Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Art therapy with refugee children: a qualitative study explored through the lens of art therapists and their experiences

This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Art Therapy on 9-11-2018, available online: https://doi.org/10.1080/17454832.2018.1533571This article sets out to explore the use of art therapy with refugee children, from the perspective of art therapists and their experiences. Three semi-structured interviews were conducted to gain insights by capturing experiences and stories. Using thematic analysis, five themes were identified: (1) giving voice; (2) rebuilding trust, opening wounds; (3) sharing stories, healing pain; (4) exploring identity, discovering new-self; and (5) understanding art therapy. Upon reflection, two key aspects of art therapy were established, these were identified as: (1) providing refugee children with a safe space to heal and discover new-self, and (2) giving refugee children a voice to express and share stories. Despite the last of the five themes (understanding art therapy) being established as a factor that limits the use of art therapy, this has created an avenue for further research. From the findings, it was concluded that art therapy can be a useful form of psychotherapy for refugee children. Art therapy can provide these children with a safe space to heal, and give them a voice to be heard

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients' selection

How Emotion Strengthens the Recollective Experience: A Time-Dependent Hippocampal Process

Emotion significantly strengthens the subjective recollective experience even when objective accuracy of the memory is not improved. Here, we examine if this modulation is related to the effect of emotion on hippocampal-dependent memory consolidation. Two critical predictions follow from this hypothesis. First, since consolidation is assumed to take time, the enhancement in the recollective experience for emotional compared to neutral memories should become more apparent following a delay. Second, if the emotion advantage is critically dependent on the hippocampus, then the effects should be reduced in amnesic patients with hippocampal damage. To test these predictions we examined the recollective experience for emotional and neutral photos at two retention intervals (Experiment 1), and in amnesics and controls (Experiment 2). Emotional memories were associated with an enhancement in the recollective experience that was greatest after a delay, whereas familiarity was not influenced by emotion. In amnesics with hippocampal damage the emotion effect on recollective experience was reduced. Surprisingly, however, these patients still showed a general memory advantage for emotional compared to neutral items, but this effect was manifest primarily as a facilitation of familiarity. The results support the consolidation hypothesis of recollective experience, but suggest that the effects of emotion on episodic memory are not exclusively hippocampally mediated. Rather, emotion may enhance recognition by facilitating familiarity when recollection is impaired due to hippocampal damage

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome

WWOX protein expression varies among ovarian carcinoma histotypes and correlates with less favorable outcome

BACKGROUND: The putative tumor suppressor WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome area 16q23.3-24.1. This region is a frequent target for loss of heterozygosity and chromosomal rearrangement in ovarian, breast, hepatocellular, prostate carcinomas and other neoplasias. The goal of these studies was to evaluate WWOX protein expression levels in ovarian carcinomas to determine if they correlated with clinico-pathological parameters, thus providing additional support for WWOX functioning as a tumor suppressor. METHODS: We performed WWOX protein expression analyses by means of immunobloting and immunohistochemistry on normal ovaries and specific human ovarian carcinoma Tissue Microarrays (n = 444). Univariate analysis of clinical-pathological parameters based on WWOX staining was determined by χ(2 )test with Yates' correction. The basic significance level was fixed at p < 0.05. RESULTS: Immunoblotting analysis from normal ovarian samples demonstrated consistently strong WWOX expression while 37% ovarian carcinomas showed reduced or undetectable WWOX protein expression levels. The immunohistochemistry of normal human ovarian tissue sections confirmed strong WWOX expression in ovarian surface epithelial cells and in epithelial inclusion cysts within the cortex. Out of 444 ovarian carcinoma samples analyzed 30% of tumors showed lack of or barely detectable WWOX expression. The remaining ovarian carcinomas (70%) stained moderately to strongly positive for this protein. The two histotypes showing significant loss of WWOX expression were of the Mucinous (70%) and Clear Cell (42%) types. Reduced WWOX expression demonstrated a significant association with clinical Stage IV (FIGO) (p = 0.007), negative Progesterone Receptor (PR) status (p = 0.008) and shorter overall survival (p = 0.03). CONCLUSION: These data indicate that WWOX protein expression is highly variable among ovarian carcinoma histotypes. It was also observed that subsets of ovarian tumors demonstrated loss of WWOX expression and is potentially associated with patient outcome

ATTAIN: Phase III study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer and brain metastases

The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744

European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group