Increased WD-repeat containing protein 1 in interstitial fluid from ovarian carcinomas shown by comparative proteomic analysis of malignant and healthy gynecological tissue

We aimed to identify differentially expressed proteins in interstitial fluid from ovarian cancer employing multiple fractioning and high resolution mass spectrometry-based proteomic analysis, and asked whether specific proteins that may serve as biomarker candidates or therapeutic targets could be identified. High throughput proteomics was conducted on immunodepleted and fractioned interstitial fluid from pooled samples of ovarian carcinomas, using endometrial carcinomas and healthy ovarian tissue as controls. Differential analysis revealed the up-regulation of extracellular proteasomes in tumor interstitial fluid compared to the healthy control. Moreover, a number of differentially expressed proteins in interstitial fluid from ovarian carcinomas compared with control tissues were identified. Detection of proteasome 20S related proteins in TIF compared to IF from healthy tissue indicates that the 20S proteasome can have a role in the tumor microenvironment. Six selected proteins, CEACAM5, FREM2, MUC5AC, TFF3, PYCARD and WDR1, were independently validated in individual tumor lysates from ovarian carcinomas by multiple reaction monitoring initiated detection and sequence analysis, Western blot and/or selected reaction monitoring. Quantification of specific proteins revealed substantial heterogeneity between individual samples. Nevertheless, WD repeat-containing protein 1 was confirmed as being significantly overexpressed in interstitial fluid from ovarian carcinomas compared to healthy ovarian tissue by Orbitrap analysis of individual native interstitial fluid from ovarian and endometrial carcinomas and healthy ovarian tissue. We suggest that this protein should be explored as a therapeutic target in ovarian carcinomas. This article is part of a Special Issue entitled: An Updated Secretome.     

阶段变化护理干预对慢性肾功能衰竭血液透析患者生活质量的影响

目的：探究阶段变化护理干预对慢性肾功能衰竭血液透析患者生活质量的影响。方法：选取2010年8月至2012年8月我院收治因慢性肾功能衰竭行血液透析的患者72例,采用随机的方法将其分为对照组和观察组,每组36例。对照组患者采取常规护理,观察组在对照组基础上采用阶段变化护理干预,观察比较两组患者的护理效果。结果：两组患者经护理后生活质量均有显著提高,对照组患者的总体生活质量为11.41±1.87,观察组患者的总体生活质量为12.47±2.33。观察组患者的总体生活质量明显高与对照组,存在显著差异,具有统计学意义（P〈0.05）。结论：采取阶段变化护理干预,可以大大提高慢性肾功能衰竭血液透析患者的生活质量,促进患者病情的改善,值得临床借鉴使用。     

The role of EMMPRIN expression in ovarian epithelial carcinomas

Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of ovarian epithelial carcinomas.

Methods: EMMPRIN siRNA were transfected into ovarian carcinoma cells with the phenotypes and their related molecules examined. EMMPRIN expression was determined in ovarian normal tissue, benign and borderline tumors, and epithelial carcinomas by real-time PCR, western blot, and immunohistochemisty.

Results: EMMPRIN siRNA treatment resulted in a lower growth, G₁ arrest, apoptotic induction, decreased migration, and invasion. The transfectants showed reduced expression of Wnt5a, Akt, p70s6k, Bcl-xL, survivin, VEGF, and MMP-9 than mock and control cells at both mRNA and protein levels. According to real-time PCR and western blot, EMMPRIN mRNA or protein level was higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumors (P < 0.05), and positively correlated with dedifferentiation and FIGO staging (P < 0.05). Immuhistochemically, EMMPRIN expression was positively correlated with FIGO staging, dedifferentiation, Ki-67 expression, the lower cumulative and relapse-free survival rate (P < 0.05).

Conclusions: Upregulated expression of EMMPRIN protein and mRNA might be involved in the pathogenesis, differentiation, and progression of ovarian carcinomas, possibly by modulating cellular events, such as proliferation, cell cycle, apoptosis, migration, and invasion.     

Hereditary ovarian cancer and two-compartment tumor metabolism

Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary ovarian cancers. Here, we used a co-culture approach to study the metabolic effects of BRCA1-null ovarian cancer cells on adjacent tumor-associated stromal fibroblasts. Our results directly show that BRCA1-null ovarian cancer cells produce large amounts of hydrogen peroxide, which can be abolished either by administration of simple antioxidants (N-acetyl-cysteine; NAC) or by replacement of the BRCA1 gene. Thus, the BRCA1 gene normally suppresses tumor growth by functioning as an antioxidant. Importantly, hydrogen peroxide produced by BRCA1-null ovarian cancer cells induces oxidative stress and catabolic processes in adjacent stromal fibroblasts, such as autophagy, mitophagy and glycolysis, via stromal NFκB activation. Catabolism in stromal fibroblasts was also accompanied by the upregulation of MCT4 and a loss of Cav-1 expression, which are established markers of a lethal tumor microenvironment. In summary, loss of the BRCA1 tumor suppressor gene induces hydrogen peroxide production, which then leads to metabolic reprogramming of the tumor stroma, driving stromal-epithelial metabolic coupling. Our results suggest that new cancer prevention trials with antioxidants are clearly warranted in patients that harbor hereditary/familial BRCA1 mutations.     

Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition

Inhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppress the growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations in EZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2. Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important to investigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the current study, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells that overexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOC cells with GSK343, a specific inhibitor of EZH2 methyltransferase, decreases the level of H3K27Me3, the product of EZH2’s enzymatic activity. However, GSK343 exhibited limited effects on the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343 significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix (ECM), which more closely mimics the tumor microenvironment in vivo. Notably, GSK343 induces apoptosis of EOC cells in 3D but not 2D culture. In addition, GSK343 significantly inhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cells to EZH2 methyltransferase inhibition, which suppresses cell growth, induces apoptosis and inhibits invasion. Our findings imply that in EZH2 wild-type solid tumors, the ECM tumor microenvironment plays an important role in determining sensitivity to EZH2 inhibition and suggest that targeting the ECM represents a novel strategy for enhancing EZH2 inhibitor efficacy.     

序贯机械通气联合尼可刹米治疗AECOPD合并Ⅱ型呼吸衰竭的临床观察

目的：观察序贯机械通气联合尼可刹米在慢性阻塞性肺疾病急性加重期（AECOPD）合并Ⅱ型呼吸衰竭中的的临床疗效及安全性。方法：按照随机原则将64例AECOPD合并Ⅱ型呼吸衰竭分成两组,对照组32例给予常规有创机械通气,治疗组患者给予序贯机械通气联合尼可刹米治疗,对两组治疗前、后24 h和48h的pH值、PaO2、PaCO2以及VAP、总机械通气时间、ICU时间,总住院时间,再插管率以及死亡率进行评价。结果：治疗组与对照组相比,pH值改善明显、PaO2明显增长、PaCO2下降显著,有统计学差异（P〈0.05）;治疗组ICU时间,总住院时间,再插管率以及死亡率与对照组相比,下降明显,有统计学差异（P〈0.05）。结论：序贯机械通气联合尼可刹米治疗AECOPD合并Ⅱ型呼吸衰竭的临床疗效确切,值得临床推广。     

组织多普勒成像对慢性心力衰竭患者再入院的预测研究

目的:探讨TDI的时间间隔在评价慢性心力衰竭(chronic heart failure,CHF)患者再入院中的价值.方法:选择2010年4月～2012年2月于我院心内科住院或门诊的162例CHF患者,进行超声心动图检查评估,并进行随访,平均287±196天.记录常规超声心动指标和TDI时间间隔指标包括收缩时间ST、射血时间ET、充盈时间FT、等容收缩时间ICT、并计算ICT/ET和心肌组织性能指标([ICT+IRT]/ET).结果:单因素分析结果显示,TDI时间间隔参数如ET、ST、FT和ICT/ET,与CHF患者随访期间再住院的发生显著相关P＜0.05.非条件多因素logistic回归分析,ET和ST是CHF患者再入院的危险因素P＜0.05和P＜0.01.结论:TDI评估的时间间隔有助于预测受试者与慢性心力衰竭患者再住院的风险.     

Galectin 3 complements BNP in risk stratification in acute heart failure

Background: Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure.

Methods: Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial.

Results: Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide.

Conclusion: In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.