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Pharmacokinetic Review associated with Dental 14C-Radiolabeled Hyzetimibe, A New Cholesterol levels Absorption Inhibitor.
Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1α). Although several studies have confirmed the interaction between p53 and PGC1α, the precise mechanism has not been completely determined in NSCLC. In this study, we investigated the specific signaling between p53 and PGC1α to improve anti-tumor drug effects on NSCLC. We found that low expression of p53 and high expression of PGC1α correlated with shorter survival time of NSCLC patients. In vitro experiments confirmed that NCI-H1299 (p53-null) cells had high levels of PGC1α and were insensitive to cisplatin (CDDP). When PGC1α was knocked down, the sensitivity to cisplatin was increased. Notably, the stability of PGC1α is an important mechanism in its activity regulation. We demonstrated that p53 decreased the stability of PGC1α via the ubiquitin proteasome pathway, which was mediated by protein kinase B (AKT) inhibition and glycogen synthase kinase (GSK-3β) activation. Therefore, p53 may regulate the stability of PGC1α through the AKT/GSK-3β pathway, thus affect the chemosensitivity of NSCLC.Background In patients with anaplastic lymphoma kinase (ALK) rearrangement-positive advanced non-small-cell lung cancer (NSCLC), ALK inhibitors are now the standard treatment, but their clinical efficacy varies widely for each patient. In this multicenter retrospective study, we evaluated the clinical efficacy of crizotinib according to the ALK rearrangement variants and concomitant mutations present. Patients and Methods A total 132 patients with ALK rearrangement advanced NSCLC from 4 centers in Guangdong province, China were evaluated. All patients received crizotinib treatment and their ALK rearrangement status was identified by next-generation sequencing (NGS). Results The median progression-free survival (PFS) in patients with EML4-ALK rearrangement (n = 121), non-EML4-ALK rearrangement (n = 5), and EML4-ALK arrangement accompanied by non-EML4-ALK rearrangement (n = 6) was 12.8, 7.5, and 7.4 months, respectively, with no significant difference between them (p = 0.1554). check details Similarly, among patients with various EML4-ALK variants (variant 1, variant 3a/b, and other variants), the median PFS values were again comparable. According to baseline NGS data, the median PFS in patients who had ALK rearrangement only, ALK rearrangement and concomitant tumor-suppressor gene mutations, and ALK rearrangement and concomitant oncogene mutations was 14.2, 10.9, and 4.9 months, respectively; (p = 0.0002). A multivariable analysis indicated that concomitant oncogene mutations and tumor-suppressor gene mutations were both negative factors influencing the efficacy of crizotinib in ALK rearrangement NSCLC. Conclusion Concomitant oncogene mutations and tumor-suppressor gene mutations had negative effects on the efficacy of crizotinib, while various ALK variants had a similar influence.Background Glioma is the most common primary intracranial tumor, accounting for the vast majority of intracranial malignant tumors. Aberrant expression of RNA5-methylcytosine(m5C) methyltransferases have recently been the focus of research relating to the occurrence and progression of tumors. However, the prognostic value of RNAm5C methyltransferases in glioma remains unclear. This study investigated RNA m5C methyltransferase expression and defined its clinicopathological signature and prognostic value in gliomas. Methods We obtained the RNA-sequence and Clinicopathological data of RNAm5C methyltransferases underlying gliomas from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. We analyzed the expression of RNAm5C methyltransferase genes in gliomas with different clinicopathological characteristics and identified different subtypes using Consensus clustering analysis. Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) was used to annotate the function of these genesurvival but also clinicopathological features in gliomas. ROC curves revealed the significant prognostic ability of this signature. In addition, Multivariate Cox regression analyses indicated that the risk score was an independent prognostic factor for glioma outcome. Conclusion We demonstrated the prognostic role of RNAm5C methyltransferases in the initiation and progression of glioma. We have expanded on the understanding of the molecular mechanism involved, and provided a unique approach to predictive biomarkers and targeted therapy for gliomas.Glioblastoma (GBM) is an aggressive malignancy with poor prognosis. New therapeutic strategies for GBM are urgently needed. Although clinical studies have demonstrated the feasibility and safety of chimeric antigen receptor (CAR) T cell therapy for GBM, its efficacy has not been that impressive. The major limitation for anti-tumor efficacy of CAR-Ts is the immunosuppressive milieu of the GBM tumor microenvironment (TME). TGFβ, a substantial component in GBM, compromises the immune response and contributes to immune evasion and tumor progression. To overcome this limitation and improve the efficacy of CAR-T cells for GBM, we optimized an EGFRvIII-specific CAR construct with TGFRII ectodomain as a TGFβ-trap and generated TGFβ-resistant CAR-Ts for GBM therapy. We demonstrated that this TGFβ-trapped architecture enhanced anti-tumor efficacy of EGFRvIII-specific CAR-T and prolonged the survival of mice bearing GBM. In addition, the GBM-infiltrated microglia, typically considered tumorigenic, showed increased expression of M1 polarization markers after treatment with the TGFβ-trap CAR-Ts group, indicating that these microglia were polarized toward a pro-inflammatory and anti-tumorigenic phenotype. Overall, these results indicated that arming CAR-T cells with a TGFβ-trap diminishes the immunosuppressive effect and is a potential strategy to improve CAR-T efficacy for GBM therapy.
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