Vorinostat is a histone deacetylase inhibitor that induces differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo and has shown clinical responses in f30% of patients with advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers predictive of vorinostat response in CTCL using preclinical model systems and to assess these biomarkers in clinical samples. The signal transducer and activator of transcription (STAT) signaling pathway was evaluated. The data indicate that persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to vorinostat in lymphoma cell lines. Simultaneous treatment with a pan-Janus-activated kinase inhibitor resulted in synergistic antiproliferative effect and down-regulation of the expression of several antiapoptotic genes. Immunohistochemical analysis of STAT1 and phosphorylated tyrosine STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response. These results suggest that deregulation of STAT activity plays a role in vorinostat resistance in CTCL, and strategies that block this pathway may improve vorinostat response. Furthermore, these findings may be of prognostic value in predicting the response of CTCL patients to vorinostat. [Cancer Res 2008;68(10):3785-94]
Major depressive disorder (MDD) is a grave debilitating mental disease with a high incidence and severely impairs quality of life. Therefore, its physiopathological basis study and diagnostic biomarker discovery are extremely valuable. In this study, a non-targeted lipidomics strategy using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to reveal differential lipids between MDD (n = 60) and healthy controls (HCs, n = 60). Validation of changed lipid species was performed in an independent batch including 75 MDD and 52 HC using the same lipidomic method. Pronouncedly changed lipid species in MDD were discovered, which mainly were lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), 1-O-alkyl-2-acyl-PE (PE O), 1-O-alkyl-2-acyl-PC (PC O), sphingomyelin (SM), diacylglycerol (DG), and triacylglycerol (TG). Among these lipid species, LPC, LPE, PC, PE, PI, TG, etc. remarkably increased in MDD and showed pronounced positive relationships with depression severity, while 1-O-alkyl-2-acyl-PE and SM with odd summed carbon number significantly decreased in MDD and demonstrated negative relationships with depression severity. A combinational lipid panel including LPE 20:4, PC 34:1, PI 40:4, SM 39:1, 2, and TG 44:2 was defined as potential diagnostic biomarker with a good sensitivity and specificity for distinguishing MDD from HCs. Our study brings insights into lipid metabolism disorder in MDD and provides a specific potential biomarker for MDD diagnose.
Lactate dehydrogenase A (LDH-A) is a key enzyme during glycolysis, which increases the synthesis of related proteins and has elevated activity in cancer cells. The role of LDH-A in lung adenocarcinoma (LUAD) progression was investigated in the present study. Expression levels of LDH-A were assessed in LUAD samples, and the relationship between LDH-A expression status and the prognosis of LUAD patients was confirmed. The effect of LDH-A on proliferation, invasion, migration, and colony formation of cancer cells was assessed. We further determined the role of LDH-A in tumor growth in vivo by using xenograft LUAD tumor models. The potential mechanism of LDH-A promotion in LUAD progression was explored. LDH-A showed an abnormally high expression in LUAD, which is closely associated with poor prognosis in patients with LUAD. In in vitro experiments, silencing LDH-A expression in LUAD cells could effectively inhibit proliferation, invasion, migration, and colony formation of cancer cells. In in vivo experiments, tumor growth was markedly inhibited by LDH-A silencing in a xenograft model of LUAD. Notably, LDH-A could also promote tumor progression by regulating epithelial–mesenchymal transition (EMT)-related molecules. LDH-A can promote the malignant biological behaviors of LUAD cells, and thus can be a potential target for LUAD treatment.
Edited by Laszlo Nagy Keywords:Retinoic acid receptor-related orphan receptor a Insulin Promoter Gene transcription a b s t r a c tInsulin plays an important role in regulation of lipid and glucose metabolism. Retinoic acid receptor-related orphan receptor a (RORa) modulates physiopathological processes such as dyslipidemia and diabetes. In this study, we found overexpression of RORa in INS1 cells resulted in increased expression and secretion of insulin. Suppression of endogenous RORa caused a decrease of insulin expression. Luciferase and electrophoretic mobility shift assay (EMSA) assays demonstrated that RORa activated insulin transcription via direct binding to its promoter. RORa was also observed to regulate BETA2 expression, which is one of the insulin active transfactors. In vivo analyses showed that the insulin transcription is increased by the synthetic RORa agonist SR1078. These findings identify RORa as a transcriptional activator of insulin and suggest novel therapeutic opportunities for management of the disease.
Background Non‐small cell lung cancer (NSCLC) is the predominant type of lung cancer, and most clinically curable patients are diagnosed with locally advanced disease. Although the efficacy of standard platinum‐based chemotherapy doublets is relatively limited. The effect of immune checkpoint inhibitors (ICIs) remains controversial, and its role in the first‐line treatment of advanced NSCLC is obscure. Thus, we carried out a systematic review and meta‐analysis to compare the efficacy and safety of ICIs for advanced NSCLC. Methods The PubMed, Cochrane Central Register Trial, and American Society of Clinical Oncology databases were searched from inception to 30 April 2018. We searched for randomized controlled trials comparing single‐agent programmed cell death protein 1/programmed death‐ligand 1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) or cytotoxic T‐lymphocyte‐associated antigen 4 inhibitor (ipilimumab) with chemotherapy in NSCLC patients. Progression‐free survival, overall survival, objective response rate, and adverse events were pooled for meta‐analysis by Review Manager (RevMan version 5.3) software. Results After exclusion of ineligible studies, 12 eligible randomized controlled trials were included. Data showed that ICIs significantly improved progression‐free survival (HR 0.66, 95% CI 0.57–0.77, P < 0.00001), overall survival (HR 0.77, 95% CI 0.64–0.91, P = 0.003), and but not objective response rate (RR 1.97, 95% CI 1.25–3.13, P = 0.004) in all unselected NSCLC populations. However, they failed to increase the OS of programmed death‐ligand 1 = 1–49% subgroup (HR 0.78, 95% CI 0.51–1.19, P = 0.25) and PFS of programmed death‐ligand 1<1% subgroup (HR 0.85; 95%CI 0.70 to 1.03, P =0.09) in ICIs+chemotherapy over chemotherapy. Meanwhile, OS of programmed death‐ligand =1‐49% subgroup (HR 0.92; 95%CI 0.77 to 1.10, P =0.36) and PFS of programmed death‐ligand 1≥50% subgroup (HR 0.76; 95%CI 0.52 to 1.11, P =0.15) showed no significant differences in ICIs over chemotherapy. Furthermore, fewer adverse events were observed in the ICIs groups than control groups. Conclusion ICIs are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for ICIs.
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