Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

Diagnosing the misuse of the Bayes factor in Applied Research

Hypothesis testing is often used for inference in the social sciences. In particular, null hypothesis significance testing (NHST) and its p-value are ubiquitous in published research for decades. Much more recently, null hypothesis Bayesian testing (NHBT) and its Bayes factor also started to be more commonplace in applied research. Following preliminary work by Wong and colleagues, we investigated how, and to what extent, researchers misapply the Bayes factor in applied psychological research by means of a literature study. Based on a final sample of 167 papers, our results indicate that, not unlike NHST and the p-value, also the use of NHBT and the Bayes factor shows signs of misconceptions. We pondered over the root causes of the identified problems. We also provided suggestions to improve the current state of affairs. This paper is aimed to assist researchers to draw the best inferences possible while using NHBT and the Bayes factor in applied research

Residual cognitive deficits 50 years after lead poisoning during childhood

The long term neurobehavioural consequences of childhood lead poisoning are not known. In this study adult subjects with a documented history of lead poisoning before age 4 and matched controls were examined with an abbreviated battery of neuropsychological tests including measures of attention, reasoning, memory, motor speed, and current mood. The subjects exposed to lead were inferior to controls on almost all of the cognitive tasks. This pattern of widespread deficits resembles that found in children evaluated at the time of acute exposure to lead rather than the more circumscribed pattern typically seen in adults exposed to lead. Despite having completed as many years of schooling as controls, the subjects exposed to lead were lower in lifetime occupational status. Within the exposed group, performance on the neuropsychological battery and occupational status were related, consistent with the presumed impact of limitations in neuropsychological functioning on everyday life. The results suggest that many subjects exposed to lead suffered acute encephalopathy in childhood which resolved into a chronic subclinical encephalopathy with associated cognitive dysfunction still evident in adulthood. These findings lend support to efforts to limit exposure to lead in childhood

Criterion A of the AMPD in HiTOP

The categorical model of personality disorder classification in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013) is highly and fundamentally problematic. Proposed for DSM-5 and provided within Section III (for Emerging Measures and Models) was the Alternative Model of Personality Disorder (AMPD) classification, consisting of Criterion A (self-interpersonal deficits) and Criterion B (maladaptive personality traits). A proposed alternative to the DSM-5 more generally is an empirically based dimensional organization of psychopathology identified as the Hierarchical Taxonomy of Psychopathology (HiTOP; Kotov etal., 2017). HiTOP currently includes, at the highest level, a general factor of psychopathology. Further down are the five domains of detachment, antagonistic externalizing, disinhibited externalizing, thought disorder, and internalizing (along with a provisional sixth somatoform dimension) that align with Criterion B. The purpose of this article is to discuss the potential inclusion and placement of the self-interpersonal deficits of the DSM-5 Section III Criterion A within HiTOP

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h 2 SNP) for European-American females of 29% that is similar to h 2 SNP for schizophrenia and is substantially higher than h 2 SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD - for both European- and African-American individuals - and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for 1/410 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci

A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder

Background: The nature and underlying mechanisms of the observed increased vulnerability to posttraumatic stress disorder (PTSD) in women are unclear. Methods: We investigated the genetic overlap of PTSD with anthropometric traits and reproductive behaviors and functions in women. The analysis was conducted using female-specific summary statistics from large genome-wide association studies (GWAS) and a cohort of 3577 European American women (966 PTSD cases and 2611 trauma-exposed controls). We applied a high-resolution polygenic score approach and Mendelian randomization analysis to investigate genetic correlations and causal relationships. Results: We observed an inverse association of PTSD with genetically determined anthropometric traits related to body shape, independent of body mass index (BMI). The top association was related to BMI-adjusted waist circumference (WCadj; R = -0.079, P < 0.001, Q = 0.011). We estimated a relative decrease of 64.6% (95% confidence interval = 27.5-82.7) in the risk of PTSD per 1-SD increase in WCadj. MR-Egger regression intercept analysis showed no evidence of pleiotropic effects in this association (Ppleiotropy = 0.979). We also observed associations of genetically determined WCadj with age at first sexual intercourse and number of sexual partners (P = 0.013 and P < 0.001, respectively). Conclusions: There is a putative causal relationship between genetically determined female body shape and PTSD, which could be mediated by evolutionary mechanisms involved in human sexual behaviors

Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.Peer reviewe