The effects of TNF-α/TNFR2 in regulatory T cells on the microenvironment and progression of gastric cancer.

TNFR2+ regulatory T cells preferentially accumulate in the tumor microenvironment, express high levels of immunosuppressive molecules and possess strong suppressive activity. Our study aimed to explore the characteristics and role of TNFR2+ Tregs in the microenvironment and progression of gastric cancer via polychromatic immunofluorescence, single-cell RNA sequencing and flow cytometry assays. The TNFR2+ Treg infiltration level in the tumor microenvironment increased significantly as gastric cancer progressed and was demonstrated to be a prognostic marker. Single-cell RNA sequencing revealed high levels of TNFR2 in tumor-infiltrating Tregs. The TNF-α/TNFR2 signaling pathway was activated, accompanied by the upregulation of costimulatory molecules. Unlike blood Tregs, tumor-infiltrating Tregs existed in activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4-1BB, OX40 and GITR, tumor-infiltrating Tregs were also characterized by high expression levels of immune checkpoints such as CTLA-4 and TIGIT and chemokines such as CCR6. In vitro studies showed that the TNF-α/TNFR2 pathway increased the Foxp3 expression in CD4+ CD25+ T cells and the latent TGF-ß production in Tregs as well as enhanced the immunosuppressive function of Tregs. In summary, our study revealed high infiltration levels of TNFR2+ Tregs that were in activated and effector states in the tumor microenvironment. The infiltration level of TNFR2+ Tregs is a prognostic marker and an independent risk factor for gastric cancer. Activation of the TNF-α/TNFR2 pathway promotes the immunosuppressive phenotype and function of Tregs. Our study provides a new theoretical basis for TNFR2+ Tregs as a therapeutic target in gastric cancer.

Alterations in mucosa-associated microbiota in the stomach of patients with gastric cancer.

PURPOSE: The purpose of this study was to characterize alterations in mucosa-associated microbiota in different anatomical locations of the stomach during gastric cancer progression and to identify associations between Helicobacter pylori infection and gastric microbial changes in patients with gastric cancer. METHODS: Twenty-five H. pylori negative subjects with chronic gastritis and thirty-four subjects with gastric cancer were recruited, including H. pylori negative and positive patients with tumors in the antrum and the corpus. Gastric mucosa-associated microbiota were determined by 16S ribosomal RNA gene sequencing using a 454 sequencing platform. RESULTS: We found that individuals with chronic gastritis from three different anatomical sites exhibited different microbiota compositions, although the microbial alpha diversity, richness and beta diversity were similar. Compared to patients with chronic gastritis, the gastric microbiota compositions were significantly different at the order level in the antrum and the corpus of patients with gastric cancer, which was dependent on the H. pylori infection status. Microbial alpha diversity and species richness, however, were similar between chronic gastritis and gastric cancer cases and independent of H. pylori status. The microbial community structure in patients with gastric cancer was distinct from that in patients with chronic gastritis. In addition, we found that the presence of H. pylori markedly altered the structure in gastric corpus cancer, but only mildly affected the antrum. CONCLUSION: Our data revealed distinct niche-specific microbiota alterations during the progression from gastritis to gastric cancer. These alterations may reflect adaptions of the microbiota to the diverse specific environmental habitats in the stomach, and may play an important, as yet undetermined, role in gastric carcinogenesis.

The prevalence and prognostic and clinicopathological value of PD-L1 and PD-L2 in renal cell carcinoma patients: a systematic review and meta-analysis involving 3,389 patients.

BACKGROUND: The research of the prognostic and clinicopathologic values of programmed cell death ligand 1/2 (PD-L1/2) in renal cell carcinoma (RCC) patients has been mired by a dearth of studies and considerable controversy. We thus conducted a systematic review and meta-analysis to report the prevalence and prognostic and clinicopathological value of programmed cell death ligand 1 (PD-L1) and programmed cell death-legend 2 (PD-L2) in RCC patients. METHODS: The PubMed, Cochrane Library, EMBASE databases were searched to find human studies limited to English language literature published through October 1, 2019. Using random or fixed effects models, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated to explore the prognostic value of PD-Ls expression, while odds ratios (ORs) and 95% CIs were evaluated to investigate clinicopathological parameters. The protocol of the study was registered in PROSPERO (CRD42019135199). RESULTS: After pooling all 16 eligible studies comprising 3,389 patients, we found that the overall prevalence of PD-L1 and PD-L2 in RCC patients was 27% and 39%, respectively. Furthermore, PD-L1 over-expression was a strong negative predictor for overall survival (OS), disease-free survival/progression-free survival (DFS/PFS), and cancer-specific survival (CSS) in renal cell carcinoma patients (HR =2.86, 95% CI: 1.83-4.47, P<0.001; HR =2.64, 95% CI: 1.99-3.52, P<0.001; HR =2.78, 95% CI: 2.17-3.56, P<0.001). Meanwhile, PD-L2 over-expression was only a weak negative predictor for CSS (HR =1.66, 95% CI: 1.05-2.65, P<0.05). Subgroup analysis showed that Caucasians had worse OS (HR =3.60, 95% CI: 1.77-7.33, P<0.001), PFS (HR =3.56, 95% CI: 2.44-5.18, P<0.001), and CSS (HR =3.13, 95% CI: 2.37-4.14, P<0.001) than Asians. PD-L1 was a strong indicator for worse prognosis (P<0.05 for all), while PD-L2 over-expression was only associated with sarcomatoid features (presence vs. absence, OR =1.80, 95% CI: 1.13-2.86, P=0.014). Notably, PD-L1 overexpression was more prevalent in women (male vs. female, OR =0.68, 95% CI: 0.51-0.90, P=0.006). CONCLUSIONS: Higher PD-L1 expression is more closely associated with poor prognosis and more advanced clinicopathological features in RCC patients than PD-L2, especially in women and Caucasian patients. PD-L2 was a weak negative predictor of poor CSS of RCC and was not a prompt for the metastasis of RCC.

UAV-YOLO: Small Object Detection on Unmanned Aerial Vehicle Perspective.

Object detection, as a fundamental task in computer vision, has been developed enormously, but is still challenging work, especially for Unmanned Aerial Vehicle (UAV) perspective due to small scale of the target. In this study, the authors develop a special detection method for small objects in UAV perspective. Based on YOLOv3, the Resblock in darknet is first optimized by concatenating two ResNet units that have the same width and height. Then, the entire darknet structure is improved by increasing convolution operation at an early layer to enrich spatial information. Both these two optimizations can enlarge the receptive filed. Furthermore, UAV-viewed dataset is collected to UAV perspective or small object detection. An optimized training method is also proposed based on collected UAV-viewed dataset. The experimental results on public dataset and our collected UAV-viewed dataset show distinct performance improvement on small object detection with keeping the same level performance on normal dataset, which means our proposed method adapts to different kinds of conditions.

Seminal plasma miR-210-3p induces spermatogenic cell apoptosis by activating caspase-3 in patients with varicocele.

The aim of this study was to investigate the role of seminal plasma miR-210-3p in the impairment of semen quality caused by varicocele. This study included 102 patients whose semen quality was normal when they were diagnosed with varicocele. A 2-year follow-up for included patients was performed, and they were divided into Group A (semen quality became abnormal) and Group B (semen quality remained normal) according to the results of semen analysis during the follow-up. Semen parameters and seminal plasma miR-210-3p expression were investigated by semen analysis and quantitative real-time polymerase chain reaction, respectively. In vitro experiments with GC-2 cells were performed to explore the role of miR-210-3p in spermatogenic cells. The results of quantitative real-time polymerase chain reaction showed that the level of seminal plasma miR-210-3p in Group A was higher than that in Group B both after 2-year follow-up and when they were diagnosed with varicocele (both P < 0.01). Apoptosis and proliferation assays showed that miR-210-3p induces apoptosis of spermatogenic cells by promoting caspase-3 activation. In conclusion, our study indicated that seminal plasma miR-210-3p induces spermatogenic cell apoptosis by activating caspase-3 in patients with varicocele. Seminal plasma miR-210-3p may be a potential biomarker for predicting impaired semen quality caused by varicocele.

Prognostic value of performance status in metastatic renal cell carcinoma patients receiving tyrosine kinase inhibitors: a systematic review and meta-analysis.

BACKGROUND: The association between performance status (PS) and the prognosis of metastatic renal cell carcinoma (mRCC) patients receiving tyrosine kinase inhibitors (TKIs) remains controversial. The aim of this study is to evaluate the prognostic value of PS in mRCC patients treated with TKIs. METHODS: Electronic databases were searched to identify the studies that had assessed the association between pretreatment PS and prognosis in mRCC patients receiving TKIs. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) and progression-free survival (PFS) from eligible studies were used to calculate combined HRs. The heterogeneity across the included studies was assessed by Cochrane's Q test and I2 statistic. The Begg's funnel plot and Egger's linear regression teats were used to evaluate the potential publication bias. The meta-analysis was performed with RevMan 5.3 and Stata SE12.0 according to the PRISMA guidelines. RESULTS: A total of 6780 patients from 19 studies were included in this meta-analysis. The results showed that a poor PS was an effective prognostic factor of both OS (pooled HR: 2.08, 95% CI: 1.78-2.45) and PFS (pooled HR: 1.51, 95% CI: 1.20-1.91). Subgroup analysis revealed that poor PS significantly associated with poor OS and PFS in studies using Karnofsky PS scale (OS, pooled HR: 2.20, 95% CI: 1.65-2.94; PFS, pooled HR: 1.74, 95% CI: 1.19-2.56), conducted in Asia (OS, pooled HR: 2.25, 95% CI: 1.71-2.95; PFS, pooled HR: 1.73, 95% CI: 1.14-2.64) and Newcastle-Ottawa Scale score of 8 (OS, pooled HR: 2.61, 95% CI: 1.92-3.55; PFS, pooled HR: 2.43, 95% CI: 1.36-4.33). CONCLUSIONS: This study suggests that a poor PS is significantly associated with poor prognosis in mRCC patients receiving TKIs.