The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

International audienceAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.

International audienceRare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Systems biology approach to understanding post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychological disorder affecting individuals that have experienced life-changing traumatic events. The symptoms of PTSD experienced by these subjects-including acute anxiety, flashbacks, and hyper-arousal-disrupt their normal functioning. Although PTSD is still categorized as a psychological disorder, recent years have witnessed a multi-directional research effort attempting to understand the biomolecular origins of the disorder. This review begins by providing a brief overview of the known biological underpinnings of the disorder resulting from studies using structural and functional neuroimaging, endocrinology, and genetic and epigenetic assays. Next, we discuss the systems biology approach, which is often used to gain mechanistic insights from the wealth of available high-throughput experimental data. Finally, we provide an overview of the current computational tools used to decipher the heterogeneous types of molecular data collected in the study of PTSD

Systems biology approach to understanding post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychological disorder affecting individuals that have experienced life-changing traumatic events. The symptoms of PTSD experienced by these subjects-including acute anxiety, flashbacks, and hyper-arousal-disrupt their normal functioning. Although PTSD is still categorized as a psychological disorder, recent years have witnessed a multi-directional research effort attempting to understand the biomolecular origins of the disorder. This review begins by providing a brief overview of the known biological underpinnings of the disorder resulting from studies using structural and functional neuroimaging, endocrinology, and genetic and epigenetic assays. Next, we discuss the systems biology approach, which is often used to gain mechanistic insights from the wealth of available high-throughput experimental data. Finally, we provide an overview of the current computational tools used to decipher the heterogeneous types of molecular data collected in the study of PTSD

Abstract 19028: Assessment of American Heart Association’s Ideal Cardiovascular Health Metrics Among Employees of Large Health Care Organization: the Baptist Health South Florida Employee Study

INTRODUCTION: Health care organizations and their employees are critical role models for healthy living for their communities. The American Heart Association (AHA) 2020 goals provide a national framework, which can be used as track success of employee wellness programs focued on improving the cardiovascular health. The current study aims to assess the baseline cardiovascular health among insured employees of Baptist Health South Florida (BHSF), a large not-for-profit health care organization. METHODS: CVD health metrics were categorized into ideal, intermediate, or poor categories based on 7 CVD risk factors/health behaviors estimated among individuals participating in a voluntary annual health risk assessment (HRA) and wellness fair available to all employees. RESULTS: The sample consists of 9996 employees who participated in 2013 annual HRA and wellness fair (mean age 43.1±12.1 years, 75% women). Screening participants on average met 4.25±1.14 ideal cardiovascular health metrics. The table describes the prevalence of ideal CVD metrics among the study participant across age and gender. Only 60 (0.6%) of participants met the AHA’s definition of ideal health in all metrics and 36% met 4 or more ideal health metric The prevalence of having “intermediate” cardiovascular health (at least 1 intermediate metric and no poor metrics) was also 29.4%. Majority (70%) had “poor” cardiovascular health (at least 1 poor health metric). Overall 3/4 th participants reached ideal status for smoking, physical activity levels, and glycemic control, whereas the majority of participants had poor to intermediate BMI and health diet score. CONCLUSIONS: Prevalence of ideal cardiovascular health is low among employees of a large health care organization. Future tracking of the CVD metrics will provide critical feedback on the impact of system wide wellness efforts as well identify proactive programs to assist in progress toward the AHA 2020 Impact Goal

Child Sexual Abuse and Adult Mental Health, Sexual Risk Behaviors, and Drinking Patterns Among Latino Men Who Have Sex With Men

One in five Latino men who have sex with men has experienced child sexual abuse. Although concerning in itself, child sexual abuse may increase an individuals' likelihood of depression and risk-taking in adult life, including engagement in HIV risk behaviors and alcohol and substance use. It is therefore urgent that researchers and practitioners better understand the long-term effects of child sexual abuse. We utilized logistic and linear regression to assess associations between child sexual abuse (operationalized as forced or coerced sexual activity before age 17) and depression, sexual behaviors, and drinking patterns in a sample of 176 adult Latino men who have sex with men from New York City. Over one-fifth (22%) of participants reported child sexual abuse. In multivariable models, participants with histories of child sexual abuse were significantly more likely than participants without such histories to screen for clinically significant depressive symptoms and heavy drinking and reported more anal sex acts, male sexual partners, and incidents of condomless anal intercourse in the previous three months. These findings confirm a high prevalence of child sexual abuse among Latino men who have sex with men and associations between child sexual abuse and adulthood depressive symptoms, high-risk alcohol consumption, and sexual risk behaviors. We recommend that providers who serve Latino men who have sex with men incorporate child sexual abuse screenings into mental health, HIV prevention, and substance use treatment programs, utilizing approaches that are inclusive of resilience