Association of the TLR4 Asp299Gly polymorphism with lung function in relation to body mass index

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown conflicting results for the association between TLR4 polymorphism (Asp299Gly) and lung function. We investigated the influence of TLR4 Asp299Gly, a polymorphism, on lung function in a community population.</p> <p>Methods</p> <p>In 2003, a cross-sectional survey was conducted to assess the respiratory health of residents living in and around the town of Humboldt, Saskatchewan, Canada. There were 2090 adults age 18-79 years who completed a questionnaire that included a medical and smoking history, as well as socio-economic and lifestyle variables. Genetic information and lung function test measurements were available on 1725 subjects (754 males and 971 females) of the 2090 respondents. These subjects were selected for further analysis to investigate the association between TLR4 Asp299Gly genotype and forced expiratory volume in the first second in liters (FEV₁), forced vital capacity in liters (FVC), FEV₁/FVC ratio, and forced expiratory flow rate in liters/second (FEF_25-75). Multivariable linear regression analysis was used to investigate associations.</p> <p>Results</p> <p><b>A</b>djusted mean values of FEV₁and FVC were significantly different between TLR4 wild type and TLR4 variant groups [Mean ± S.E.: (TLR4 wild type - FEV₁: 3.18 ± 0.02, FVC: 3.95 ± 0.03; TLR4 variant - FEV₁: 3.31 ± 0.06, FVC: 4.14 ± 0.07)]. Based on multivariable regression analysis, we observed that body mass index (BMI) was associated with decreased FEV₁/FVC ratio and FEF_25-75in TLR4 variant group but not in wild type group.</p> <p>Conclusion</p> <p>BMI may modify the associations of TLR4 Asp299Gly polymorphism with FEV₁/FVC ratio and FEF_25-75.</p

Alterations in integrin expression modulates invasion of pancreatic cancer cells

Background Factors mediating the invasion of pancreatic cancer cells through the extracellular matrix (ECM) are not fully understood. Methods In this study, sub-populations of the human pancreatic cancer cell line, MiaPaCa-2 were established which displayed differences in invasion, adhesion, anoikis, anchorage-independent growth and integrin expression. Results Clone #3 displayed higher invasion with less adhesion, while Clone #8 was less invasive with increased adhesion to ECM proteins compared to MiaPaCa-2. Clone #8 was more sensitive to anoikis than Clone #3 and MiaPaCa-2, and displayed low colony-forming efficiency in an anchorage-independent growth assay. Integrins beta 1, alpha 5 and alpha 6 were over-expressed in Clone #8. Using small interfering RNA (siRNA), integrin β1 knockdown in Clone #8 cells increased invasion through matrigel and fibronectin, increased motility, decreased adhesion and anoikis. Integrin alpha 5 and alpha 6 knockdown also resulted in increased motility, invasion through matrigel and decreased adhesion. Conclusion Our results suggest that altered expression of integrins interacting with different extracellular matrixes may play a significant role in suppressing the aggressive invasive phenotype. Analysis of these clonal populations of MiaPaCa-2 provides a model for investigations into the invasive properties of pancreatic carcinoma

Drug Off-Target Effects Predicted Using Structural Analysis in the Context of a Metabolic Network Model

Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been observed to impact renal function in gene-deficient patients and may play a role in the adverse side effects observed in clinical trials. Genetic risk factors for drug treatment were also predicted that correspond to both characterized and unknown renal metabolic disorders as well as cryptic genetic deficiencies that are not expected to exhibit a renal disorder phenotype except under drug treatment. This study represents a novel integration of structural and systems biology and a first step towards computational systems medicine. The methodology introduced herein has important implications for drug development and personalized medicine

Combining motivational and volitional approaches to reducing excessive alcohol consumption in pre-drinkers: A theory-based intervention protocol

Background: Pre-drinking refers to the consumption of alcohol at home or a private residence prior to attending a subsequent social event. We present the study protocol of an online theory-based intervention to reduce pre-drinking and related harm in pre-drinking undergraduates, using behavior change techniques targeting the motivational and volitional phases of behaviour. Design: A fully randomized 2 (autonomy support: present vs. absent) x 2 (implementation intention: present vs. absent) between-participants design will be used to ascertain the effectiveness of the intervention in reducing pre-drinking alcohol consumption and alcohol-related harm. Participants will complete a range of theory-based measures prior to being allocated to one of the four experimental conditions. Four weeks later, participants will complete a follow-up questionnaire comprised of theoretical and behavioral measures. Analyses: The main and interactive effects of the intervention components in reducing our primary dependent variables, namely, pre-drinking alcohol consumption and alcohol-related harm at four-week follow-up will be tested. Baseline alcohol consumption and demographic information will be included in the analysis as covariates. Discussion: This online intervention is the first to be developed to reduce pre-drinking alcohol consumption, a behaviour linked to increased risk of alcohol-related harm. The intervention targets motivational and volitional components of the behaviour change process and is therefore likely to lead to greater reductions in pre-drinking alcohol consumption and experience of alcohol-related harm compared to either approach in isolation. If successful, the intervention can be implemented across various contexts and in populations where pre-drinking is prevalent. © 2016 Caudwell et al

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Decoding accuracy in supplementary motor cortex correlates with perceptual sensitivity to tactile roughness

Perceptual sensitivity to tactile roughness varies across individuals for the same degree of roughness. A number of neurophysiological studies have investigated the neural substrates of tactile roughness perception, but the neural processing underlying the strong individual differences in perceptual roughness sensitivity remains unknown. In this study, we explored the human brain activation patterns associated with the behavioral discriminability of surface texture roughness using functional magnetic resonance imaging (fMRI). First, a wholebrain searchlight multi-voxel pattern analysis (MVPA) was used to find brain regions from which we could decode roughness information. The searchlight MVPA revealed four brain regions showing significant decoding results: the supplementary motor area (SMA), contralateral postcentral gyrus (S1), and superior portion of the bilateral temporal pole (STP). Next, we evaluated the behavioral roughness discrimination sensitivity of each individual using the just-noticeable difference (JND) and correlated this with the decoding accuracy in each of the four regions. We found that only the SMA showed a significant correlation between neuronal decoding accuracy and JND across individuals; Participants with a smaller JND (i.e., better discrimination ability) exhibited higher decoding accuracy from their voxel response patterns in the SMA. Our findings suggest that multivariate voxel response patterns presented in the SMA represent individual perceptual sensitivity to tactile roughness and people with greater perceptual sensitivity to tactile roughness are likely to have more distinct neural representations of different roughness levels in their SMA. &amp;#169; 2015 Kim et al.close0