Arriel Benis

Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects

Adipose tissue produces inflammation and immunity molecules suspected to be involved in obesity‐related complications. The pattern of expression and the nutritional regulation of these molecules in humans are poorly understood. We analyzed the gene expression profiles of subcutaneous white adipose tissue from 29 obese subjects during very low calorie diet (VLCD) using cDNA microarray and reverse transcription quantitative PCR. The patterns of expression were compared with that of 17 non‐obese subjects. We determined whether the regulated genes were expressed in adipocytes or stromavascular fraction cells. Gene expression profiling identified 100 inflammation‐related transcripts that are regulated in obese individuals when eating a 28 day VLCD but not a 2 day VLCD. Cluster analysis showed that the pattern of gene expression in obese subjects after 28 day VLCD was closer to the profile of lean subjects than to the pattern of obese subjects before VLCD. Weight loss improves the inflammatory profile of obese subjects through a decrease of proinflammatory factors and an increase of anti‐inflammatory molecules. The genes are expressed mostly in the stromavascular fraction of adipose tissue, which is shown to contain numerous macrophages. The beneficial effect of weight loss on obesity‐related complications may be associated with the modification of the inflammatory profile in adipose tissue.— Clément, K., Viguerie, N., Poitou, C., Carette, C., Pelloux, V., Curat, C. A., Sicard, A., Rome, S., Benis, A., Zucker, J.‐D., Vidal, H., Laville, M., Barsh, G. S., Basdevant, A., Stich, V., Cancello R., Langin, D. Weight loss regulates inflammation‐related genes in white adipose tissue of obese subjects. FASEB J. 18, 1657–1669 (2004)

Cathepsin S, a novel biomarker of adiposity: relevance to atherogenesis

The molecular mechanisms by which obesity increases the risk of cardiovascular diseases are poorly understood. The purpose of this study was to identify candidate biomarkers overexpressed in adipose tissue of obese subjects that could link expanded fat mass to atherosclerosis. We compared gene expression profile in subcutaneous adipose tissue (scWAT) of 28 obese and 11 lean subjects using microarray technology. This analysis identified 240 genes significantly overexpressed in scWAT of obese subjects. The genes were then ranked according to the correlation between gene expression and body mass index (BMI). In this list, the elastolytic cysteine protease cathepsin S was among the highly correlated genes. RT‐PCR and Western blotting confirmed the increase in cathepsin S mRNA (P=0.006) and protein (P<0.05) in obese scWAT. The circulating concentrations of cathepsin S were also significantly higher in obese than in nonobese subjects (P<0.0001). Both cathepsin S mRNA in scWAT and circulating levels were positively correlated with BMI, body fat, and plasma triglyceride levels. In addition, we show that the proinflammatory factors, lipopolysaccharide, interleukin‐lβ, and tumor necrosis factor‐α increase cathepsin S secretion in human scWAT explants. This study identifies cathepsin S as a novel marker of adiposity. Since this enzyme has been implicated in the development of atherosclerotic lesions, we propose that cathepsin S represents a molecular link between obesity and atherosclerosis.

Improving classification of microarray data using prototype-based feature selection

This paper addresses the problem of improving accuracy in the machine-learning task of classification from microarray data. One of the known issues specifically related to microarray data is the large number of inputs (genes) versus the small number of available samples (conditions). A promising direction of research to decrease the generalization error of classification algorithms is to perform gene selection so as to identify those genes which are potentially most relevant for the classification. Classical feature selection methods are based on direct statistical methods. We present a reduction algorithm based on the notion of prototypegene. Each prototype represents a set of similar gene according to a given clustering method. We present experimental evidence of the usefulness of combining prototype-based feature selection with statistical gene selection methods for the task of classifying adenocarcinoma from gene expressions.

Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab

OBJECTIVE Bevacizumab is an antiangiogenic agent under investigation for use in patients with high-grade glioma. It produces a high rate of radiological response; however, this response should be interpreted with caution because it may reflect normalization of the tumor vasculature and not necessarily a true antitumor effect. The authors previously demonstrated that 4 hypoxia-mediated microRNAs (miRNA)-miR-210, miR-21, miR-10b, and miR-196b-are upregulated in glioma as compared with normal brain tissue. The authors hypothesized that the regulation and expression of these miRNAs would be altered in response to bevacizumab treatment. The object of this study was to perform longitudinal monitoring of circulating miRNA levels in patients undergoing bevacizumab treatment and to correlate it with tumor response. METHODS A total of 120 serum samples from 28 patients with high-grade glioma were prospectively collected prior to bevacizumab (n = 15) or temozolomide (TMZ; n = 13) treatment and then longitudinally during treatment. Quantification of the 4 miRNAs was evaluated by real-time polymerase chain reaction using total RNA extracted from the serum. At each time point, tumor response was assessed by Response Assessment in Neuro-Oncology criteria and by performing MRI using fluid attenuated inversion recovery (FLAIR) and contrast-enhanced images. RESULTS As compared with pretreatment levels, high levels of miR-10b and miR-21 were observed in the majority of patients throughout the bevacizumab treatment period. miR-10b and miR-21 levels correlated negatively and significantly with changes in enhancing tumor diameters (r = -0.648, p < 0.0001) in the bevacizumab group but not in the TMZ group. FLAIR images and the RANO assessment did not correlate with the sum quantification of these miRNAs in either group. CONCLUSIONS Circulating levels of miR-10b and miR-21 probably reflect the antiangiogenic effect of therapy, but their role as biomarkers for tumor response remains uncertain and requires further investigation.

Stimulant use for ADHD and relative age in class among children in Israel.

Diagnosis of children with attention‐deficit/hyperactivity disorder (ADHD) is increasing. The present study sought to identify characteristics and medication treatment patterns of children with ADHD and compare them by relative age in class, sex, ethnicity, family size, sibling order, and other socioeconomic status, as well as find trends in disparity of pharmacotherapy.

Obesity or smoking: Which factor contributes more to the incidence of myocardial infarction?

OBJECTIVE Comparing the contributions of smoking and obesity to the risk of myocardial infarction (MI) can help prioritize behavioral modifications. The objective of this study was to determine the relative risk of smoking, obesity and the joint burden on the risk of MI. METHODS This is a retrospective cohort study of data accessed from electronic medical records of the largest health care organization in Israel. The study population included all 738,380 members of Clalit Health Services, with at least one smoking status and one BMI assessment recorded in 2009 or 2010, aged 40-74years, who were MI-free before 2009. Obesity was defined as BMI >30kg/m(2). New and primary MI between January 1 and December 31, 2011 were recorded. RESULTS Rates of MI were: 0.18% for non-obese never smokers, 0.25% for obese never smokers, 0.40% for non-obese past smokers, 0.50% for obese past smokers, 0.53% for non-obese current smokers and 0.66% for obese current smokers. Among non-obese individuals, past smokers and current smokers had a greater risk of MI than did never smokers, after adjusting for age, gender and socioeconomic position (OR, 1.45; 95% CI, 1.23-1.70 and OR, 2.35; 95% CI, 2.10-2.63, respectively). The burden of obesity increased the risk of MI for never smokers but the burden of obesity did not elevate the risk of MI when combined with current or past smoking groups, after adjusting for comorbidities. CONCLUSIONS Past and, more so, current smoking confers greater risk for MI than obesity.

Sex-specific prediction of interferon beta therapy response in relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disorder predominantly affecting young people. Currently, interferon beta (IFNβ) is a common treatment for MS. Despite a large effort in recent years, valid biomarkers with predictive value for clinical outcome and response to therapy are lacking. In order to identify predictive biomarkers of response to IFNβ therapy in relapsing-remitting MS patients, we analyzed expression of 526 immune-related genes with the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) on total RNA extracted from peripheral blood mononuclear cells of 30 relapsing-remitting MS patients. We used a Wilcoxon signed-rank test to find an association between certain gene expression profiles and clinical responses to IFNβ. We compared the expression profile of patients who responded to IFNβ treatment (n=16) and non-responsive IFNβ patients (n=14). The analysis revealed that the expression of eight genes could differentiate between responsive and non-responsive men (p⩽0.005). This differentiation was not evident in women. We analyzed results from an additional cohort of 47 treated and untreated patients to validate the results and explore whether this eight gene cluster could also predict treatment response. Analysis of the validation cohort demonstrated that three out of the eight genes remained significant in only the treated men (p⩽0.05). Our findings could be used as a basis for establishing a routine test for objective prediction of IFNβ treatment response in male MS patients.

Biomarkers Discovery in Medical Genomics Data

This chapter presents a system, called DiscoCini, assisting the biology experts to explore medical genomics data. First, it computes all the correlations (based on ranks) between gene expression and bioclinical data. The amount of generated results is huge. In a second step, we propose an original visual approach to simply and efficiently explore these results. Thanks to sets of data generated during experiments in the field of the obesities genomics, we show how DiscoClini allows easily identification of complex disease biomarkers.

Categorizing gene expression correlations with bioclinical data: an abstraction based approach

Our research takes place in a bioinformatics team embedded in a biological unit where the biologists are using pangenomics cDNA chips to measure expression level of thousands of genes at a time. The goal of our research is to systematically categorize of relations between genes expression levels (1) and biomedical values to support finding of candidate genes allowing a better diagnostic of obesities and related diseases (2). A key issue in the analysis of cDNA chips is that the number of expression levels per chip is very high compared to the number of chips. We are working with 40 cDNA chips with ±40000 spots each one and with 2 biomedical parameters. One way used by biologists to discover relationships between these types of data consists in computing correlations for a small number of them based on their biological knowledge. To go beyond such a biased and manual selection, we propose to explore automatically combinations between all available bioclinical parameters with all gene expressions. These new data need to be classify to identify significant Linear Correlation Discoveries (3). Our method, DISCOCLINI, consists in using abstraction operators to remove outliers, approximation to define correlations and reformulation to describe and to cluster correlations by variations patterns.