Downregulation of APRIN expression increases cancer cell proliferation via an interleukin-6/STAT3/cyclin D axis

APRIN is a putative tumor suppressor whose expression is low in a variety of cancer cells. While decreased expression of APRIN leads to increased cell proliferation, unfavorable diagnosis or metastases in various cancer types, there is limited knowledge on the cellular mechanism of APRIN in cellular responses. The effect of APRIN depletion on cancer cell proliferation was examined in the present study, and the IL-6/STAT3/cyclin D axis was identified as a novel regulatory mechanism. Stable depletion of APRIN in cancer cells resulted in increased cell proliferation. Cytokine array analysis of the cells revealed that downregulation of APRIN induced secretion of interleukin-6 (IL-6) with corresponding activation of STAT3, a downstream intracellular mediator. Levels of cyclin D1 were increased in cells with APRIN depletion and cyclin D1 expression was associated with increased STAT3 binding on cyclin D1 promoter sequence; assessed by chromatin immunoprecipitation assay. The addition of an IL-6 neutralizing antibody P620 to the cell culture attenuated STAT3 activation and cyclin D1 expression in APRIN-depleted cells with corresponding decrease in cell proliferation. These experiments suggest that APRIN regulates cancer cell proliferation via an IL-6/STAT3/cyclin D axis and that targeting this axis in APRIN-associated cancer might provide a novel therapeutic approach.     

Prevalence of and Factors Associated with Arterial Aneurysms in Patients with Hereditary Hemorrhagic Telangiectasia: 17-Year Retrospective Series of 418 Patients

PurposeTo estimate the prevalence of and identify characteristics associated with the presence of aneurysms in a cohort of patients with hereditary hemorrhagic telangiectasia (HHT).Materials and MethodsIn the study institution’s HHT database, 418 patients with a definite HHT diagnosis were identified based on the clinical Curaçao criteria and/or an HHT-associated genetic mutation. Regression modeling was used to evaluate the association between arterial aneurysms and older age, male sex, smoking, alcohol consumption, hypertension, hyperlipidemia, genetic mutations, the presence of arteriovenous malformations (AVMs) unrelated to the aneurysms, and HHT-related genetic mutations.ResultsForty-three (10.3%) patients had at least 1 aneurysm. Sixteen (3.8%) patients had multiple aneurysms. Of the variables analyzed, older age (odds ratio [OR] = 1.02; 95% confidence interval [CI]: 1.0–1.1), the presence of anatomically and flow-unrelated AVMs (OR = 3.2; 95% CI: 1.3–8.0), and the presence of activin A receptor type II-like 1 (ACVRL1) mutation (OR = 4.0; 95% CI: 1.5–10) were associated with the presence of at least 1 aneurysm.ConclusionsIn this cohort of patients with HHT, the prevalence of intracranial and visceral arterial aneurysms was estimated to be 10.3%. Older age, the presence of unrelated AVMs, and the presence of the ACVRL1 mutation were associated with the presence of arterial aneurysms. Further study is required to assess the clinical importance and risk of rupture of aneurysms in patients with HHT.     

PTGS1基因多态性与急性脑梗死患者阿司匹林抗血栓疗效的相关性

目的 探讨前列腺素内过氧化物合酶1(Prostaglandin-endoperoxide synthase1, PTGS1)基因多态性与急性脑梗死患者阿司匹林抗血栓疗效的相关性。方法 回顾性分析2017年10月-2020年10月在本院接受治疗的200例急性脑梗死患者的临床资料,按照其阿司匹林抗血栓疗效将其分为阿司匹林抵抗组(n=69)和阿司匹林敏感组(n=131),分析所有患者PTGS1基因多态性情况,比较2组性别、年龄、身体质量指数(Body Mass Index,BMI)、合并症(高血压病、冠心病、糖尿病)、PTGS1基因突变、不良嗜好(吸烟、酗酒)等临床特征及生化指标[血小板计数(Blood platelet,PLT)、超敏C反应蛋白(Hypersensitive-C reactive protein,hs-CRP)]水平,利用受试者工作特征(Receiver operating characteristic,ROC)曲线分析PLT,hs-CRP预测急性脑梗死患者阿司匹林抵抗的价值,将2组有差异的指标纳入Logistic回归分析模型,进行量化赋值,明确引起急性脑梗死患者阿司匹林抵抗的危险因素。结果 本研究200例急性脑梗死患者中PTGS1基因位点以AA为主,发生率为81.50%,其突变基因位点分别为AG,GG,占人数的14.00%、4.50%。阿司匹林抵抗组年龄≥60岁、合并糖尿病、PTGS1基因突变、吸烟患者的比例及PLT,hs-CRP水平显著高于阿司匹林敏感组(P<0.05)。经ROC曲线分析PLT,hs-CRP预测急性脑梗死患者阿司匹林抵抗的曲线下面积分别为0.879、0.866。年龄≥60岁、合并糖尿病、PTGS1基因突变、吸烟、PLT≥202.255×10⁹/L,hs-CRP≥24.695 mg/L是引起急性脑梗死患者阿司匹林抵抗的危险因素。结论 PTGS1基因多态性会增加急性脑梗死患者阿司匹林抵抗风险。除此之外,高龄、糖尿病、抽烟及PLT,hs-CRP异常高表达均可能影响阿司匹林抗血栓治疗效果。     

HIF-1α和miR210与子痫前期的相关性研究

目的:研究HIF-1α和miR210与子痫前期的相关性。方法:回顾性分析本院2017年9月至2018年9月收治的子痫前期患者40例作为研究组,并选择本院同期健康妊娠妇女40例作为对照组,观察两组入选者HIF-1α、miR210表达水平;观察研究组中合并胎儿生长受限(FGR)的患者的HIF-1、miR210表达水平与无FGR组患者的对比情况。结果:研究组HIF-1α、miR210表达水平均高于对照组,合并FGR子痫前期患者HIF-1α、miR210表达水平高于无FGR子痫前期,差异有统计学意义,子痫前期发生率与HIF-1α、miR210呈正相关,P<0.05。结论:对于子痫前期诊断可配合HIF-1α和miR210表达水平检测,能够预测患者是否出现子痫前期,有利于对疾病的判断,改善预后,值得在临床上应用。     

Clinical evaluation of colony-stimulating factor 1 receptor inhibitors

Signaling through colony-stimulating factor 1 receptor (CSF1R) regulates the development, differentiation, and activation of mononuclear phagocytic cells. Inhibition of this pathway provides an opportunity for therapeutic intervention in diseases in which these cells play a pathogenic role, including cancers, inflammation, fibrosis, and others. Multiple monoclonal antibodies and small molecule inhibitors targeting CSF1R or its known ligands CSF1 and IL-34 have been clinically tested and are generally well tolerated with side effects associated with on-target macrophage inhibition or depletion. To date, clinical activity of CSF1R inhibitors has been primarily observed in diffuse-type tenosynovial giant cell tumors, a disease characterized by genetic alterations in CSF1 leading to dysregulated CSF1R signaling. Expanded development into novel indications such as chronic graft vs host disease may provide new opportunities to further explore areas where a role for CSF1R dependent monocytes and macrophages has been established. This review presents key findings from the clinical development of 12 CSF1/CSF1R targeted therapies as monotherapy or in combination with immune checkpoint inhibitors and chemotherapy.     

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

1. Download : Download high-res image (269KB)
2. Download : Download full-size image

     

The effect of soy protein containing soy isoflavones on serum concentration of cell adhesion molecules: A systematic review and meta-analysis of randomized controlled trials

BackgroundSoy protein in combination with soy isoflavones might reduce the serum concentration of inflammatory mediators. In this study, we attempted to summarize the effect of soy protein combined with soy isoflavones on circulating E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in adults.MethodsClinicaltrials.gov, Web of Science, Cochrane Library, PubMed, and Scopus were searched for English articles with no time limit regarding publication up to December 2020. Thereafter, the mean changes from baseline and their standard deviations (SDs) for both intervention and comparison groups were used to calculate the effect size. We used DerSimonian and Laird random-effects model if the heterogeneity test was statistically significant. Cochran's Q test and I-squared statistic were also used to calculate the statistical heterogeneity of the intervention effects.ResultsEight articles were found as eligible for this study. The treatment duration was between 6 and 24 weeks. Soy isoflavones dose was in a range of 30–112 mg/day and soy protein dose was in a range of 11.25–52 g/day. Overall, taking soy protein supplements containing soy isoflavones was not associated with changes in cell adhesion molecules, E-selectin, ICAM-1, or VCAM-1 (WMD = 0.65, 95 % CI: -2.58, 3.89; p = 0.692; WMD = 2.68, 95 % CI: -0.98, 6.34; p = 0.151; WMD = 2.66, 95 % CI: -6.28, 11.61; p = 0.559, respectively).ConclusionThe combination of soy protein and soy isoflavones was not significantly associated with changes in levels of E-selectin, ICAM-1, and VCAM-1. However, we need more studies with a large sample size and more participants with different age categories in this regard.     

Pannexin 1 channels facilitate communication between T cells to restrict the severity of airway inflammation

1. Download : Download high-res image (165KB)
2. Download : Download full-size image