The landscape of somatic copy-number alteration across human cancers

available in PMC 2010 August 18.A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κΒ pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types.National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109038))National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, R01CA109467)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA085859)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P01CA 098101)National Institutes of Health (U.S.) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, K08CA122833

The landscape of somatic copy-number alteration across human cancers

A powerful way to discover key genes playing causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here, we report high-resolution analyses of somatic copy-number alterations (SCNAs) from 3131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across multiple cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-κB pathway. We show that cancer cells harboring amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend upon expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in multiple cancer types

Persistence and Subtype Stability of ADHD Among Substance Use Disorder Treatment Seekers

OBJECTIVE: To examine ADHD symptom persistence and subtype stability among substance use disorder (SUD) treatment seekers. METHOD: In all, 1,276 adult SUD treatment seekers were assessed for childhood and adult ADHD using Conners' Adult ADHD Diagnostic Interview for Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; CAADID). A total of 290 (22.7%) participants met CAADID criteria for childhood ADHD and comprise the current study sample. RESULTS: Childhood ADHD persisted into adulthood in 72.8% (n = 211) of cases. ADHD persistence was significantly associated with a family history of ADHD, and the presence of conduct disorder and antisocial personality disorder. The combined subtype was the most stable into adulthood (78.6%) and this stability was significantly associated with conduct disorder and past treatment of ADHD. CONCLUSION: ADHD is highly prevalent and persistent among SUD treatment seekers and is associated with the more severe phenotype that is also less likely to remit. Routine screening and follow-up assessment for ADHD is indicated to enhance treatment management and outcomes

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Wisconsin Adolescents’ Attitudes, Beliefs, Motivations, and Behaviors Surrounding E-Cigarette Use and Cessation

Abstract: Background: E-cigarettes are the most common tobacco product used by adolescents yet no evidence-based cessation treatment for adolescents exists. Methods: Wisconsin residents, aged 13-17 (N=227), completed an online survey assessing e-cigarette use, knowledge, motivations around using and quitting, and recommendations for cessation intervention content. Results: Most of our sample never vaped (76.2%), reporting concerns with health effects and addiction as motivations preventing initiation. Amongst adolescents who used e-cigarettes, friend use was the main motivation for initiation and mental health symptoms promoted ongoing use. Motivations for quitting included health harms, cost, and addiction. Discussion: This study identified various topics that motivate and demotivate e-cigarette use amongst adolescents. This information can be incorporated into prevention and treatment strategies tailored to adolescents

Wisconsin Young Adults’ Attitudes, Beliefs, Motivations, and Behaviors Surrounding E-Cigarette Use and Cessation

Abstract: Background: E-cigarette use is prevalent amongst young adults, yet cessation treatment options are limited and underutilized. Methods: Wisconsin residents, aged 18-24, who had vaped in the past month (N=480), completed an online survey assessing vaping initiation, quit experiences and intentions, and treatment knowledge and preferences. Results: Most young adults had made a prior quit attempt, commonly motivated by concerns about addiction, cost, and health problems. Though 80% want support to quit, preferred methods of support were highly variable. Discussion: Vaping cessation resources that are responsive to young adults’ needs and preferences are needed. Strategies to reach, motivate, and engage young adults in e-cigarette cessation and cessation treatment should highlight their concerns about addiction, costs, health harms, and desired treatment options

Acute prazosin administration does not reduce stressor reactivity in healthy adults

Pre-registration of Study Design and Analysis Plan: https://osf.io/m8jmp/register/564d31db8c5e4a7c9694b2c0 PsyArXiv Preprint Manuscript: https://osf.io/z2kvh/ The objective of the current study is to examine norepinephrine alpha1 (NE-α1) receptor involvement in reactivity to unpredictable stressors in humans, by using the NPU stress task in conjunction with an alpha1-blocker, prazosin

NIAAA F31: Repurposing alpha1 noradrenergic antagonists for alcoholism treatment

Project Summary: The first objective of the current proposal is to implicate norepinephrine alpha1 receptor involvement in reactivity to stressful events in humans by using a sophisticated laboratory stress task in conjunction with an alpha1-blocker, prazosin. The second objective is to determine whether prazosin, an FDA-approved blood pressure medication, is effective at reducing stress-reactivity among abstinent alcoholics who are trying to quit drinking. No currently available pharmacotherapy treatment options for alcoholism are specifically designed to prevent relapse caused by stress, which is a common hurdle in the way of attaining long-term recovery. As the pharmaceutical industry has drastically reduced its investment in developing novel medications to treat alcoholism in recent years, it is becoming increasingly essential to identify currently available drugs with known neurobiological mechanisms, such as prazosin, that may be effective treatment alternatives for addiction. The current study aims to evaluate the effects of prazosin on stress-reactivity in alcoholics in early abstinence versus healthy volunteers. Participants will take either prazosin or a placebo pill at two laboratory sessions, after which they will complete a stress task. The task will consist of three conditions exposing participants to unpredictable shock, predictable shock, or no shock. The eye blink startle response will be measured as a physiological index of the participants’ reactivity to the stressful task (i.e., predictable and unpredictable shocks). Previous research has consistently demonstrated that drugs that reduce the stress response, such as alcohol and benzodiazepines, reduce the startle response specifically to unpredictable stressors. Furthermore, drug deprivation among drug dependent individuals (e.g., nicotine, marijuana or alcohol) selectively increases the startle response during unpredictable stressors. This is an attractive lab task as very similar methods (e.g. unpredictable shock) and measures (e.g., startle) have been used extensively in rodents and non-human primates, so the field has a rich understanding of the neurobiology involved in this stress system. In particular, the neurotransmitter norepinephrine has been critically implicated in the stress response, and prazosin, a drug that blocks norepinephrine alpha1 receptors, has been shown to reduce stress-induced relapse in rodent models of alcoholism. This study will examine whether prazosin reduces the startle response during unpredictable stressors in abstinent alcoholics in early recovery vs. healthy volunteers. These findings would suggest that norepinephrine alpha1 receptors are involved in stress-reactivity in humans and that prazosin may be an effective treatment of stress-induced relapse for alcoholics pursuing abstinence. Given the tremendous cost associated with conducting large scale clinical trials to vet treatments for addiction, the current proposal represents an efficient laboratory-based screening procedure to evaluate the potential efficacy of novel pharmacotherapies. This type of translational research aims to expand treatment options for the eighteen million people in the United States who suffer from an alcohol use disorder. Public Health Relevance: Eighteen million people in the United States suffer from an alcohol use disorder and current pharmacotherapy treatment for alcoholism yields relatively low probability of a patient successfully attaining long-term recovery. The recent dramatic reduction in Research and Development by the pharmaceutical industry for novel medications to treat neuropsychiatric conditions, particularly substance use disorders, provides a strong impetus to repurpose currently available compounds that may be effective treatment alternatives. The current project aims to 1) implicate norepinephrine mechanisms in stress-reactivity in humans via direct pharmacological antagonism of the norepinephrine system via Prazosin, an FDA-approved blood pressure medication, and 2) examine the effects of Prazosin on stress-reactivity in abstinent alcoholics in a laboratory procedure to screen its potential utility as a treatment for stress-induced relapse for alcoholism. National Institute on Alcohol Abuse and Alcoholism, National Research Service Award (F31 AA022845) Jesse Kaye (PI/Trainee), John Curtin (Sponsor), Craig Berridge (Co-Sponsor). Direct costs: $93,075 Status: Funded. 09/2014 – 08/2017 For more information see: http://dionysus.psych.wisc.ed

Psychometric properties of psychophysiological paradigms in the NIMH RDoC: startle and corrugator response in NPU, affective picture viewing, and resting state tasks.

Poster presented at Association for Psychological Science (APS) Convention 2016. Published peer-reviewed article: Kaye JT, Bradford DE and Curtin JJ (2016). Psychometric properties of startle and corrugator response in NPU, Affective Picture Viewing, and Resting State tasks. Psychophysiology. E-pub online 11 MAY 2016 DOI: 10.1111/psyp.12663 OSF link to data and analysis: https://osf.io/fdjg9