High expression of PD-L1 mainly occurs in non-small cell lung cancer patients with squamous cell carcinoma or poor differentiation.

Background: Lung cancer is one of the most lethal cancers worldwide, but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), the more likely it will benefit from anti-PD-L1 immunotherapy. The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans. Methods: On the one hand, we obtained cases from The Cancer Genome Atlas (TCGA) database, including 498 lung squamous cell cancer (LUSC) patients and 515 lung adenocarcinoma (LUAD) patients. We studied the lung caner driver gene in LUSC and LUAD. On the other hand, PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining (IHC), and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics. Results: PD-L1 expression was higher in LUSC than in LUAD at the mRNA level. In univariate analysis, PD-L1 expression at the protein level was higher in patients who were males, were LUSC, were smokers, had a tumor diameter >3 cm, had poor differentiation, or had stages III~IV disease. In multivariate analysis, PD-L1 expression was higher in patients who were LUSC or in poor differentiation. Conclusion: In term of protein level, PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation. We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.

Circ_0002711 knockdown suppresses cell growth and aerobic glycolysis by modulating miR-1244/ROCK1 axis in ovarian cancer.

It has been well investigated that circular RNAs (circRNAs) play important roles in various cancers. The function of circ_0002711 and its underlying mechanisms in ovarian cancer (OC) remain unknown. qRT-PCR and western blot were performed to detect the expressions of circ_0002711, microRNA-1244 (miR-1244), and Rho kinase 1 (ROCK1) in OC tissues and cells. MTT assay and colony formation assay were employed to evaluate cell proliferation. Detection of lactate production, glucose uptake, and ATP level and oxygen consumption were used to determine Warburg effect. Western blot was used to examine glycolysis or proliferationrelated genes. Dual-luciferase reporter assay and RIP pull down assay were used to address the relationship among circ_0002711, miR-1244, and ROCK1. In vivo tumor growth was evaluated in nude mice. Circ_0002711 was upregulated in OC tissues and cell lines. Circ_0002711 downregulation inhibited cell viability, colony formation ability and aerobic glycolysis. Circ_0002711 contained binding sites with miR1244. Moreover, loss of miR-1244 undermined circ_0002711 downregulation-mediated function. ROCK1 contained binding sites with miR-1244. MiR-1244 upregulation suppressed cell proliferation and aerobic glycolysis, which was rescued by enhanced expression of ROCK1. Circ_0002711 knockdown hampered ROCK1 expression by upregulating miR-1244 expression. Finally, decreased expression of circ_0002711 inhibited tumor growth in vivo. Circ_0002711/miR-1244/ROCK1 axis regulated Warburg effect and tumor growth in vivo.

Expression of Smad4, TGF-ßRII, and p21waf1 in esophageal squamous cell carcinoma tissue.

Esophageal squamous cell carcinoma (SCC) possesses one of the worst prognoses out of the digestive carcinomas. Several studies have suggested that transforming growth factor ß receptor type II (TGF-ßRII), Smad family member 4 (Smad4) and p21 wild-type p53-activated factor 1 (p21waf1) are associated with esophageal SCC. The aim of the present study was to evaluate the effect of Smad4, TGF-ßRII and p21waf1 in esophageal squamous cancer tissue and the pathological significance of the effect. An immunohistochemical method was used to evaluate the expression levels of Smad4, TGF-ßRII and p21waf1 in specimens of esophageal SCC lesions obtained from 80 patients. It was found that the expression of Smad4, TGF-ßRII and p21waf1 in histologically-classified grade I esophageal SCC, without invasion or lymph node metastasis, was markedly higher compared with grade III esophageal SCC that had invaded into the deep muscular or serous layer and metastasized to the lymph nodes (P<0.05). Analysis of the expression level of Smad4, TGF-ßRII and p21waf1, as well as the clinical and pathological characteristics of esophageal SCC, revealed that the three proteins may be associated with the carcinogenesis, biological behavior and prognosis of esophageal SCC, parallel to the pathological stage and cell grade.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir.

BACKGROUND: Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients. AIM: To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting. METHODS: Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event. RESULTS: Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03). CONCLUSIONS: Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.

Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus recurrence after liver transplantation.

BACKGROUND: Because of a critical shortage of deceased donor (DD) livers, more extended criteria allografts are being utilized; these allografts are at increased risk for ischemia-reperfusion injury (IRI). We assessed whether, in a large cohort of patients transplanted for hepatitis C virus (HCV) either via a DD or live donor (LD), there was a relationship between the degree of IRI and the frequency and timing of acute cellular rejection (ACR) and histologic HCV recurrence. METHODS: During an 8-year study, patients were separated into four groups based on peak alanine aminotransferase (ALT) levels and three groups based on severity of IRI on postreperfusion liver biopsy. RESULTS: The mean follow-up time of 433 DD and 44 LD recipients was 1212 days. We noted a strong correlation in DD between peak ALT and the histologic degree of IRI (P = .01). There was no difference in the incidence or grade of ACR among the four groups. There was no correlation between the severity of IRI and the incidence or time to histologic recurrence of HCV. CONCLUSIONS: The magnitude of peak ALT correlated with the severity of IRI on postreperfusion liver biopsy. Among this large HCV cohort, there was no correlation between the severity of IRI and the incidence or timing of histologic HCV recurrence or incidence of ACR.

Helicobacter pylori decreases gastric mucosal glutathione.

Activation of oxidative stress pathways may contribute to gastric epithelial damage and mutagenesis caused by Helicobacter pylori. We measured the effect of H. pylori on the concentrations of reduced glutathione (GSH), an important endogenous defense against oxidant damage, in gastric epithelial cells in vivo and in vitro. GSH concentrations were significantly lower in gastric biopsies from 19 H. pylori-infected patients than 38 normal controls, and correlated inversely with inflammatory cell numbers. In vitro, H. pylori initially increased GSH levels in AGS cells, but subsequently depleted intracellular GSH stores completely after 24 h. No GSH was detected in H. pylori. Our data suggest that diminished GSH levels with H. pylori colonization of the gastric mucosa may be due to a direct effect of the bacterium as well as through the associated inflammatory response.

Human right and left colon differ in epithelial cell apoptosis and in expression of Bak, a pro-apoptotic Bcl-2 homologue.

BACKGROUND: Propensity to colonic neoplasia differs between the right and left colon. AIMS: To examine whether this difference may be related to regional differences in epithelial apoptosis, in expression of a proapoptotic regulatory protein, Bak, and in proliferation. PATIENTS: Individuals with no history of colorectal neoplasia. METHODS: Archival blocks of colorectal tissues were immunostained for proliferating cells (antibody to Ki-67 antigen), and Bak expression (polyclonal antiserum). Cells containing DNA strand breaks, a marker of apoptosis, were identified by terminal deoxyuridine nucleotidyl nick end labelling (TUNEL). RESULTS: There were fewer TUNEL positive epithelial cells in the right colon (mean 1.2 (SE 0.1)% of all epithelial cells) than the left colon (2.2 (0.1)%, p<0.0001) or rectum (2.2 (0.3)%, p<0.05). Bak expression was less common in the right colon (mean 46 (2.3)% of epithelial cells immunoreactive) than the left colon (66 (2.7)%, p<0.0001), or rectum (67 (2.3)%, p<0.001). Bak expression and TUNEL positivity were highly positively correlated (p<0.0001). In contrast to apoptosis, mean whole crypt proliferation labelling index was similar throughout the colorectum (right colon: 15.6 (3.2)%; left colon: 13. 5 (1.2)%; rectum: 13.3 (2.3)%). CONCLUSION: The percentage of proliferating colonic epithelial cells is constant throughout the colon, but fewer epithelial cells undergo Bak mediated apoptosis in the right than in the left colon or rectum. This suggests that colonocytes may be lost by methods other than apoptosis in the right colon.