Brk is coamplified with ErbB2 to promote proliferation in breast cancer

Amplification of the receptor tyrosine kinase ErbB2 is frequently observed in breast cancer. Amplification of erbB2 is also associated with multiple genomic gains and losses; however, the importance of these associated changes is largely unknown. We demonstrate that Brk, a cytoplasmic tyrosine kinase, is coamplified and coexpressed with ErbB2 in human breast cancers. ErbB2 interacts with Brk and increases its intrinsic kinase activity. Expression of Brk enhances the ErbB2-induced activation of Ras/MAPK signaling and cyclin E/cdk2 activity to induce cell proliferation of mammary 3-dimensional acini in culture. In a murine model of breast cancer, expression of Brk was found to shorten the latency of ErbB2-induced tumors by promoting cell proliferation, with no effect on protection from apoptosis. Furthermore, overexpression of Brk conferred resistance to the ability of Lapatinib, an ErbB2 kinase inhibitor, to inhibit ErbB2-induced proliferation. Thus, we identified Brk as a drug target for ErbB2-positive cancers.     

抵抗素基因-420C>G位点多态性对脑出血患者血浆抵抗素水平的影响

目的探讨抵抗素基因-420C>G位点单核苷酸多态性对脑出血患者血浆抵抗素水平的影响。方法选取344例高血压性基底核出血患者,入院时抽取外周血提取DNA,采用聚合酶反应-限制性片断多态性分析基因型,同时采用ELISA法检测血浆抵抗素浓度,进行统计分析。结果酶切后可见抵抗素基因-420C>G位点有CC、CG和GG三种基因型,等位基因C和G的频率分别为71.08%和28.92%,基因型CC、CG和GG的频率依次为50.29%、41.57%和8.14%。经Hardy-Weinberg遗传平衡定律检验,各基因型频率符合遗传平衡。CC、CG和GG基因型患者血浆抵抗素浓度依次为(23.83±7.09)ng/mL、(26.54±7.32)ng/mL和(27.18±9.97)ng/mL。CC基因型患者血浆抵抗素均显著低于CG和GG基因型患者(P<0.01,P<0.05)。结论抵抗素基因-420C>G位点单核苷酸多态性显著影响脑出血患者血浆抵抗素水平,可能参与脑出血炎症反应。     

血清脂联素、抵抗素与冠状动脉病变程度的相关性研究

目的 测定冠心病患者血清脂联素(APN)、血清抵抗素(FSR),探讨二者与冠状动脉病变程度的关系.方法 将138 例进行冠状动脉造影检查的疑诊冠心病患者分为正常对照组、单支病变组、双支病变组和多支病变组.应用自动生化仪测定空腹血糖、高敏C反应蛋白(hsCRP),ELISA 法测定血清APN、FSR.结果 冠心病患者各亚组随着冠状动脉病变程度的增加,FSR增加,APN 水平下降.结论 血清 APN 和FSR与冠状动脉病变程度密切相关.     

北京市石景山区人群血浆抵抗素浓度变化与同期体重变化的关系

目的:探讨北京市石景山区人群血浆抵抗素浓度变化与同期体重变化的关系。方法:选取我们2005年和2010年两次在北京市石景山区调查的同一人群,心血管病危险因素资料完整的研究对象943例,其中男316例,女627例,男性平均年龄为(58.2±8.5)岁,女性平均年龄为(59.3±7.5)岁。按照两次调查测定血浆抵抗素浓度变化的4分位数将943例研究对象分为:≤-0.66 mmol/L组(n=239)、-0.67~0.25 mmol/L组(n=233)、0.26~1.24 mmol/L组(n=235)和≥1.25 mmol/L组(n=236)。运用Pearson相关及多元线性回归等统计学方法,分析血浆抵抗素浓度变化与同期的体重变化指标之间的关系。结果:单因素相关分析显示,女性血浆抵抗素浓度变化与体重变化百分比、体重指数变化量及其变化百分比、腰围变化量及其变化百分比均显著相关(相关系数分别为0.1173、0.1521、0.1412、0.1228、0.1057,P均0.05),男性均不显著(P均0.05)。多元线性回归分析:在调整基线变量因素后,女性血浆抵抗素浓度变化与体重变化量及其变化百分比、体重指数变化量及其变化百分比、腰围变化量及其变化百分比均显著相关(回归系数分别为0.0261与0.2916、0.2157与0.3072和0.0532与0.2738,P均0.05),男性均不显著(P均0.05)。结论:女性血浆抵抗素浓度的变化与同期体重变化之间存在显著相关,而男性相关不显著。     

Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression

AIM: To investigate the expression pattern of clusterin in colorectal adenoma-carcinoma-metastasis series,and to explore the potential role of clusterin in multistage colorectal tumorigenesis and progression. METHODS: A colorectal carcinoma (CRC)-tissue microarray (TMA), which contained 85 advanced CRCs including 43 cases of Dukes B,21 of Dukes C and 21 of Dukes D tumors, were used for assessing the expression of clusterin (clone 41D) and tumor cell apoptotic index (AI) by immunohist-ochemistry and TUNEL assay,respectively.Moreover the potential correlation of dusterin expression with the patient's clinical-pathological features were also examined. RESULTS: The positive staining of clusterin in different colorectal tissues was primarily a cytoplasmic pattern. Cytoplasmic overexpression of clusterin was detected in none of the normal colorectal mucosa, 17% of the adenomas, 46% of the primary CRCs, and 57% of the CRC metastatic lesions. In addition, a significant positive correlation between overexpression of clusterin and advanced clinical (Dukes) stage was observed (P<0.01).Overexpression of cytoplasmic clusterin in CRCs was inversely correlated with tumor apoptotic index (P<0.01),indicating the anti-apoptotic function of cytoplasmic clusterin in CRCs. CONCLUSION:These data suggests that overexpression of cytoplasmic dusterin might be involved in the tumorigenesis and/or progression of CRCs. The anti-apoptotic function of cytoplasmic dusterin may be responsible, at least in part, for the development and biologically aggressive behavior of CRC.     

高脂大鼠抵抗素基因的上调表达及与胰岛素、瘦素的相关性

目的 观察SD大鼠高脂饮食状态下脂肪组织中抵抗素的表达及其与胰岛素抵抗以及糖尿病、瘦素等的关系。方法 采用RT—PCR、割胶纯化、基因构建测序的方法，证实为目的片段后，对高脂饮食SD大鼠的脂肪组织进行mRNA抽提，再以此为模板进行半定量RT—PCR扩增及Northern印迹分析。同时检测血清中胰岛素、瘦素水平，并行糖耐量试验、胰岛素释放试验等。结果 (1)成功构建了抵抗素的基因，并经测序证实。(2)与对照组相比，高脂饮食组大鼠脂肪组织中抵抗素表达明显升高，血糖水平、胰岛素水平以及瘦素水平升高。(3)高脂饮食组大鼠在4个月时下丘脑中瘦素受体表达较对照组明显降低。结论 抵抗素表达量的变化与饮食有关，抵抗素可能是胰岛素抵抗、糖尿病发病的一个前期信号，其作用可能与瘦素、瘦素受体有一定关系。     

老年高血压患者血浆抵抗素水平与胰岛素抵抗的相关性

目的了解老年高血压患者血浆抵抗素水平与胰岛素抵抗的关系。方法选择41例中青年人(对照组)和43例老年人(老年组),分别分为高血压组和正常血压组,用竞争性酶联免疫吸附试验测定各组空腹血浆抵抗素水平,同时测定空腹血糖、空腹胰岛素、血脂和胰岛素敏感指数,测量受试对象腰围、臀围和腰臀比。结果老年组血浆抵抗素水平与对照组相比明显升高(P<0.05),老年组中高血压亚组血浆抵抗素与正常血压亚组相比差异无显著性。对照组高血压亚组抵抗素水平略高于正常血压亚组,但差异无统计学意义(P>0.05)。抵抗素与年龄呈正相关(r=0.31,P<0.01;r=0.28,P<0.05),与体质指数呈正相关(r=0.23,P<0.05),与胰岛素抵抗指数呈负相关(r=-0.31,P<0.05),但在各实验组中,抵抗素与体质指数无明显相关性。结论空腹血浆抵抗素水平与年龄和体质指数呈正相关,与胰岛素抵抗指数呈负相关。     

抵抗素基因420G/G基因型与高血压发病年龄相关

目的 研究在中国北方汉族人群中抵抗素基因5'末端启动子区g-420 C>G多态性与高血压发病年龄的相关性.方法 选取高血压病组121例,其中年龄<40岁的43例,年龄≥40岁的78例,对照组92例,其中年龄<40岁的42例,年龄≥40岁的50例,采用聚合酶链反应-限制性片长多态性方法分析抵抗素420 C/G多态性基因型.结果 高血压痛患者中,年轻患者的抵抗素基因420 G/G基因型频率高于年长组(P=0.006),其与发病年龄相关;年龄<40岁的年轻人群中,高血压病患者的抵抗素基因420 G/G基因型频率也显著高于对照组(P=0.001),其与高血压病发病相关.结论 高血压病青年发病与抵抗素基因420 G/G基因型相关.     

Resistin is not an appropriate biochemical marker to predict severity of acute pancreatitis: A case-controlled study

AIM: To assess levels of serum resistin upon hospital admission as a predictor of acute pancreatitis (AP) severity.METHODS: AP is both a common and serious disease, with severe cases resulting in a high mortality rate. Several predictive inflammatory markers have been used clinically to assess severity. This prospective study collected data from 102 patients who were diagnosed with an initial acute biliary pancreatitis between March 2010 and February 2013. Measurements of body mass index (BMI) and waist circumference (WC) were obtained and serum resistin levels were analyzed at the time of hospital admission using enzyme-linked immunosorbent assay. Additionally, resistin levels were measured from a control group after matching gender, BMI and age.RESULTS: A total of 102 patients (60 females and 42 males) were diagnosed with acute gallstone-induced pancreatitis. The mean age was 45 years, and mean BMI value was 30.5 kg/m² (Obese, class I). Twenty-two patients (21.6%) had severe AP, while eighty-eight patients had mild pancreatitis (78.4%). Our results showed that BMI significantly correlated with pancreatitis severity (P = 0.007). Serum resistin did not correlate with BMI, weight or WC. Furthermore, serum resistin was significantly higher in patients with AP compared to control subjects (P < 0.0001). The mean resistin values upon admission were 17.5 ng/mL in the severe acute biliary pancreatitis group and 16.82 ng/mL in the mild AP group (P = 0.188), indicating that resistin is not an appropriate predictive marker of clinical severity.CONCLUSION: We demonstrate that obesity is a risk factor for developing severe AP. Further, although there is a correlation between serum resistin levels and AP at the time of hospital admission, resistin does not adequately serve as a predictive marker of clinical severity.     

2型糖尿病患者血浆脂联素和抵抗素水平的测定及意义

为探讨2型糖尿病患者血浆脂联素和抵抗素水平的变化及意义。将60例2型糖尿病患者分为非肥胖糖尿病组30例(体质指数<25kg/m2)和肥胖糖尿病组30例(体质指数>25kg/m2);并选择28例健康者作对照。用酶联免疫吸附检测法测空腹血浆脂联素和抵抗素浓度;并测定各组的空腹血糖、胰岛素和血脂的水平;根据HOMA稳态模型提出的公式,计算胰岛素抵抗指数和胰岛素敏感指数,分析各指标间的相关性。结果发现,①糖尿病各组血浆脂联素的水平明显低于对照组,且肥胖糖尿病组低于非肥胖组,差异有显著性(P<0.01)。②糖尿病各组血浆抵抗素的水平明显高于对照组,而且肥胖糖尿病组明显高于非肥胖组,差异有显著性(P<0.01)。③相关分析发现,血浆脂联素浓度与体质指数、空腹血糖、胰岛素抵抗指数和甘油三酯呈显著负相关(分别为r=-0.55,P<0.01;r=-0.51,P<0.01;r=-0.52,P<0.01;r=-0.39,P<0.05),而与胰岛素敏感指数呈显著正相关(r=0.45,P<0.01);抵抗素则与体质指数、空腹血糖、胰岛素抵抗指数和甘油三酯呈显著正相关(r=0.40,P<0.01;r=0.52,P<0.01;r=0.46,P<0.01;r=0.27,P<0.05);与胰岛素敏感指数)呈显著负相关(r=-0.32,P<0.01)。此结果提示,脂联素和抵抗素都参与了胰岛素抵抗的发生过程,可能与2型糖尿病的糖脂代谢紊乱有关。     

Insights into the role of genetic alterations in adrenocortical tumorigenesis

Whereas benign adrenocortical tumors are frequent in the population, adrenocortical carcinoma (ACC) is a rare cancer. Significant advances in the understanding of the pathogenesis of sporadic ACCs have been possible through the study of hereditary syndromes responsible for ACCs. The genetic alterations involved in these syndromes have also been found in sporadic ACCs. Several specific genes have been shown to be altered in sporadic ACCs. Despite these progresses, the underlying sequence(s) of events remains to be elucidated. Progressive transformation of a normal tissue into a benign tumor and ultimately into a carcinoma occurs via accumulation of genetic and epigenetic alterations. Likewise, a multistage model has been proposed for the adrenal tumor development. This review summarizes the molecular alterations likely involved in the multistage tumorigenesis and describes a mouse model which allows us to evaluate the effect of individual genes or combination of genes in the development of adrenocortical tumors.     

A paradox： Insulin inhibits expression and secretion of resistin which induces insulin resistance

AIM： To confirm whether insulin regulates resistin expression and secretion during differentiation of 3T3-L1 preadipocytes and the relationship of resistin with insulin resistance both in vivo and in vitro. METHODS： Supernatant resistin was measured during differentiation of 3T3-L1 preadipocytes. L6 rat myoblasts and hepatoma cell line H4IIE were used to confirm the cellular function of resistin. Diet-induced obese rats were used as an insulin resistance model to study the relationship of resistin with insulin resistance. RESULTS： Resistin expression and secretion were enhanced during differentiation 3T3-L1 preadipocytes. This cellular differentiation stimulated resistin expression and secretion, but was suppressed by insulin. Resistin also induced insulin resistance in H4IIE hepatocytes and L6 myoblasts. In diet-induced obese rats, serum resistin levels were negatively correlated with insulin sensitivity, but not with serum insulin. CONCLUSION： Insulin can inhibit resistin expression and secretion in vitro, but insulin is not a major regulator of resistin in vivo. Fat tissue mass affects insulin sensitivity by altering the expression and secretion of resistin.     

Differential effects of phorbol ester tumor promoters on 3-methylcholanthrene-induced epithelial and mesenchymal skin tumorigenesis

Summary The effects of TPA, PDD, PDB, PDA, or MEZ on epithelial and mesenchymal skin tumors induced by a s.c. injection of MCA were studied histologically. Group-I mice received only MCA. At 6 weeks after MCA injection, mice in groups II to VII received acetone, 1.8 nmol TPA, PDD, PDB, PDA, or 6.1 nmol MEZ respectively in 0.1 ml acetone twice weekly until tumor development. Alterations in skin tumor induction patterns were also studied in animals that had been exposed to TPA or acetone for 10 weeks prior to s.c. injection of MCA. Exposure of mouse skin to TPA before or after carcinogen administration increased 2- to 3.5-fold, the incidence of carcinoma and mixed tumors of epithelial and mesenchymal histogenesis. The average time of tumor induction decreased in mice treated with MCA+TPA and 100% of the test animals in the TPA+MCA group developed tumors. In contrast, TPA-related phorbol esters inhibited skin tumor development, particularly trichoepithelioma and fibrosarcoma and increased the average time of tumor induction.Abbreviations MCA 3-methylcholanthrene - TPA 12-O-tetradecanoylphorbol-13-acetate - PDD phorbol didecanoate - PDB phorbol dibenzoate - PDA phorbol diacetate - MEZ mezerein     

Resistin as a predictor of cardiovascular hospital admissions and renal deterioration in diabetic patients with chronic kidney disease

BackgroundHigh resistin levels have been associated with cardiovascular disease (CVD). Cardiovascular hospitalizations are common, especially in diabetic and renal impaired patients. The purpose of this study is to determine the role of serum resistin as a predictor of cardiovascular hospitalizations in type 2 diabetic patients with mild to moderate chronic kidney disease (CKD).MethodsWe conducted a prospective, observational study. 78 diabetic patients with mild to moderate CKD and no previous CVD were included. The population was divided in two groups: G-1 with cardiovascular related admission (n = 13) and G-2 without cardiovascular related admission (n = 65). A Student's t-test was conducted to determine correlations between laboratory findings and hospitalization. We used logistic regression to assess predictors of cardiovascular events requiring hospitalization and Cox regression to identify predictors of end-stage renal disease (ESRD).ResultseGFR, albumin, HbA1c, phosphorous, PTH, IR, CRP, resistin and active vitamin D, were related to cardiovascular admissions. In a multivariate regression model, resistin (OR = 2.074, p = 0.047) was an independent predictor of cardiovascular hospitalization. Cox regression showed that resistin (HR = 1.931, p = 0.031) and UACr (HR = 1.151, p = 0.048) were also independent predictors of renal disease progression.ConclusionResistin demonstrated to be valuable in predicting hospital admissions and progression to ESRD.