Derivation of a Protein Risk Score for Cardiovascular Disease Among a Multiracial and Multiethnic HIV+ Cohort

Background Cardiovascular disease risk prediction models underestimate CVD risk in people living with HIV (PLWH). Our goal is to derive a risk score based on protein biomarkers that could be used to predict CVD in PLWH. Methods and Results In a matched case-control study, we analyzed normalized protein expression data for participants enrolled in 1 of 4 trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials). We used dimension reduction, variable selection and resampling methods, and multivariable conditional logistic regression models to determine candidate protein biomarkers and to generate a protein score for predicting CVD in PLWH. We internally validated our findings using bootstrap. A protein score that was derived from 8 proteins (including HGF [hepatocyte growth factor] and interleukin-6) was found to be associated with an increased risk of CVD after adjustment for CVD and HIV factors (odds ratio: 2.17 [95% CI: 1.58-2.99]). The protein score improved CVD prediction when compared with predicting CVD risk using the individual proteins that comprised the protein score. Individuals with a protein score above the median score were 3.10 (95% CI, 1.83-5.41) times more likely to develop CVD than those with a protein score below the median score. Conclusions A panel of blood biomarkers may help identify PLWH at a high risk for developing CVD. If validated, such a score could be used in conjunction with established factors to identify CVD at-risk individuals who might benefit from aggressive risk reduction, ultimately shedding light on CVD pathogenesis in PLWH

The self-regulation skills instrument in transplantation (SSIt):Development and measurement properties of a self-report self-management instrument

Objective: To develop a self-management instrument for organ transplant recipients that incorporates self-regulations skills and to determine its measurement properties. Methods: The instrument includes concepts from social cognitive models: problem awareness, attitude, self-efficacy, motivation, social support, goal setting, goal pursuit, skills and goal affect. The measurement properties were evaluated based on the COSMIN guidelines. Face and content validity were determined through patient assessment, Three-Step Test-Interview and expert assessment using the Content Validity Index. Structural validity and reliability were tested using exploratory factor analysis and Cronbach's alpha. Construct validity was tested by comparing subscales with the Health Education Impact Questionnaire (heiQ). Results: After face and content validity assessment 47 items were entered into the exploratory factor analysis. The analysis showed two meaningful factors, with internal consistency of 0.90 and 0.89. Spearman correlations between the subscales and heiQ were moderate (0.55; 0.46). The final version consists of 21 items, divided into two scales: ‘Setbacks’ and ‘Successes’. Conclusions: The Self-regulation skills instrument in transplantation (SSIt) is a valid and reliable instrument to asses necessary skills for self-management after transplantation and may be useful for other patients as well. Practice implications: Insight into self-regulation competencies can help healthcare professionals to tailor self-management support.</p

The self-regulation skills instrument in transplantation (SSIt):Development and measurement properties of a self-report self-management instrument

Objective: To develop a self-management instrument for organ transplant recipients that incorporates self-regulations skills and to determine its measurement properties. Methods: The instrument includes concepts from social cognitive models: problem awareness, attitude, self-efficacy, motivation, social support, goal setting, goal pursuit, skills and goal affect. The measurement properties were evaluated based on the COSMIN guidelines. Face and content validity were determined through patient assessment, Three-Step Test-Interview and expert assessment using the Content Validity Index. Structural validity and reliability were tested using exploratory factor analysis and Cronbach's alpha. Construct validity was tested by comparing subscales with the Health Education Impact Questionnaire (heiQ). Results: After face and content validity assessment 47 items were entered into the exploratory factor analysis. The analysis showed two meaningful factors, with internal consistency of 0.90 and 0.89. Spearman correlations between the subscales and heiQ were moderate (0.55; 0.46). The final version consists of 21 items, divided into two scales: ‘Setbacks’ and ‘Successes’. Conclusions: The Self-regulation skills instrument in transplantation (SSIt) is a valid and reliable instrument to asses necessary skills for self-management after transplantation and may be useful for other patients as well. Practice implications: Insight into self-regulation competencies can help healthcare professionals to tailor self-management support.</p

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

Habitat restoration weakens negative environmental effects on telomere dynamics

Habitat quality can have far-reaching effects on organismal fitness, an issue of concern given the current scale of habitat degradation. Many temperate upland streams have reduced nutrient levels due to human activity. Nutrient restoration confers benefits in terms of invertebrate food availability and subsequent fish growth rates. Here we test whether these mitigation measures also affect the rate of cellular ageing of the fish, measured in terms of the telomeres that cap the ends of eukaryotic chromosomes. We equally distributed Atlantic salmon eggs from the same 30 focal families into 10 human-impacted oligotrophic streams in northern Scotland. Nutrient levels in five of the streams were restored by simulating the deposition of a small number of adult Atlantic salmon Salmo salar carcasses at the end of the spawning period, while five reference streams were left as controls. Telomere lengths and expression of the telomerase reverse transcriptase (TERT) gene that may act to lengthen telomeres were then measured in the young fish when 15 months old. While TERT expression was unrelated to any of the measured variables, telomere lengths were shorter in salmon living at higher densities and in areas with a lower availability of the preferred substrate (cobbles and boulders). However, the adverse effects of these habitat features were much reduced in the streams receiving nutrients. These results suggest that adverse environmental pressures are weakened when nutrients are restored, presumably because the resulting increase in food supply reduces levels of both competition and stress

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Baseline cardiovascular risk in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial: Baseline CVD in START

The Strategic Timing of AntiRetroviral Treatment (START) trial has recruited antiretroviral-naïve individuals with high CD4 cell counts from all world regions. We describe the distribution of cardiovascular (CVD) risk factors, overall and by geographic region, at study baseline

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death