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Background: There are currently no satisfactory biomarkers to predict prognosis and evaluate the benefit of immunotherapy in bladder urothelial carcinoma (BLCA) patients. This study aimed to develop a predictive signature that could accurately predict prognosis and evaluate the response to immunotherapy in BLCA. Methods: Differentially expressed genes (DEGs) were identified using the GEPIA and Oncomine databases, and the common genes between the two database were selected using a Venn diagram. In addition, gene ontology enrichment and protein–protein interaction (PPI) network analyses were performed. We further identified the prognosis-related hub genes using the survival R package and confirmed in three online databases (PROGgenesV2, PrognoScan, and OSblca). Moreover, the correlation between prognosis-related hub genes and clinical characteristics was analyzed. Finally, comprehensive bioinformatics analysis was carried out to investigate the association between the three genes and immunity. Results: A total of 750 and 1881 DEGs were identified from GEPIA and Oncomine, respectively, and 69 common DEGs were selected. The most significantly enriched term among the 69 common DEGs was “mitotic cell cycle”, and 11 hub genes were detected by PPI analysis. Moreover, three prognosis-related hub genes, AURKA, BIRC5, and CKS1B, were identified, and which were associated with clinical characteristics, in particular, histological subtypes and TP53 mutation status. Furthermore, our results showed that the expression levels of the three genes were positively correlated with CD8+ T cells and tumor mutation burden (TMB), and with PD-L1, which had higher expression in responders to immunotherapy and in the C2 (IFN-gamma dominant) subtype. Drug–gene interaction network analysis demonstrated that these genes and related drugs could be used to help develop new targets for BLCA immunotherapy. Conclusions: Our study suggested that three key genes in BLCA were correlated with poor prognosis and immune cell infiltration, especially that of CD8+ T cells. The responses of these prognosis-related genes to immunotherapy in BLCA may be associated with CD8+ T cells, TMB, and PD-L1 expression. These key genes and their related drugs may help to develop new targets for BLCA immunotherapy.

BACKGROUND: Chemotherapy is the major choice for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor exon 20 insertion (EGFR ex20ins). The efficacy of pemetrexed-based with other chemotherapy regimens and EGFR ex20ins subtypes in this population has not been well studied. METHODS: We screened patients with EGFR ex20ins by next-generation sequencing (NGS) from a large cohort. The clinicopathologic and medical information were collected in advanced NSCLC patients with EGFR ex20ins. We also compared the clinical outcomes among patients with different subtypes of EGFR ex20ins. RESULTS: We retrospectively collected 119 stage IIIB/IV NSCLC patients with EGFR ex20ins from 9142 NSCLC patients across China from June 2013 to December 2018. The subtypes of EGFR ex20ins included A767_V769dupASV (33/119, 27.73%), S768_D770dupSVD (19/119, 15.97%), N771_H773dupNPH (11/119, 9.24%), A763_Y764insFQEA (2/119, 1.68%) and others (54/119, 45.38%). A total of 64.7% (77/119) of patients received pemetrexed-based first-line chemotherapy and 13.45% (16/119) of patients received pemetrexed-based second-line chemotherapy. Pemetrexed-based chemo-treated patients had longer median progression-free survival (PFS) than patients without pemetrexed-based chemo-treated (5.5 vs. 3.0 months, P=0.0026). Survival data was available for 66 patients and the median overall survival (OS) was 24.7 months. Pemetrexed-based chemo-treated patients had longer OS tendency than patients without pemetrexed-based chemo-treated (25.0 vs. 19.6 months, P=0.0769). Patients harboring A767_V769dupASV had better OS than other subtypes of EGFR ex20ins but without statistical significance (P=0.0676). Multivariate analysis revealed that histological type of NSCLC and bone-metastasis before treatment were independent prognostic factors for OS in all patients after adjusting all characteristic and treatment factors (P

Vessel disease is a kind of severe complication in diabetic patients. However, few pharmacologic agents can directly recover diabetic vascular function. Salidroside (SAL), a major ingredient from Rhodiola rosea, has been found to have an obvious hypoglycemic effect and a beneficial protection on vascular function in diabetes. However, whether SAL is a suitable treatment for diabetes has not so far been evaluated and the underlying mechanisms remain unknown. The present work aims to (1) investigate the potential effects of SAL on cerebrovascular relaxation in streptozotocin-induced diabetic rats or when exposed to acute hyperglycemia condition and (2) examine whether function of the BK

Background Vascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca2+ handling in vascular smooth cells (VSMCs) under hyperglycemia. Methods Sprague–Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca2+ handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca2+ channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca2+ in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca2+ ([Ca2+]i) level, and suppressed the Ca2+ releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca2+ releases from RyRs in cerebral VSMCs isolated from normal control rats. Conclusions Our study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca2+ handling of smooth muscle cells.