BRCA1-associated protein 1 serves as a tumor suppressor in hepatocellular carcinoma by deubiquitinating and stabilizing PTEN

BRCA1-associated protein 1 (BAP1) or its mutants have been known to play critical regulatory roles in tumor biology, yet their role in hepatocellular carcinoma (HCC) remains largely unclear. In this study, we detected the mutations of all the exons of BAP1 in 105 HCC patients using Sanger sequencing, and found eight somatic mutations in 6 (5.71%) patients. We also found that the mRNA and protein levels of BAP1 were markedly downregulated in HCC versus the adjacent non-tumor tissues. Wild-type BAP1 but not mutant BAP1 significantly inhibited HCC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) in vitro, and tumor progression and metastasis in vivo. Mechanistically, BAP1 complexed with PTEN and stabilized PTEN via deubiquitination and, furthermore, negatively regulated HCC cell EMT by deactivating the AKT/GSK-3β/Snail pathway. However, those tumor-inhibitory effects of BAP1 were abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated to aggressive tumor phenotypes, which also independently associated with poorer recurrence-free survival and overall survival after curative hepatectomy. Conclusively, our results indicate that BAP1, significantly downregulated, somatically mutated and negatively regulating EMT in HCC, serves as a tumor suppressor of HCC by deubiquitinating and stabilizing PTEN.     

Exceeding 30 ELNs is strongly recommended for pT3-4N0 patients with gastric cancer: A multicenter study of survival,recurrence, and prediction model

The argument concerning the exact minimum number of examined lymph nodes (ELNs) has continued for a long time among various regions, and no consensus has been reached for stratified pathological T stages for data to date. Data from 4607 pN0 patients with gastric cancer were analyzed. Kaplan-Meier analysis showed the similar overall survival (OS) outcomes among the 3 groups (ELNs ≤ 15, 16 ≤ ELNs ≤ 29 and ELNs ≥ 30, P = .171). However, the ELNs ≥ 30 group had a better disease-free survival (DFS) outcome compared with the others (all P < .05). An increased ELN group (ELNs ≥ 30) showed an improved OS only for pT3 patients (hazard ratio [HR] = 0.397, 95% confidence interval (CI): 0.182-0.866, P = .020), while an improved DFS for pT3 patients (HR = 0.362, 95%CI: 0.152-0.860, P = .021) and pT4 patients (HR = 0.484, 95%CI: 0.277-0.844, P = .011) in the multivariate analysis. A well discriminated and calibrated nomogram was constructed to predict the probability of the OS and DFS, with the C-index for OS and DFS prediction of 0.782 (95%CI: 0.735 to 0.829) and 0.738 (95%CI: 0.685 to 0.791), respectively. This study provides new and useful insights into the impact of ELN count on reducing stage migration and postoperative recurrence of pN0 patients with gastric cancer in 2000-2017. In conclusion, a larger number of ELNs is suggested for surgeons to prolong the prognosis of pN0 gastric cancer, especially for pT3 patients.     

Prediction model for malignant pulmonary nodules based on cfMeDIP-seq and machine learning

Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a new bisulfite-free technique, which can detect the whole-genome methylation of blood cell-free DNA (cfDNA). Using this technique, we identified differentially methylated regions (DMR) of cfDNA between lung tumors and normal controls. Based on the top 300 DMR, we built a random forest prediction model, which was able to distinguish malignant lung tumors from normal controls with high sensitivity and specificity of 91.0% and 93.3% (AUROC curve of 0.963). In summary, we reported a non–invasive prediction model that had good ability to distinguish malignant pulmonary nodules.     

Standardized Pathology Report for Breast Cancer

Given the recent advances in management and understanding of breast cancer, a standardized pathology report reflecting these changes is critical. To meet this need, the Breast Pathology Study Group of the Korean Society of Pathologists has developed a standardized pathology reporting format for breast cancer, consisting of ‘standard data elements,’ ‘conditional data elements,’ and a biomarker report form. The ‘standard data elements’ consist of the basic pathologic features used for prognostication, while other factors related to prognosis or diagnosis are described in the ‘conditional data elements.’ In addition to standard data elements, all recommended issues are also presented. We expect that this standardized pathology report for breast cancer will improve diagnostic concordance and communication between pathologists and clinicians, as well as between pathologists inter-institutionally.     

The Ability of Stroke Volume Variation Measured by a Noninvasive Cardiac Output Monitor to Predict Fluid Responsiveness in Mechanically Ventilated Children

Continuous noninvasive cardiac output monitoring (NICOM) is a clinically useful tool in the pediatric setting. This study compared the ability of stroke volume variation (SVV) measured by NICOM with that of respiratory variations in the velocity of aortic blood flow (△Vpeak) and central venous pressure (CVP) to predict of fluid responsiveness in mechanically ventilated children after ventricular septal defect repair. The study investigated 26 mechanically ventilated children after the completion of surgery. At 30 min after their arrival in an intensive care unit, a colloid solution of 10 ml/kg was administrated for volume expansion. Hemodynamic variables, including CVP, stroke volume, and △Vpeak in addition to cardiac output and SVV in NICOM were measured before and 10 min after volume expansion. The patients with a stroke volume increase of more than 15 % after volume expansion were defined as responders. The 26 patients in the study consisted of 13 responders and 13 nonresponders. Before volume expansion, △Vpeak and SVV were higher in the responders (both p values <0.001). The areas under the receiver operating characteristic curves of △Vpeak, SVV, and CVP were respectively 0.956 (95 % CI 0.885–1.00), 0.888 (95 % CI 0.764–1.00), and 0.331 (95 % CI 0.123–0.540). This study showed that SVV by NICOM and △Vpeak by echocardiography, but not CVP, reliably predicted fluid responsiveness during mechanical ventilation after ventricular septal defect repair in children.     

轻度慢性乙型肝炎患者脾胃湿热证的microRNAs研究

目的从micro RNAs调控角度揭示轻度慢性乙型肝炎脾胃湿热证发生的分子生物学机制。方法将符合标准的病例分为轻度慢性乙型肝炎无症状者组、轻度慢性乙型肝炎脾胃湿热证组,另设健康正常人组,空腹采集静脉血,借助Agilent Human mi RNA 8×60k微阵列芯片检测血浆中micro RNAs表达谱,运用SPSS19.0软件及在线SAS系统分析数据,求得各组间的差异表达micro RNAs谱(P0.05),借助mi RNA生物信息学分析软件Target Scan(V5.2)预测其靶基因并行靶基因功能富集分析。结果轻度慢性乙型肝炎脾胃湿热证的差异表达micro RNAs共60条(P0.05),26条上调,34条下调;2倍以上差异表达的micro RNAs23条,上调10条,其靶基因共500个,通过GO分析其功能主要涉及转录因子活性、免疫系统的发育、转运活动、细胞粘附等生命过程;下调13条,其靶基因共499个,通过GO分析其功能主要涉及转录因子活性、转移酶的活性、核酸结合、蛋白结合、转运、免疫系统的发育等生命过程。结论轻度慢性乙型肝炎脾胃湿热证存在特异性差异micro RNAs表达谱,涉及多个生命过程,揭示了轻度慢性乙型肝炎脾胃湿热证的分子机制。     

Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Deficiencies in vitamins or other factors (B6, B12, folic acid, betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (HHcy). HHcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. HHcy unleashes mediators of inflammation such as NFkB, IL-1β, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of HHcy. ER stress may also be involved in other liver diseases such as a1-antitrypsin (a1-AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans, and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease.     

西部高原地区基层中西医结合医疗卫生情况调查分析

目的:通过调查分析青海省西宁市大通县地区基层中西医结合医疗卫生实施情况,以期对西部高原多民族聚集地区的基层中西医结合医疗卫生发展有一定的指导作用。方法:根据现有文献资料,结合当地实际情况设计调查问卷,对青海大通地区居民进行基层中西医结合医疗情况问卷调查,统计分析数据。结果:目标人群对基层中西医结合医疗需要迫切,但需求未得到充分满足。结论:针对以青海大通县为代表的西部高原多民族聚集地区居民基层中西医结合医疗保障亟需加强的情况,应积极完善提高当地卫生医疗水平,推广中西医结合优势治疗,加大中医药治疗的力度等,以满足基层群众对高质量的中西医结合医疗卫生服务的迫切需求。     

鞣花酸抗S180,H22肿瘤及其抑制新生血管机制探讨

目的: 观察鞣花酸对S180,H22荷瘤小鼠肿瘤生长及微血管生成的影响,以及对血小板衍生因子B(PDGFB),转录激活因子-3(STAT3)及磷酸化STAT3(p-STAT3)基因和蛋白表达的影响,探讨其抗血管生成作用可能的机制。方法: SPF级昆明种小鼠100只,建立S180,H22皮下荷瘤小鼠2种模型,分别随机分为模型组(0.5% CMC溶液)、环磷酰胺组(阳性药,20 μg·g^-1·d^-1)、鞣花酸高、中、低(200,100,50 μg·g^-1·d^-1)剂量组,每组10只,连续给药ig 10 d,观察鞣花酸对荷瘤小鼠肿瘤生长、体重、胸腺指数及脾脏指数,免疫组化法检测肿瘤微血管密度,PDGFB,STAT3及p-STAT3的表达情况。结果: 鞣花酸高、中、低剂量组对S180小鼠抑瘤率分别为35.3%,10.6%,5.6%,对H22小鼠抑瘤率分别为36.3%,38.8%,20.6%,其对小鼠体重无明显影响;与模型组比较,高剂量组对S180,H22小鼠脾脏指数较模型组明显上升(P<0.05),鞣花酸高、中剂量组能明显降低S180,H22小鼠肿瘤微血管密度(P<0.05),鞣花酸高、中、低剂量组在S180,H22 2种瘤体中PDGFB,STAT3和p-STAT3的表达明显降低。结论: 鞣花酸抑制S180,H22荷瘤小鼠肿瘤生长及微血管形成,其机制可能与下调肿瘤组织中PDGFB表达并抑制下游STAT3的蛋白表达及磷酸化有关。