADR cells"
PAIR0040742	"GSK690693 markedly increased cytotoxicity in drug-sensitive MCF-7 cancer cells, although it failed to increase cytotoxicity in drug-resistant MCF-7/ADR cells"
PAIR0040743	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040744	"The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells."
PAIR0040745	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040746	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040747	"The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when?tcaA?was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when?tcaA?was deleted, all selected strains were more susceptible to beta-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when?tcaA?was deleted.?tcaA?knockout caused ""log-like"" abnormal division of MRSA, and?tcaA?deficiency mediated low expression of?mecA, ponA, and?murA2. tcaA is a potential resistance breaker target for beta-lactams, including ceftobiprole, in MRSA."
PAIR0040748	"The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when?tcaA?was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when?tcaA?was deleted, all selected strains were more susceptible to beta-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when?tcaA?was deleted.?tcaA?knockout caused ""log-like"" abnormal division of MRSA, and?tcaA?deficiency mediated low expression of?mecA, ponA, and?murA2. tcaA is a potential resistance breaker target for beta-lactams, including ceftobiprole, in MRSA."
PAIR0040749	SOD enzymatic activity and SodM protein levels are reduced in the ksgA mutant strain;The absence of ksgA contributes to an altered antibiotic response
PAIR0040750	"CCK-8 assays demonstrated that HCC cells carrying the?XIRP2?mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the?XIRP2?wildtype. The?XIRP2?mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of?XIRP2?resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the?XIRP2?mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin."
PAIR0040751	"In this study, the topical application of remetinostat significantly improved psoriasiform inflammation in an imiquimod-induced mice model by inhibiting CD86 expression of CD11C+I-A/I-E+ dendritic cells (DCs) in the skin. Moreover, remetinostat could dampen the maturation and activation of bone marrow-derived DCs in vitro, as well as the expression of psoriasis-related inflammatory mediators by keratinocytes. In addition, remetinostat could promote keratinocyte differentiation without affecting its proliferation. Our findings demonstrate that remetinostat improves psoriasis by inhibiting the maturation and activation of DCs and the differentiation and inflammation of keratinocytes, which may facilitate the potential application of remetinostat in anti-psoriasis therapy."
PAIR0040752	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040753	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040754	"This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC),?n?= 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n?= 9) and genotype 5 (n?= 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs."
PAIR0040755	"A wide range of amino acid substitutions in NS3A, NS5A, and NS5B target proteins for DAAs, which were associated with resistance to various FDA-approved DAAs for the treatment of HCV infection, were determined across the HCV genotypes. Multidrug-resistant NS3/4A variants in genotype 1 and genotype 5 were determined. Amino acid substitution-dependent resistance to NS3/4A protease inhibitors, NS5A, and NS5B inhibitors was assessed across the HCV genotypes. V1062L and L2003M were observed to be highly frequent, followed by Q2005H. These RAASs may impact the efficacy of the DAA-based HCV treatment, leading to virologic failure even in patients treated/retreated with multiple DAAs due to the emergence of multidrug-resistant variants of HCV. "
PAIR0040756	"In this study, we firstly identified the Thr167 and Ser175 residues in the activation loop of S. suis STK (ssSTK) as the kinase autophosphorylation sites. Phenotyping results demonstrated that the autophosphorylation deficient strain resembled the stk deletion strain showing essentiality for bacterial growth in minimal medium, abnormal morphology, and decreased virulence when compared with the wild-type S. suis SC19 strain. Based on these findings, we established an ssSTK inhibitor screening approach by measuring the growth of S. suis in a minimal medium and testing the autophosphorylation inhibition by measuring the consumption of ATP in an enzymatic reaction by ssSTK. A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29. These inhibitors showed antimicrobial activity in vitro. Moreover, by using Galleria mellonella larvae infection assay, compound APY29 displayed in vivo efficacy against S. suis infection. Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds."
PAIR0040757	"Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts."
PAIR0040758	"Exert their activity exclusively through histone eviction and are generally more cytotoxic to tumor cells than their parent compound;DNA double-strand break generation versus histone eviction;Anthracyclines featuring an N,N-dimethyl aminosugar in general are poor substrates for the ABCB1 drug transporter as compared to their non-alkylated counterparts."
PAIR0040759	"In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation."
PAIR0040760	"In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation."
PAIR0040761	"In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation."
PAIR0040762	"In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation."
PAIR0040763	"This study demonstrated that TRIM21 has a function in promoting K27-polyubiquitination and subsequent phosphorylation of ERK1/2, leading to cell proliferation and resistance to drugs. Fimepinostat and Quisinostat, were able to reduce TRIM21 protein, inhibit cell proliferation, and increase drug sensitivity."
PAIR0040764	Tanespimycin and Coumermycin A1 was attained by MDR1 efflux pump overexpression. 
PAIR0040765	"Chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90 overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90 overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone."
PAIR0040766	"CCK-8 assays demonstrated that HCC cells carrying the?XIRP2?mutation exhibited increased resistance to fludarabine and oxaliplatin, but enhanced sensitivity to WEHI-539 and LCL-161 as compared with those HCC cells with the?XIRP2?wildtype. The?XIRP2?mutation was found to have no impact on the mRNA levels of XIRP2 in tissues and cells, but it did enhance the stability of the XIRP2 protein. Mechanically, the inhibition of?XIRP2?resulted in a significant increase in sensitivity to oxaliplatin through an elevation in zinc ions and a calcium ion overload. In conclusion, the?XIRP2?mutation holds potential as a biomarker for predicting the prognosis and drug sensitivity of HCC and serves as a therapeutic target to enhance the efficacy of oxaliplatin."
PAIR0040767	"Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo . "
PAIR0040768	"In conclusion, the resistance risk of B. cinerea to cyclobutrifluram is high, and the point mutations in BcSDHB (P225F, N230I, or H272R) confer cyclobutrifluram resistance in B. cinerea. This study provided important insights into cyclobutrifluram resistance in B. cinerea and offered valuable information for monitoring and managing cyclobutrifluram resistance in the future."
PAIR0040769	"LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations."
PAIR0040770	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040771	Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported.
PAIR0040772	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040773	"Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors."
PAIR0040774	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040775	SpiD3 Induces a Unique Transcriptional Program in Ibrutinib-Resistant CLL Cells;SpiD3 Modulates Critical Cancer Pathways in Ibrutinib-Resistant CLL Cells;SpiD3 Synergizes with Venetoclax and Displays Potent Cytotoxicity in Venetoclax-Resistant CLL Cells;SpiD3 Alters Gene Expression of Key CLL Pathways in Venetoclax-Resistant CLL Cells;SpiD4 Modulates Critical Pathways in Venetoclax-Resistant CLL Cells
PAIR0040776	SpiD3 Induces a Unique Transcriptional Program in Ibrutinib-Resistant CLL Cells;SpiD3 Modulates Critical Cancer Pathways in Ibrutinib-Resistant CLL Cells;SpiD3 Synergizes with Venetoclax and Displays Potent Cytotoxicity in Venetoclax-Resistant CLL Cells;SpiD3 Alters Gene Expression of Key CLL Pathways in Venetoclax-Resistant CLL Cells;SpiD3 Modulates Critical Pathways in Venetoclax-Resistant CLL Cells
PAIR0040777	SpiD3 Induces a Unique Transcriptional Program in Ibrutinib-Resistant CLL Cells;SpiD3 Modulates Critical Cancer Pathways in Ibrutinib-Resistant CLL Cells;SpiD3 Synergizes with Venetoclax and Displays Potent Cytotoxicity in Venetoclax-Resistant CLL Cells;SpiD3 Alters Gene Expression of Key CLL Pathways in Venetoclax-Resistant CLL Cells;SpiD5 Modulates Critical Pathways in Venetoclax-Resistant CLL Cells
PAIR0040778	"In this study, we firstly identified the Thr167 and Ser175 residues in the activation loop of S. suis STK (ssSTK) as the kinase autophosphorylation sites. Phenotyping results demonstrated that the autophosphorylation deficient strain resembled the stk deletion strain showing essentiality for bacterial growth in minimal medium, abnormal morphology, and decreased virulence when compared with the wild-type S. suis SC19 strain. Based on these findings, we established an ssSTK inhibitor screening approach by measuring the growth of S. suis in a minimal medium and testing the autophosphorylation inhibition by measuring the consumption of ATP in an enzymatic reaction by ssSTK. A series of inhibitors against ssSTK are identified from a commercial kinase inhibitors library, including Staurosporine, K252a, AT9283, and APY29. These inhibitors showed antimicrobial activity in vitro. Moreover, by using Galleria mellonella larvae infection assay, compound APY29 displayed in vivo efficacy against S. suis infection. Additionally, it was predicted by molecular docking that these inhibitors could interact with ssSTK. Collectively, our data illustrated the essential roles of ssSTK autophosphorylation in the physiology and pathogenicity of S. suis and consider these inhibitors as promising antimicrobial lead compounds."
PAIR0040779	"Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools to study therapy resistance of NTRK fusion tumors."
PAIR0040780	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040781	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040782	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040783	"Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of alphaPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with alphaPD-1 did not improve the outcome."
PAIR0040784	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040785	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040786	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040787	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040788	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040789	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040790	"Our results demonstrated that treatment of PDAC cell lines with KRAS inhibitors led to reactivation of the MAPK pathway and increased STAT3 phosphorylation. The combination of MEK and JAK2 inhibitors successfully suppressed this feedback upregulation, showing synergistic inhibitory effects on PDAC cell lines both?in vitro?and?in vivo. In MRTX1133-resistant cells, STAT3 phosphorylation increased, whereas in sotorasib-resistant cell lines, it paradoxically decreased. However, in both cell types, this resistance was overcome by the combined use of MEK and JAK2 inhibitors.?"
PAIR0040791	"Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer."
PAIR0040792	"Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer."
PAIR0040793	VZV acquired the resistance against amenamevir by a single mutation K350N in the helicase
PAIR0040794	Imlunestrant displays potent activity in ESR1 wild-type and mutant breast cancer
PAIR0040795	"HEA significantly decreased osteosarcoma cell viability and induced apoptosis in a dose- and time-dependent manner. It also inhibited cell migration and invasion, and modulated EMT markers by upregulating E-cadherin and downregulating N-cadherin and vimentin. HEA downregulated IGF1 at both the mRNA and protein levels, and reduced IGF1 secretion. Furthermore, HEA inhibited the PI3K-AKT signaling pathway, which is activated by IGF1. IGF1 silencing mimicked HEA's effects, whereas recombinant IGF1 pre-treatment partially reversed HEA's effects on cell viability, apoptosis, and EMT markers."
PAIR0040796	"PI3Kdelta activation, IL-6 overexpression, and CD37 loss are resistance mechanisms to naratuximab emtansine."
PAIR0040797	"PI3Kdelta activation, IL-6 overexpression, and CD37 loss are resistance mechanisms to naratuximab emtansine."
PAIR0040798	"PI3Kdelta activation, IL-6 overexpression, and CD37 loss are resistance mechanisms to naratuximab emtansine."
PAIR0040799	"Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective ER degrader. Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared with vehicle or alternative selective ER degrader therapies. Together, these findings support the potential of imlunestrant to degrade ERalpha and suppress the growth of ESR1-WT and mutant breast cancer, including brain metastatic tumors. Significance: Imlunestrant, a next-generation, brain-penetrant oral ERalpha degrader, displays potent activity in ESR1 wild-type and mutant breast cancer, enhances combination activity with standard-of-care agents, and inhibits growth of ER+ intracranial tumors"
PAIR0040800	"MTX-HOPE is a combination of classical chemotherapy agents originally developed for palliative chemotherapy in frail patients with refractory lymphoma. MTX-HOPE has been reported to be effective against T-cell tumors. Severe nonhematologic adverse events are rarely reported; however, bone marrow suppression is commonly observed."
PAIR0040801	Prostate tumors in Pb-Cre;PTENfl/flTrp53fl/fl?mice are resistant to ADT/PI3Ki/aPD-1/PORCNi combination therapy due to feedback activation of MEK signaling.
PAIR0040802	"Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, -difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines."
PAIR0040803	"Polyamines have been reported to facilitate the DNA damage repair functions of PARP. Given the elevated levels of polyamines in tumors, we hypothesized that treatment with the polyamine synthesis inhibitor, -difluoromethylornithine (DFMO), may enhance ovarian tumor sensitivity to the PARP inhibitor, rucaparib. In HR-competent ovarian cancer cell lines with varying sensitivities to rucaparib, we show that co-treatment with DFMO increases the sensitivity of ovarian cancer cells to rucaparib. Immunofluorescence assays demonstrated that, in the presence of hydrogen peroxide-induced DNA damage, DFMO strongly inhibits PARylation, increases DNA damage accumulation, and reduces cell viability in both HR-competent and deficient cell lines."
PAIR0040804	"The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 ug/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation."
PAIR0040805	"The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 ug/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation."
PAIR0040806	"Altogether, BRAFi/MEKi induce immune stimulatory molecules and APM components in sensitive NRAS-mutant melanoma cells, while the expression of these molecules is reversed in the resistant NRAS-mutant melanoma cells."
PAIR0040807	"The results showed that compared with control group, the concentrations of HBeAg and HBsAg in Chinese Yam polysaccharide group, entecavir group and combination group decreased(P&lt;0.01 or P&lt;0.001), and both of them inhibited HBV-DNA in HepG2.2.15 cells(P&lt;0.01), and the HBV-DNA inhibition of HepG2.2.15 cells in the combination group was more obvious(P&lt;0.001), and the protein expression levels of p-p38 MAPK and NTCP were significantly decreased(P&lt;0.05 or P&lt;0.01), the mRNA expression level of p38 MAPK increased, and the mRNA expression level of NTCP decreased(P&lt;0.05 or P&lt;0.01). To sum up, Chinese Yam polysaccharide can reduce the expression of NTCP protein and mRNA through p38 MAPK signaling pathway and cooperate with entecavir in anti-HBV."
PAIR0040808	"We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance."
PAIR0040809	"We confirmed that BYL-719 could inhibit BCSC-like cell proliferation in 3D cultures and that the stemness characteristics of BCSC-like cells were inhibited. The PI3K/AKT/mTOR signaling pathway could be inhibited by BYL-719, and the Notch, JAK-STAT and MAPK/ERK signaling pathways which have crosstalk in the tumor microenvironment (TME) are also inhibited. By comparing eribulin-resistant breast cancer cell lines, we confirmed that BYL-719 could effectively overcome drug resistance."
PAIR0040810	"The expression of EGFR, a member of the receptor tyrosine kinase (RTK) family, was significantly increased in acquired regorafenib-resistant HCC cells compared with parental cells. Pharmacological inhibition of EGFR with gefitinib restored the sensitivity of regorafenib-resistant HCC cells to regorafenib. In a xenograft mouse model, gefitinib sensitized resistant tumors to regorafenib. Additionally, levels of RAS, RAF, and P-ERK1/2, components of the downstream EGFR signaling pathway, were positively associated with EGFR expression. EGFR overexpression promotes acquired resistance to regorafenib through RAS/RAF/ERK bypass activation in HCC."
PAIR0040811	"Our results showed higher autophagic flux in cisplatin-resistant Ooral squamous cell carcinoma (CAL27 and SCC9) cells than in parental cells. The combinations of an autophagy inhibitor (chloroquine) or an autophagy inducer/sphingosine kinase 1 antagonist (FTY720) with paclitaxel (PTX) had a synergistic antitumor effect. Treated CisR cells lost clonogenicity and tumor sphere abilities and reduced proteins associated with proliferation, survival, and cancer stem cells. FTY720 plus PTX had higher antitumor efficacy than PTX against CAL27 CisR xenograft tumor formation. Additionally, increases in glucosylceramide, dehydroglucosylceramide, and sphingomyelin were presented in responsive tumors."
PAIR0040812	"It was firstly proved that foretinib increased the intracellular accumulation of?rhodamine 123?and?mitoxantrone?in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25?uM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of?doxorubicin?and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64?&plusmn;?0.08 and 0.47?&plusmn;?0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively.?In silico?analysis also suggested that the drug-binding domain of ABCB1 and?ABCG2?transporters could be considered as potential target for foretinib."
PAIR0040813	"It was firstly proved that foretinib increased the intracellular accumulation of rhodamine 123 and mitoxantrone in MES-SA/DX5 and MCF-7/MX cancer cells, with accumulation ratios of 12 and 2.2 at 25uM concentration, respectively. However, it did not affect the accumulation of fluorescent substrates in the parental cells. Moreover, foretinib synergistically improved the cytotoxic effects of?doxorubicin?and mitoxantrone. The means of combination index (CI) values at fraction affected (Fa) values of 0.5, 0.75, and 0.9 were 0.64 &plusmn; 0.08 and 0.47 &plusmn; 0.09, in MES-SA/DX5 and MCF-7/MX cancer cells, respectively. In silico analysis also suggested that the drug-binding domain of ABCB1 and?ABCG2?transporters could be considered as potential target for foretinib."
PAIR0040814	"Aerobic glycolysis, a metabolic process, has been implicated in chemotherapeutic resistance. In this study, we demonstrate that elevated glycolysis plays a central role in TAM resistance and can be effectively targeted and overcome by Rg3. Mechanistically, we observed upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key mediator of glycolysis, in TAM-resistant MCF-7/TamR and T-47D/TamR cells. Crucially, PFKFB3 is indispensable for the synergistic effect of TAM and Rg3 combination therapy, which suppresses cell proliferation and glycolysis in MCF-7/TamR and T-47D/TamR cells, both in vitro and in vivo. Moreover, overexpression of PFKFB3 in MCF-7 cells mimicked the TAM resistance phenotype. Importantly, combination treatment significantly reduced TAM-resistant MCF-7 cell proliferation in an in vivo model."
PAIR0040815	"The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-kappaB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-kappaB activity."
PAIR0040816	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040817	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040818	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040819	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040820	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040821	"We found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells.Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies."
PAIR0040822	"Palbociclib is not only an effective combination partner with FLT3 inhibitor, but it acted synergistically with PI3K inhibitors in inhibiting the growth of AML cells. The cells have some sensitivity to palbociclib and pan-PI3K inhibitors, but lower sensitivity to idelalisib. We discovered that combinations of palbociclib or abemacicilib with FLT3 or PI3K inhibitors might overcome resistance to treatment. Here too, cell growth was inhibited with lower inhibitor concentrations, which is expected to reduce toxicities and lead to better tolerance in patients."
PAIR0040823	"Palbociclib is not only an effective combination partner with FLT3 inhibitor, but it acted synergistically with PI3K inhibitors in inhibiting the growth of AML cells. The cells have some sensitivity to palbociclib and pan-PI3K inhibitors, but lower sensitivity to idelalisib. We discovered that combinations of palbociclib or abemacicilib with FLT3 or PI3K inhibitors might overcome resistance to treatment. Here too, cell growth was inhibited with lower inhibitor concentrations, which is expected to reduce toxicities and lead to better tolerance in patients."
PAIR0040824	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040825	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040826	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040827	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040828	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040829	"The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment."
PAIR0040830	"The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs."
PAIR0040831	"The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial-mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs."
PAIR0040832	"Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients."
PAIR0040833	Quinic acid was able to disrupt the MRSA biofilms.The combination of quinic acid with kanamycin exhibited synergistic effect against MRSA biofilms.The synergistic effect of quinic acid and kanamycin highly reduced the EPS and eDNA of biofilm matrix.Quinic acid could be used in combination with antibiotics against MRSA biofilms.
PAIR0040834	"Gentamicin-ketorolac (GS-KT) combination demonstrated synergistic antibacterial action against planktonic Staphylococci. Control and clinical strains showed distinct biofilm growth dynamics and an increase in biofilm maturity was shown to confer further resistance to gentamicin for both 'low-risk' and 'high-risk' biofilms. The addition of ketorolac enhanced the antibiofilm activity of gentamicin against acquired resistance in staphylococcal biofilms. Mechanistic studies revealed that the synergistic action of gentamicin-ketorolac interferes with biofilm morphology and subverts bacterial stress response altering bacterial physiology, membrane dynamics, and biofilm properties."
PAIR0040835	"In a model of AI-resistant breast cancer without ESR1 mutations, LAS alone or combined with PAL inhibited the growth of primary tumors more effectively than FUL. In addition, the LAS/PAL combination significantly reduced bone metastases. These results suggest that LAS alone or in combination with a CDK4/6i may be a promising therapy for patients with AI-resistant breast cancer, independent of ESR1 mutations. These results also suggest that LAS might be effective in tumors that express low levels of ERalpha."
PAIR0040836	"In a model of AI-resistant breast cancer without ESR1 mutations, LAS alone or combined with PAL inhibited the growth of primary tumors more effectively than FUL. In addition, the LAS/PAL combination significantly reduced bone metastases. These results suggest that LAS alone or in combination with a CDK4/6i may be a promising therapy for patients with AI-resistant breast cancer, independent of ESR1 mutations. These results also suggest that LAS might be effective in tumors that express low levels of ERalpha."
PAIR0040837	"This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells."
PAIR0040838	"This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells."
PAIR0040839	MET pathway activation is one of the most common mechanisms of resistance to osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC). MET polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select MET polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than MET polysomy PDX tumors without phospho-MET expression.Osimertinib and savolitinib combination is most effective for osimertinib-resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET.
PAIR0040840	"In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance."
PAIR0040841	"Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."
PAIR0040842	"SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3?-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer."
PAIR0040843	"SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3?-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer."
PAIR0040844	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7028 re-sensitised resistant cells. "
PAIR0040845	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7029 re-sensitised resistant cells. "
PAIR0040846	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7030 re-sensitised resistant cells. "
PAIR0040847	"Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7031 re-sensitised resistant cells. "
PAIR0040848	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040849	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040850	"Imlunestrant degraded ERalpha and decreased ERalpha-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status."
PAIR0040851	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040852	"The comprehensive analyses revealed DDR1 as a potential factor implicated in mediating resistance to CDK4/6i. Specifically, DDR1 inhibition in combination with palbociclib exhibited remarkable synergistic effects, reducing cell survival signaling and promoting apoptosis in resistant cells. In-vivo xenograft model further validated the synergistic effects, showing a significant reduction in the resistant tumor growth. Exploration into DDR1 activation uncovered TFAP2C as a key transcription factor regulating DDR1 expression in palbociclib resistant cells and inhibition of TFAP2C re-sensitized resistant cells to palbociclib. Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. "
PAIR0040853	"Overall, this study illustrates that Huaier augments the tumor-killing effect of gemcitabine through suppressing the stemness induced by gemcitabine in a FoxM1-dependent way. These results indicate that Huaier can be applied to overcome gemcitabine resistance."
PAIR0040854	"The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. "
PAIR0040855	"The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression."
PAIR0040856	"The investigated bis-benzimidazole-pyrroles did not belong to the P-gp substrates. The HBL-100/DOX resistance to DB2Py(4) was 9-fold higher if compared to that to HBL-100, whereas the resistance of P-gpoverexpressing cells to such classical P-gp substrates as doxorubicin and paclitaxel increased 50-100 times and more. In this respect, a conclusion can be drawn that DB2Py(4) is a weak P-gp substrate; i.e., only the monomeric MB2Py and MB2Py(Ac) are able to completely overcome the MDR associated with P-gp overexpression."
PAIR0040857	"Acquired resistance to?vemurafenib?(PLX4032) is a thorny issue in BRAFV600E?mutant?melanoma?therapy. Ferroptotic?programmed cell death?is a potential strategy for combating therapy-resistant cancers. This study uncovers the adaptation and abnormal upregulation of PUFAs and bioactive?oxylipin?metabolism in PLX4032 resistant melanoma cells. Phyto-sesquiterpene lactone, DET, and its derivative, DETD-35, induced?lipid?ROS?accumulation and triggered?ferroptotic cell death?in PLX4032 sensitive (A375) and resistant (A375-R) BRAFV600E?melanoma cells by reprogramming?glutathione?and primary metabolisms, lipid/oxylipin metabolism, and causing mitochondrial damage in which DETD-35 showed superior efficiency to DET."
PAIR0040858	IDH2 mutations reduce AML sensitivity to Enasidinib
PAIR0040859	"The IDH2 mutations are involved in Ara-C resistance by affecting the process of glycolysis in AML, and the PI3K-Akt signaling pathway plays an important role in this process. These pathways are expected to be important targets for targeted therapeutic intervention in the AML setting. 2-DG significantly inhibited cell proliferation and glycolysis in IDH2 mutation cell lines."
PAIR0040860	"We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML."
PAIR0040861	"JQ1, I-BET151, or BRD5 silencing all downregulated Met and inhibited both NSCLC cell viability in vitro and tumor growth in vivo."
PAIR0040862	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040863	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040864	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040865	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040866	JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.
PAIR0040867	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040868	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040869	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040870	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040871	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040872	"A mechanism of secondary resistance to the PI3Kdelta and BTK inhibitors in B cell neoplasms driven by secreted factors.Here, we show that the overexpression of ERBB4 and its ligands represents a modality for B cell neoplastic cells to bypass the anti-tumor activity of BTK and PI3K inhibitors.Cellular and genetic experiments demonstrated the involvement of this axis in blocking the anti-tumor activity of various BTK and PI3K inhibitors, currently used in the clinical setting.Multi-omics analysis underlined that an epigenetic reprogramming affected the expression of the resistance-related factors.Our results indicate that activation of ERBB signaling driven by secreted ligands and upregulation of receptors can sustain resistance to BTK and PI3K inhibitors.The mechanism of resistance appeared driven by extensive methylation changes. Promoter methylation changes largely sustained the resistance via downregulation of miRNAs (miR-29 and let-7).In conclusion, we identified a novel ERBB4-driven mechanism of resistance to BTK and PI3K inhibitors"
PAIR0040873	Our findings demonstrate that stimulation of breast cancer patients' lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients' own tumor cells. Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.
PAIR0040874	Our findings demonstrate that stimulation of breast cancer patients' lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients' own tumor cells. Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.
PAIR0040875	Our findings demonstrate that stimulation of breast cancer patients' lymphocytes with autologous IFN-DC led to efficient Th1-biased response and the generation in vitro of potent cytotoxic activity toward the patients' own tumor cells. Conclusions: This approach can be potentially applied in association with checkpoint blockade and chemotherapy in the design of new combinatorial therapies for breast cancer.
PAIR0040876	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040877	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040878	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040879	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040880	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040881	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040882	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040883	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040884	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040885	"In this study, we designed and synthesized dual cyclooxygenase-2 (COX-2) and histone deacetylase (HDAC) inhibitors, IMC-HA and IMC-OPD, and applied them for the treatment of AML. IMC-HA comprised a COX-2 inhibitor skeleton of indomethacin (IMC) and an HDAC inhibitor moiety of the hydroxamic group and was found to exhibit potent antiproliferative activity against AML cells (THP-1 and U937) and low cytotoxicity toward normal cells. Molecular docking simulations suggested that IMC-HA had a high binding affinity for HDAC and COX-2, with binding energies of -6.8 and -9.0 kcal/mol, respectively. Mechanistic studies revealed that IMC-HA induced apoptosis and G0/G1 phase arrest in AML cells, which were characterized by alterations in the expression of apoptotic and cell cycle-related proteins. Further study demonstrated that IMC-HA also inhibited the MEK/ERK signaling pathway in AML cells. Overall, we believe that IMC-HA could serve as a potent COX-2/HDAC dual inhibitor and improve the treatment of AML."
PAIR0040886	DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
PAIR0040887	DLBCL-associated NOTCH2 mutations evade ubiquitin-dependent degradation via the E3 ligases KLHL6 and FBXW7 and promote chemoresistance.Inhibition of gamma-secretase and AKT with nirogacestat and ipatasertib synergistically promotes CHOP-resistant DLBCL destruction.
PAIR0040888	"Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase gamma (PI3K-gamma) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kgamma expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kgamma, and PI3Kdelta were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kgamma isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kgamma/delta inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kgamma or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL."
PAIR0040889	"In this study, we investigated the role of Interleukin-1 receptor-associated kinases (IRAK) mediated Toll-like receptor (TLR)-signaling in chemo-resistance using a cell line-based in-vitro TPF-resistant HNSCC model of laryngeal origin. TPF chemo-resistant state showed over-expression and phosphorylation of the active downstream kinases IRAK-1 and IRAK-4 along with enhanced proliferative potential, survival, stemness and metastatic capability as compared to the parent cell line. Pharmacological inhibition of IRAK-1 and -4 had a cytostatic effect on chemo-resistant cells and re-sensitized them to chemotherapy. The treatment also decreased the pro-oncogenic effects of the chemo-resistant cells. Our study provides insights into the pro-oncogenic role of amplified IRAK-1 and-4 mediated TLR signaling in TPF-resistant HNSCC. Pharmacological inhibition of IRAK-1 and-4 signaling is a promising therapeutic strategy for TPF-resistant HNSCC. It can also be used as a combination therapy or a chemo-drug sparing regimen in HNSCC."
PAIR0040890	Marinopyrrole A derivative MA-D1 shows anti-MRSA activity by targeting GlmS to inhibit cell wall biosynthesis. This discovery provides a novel target and a lead for developing new antibiotics.
PAIR0040891	"Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse."
PAIR0040892	"Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse."
PAIR0040893	"In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized alpha-mangostin (alpha-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2. alpha-MG-4, featuring an allyl group at C3 of the lead compound alpha-MG, restored the sensitivity of MRSA2 to penicillin, enrofloxacin, and gentamicin, while also demonstrating improved safety profiles. Although alpha-MG-4 alone was ineffective against MRSA2, it exhibited an optimal synergistic ratio in vitro when combined with these antibiotics. This significant synergistic antibacterial effect was further confirmed in vivo using a mouse skin abscess model. Additionally, the synergistic mechanisms revealed that alpha-MG-4 was associated with changes in membrane permeability and inhibition of the MepA and NorA genes, which encode the efflux pumps of MRSA2. alpha-MG-4 also inhibited PBP2a expression, potentially by occupying a crucial binding site in a dose-dependent manner.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA)'s resistance to multiple antibiotics poses significant health and safety concerns. A novel alpha-mangostin (alpha-MG) derivative, alpha-MG-4, was first identified as a xanthone-based PBP2a inhibitor that reverses MRSA2 resistance to penicillin. The synergistic antibacterial effects of alpha-MG-4 were linked to increased cell membrane permeability and the inhibition of genes involved in efflux pump function."
PAIR0040894	"In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance."
PAIR0040895	"HCT8/T cells demonstrated significant resistance to PTX, up-regulating the expression levels of ABCB1 mRNA, P-gp, LC3-I, and LC3-II protein, and increasing intracellular reactive oxygen species (ROS) content. PMFs mainly contain two active ingredients, nobiletin, and tangeretin, which were able to reverse drug resistance in HCT8/T cells in a concentration-dependent manner. PMFs exhibited high tolerance in the HCT8/T nude mouse model while increasing the sensitivity of PTX-resistant cells and suppressing tumor growth significantly. PMFs combined with PTX reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in HCT8/T cells. Additionally, PMFs reduced intracellular ROS content, down-regulated the expression levels of autophagy-related proteins LC3-I, LC3-II, Beclin1, and ATG7, and significantly reduced the number of autophagosomes in HCT8/T cells."
PAIR0040896	"The sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCdelta and effectively suppressed nuclear PKCdelta in resistant cells in comparison to sotrastaurin. Protein kinase C (PKC) is a family of serine/threonine kinases that play important roles in signal transduction, cell proliferation, differentiation, and apoptosis. In lung cancers, the nuclear localization of PKC delta (nPKCdelta) has emerged as a common resistant mediator across various known TKI-resistant pathways. nPKCdelta is actively expressed in a significant portion of TKI-resistant patients and is associated with poor survival in EGFR-mutant patients treated with TKIs. The nPKCdelta-mediated pathway, including AKT and NF-kB, has been implicated in promoting resistance to EGFR inhibitors by activating alternative survival signaling pathways that bypass the blocked EGFR signaling and bolster tumor growth."
PAIR0040897	These results support the model that the roles of OmpA as a porin protein overexpressing in mycobacteria can increase the hydrophilic ability of the cell wall which can facilitate the streptomycin uptakes and increase the mycobacteria's sensitivity to aminoglycosides.
PAIR0040898	"PEG-Loxe mitigated inflammatory response and oxidative stress. High-PEG-Loxe reduced RhoA and Rho-associated coiled-coil kinase 2 (ROCK2) in liver tissues of type 2 diabetes mellitus rats, while both doses of PEG-Loxe decreased steroid receptor RNA activator (SRA). SRA overexpression reversed the protective functions of high-PEG-Loxe. SRA cooperated with cellular nucleic acid binding protein (CNBP) to enhance ROCK2 mRNA stability.High-PEG-Loxe relieves insulin resistance and lipid metabolism disorder in type 2 diabetes mellitus through SRA/CNBP/ROCK2 axis. This research provides a molecular mechanism of PEG-Loxe for treating type 2 diabetes mellitus."
PAIR0040899	"PEG-Loxe mitigated inflammatory response and oxidative stress. High-PEG-Loxe reduced RhoA and Rho-associated coiled-coil kinase 2 (ROCK2) in liver tissues of type 2 diabetes mellitus rats, while both doses of PEG-Loxe decreased steroid receptor RNA activator (SRA). SRA overexpression reversed the protective functions of high-PEG-Loxe. SRA cooperated with cellular nucleic acid binding protein (CNBP) to enhance ROCK2 mRNA stability.High-PEG-Loxe relieves insulin resistance and lipid metabolism disorder in type 2 diabetes mellitus through SRA/CNBP/ROCK2 axis. This research provides a molecular mechanism of PEG-Loxe for treating type 2 diabetes mellitus."