Whole Blood Gene Expression Profiles of Patients with a Past Aneurysmal Subarachnoid Hemorrhage

BackgroundThe pathogenesis of development and rupture of intracranial aneurysms (IA) is largely unknown. Also, screening for IA to prevent aneurysmal subarachnoid hemorrhage (aSAH) is inefficient, as disease markers are lacking. We investigated gene expression profiles in blood of previous aSAH patients, who are still at risk for future IA, aiming to gain insight into the pathogenesis of IA and aSAH, and to make a first step towards improvement of aSAH risk prediction.ConclusionsNo gene expression differences were present in blood of previous aSAH patients compared to controls, besides one differentially co-expressed gene network without a clear relevant biological function. Our findings suggest that gene expression profiles, as detected in blood of previous aSAH patients, do not reveal the pathogenesis of IA and aSAH, and cannot be used for aSAH risk prediction.     

MicroRNA Expression Profiles of Whole Blood in Lung Adenocarcinoma

The association of lung cancer with changes in microRNAs in plasma shown in multiple studies suggests a utility for circulating microRNA biomarkers in non-invasive detection of the disease. We examined if presence of lung cancer is reflected in whole blood microRNA expression as well, possibly because of a systemic response. Locked nucleic acid microarrays were used to quantify the global expression of microRNAs in whole blood of 22 patients with lung adenocarcinoma and 23 controls, ten of whom had a radiographically detected non-cancerous lung nodule and the other 13 were at high risk for developing lung cancer because of a smoking history of >20 pack-years. Cases and controls differed significantly for age with a mean difference of 10.7 years, but not for gender, race, smoking history, blood hemoglobin, platelet count, or white blood cell count. Of 1282 quantified human microRNAs, 395 (31%) were identified as expressed in the study’s subjects, with 96 (24%) differentially expressed between cases and controls. Classification analyses of microRNA expression data were performed using linear kernel support vector machines (SVM) and top-scoring pairs (TSP) methods, and classifiers to identify presence of lung adenocarcinoma were internally cross-validated. In leave-one-out cross-validation, the TSP classifiers had sensitivity and specificity of 91% and 100%, respectively. The values with SVM were both 91%. In a Monte Carlo cross-validation, average sensitivity and specificity values were 86% and 97%, respectively, with TSP, and 88% and 89%, respectively, with SVM. MicroRNAs miR-190b, miR-630, miR-942, and miR-1284 were the most frequent constituents of the classifiers generated during the analyses. These results suggest that whole blood microRNA expression profiles can be used to distinguish lung cancer cases from clinically relevant controls. Further studies are needed to validate this observation, including in non-adenocarcinomatous lung cancers, and to clarify upon the confounding effect of age.     

Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer

Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.     

5-氟尿嘧啶敏感与非敏感的人胃癌BGC-823细胞基因表达谱差异分析

利用化疗药物5-氟尿嘧啶(5-Fu)对胃癌细胞株进行筛选和诱导,建立具有耐药性的胃癌细胞株.与亲代细胞株对比生长特性及基因表达谱,初步探讨胃癌细胞的耐药机制.采用四唑盐比色法(MTT)测定5-Fu对胃癌细胞株BGC-823的半数抑制浓度(IC50);根据IC50设计5-Fu剂量,用大剂量的5-Fu逐渐递增间歇给药的方法,反复筛选,获得5株胃癌耐药细胞株.比较耐药细胞株和亲本细胞株的形态和生长特性,继而再用人类肿瘤基因芯片(human cancer arrays)比较测试亲本与耐药细胞株的基因表达谱差异;对其中189个上调基因和133个下调基因采用Gene Ontology中的BP(Biological Process)分析这些基因相关的功能,并用MAS2.0分析这些基因可能涉及的信号通路.结果提示,胃癌细胞株耐药(5-Fu)相关基因可能与转录因子信号转导、TNF受体介导的细胞凋亡和抗凋亡、细胞周期调节、细胞粘附及MAP激酶类的功能相关.对细胞周期、信号转导相关的6个基因采用定量PCR验证,结果与基因表达芯片结果一致.上述结果有利于进一步发现胃癌细胞的耐药基因和相关信号通路,探索抗胃癌治疗的耐药机制.     

Altered Clock Gene Expression in Obese Visceral Adipose Tissue Is Associated with Metabolic Syndrome

Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21–25 kg/m²; n = 21) and morbidly obese women (BMI >40 kg/m²; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.     

Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor

Threatened preterm labor (TPTL) is defined as persistent premature uterine contractions between 20 and 37 weeks of gestation and is the most common condition that requires hospitalization during pregnancy. Most of these TPTL women continue their pregnancies to term while only an estimated 5% will deliver a premature baby within ten days. The aim of this work was to study differential whole blood gene expression associated with spontaneous preterm birth (sPTB) within 48 hours of hospital admission. Peripheral blood was collected at point of hospital admission from 154 women with TPTL before any medical treatment. Microarrays were utilized to investigate differential whole blood gene expression between TPTL women who did (n = 48) or did not have a sPTB (n = 106) within 48 hours of admission. Total leukocyte and neutrophil counts were significantly higher (35% and 41% respectively) in women who had sPTB than women who did not deliver within 48 hours (p<0.001). Fetal fibronectin (fFN) test was performed on 62 women. There was no difference in the urine, vaginal and placental microbiology and histopathology reports between the two groups of women. There were 469 significant differentially expressed genes (FDR<0.05); 28 differentially expressed genes were chosen for microarray validation using qRT-PCR and 20 out of 28 genes were successfully validated (p<0.05). An optimal random forest classifier model to predict sPTB was achieved using the top nine differentially expressed genes coupled with peripheral clinical blood data (sensitivity 70.8%, specificity 75.5%). These differentially expressed genes may further elucidate the underlying mechanisms of sPTB and pave the way for future systems biology studies to predict sPTB.     

Relationships of Hair Mineral Concentrations with Insulin Resistance in Metabolic Syndrome

Mineral deficiencies can cause impaired insulin release and insulin resistance. This study was conducted to investigate the relationship between hair mineral concentrations and insulin resistance in patients with metabolic syndrome (MS). A total of 456 subjects (161 patients with MS and 295 subjects without MS) were reviewed, and fasting plasma glucose, triglycerides, HDL-cholesterol, homeostasis assessment model-insulin resistance (HOMA-IR), and hair mineral concentrations were analyzed. While hair sodium and potassium concentrations were significantly higher, the hair calcium, magnesium, and zinc concentrations were lower in the MS group than in the control group. Regarding toxic element measurements, the hair arsenic (As) and lead (Pb) concentrations were higher in the MS group than in the control group. The results of multiple regression analysis, after adjusting for age, showed significant relationships between the Na/Mg and Ca/P ratios and HOMA-IR (R ²?=?0.109, p?<?0.05). The Ca, Na, K, and B concentrations were also associated with HOMA-IR (R ²?=?0.116, p?<?0.05). The hair Na concentration was significantly associated with MS, even after adjusting for age, visceral adipose tissue, and HOMA-IR (OR 1.020; 95 % CI 1.001–1.040; p?=?0.036). Our findings suggest that hair mineral concentrations, such as calcium, magnesium, zinc, sodium, and potassium concentrations, may play a role in the development of insulin resistance.     

Diagnosis of Partial Body Radiation Exposure in Mice Using Peripheral Blood Gene Expression Profiles

In the event of a terrorist-mediated attack in the United States using radiological or improvised nuclear weapons, it is expected that hundreds of thousands of people could be exposed to life-threatening levels of ionizing radiation. We have recently shown that genome-wide expression analysis of the peripheral blood (PB) can generate gene expression profiles that can predict radiation exposure and distinguish the dose level of exposure following total body irradiation (TBI). However, in the event a radiation-mass casualty scenario, many victims will have heterogeneous exposure due to partial shielding and it is unknown whether PB gene expression profiles would be useful in predicting the status of partially irradiated individuals. Here, we identified gene expression profiles in the PB that were characteristic of anterior hemibody-, posterior hemibody- and single limb-irradiation at 0.5 Gy, 2 Gy and 10 Gy in C57Bl6 mice. These PB signatures predicted the radiation status of partially irradiated mice with a high level of accuracy (range 79–100%) compared to non-irradiated mice. Interestingly, PB signatures of partial body irradiation were poorly predictive of radiation status by site of injury (range 16–43%), suggesting that the PB molecular response to partial body irradiation was anatomic site specific. Importantly, PB gene signatures generated from TBI-treated mice failed completely to predict the radiation status of partially irradiated animals or non-irradiated controls. These data demonstrate that partial body irradiation, even to a single limb, generates a characteristic PB signature of radiation injury and thus may necessitate the use of multiple signatures, both partial body and total body, to accurately assess the status of an individual exposed to radiation.     

代谢调衡饮对代谢综合征胰岛素抵抗的影响

目的:初步探讨代谢调衡饮对代谢综合征胰岛素抵抗的影响。方法:将60例代谢综合征患者随机分为试验组和对照组,对照组口服卡托普利和二甲双胍,试验组在此基础上加服代谢调衡饮,疗程3个月。结果:两组各个时间点的血糖和HbA1c与治疗前相比,均有显著下降(P<0.01);显著降低空腹、糖负荷后0.5h、1h、2h、3h胰岛素水平(P<0.01),与对照组相比,试验组降低糖负荷后0.5h胰岛素水平更具优势(P<0.01);明显降低HOMA-IR,升高ISI。结论:代谢调衡饮对于改善代谢综合征患者的胰岛素抵抗具有一定疗效。     

表达谱基因芯片

表达谱基因芯片具有高通量、缩微、多参数、平行化等优点.在功能基因组学研究中正发挥越来越重要的作用.就其原理、应用、存在问题及解决策略等进行了综述.