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Translational Epidemiology: Entering a Brave New World of Team Science

Mon, 04/17/2017 - 6:09pm

Translational epidemiology is the study of risk factors and diseases in large populations, harnessing the power of modern phenotyping, including large-scale omics approaches. In this review, we comment on the power and limitations of modern molecular translational epidemiology and suggest collaborative team science as a specific avenue to secure its existence in the next era of genomic research.

Sampling Serum in Patients With Vitiligo to Measure Disease Activity in the Skin

Mon, 04/17/2017 - 6:09pm

In this issue of JAMA Dermatology, Speeckaert and colleagues report that levels of the soluble CD25 and CD27 molecules (sCD25 and sCD27) are elevated in the serum of patients with active vitiligo compared with patients with stable disease. In addition, sCD25 levels were found to be significantly lower in the serum of patients being treated with topical immunosuppressants (including steroids and calcineurin inhibitors) and the serum level of sCD27 was significantly lower in patients with recent repigmentation, suggesting a potential to use these as biomarkers to monitor treatment responses. Interestingly, the authors continued to prospectively study a relatively large number of participants and demonstrated that serum levels of both sCD25 and sCD27 were associated with disease progression during follow-up. These important findings suggest that monitoring of these markers in the serum of patients with vitiligo may provide a glimpse into what is happening in the skin, a process that is not obvious by simple observation in vitiligo, in contrast to more inflammatory diseases.

Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model

Mon, 04/17/2017 - 6:09pm

Retinitis pigmentosa (RP) is a family of inherited retinal degenerative diseases that leads to blindness. In many cases the disease-causing allele encodes for a gene exclusively expressed in the night active rod photoreceptors. However, because rod death always leads to cone death affected individuals eventually lose their sight. Many theories have been proposed to explain the secondary loss of cones in RP; however, most fail to fully explain the different pathological transition stages seen in humans. Incorporating experimental data of rod and cone death kinetics from two mouse models of RP, we use a mathematical model to investigate the interplay and role of energy consumption and uptake of the photoreceptors as well as nutrient availability supplied through the retinal pigment epithelium (RPE) throughout the progression of RP. Our data driven mathematical model predicts that the system requires a total reduction of approximately 27-31% in nutrients available to result in the complete demise of all cones. Simulations utilizing retinal degeneration 1 (rd1) mouse cell count data in which cone death was delayed by altering cell metabolism in cones show that preventing a 1-2% decrease in nutrients available can permanently halt cone death even when 90% have already died. Our results also indicate that the ratio of energy consumption to uptake of cones, Dc, is mainly disrupted during the death wave of the rods with negligible changes thereafter and that the subsequent nutrient decrease is mainly responsible for the demise of the cones. The change in this ratio Dc highlights the compensation that the cones must undergo during rod death to meet the high metabolic demands of the entire photoreceptor population. Global sensitivity analysis confirms the results and suggests areas of focus for halting RP, even at later stages of the disease, through feasible therapeutic interventions.

Micro-C XL: assaying chromosome conformation from the nucleosome to the entire genome

Mon, 04/17/2017 - 6:09pm

We present Micro-C XL, an improved method for analysis of chromosome folding at mononucleosome resolution. Using long crosslinkers and isolation of insoluble chromatin, Micro-C XL increases signal-to-noise ratio. Micro-C XL maps of budding and fission yeast genomes capture both short-range chromosome fiber features such as chromosomally interacting domains and higher order features such as centromere clustering. Micro-C XL provides a single assay to interrogate chromosome folding at length scales from the nucleosome to the full genome.

Cancer Metabolism: Fueling More than Just Growth

Mon, 04/17/2017 - 6:09pm

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy.

Understanding mechanisms of autoimmunity through translational research in vitiligo

Mon, 04/17/2017 - 6:09pm

Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-gamma-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible.

The mitokine quest(ion)

Mon, 04/17/2017 - 6:09pm

Cells and organisms adapt to mitochondrial dysfunction by activating the mitochondrial unfolded protein response (UPR), which is regulated by mitochondrial-to-nuclear communication; and UPR activation can also be transmitted between different cell types suggesting a role in tissue coordination. Shao and colleagues now identify a neuronal circuit and a secreted neuropeptide required for cell non-autonomous UPR regulation.

PGC-1alpha dictates endothelial function through regulation of eNOS expression

Mon, 04/17/2017 - 6:09pm

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1alpha (PGC-1alpha) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1alpha in vascular function using mice with endothelial specific loss of function (PGC-1alpha EC KO) and endothelial specific gain of function (PGC-1alpha EC TG). Here we report that endothelial PGC-1alpha is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1alpha sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1alpha EC TG mice were protected. Mechanistically, PGC-1alpha promotes eNOS expression and activity, which is necessary for protection from ATII-induced dysfunction as mice either treated with an eNOS inhibitor (LNAME) or lacking eNOS were no longer responsive to transgenic endothelial PGC-1alpha expression. Finally, we determined that the orphan nuclear receptor, estrogen related receptor alpha (ERRalpha) is required to coordinate the PGC-1alpha -induced eNOS expression. In conclusion, endothelial PGC-1alpha expression protects from vascular dysfunction by promoting NO* bioactivity through ERRalpha induced expression of eNOS.

Mechanism of early dissemination and metastasis in Her2+ mammary cancer

Mon, 04/17/2017 - 6:09pm

Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis-initiating cells are thought to originate from a subpopulation present in progressed, invasive tumours. However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2+p-p38lop-Atf2loTwist1hiE-cadlo early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2+ eDCC precursors invaded locally, intravasated and lodged in target organs. Her2+ eDCCs activated a Wnt-dependent epithelial-mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1hiE-cadlo and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.

Hepatic steatosis is associated with cardiometabolic risk in a rural Indian population: A prospective cohort study

Mon, 04/17/2017 - 6:09pm

BACKGROUND/OBJECTIVES: While adiposity and hepatic steatosis are linked to cardiovascular risk in developed countries, their prevalence and impact in low-income countries are poorly understood. We investigated the association of anthropomorphic variables and hepatic steatosis with cardiometabolic risk profiles and subclinical cardiovascular disease (CVD) in a large rural Indian cohort.

METHODS: In 4691 individuals in the Birbhum Population Project in West Bengal, India, we performed liver ultrasonography, carotid ultrasound and biochemical and clinical profiling. We assessed the association of hepatic steatosis and anthropomorphic indices (BMI, waist circumference) with CVD risk factors (dysglycemia, dyslipidemia, hypertension) and subclinical CVD (by carotid intimal-medial thickness).

RESULTS: Rural Indians exhibited a higher visceral adiposity index and pro-atherogenic dyslipidemia at a lower BMI than Americans. Individuals with any degree of hepatic steatosis by ultrasound had a greater probability of dysglycemia (adjusted odds ratio, OR=1.67, 95% CI 1.31-2.12, P < 0.0001) and pro-atherogenic dyslipidemia (OR=1.33, 95% CI 1.07-1.63, P=0.009). We observed a positive association between liver fat, adiposity and carotid intimal-medial thickness (CIMT) in an unadjusted model (beta=0.02, P=0.0001); the former was extinguished after adjustment for cardiometabolic risk factors.

CONCLUSIONS: In a large population of rural Indians, hepatic steatosis and waist circumference were associated with prevalent cardiometabolic risk and subclinical CVD at lower BMI relative to multi-ethnic Americans, though the association of the former with subclinical CVD was extinguished after adjustment. These results underscore the emerging relevance of hepatic steatosis and adiposity in the developing world, and suggest efforts to target these accessible phenotypes for cardiometabolic risk prevention.

Human white adipocytes convert into "rainbow" adipocytes in vitro

Mon, 04/17/2017 - 6:09pm

White adipocytes are plastic cells able to reversibly transdifferentiate into brown adipocytes and into epithelial glandular cells under physiologic stimuli in vivo. These plastic properties could be used in future for regenerative medicine, but are incompletely explored in their details. Here, we focused on plastic properties of human mature adipocytes (MA) combining gene expression profile through microarray analysis with morphologic data obtained by electron and time lapse microscopy. Primary MA showed the classic morphology and gene expression profile of functional mature adipocytes. Notably, despite their committed status, MA expressed high levels of reprogramming genes. MA from ceiling cultures underwent transdifferentiation towards fibroblast-like cells with a well-differentiated morphology and maintaining stem cell gene signatures. The main morphologic aspect of the transdifferentiation process was the secretion of large lipid droplets and the development of organelles necessary for exocrine secretion further supported the liposecretion process. Of note, electron microscope findings suggesting liposecretion phenomena were found also in explants of human fat and rarely in vivo in fat biopsies from obese patients. In conclusion, both MA and post-liposecretion adipocytes show a well-differentiated phenotype with stem cell properties in line with the extraordinary plasticity of adipocytes in vivo.

WZB117 (2-Fluoro-6-(m-hydroxybenzoyloxy) Phenyl m-Hydroxybenzoate) Inhibits GLUT1-mediated Sugar Transport by Binding Reversibly at the Exofacial Sugar Binding Site

Mon, 04/17/2017 - 6:09pm

WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits passive sugar transport in human erythrocytes and cancer cell lines and, by limiting glycolysis, inhibits tumor growth in mice. This study explores how WZB117 inhibits the erythrocyte sugar transporter glucose transport protein 1 (GLUT1) and examines the transporter isoform specificity of inhibition. WZB117 reversibly and competitively inhibits erythrocyte 3-O-methylglucose (3MG) uptake with Ki(app) = 6 mum but is a noncompetitive inhibitor of sugar exit. Cytochalasin B (CB) is a reversible, noncompetitive inhibitor of 3MG uptake with Ki(app) = 0.3 mum but is a competitive inhibitor of sugar exit indicating that WZB117 and CB bind at exofacial and endofacial sugar binding sites, respectively. WZB117 inhibition of GLUTs expressed in HEK293 cells follows the order of potency: insulin-regulated GLUT4 - GLUT1 - neuronal GLUT3. This may explain WZB117-induced murine lipodystrophy. Molecular docking suggests the following. 1) The WZB117 binding envelopes of exofacial GLUT1 and GLUT4 conformers differ significantly. 2) GLUT1 and GLUT4 exofacial conformers present multiple, adjacent glucose binding sites that overlap with WZB117 binding envelopes. 3) The GLUT1 exofacial conformer lacks a CB binding site. 4) The inward GLUT1 conformer presents overlapping endofacial WZB117, d-glucose, and CB binding envelopes. Interrogating the GLUT1 mechanism using WZB117 reveals that subsaturating WZB117 and CB stimulate erythrocyte 3MG uptake. Extracellular WZB117 does not affect CB binding to GLUT1, but intracellular WZB117 inhibits CB binding. These findings are incompatible with the alternating conformer carrier for glucose transport but are consistent with either a multisubunit, allosteric transporter, or a transporter in which each subunit presents multiple, interacting ligand binding sites.

Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice

Mon, 04/17/2017 - 6:09pm

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present study, we have generated an Mdm2 mutant mouse (Mdm2Y393F) to determine whether c-Abl phosphorylation of Mdm2 regulates the p53-mediated DNA damage response or p53 tumor suppression in vivo. The Mdm2Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Although apoptosis is unaltered in these mice, they recover more rapidly from radiation-induced bone marrow ablation and are more resistant to whole-body radiation-induced lethality. These data reveal an in vivo role for c-Abl phosphorylation of Mdm2 in regulation of p53 tumor suppression and bone marrow failure. However, c-Abl phosphorylation of Mdm2 Tyr393 appears to play a lesser role in governing Mdm2-p53 signaling than ATM phosphorylation of Mdm2 Ser394. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2Y393F/S394A mice and Mdm2S394A mice display similar phenotypes.

Thrombosis and platelets: an update

Mon, 04/17/2017 - 6:09pm

Haemostasis and thrombosis are complex, multifactorial processes. There is an evolving understanding of the mechanisms influencing vascular occlusion and the role of inflammation and immunity. Despite major advances in elucidating the mechanistic pathways mediating platelet function and thrombosis, challenges in the treatment of vascular occlusive diseases persist. Pharmacological advances have greatly affected thrombotic outcomes, but this has led to the unwanted side effect of bleeding. Detailed assessment of the impact of non-thrombotic diseases on haemostasis and thrombosis is necessary to better evaluate thrombotic risk and establish optimal treatment. This review will focus on recent advances in understanding the contribution of evolving risk factors to thrombosis.

Cardiometabolic disease in South Asians: A global health concern in an expanding population

Mon, 04/17/2017 - 6:09pm

Cardiovascular disease (CVD) is one of the main causes of mortality and morbidity worldwide. As an emerging population, South Asians (SAs) bear a disproportionately high burden of CVD relative to underlying classical risk factors, partly attributable to a greater prevalence of insulin resistance and diabetes and distinct genetic and epigenetic influences. While the phenotypic distinctions between SAs and other ethnicities in CVD risk are becoming increasingly clear, the biology of these conditions remains an area of active investigation, with emerging studies involving metabolism, genetic variation and epigenetic modifiers (e.g., extracellular RNA). In this review, we describe the current literature on prevalence, prognosis and CVD risk in SAs, and provide a landscape of translational research in this field toward ameliorating CVD risk in SAs.

A double-blind, placebo-controlled, phase-II clinical trial to evaluate oral simvastatin as a treatment for vitiligo

Mon, 04/17/2017 - 6:09pm

We conducted a small, randomized, double-blind, placebo-controlled, phase-II clinical trial to test simvastatin as a treatment for vitiligo.

CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells

Mon, 04/17/2017 - 6:08pm

Here we show that CK2 inhibition by CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells, implicating an alternative strategy to target NOTCH1 signaling in refractory/relapsed T-ALL.

Challenges and Opportunities in Linking Long Noncoding RNAs to Cardiovascular, Lung, and Blood Diseases

Mon, 04/17/2017 - 6:08pm

The new millennium heralds an unanticipated surge of genomic information, most notably an expansive class of long noncoding RNAs (lncRNAs). These transcripts, which now outnumber all protein-coding genes, often exhibit the same characteristics as mRNAs (RNA polymerase II-dependent, 5' methyl-capped, multiexonic, polyadenylated); yet, they do not encode for stable, well-conserved proteins. Elucidating the function of all relevant lncRNAs in heart, vasculature, lung, and blood is essential for generating a complete interactome in these tissues. This is particularly evident because an increasing number of investigators perform RNA-sequencing experiments where, typically, annotated lncRNAs exhibit impressive changes in gene expression. How does one go about evaluating an lncRNA when the sequence of the transcript lends no insight into how it may function within a cell type? Here, we provide a brief overview for the rational study of lncRNAs.

Antidepressant Medication Treatment and Risk of Death

Fri, 04/14/2017 - 3:02pm

OBJECTIVE: Although previous studies have assessed whether depression is a mortality risk factor, few have examined whether antidepressant medications (ADMs) influence mortality risk.

METHODS: We estimated hazards of 1-year all-cause mortality associated with ADMs, with use occurring within 90 days of depression diagnosis among 720 821 patients who received treatment in a Veterans Health Administration facility during fiscal year 2006. We addressed treatment selection biases using conventional Cox regression, propensity-stratified Cox regression (propensity score), and 2 forms of marginal structural models. Models accounted for multiple potential clinical and demographic confounders, and sensitivity analyses compared findings by antidepressant class.

RESULTS: Antidepressant medication use compared with no use was associated with significantly lower hazards of 1-year mortality risk in Cox (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.90-0.97) and propensity score estimates (HR, 0.94; 95% CI, 0.91-0.98), whereas marginal structural model-based estimates showed no difference in mortality risk when the exposure was specified as "as-treated" in every 90-day intervals of the 1-year follow-up (HR, 0.91; 95% CI, 0.66-1.26) but showed increased risk when specified as "intent-to-treat" (HR, 1.07; 95% CI, 1.02-1.13).

CONCLUSIONS: Among patients treated with ADMs belonging to a single class in the first 90 days, there were no significant differences in 1-year all-cause mortality risks. When accounting for clinical and demographic characteristics and treatment selection bias, ADM use was associated with no excess harm.

Dignity in mental health practice and research: Time to unite on innovation, outreach and education

Fri, 04/14/2017 - 3:01pm

Dignity has been described as ‘the inherent and inalienable worth of all human beings irrespective of social status such as race, gender, physical or mental state. Dignity is, therefore, at the core of psychological well-being, social connection and humanity. Mental health interventions that explicitly promote and preserve dignity for people experiencing mental distress are growing in clinical practice and research in the USA, India, Europe and elsewhere. However, there is a need for more research and policy supporting the implementation and evaluation of these initiatives. Here, we highlight some of these programmes and make recommendations on how to further integrate dignity in mental health research, practice, outreach and education in India and the world.