Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

Targeting cancer metabolism: a therapeutic window opens

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.Burroughs Wellcome FundSmith Family FoundationStarr Cancer ConsortiumDamon Runyon Cancer Research FoundationNational Institutes of Health (U.S.

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Adverse Events in a Cohort of HIV Infected Pregnant and Non-Pregnant Women Treated with Nevirapine versus Non-Nevirapine Antiretroviral Medication

BACKGROUND: Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women. METHODOLOGY: AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses. PRINCIPAL FINDINGS: Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant. LEE: No significant difference was found between regimens in the development of new grade ≥2 LEE (p  =  0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p =  0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm(3) were not associated with this toxicity. RASH: NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14-6.76), as was baseline CD4 >250 cells/mm(3) when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19-6.02 p  =  0.017). CONCLUSIONS: CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication

Dual Energy X-Ray Absorptiometry Body Composition Reference Values from NHANES

In 2008 the National Center for Health Statistics released a dual energy x-ray absorptiometry (DXA) whole body dataset from the NHANES population-based sample acquired with modern fan beam scanners in 15 counties across the United States from 1999 through 2004. The NHANES dataset was partitioned by gender and ethnicity and DXA whole body measures of %fat, fat mass/height2, lean mass/height2, appendicular lean mass/height2, %fat trunk/%fat legs ratio, trunk/limb fat mass ratio of fat, bone mineral content (BMC) and bone mineral density (BMD) were analyzed to provide reference values for subjects 8 to 85 years old. DXA reference values for adults were normalized to age; reference values for children included total and sub-total whole body results and were normalized to age, height, or lean mass. We developed an obesity classification scheme by using estabbody mass index (BMI) classification thresholds and prevalences in young adults to generate matching classification thresholds for Fat Mass Index (FMI; fat mass/height2). These reference values should be helpful in the evaluation of a variety of adult and childhood abnormalities involving fat, lean, and bone, for establishing entry criteria into clinical trials, and for other medical, research, and epidemiological uses

Is Aquatic Life Correlated with an Increased Hematocrit in Snakes?

Background: Physiological adaptations that allow air-breathing vertebrates to remain underwater for long periods mainly involve modifications of the respiratory system, essentially through increased oxygen reserves. Physiological constraints on dive duration tend to be less critical for ectotherms than for endotherms because the former have lower mass-specific metabolic rates. Moreover, comparative studies between marine and terrestrial ectotherms have yet to show overall distinct physiological differences specifically associated with oxygen reserves. Methodology/Principal Findings: We used phylogenetically informed statistical models to test if habitat affects hematocrit (an indicator of blood oxygen stores) in snakes, a lineage that varies widely in habitat use. Our results indicate that both phylogenetic position (clade) and especially habitat are significant predictors of hematocrit. Our analysis also confirms the peculiar respiratory physiology of the marine Acrochordus granulatus. Conclusion/Significance: Contrary to previous findings, marine snakes have significantly–albeit slightly–elevated hematocrit, which should facilitate increased aerobic dive times. Longer dives could have consequences for foraging, mate searching, and predation risks. Alternatively, but not exclusively, increased Hct in marine species might also help t

Mammary stem cells, self-renewal pathways, and carcinogenesis

The mammary gland epithelial components are thought to arise from stem cells that undergo both self-renewal and differentiation. Self-renewal has been shown to be regulated by the Hedgehog, Notch, and Wnt pathways and the transcription factor B lymphoma Mo-MLV insertion region 1 (Bmi-1). We review data about the existence of stem cells in the mammary gland and the pathways regulating the self-renewal of these cells. We present evidence that deregulation of the self-renewal in stem cells/progenitors might be a key event in mammary carcinogenesis. If 'tumor stem cells' are inherently resistant to current therapies, targeting stem cell self-renewal pathways might provide a novel approach for breast cancer treatment

The gait and balance of patients with diabetes can be improved: a randomised controlled trial

Item does not contain fulltextAIMS/HYPOTHESIS: Gait characteristics and balance are altered in diabetic patients. Little is known about possible treatment strategies. This study evaluates the effect of a specific training programme on gait and balance of diabetic patients. METHODS: This was a randomised controlled trial (n=71) with an intervention (n=35) and control group (n=36). The intervention consisted of physiotherapeutic group training including gait and balance exercises with function-orientated strengthening (twice weekly over 12 weeks). Controls received no treatment. Individuals were allocated to the groups in a central office. Gait, balance, fear of falls, muscle strength and joint mobility were measured at baseline, after intervention and at 6-month follow-up. RESULTS: The trial is closed to recruitment and follow-up. After training, the intervention group increased habitual walking speed by 0.149 m/s (p<0.001) compared with the control group. Patients in the intervention group also significantly improved their balance (time to walk over a beam, balance index recorded on Biodex balance system), their performance-oriented mobility, their degree of concern about falling, their hip and ankle plantar flexor strength, and their hip flexion mobility compared with the control group. After 6 months, all these variables remained significant except for the Biodex sway index and ankle plantar flexor strength. Two patients developed pain in their Achilles tendon: the progression for two related exercises was slowed down. CONCLUSIONS/INTERPRETATION: Specific training can improve gait speed, balance, muscle strength and joint mobility in diabetic patients. Further studies are needed to explore the influence of these improvements on the number of reported falls, patients' physical activity levels and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637546 FUNDING: This work was supported by the Swiss National Foundation (SNF): PBSKP-123446/1/1 maart 201

Identification of Hepatic Niche Harboring Human Acute Lymphoblastic Leukemic Cells via the SDF-1/CXCR4 Axis

In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc null mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis