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Deficiency of STING attenuated MCD-induced hepatic steatosis and fibrosis in mice. WT and STING-deficient mice (Tmem173 gt) were fed with MCD for 8 weeks to induce NASH. H&E (Figure 1A) and Masson staining (Figure 1B) revealed steatosis, ballooning, inflammation, and fibrosis in the livers of MCD-fed mice, which was attenuated by deficiency of STING. Levels of cholesterol (Figure 1C), triglyceride (Figure 1D), and hydroxyproline (a marker of fibrosis, Figure 1E) in livers and levels of ALT (Figure 1F) and aspartate aminotransferase (AST) (Figure 1G

Background: Recently, Coronavirus Disease 2019 (COVID-19) outbreak started in Wuhan, China. Although the clinical features of have been reported previously, data regarding the risk factors associated with the clinical outcomes are lacking.Objectives: To summary and analyze the clinical characteristics and identify the predictors of disease severity and mortality. Methods:The PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv databases were searched through February 25, 2020. Meta-analysis of Observational Studies in Epidemiology (MOOSE) recommendations were followed. We extracted and pooled data using random-e ects meta-analysis to summary the clinical feature of the confirmed COVID-19 patients, and further identify risk factors for disease severity and death. Heterogeneity was evaluated using the I² method and explained with subgroup analysis and meta-regression. Results:A total of 30 studies including 53000 patients with were included in this study, the mean age was 49.8 years (95% CI, 47.5-52.2 yrs) and 55.5% were male. The pooled incidence of severity and mortality were 20.2% (95% CI, 15.1-25.2%) and 3.1% (95% CI, 1.9-4.2%), respectively. The predictor for disease severity included old age (≥ 50 yrs, odds ratio [OR] = 2.61; 95% CI, 2.29-2.98), male (OR =1.348, 95% CI, 1.195-1.521), smoking (OR =1.734, 95% CI, All rights reserved. No reuse allowed without permission. : medRxiv preprint 1.146-2.626) and any comorbidity (OR = 2.635, 95% CI, 2.098-3.309), especially chronic kidney disease (CKD, OR = 6.017; 95% CI, 2.192-16.514), chronic obstructive pulmonary disease (COPD, OR = 5.323; 95% CI, 2.613-10.847) and cerebrovascular disease (OR = 3.219; 95% CI, 1.486-6.972). In terms of laboratory results, increased lactate dehydrogenase (LDH), C-reactive protein (CRP) and D-dimer and decreased blood platelet and lymphocytes count were highly associated with severe COVID-19 (all for P < 0.001). Meanwhile, old age (≥ 60 yrs, RR = 9.45; 95% CI, 8.09-11.04), followed by cardiovascular disease (RR = 6.75; 95% CI, 5.40-8.43) hypertension (RR = 4.48; 95% CI, and diabetes (RR = 4.43; 95% CI, 3.49-5.61) were found to be independent prognostic factors for the COVID-19 related death. Conclusions:To our knowledge, this is the first evidence-based medicine research to explore the risk factors of prognosis in patients with COVID-19, which is helpful to identify early-stage patients with poor prognosis and adapt effective treatment.Compared with two other types of coronaviruses, the present new coronavirus is spreading far more quickly and has higher contagiousness 5 .As of March 17, 2020, a total of 187, 361 COVID-19 cases in 151 countries have been confirmed, which almost 22.2 times the number of people infected by the SARS in 2003. Although COVID-19 has a relatively low mortality rate, it can be highly deadly and lethal, especially in high-risk patients 6 . The reported incidence of COVID-19 accompanied with underlying comorbidities in the literature were up to 26.0%, and most of them (65.3%) had cardiovascula...

It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF-α (tmTNF-α) is the primary ligand for TNFR2, we hypothesized that tmTNF-α is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF-α, rather than secretory TNF-α (sTNF-α), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-β, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF-α was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF-α–induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF-α caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF-α–mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF-α mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-β, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF-α mutant by 4T1 cells that only released sTNF-α without expression of surface tmTNF-α markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF-α acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.

Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3(+) regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8(+) cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3(+)/CD4(+) and Foxp3(+)/CD8(+) in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor-1α, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.

Rationale Abnormal phenotypic switch of vascular smooth muscle cell (VSMC) is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty. MicroRNAs (miRNAs) have emerged as important regulators for VSMC function, and we recently identified miR-663 as critical for controlling human aortic smooth muscle cell proliferation. Objective To investigate whether miR-663 plays a role in human VSMC phenotypic switch and the development of neointima formation. Methods and Results By using quantitative reverse-transcription polymerase chain reaction, we found that miR-663 was significantly downregulated in human aortic VSMCs on platelet-derived growth factor treatment, whereas expression was markedly increased during VSMC differentiation. Furthermore, we demonstrated that overexpression of miR-663 increased expression of VSMC differentiation marker genes, such as smooth muscle 22α, smooth muscle α-actin, calponin, and smooth muscle myosin heavy chain, and potently inhibited platelet-derived growth factor-induced VSMC proliferation and migration. We identified the transcription factor JunB and myosin light chain 9 as downstream targets of miR-663 in human VSMCs, because overexpression of miR-663 markedly inhibited expression of JunB and its downstream molecules, such as myosin light chain 9 and matrix metalloproteinase 9. Finally, we showed that adeno-miR-663 markedly suppressed the neointimal lesion formation by ≈50% in mice after vascular injury induced by carotid artery ligation, specifically via decreased JunB expression. Conclusions These results indicate that miR-663 is a novel modulator of human VSMC phenotypic switch by targeting JunB/myosin light chain 9 expression. These findings suggest that targeting miR-663 or its specific downstream targets in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.

These results indicate that miR-638 is a key molecule in regulating human VSMC proliferation and migration by targeting the NOR1/cyclin D pathway and suggest that specific modulation of miR-638 in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.

Epidemiological studies have found obesity to be a risk factor for women's breast cancer. The present study was to investigate whether there is a relationship between serum levels of leptin, insulin, and lipids and breast cancer incidence, in order to find experimental evidence that would be helpful in the diagnosis and prevention of breast cancer. Blood samples were collected from 130 patients with mammary disease and 103 healthy control subjects. Serum leptin, insulin, and lipids were determined by radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISA), and Biochemistry Auto-analyzer, respectively. The data analysis was performed by use of the SPSS10.0 computer software. We found that the serum levels of leptin, insulin, and triglyceride (TG) were clearly higher in patients with breast cancer than in patients with benign breast disease and healthy controls, while serum HDL-C levels were lower in breast cancer patients (p < 0.03). Moreover, serum leptin levels were significantly correlated with BMI (body mass index) among three groups, whereas serum insulin levels were unrelated to BMI among three groups. Furthermore, the serum levels of leptin and insulin were not associated with menopausal status in patients with mammary disease (p > 0.05); however, the serum levels of F-Chol, T-Chol, TG, LDL-C, and APOB were significant higher in postmenopausal cases than those in premenopausal cases (p < 0.025). Interestingly, logistic regression analysis showed that subjects with elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C displayed increased risk of developing breast cancer than those with the normal levels, respectively. In conclusion, the present study suggested that aberrant serum levels of leptin, insulin, and lipids might play an important role in carcinogenesis of breast cancer. The elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C may be correlated with increased risk of breast cancer, suggesting that one way of preventing breast cancer would be carried out by controlling the intake of food.