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Suicide is one of the leading causes of death in people with schizophrenia. Identifying risk factors for suicide in schizophrenia is therefore an important clinical and research priority.A cross-sectional secondary analysis was conducted on the DNA Polymorphisms in Mental Illness Study (DPIM) data. Suicidality data was extracted, and the number of positive and negative symptoms were established for a total of 1494 participants. Logistic and negative binomial regression analyses were conducted to assess for associations between positive or negative symptoms and suicidal ideation, attempt, or number of attempts, whilst adjusting for potential confounders.Negative symptoms were associated with a reduction in the risk of suicidal ideation (odds ratio [OR]: 0.83; 95 % CI: 0.75-0.91) and suicide attempt (OR: 0.79; 95 % CI: 0.71-0.88) after adjusting for age and sex. Positive symptoms were associated with an increased risk of suicidal ideation (OR: 1.06; 95 % CI: 1.03-1.09), suicide attempt (OR: 1.04; 95 % CI: 1.00-1.07) and number of suicide attempts (incidence rate ratio [IRR]: 1.05; 95 % CI: 1.01-1.08). Further adjusting for depressive symptoms slightly increased the magnitude of associations with negative symptoms but attenuated associations between positive symptoms and suicidality to the null.Negative symptoms are associated with a reduced risk of suicidality, whilst positive symptoms are associated with an increased risk of suicidality. Depressive symptoms may confound or mediate these associations.

The characteristics that a supervisor of multiple autonomous and semi-autonomous systems should possess remain unclear. Determination of these qualities would support job performance as well as recruiting and training. To evaluate the human characteristics currently being considered by human-in-the-loop experiments, a review of the multiple remote vehicle supervision literature was conducted. The human characteristics addressed included: gender, domain relevant experience, working memory, supervisory relevant skills and abilities (e.g., visual skills, spatial ability, attentional control, vigilance), and traits related to multi-tasking (e.g., stress, resilience). The discussion identifies gaps in the current state of the art with respect to the consideration of human characteristics for multi-autonomous and semi-autonomous systems supervision where at least one vehicle is an aircraft.

IMPORTANCE: Patients with language barriers have a higher risk of experiencing hospital safety events. This study hypothesized that language barriers would be associated with poorer perceptions of hospital safety climate relating to communication openness. OBJECTIVE: To examine disparities in reported hospital safety climate by language proficiency in a cohort of hospitalized children and their families. DESIGN, SETTING, AND PARTICIPANTS: This cohort study conducted from April 29, 2019, through March 1, 2020, included pediatric patients and parents or caregivers of hospitalized children at general and subspecialty units at 21 US hospitals. Randomly selected Arabic-, Chinese-, English-, and Spanish-speaking hospitalized patients and families were approached before hospital discharge and were included in the analysis if they provided both language proficiency and health literacy data. Participants self-rated language proficiency via surveys. Limited English proficiency was defined as an answer of anything other than “very well” to the question “how well do you speak English?” MAIN OUTCOMES AND MEASURES: Primary outcomes were top-box (top most; eg, strongly agree) 5-point Likert scale ratings for 3 Children’s Hospital Safety Climate Questionnaire communication openness items: (1) freely speaking up if you see something that may negatively affect care (top-box response: strongly agree), (2) questioning decisions or actions of health care providers (top-box response: strongly agree), and (3) being afraid to ask questions when something does not seem right (top-box response: strongly disagree [reverse-coded item]). Covariates included health literacy and sociodemographic characteristics. Logistic regression was used with generalized estimating equations to control for clustering by site to model associations between openness items and language proficiency, adjusting for health literacy and sociodemographic characteristics. RESULTS: Of 813 patients, parents, and caregivers who were approached to participate in the study, 608 completed surveys (74.8% response rate). A total of 87.7% (533 of 608) of participants (434 [82.0%] female individuals) completed language proficiency and health literacy items and were included in the analyses; of these, 14.1% (75) had limited English proficiency. Participants with limited English proficiency had lower odds of freely speaking up if they see something that may negatively affect care (adjusted odds ratio [aOR], 0.26; 95% CI, 0.15-0.43), questioning decisions or actions of health care providers (aOR, 0.19; 95% CI, 0.09-0.41), and being unafraid to ask questions when something does not seem right (aOR, 0.44; 95% CI, 0.27-0.71). Individuals with limited health literacy (aOR, 0.66; 95% CI, 0.48-0.91) and a lower level of educational attainment (aOR, 0.59; 95% CI, 0.36-0.95) were also less likely to question decisions or actions. CONCLUSIONS AND RELEVANCE: This cohort study found that limited English proficiency was associated with lower odds of speaking up, questioning decisions or actions of providers, and being unafraid to ask questions when something does not seem right. This disparity may contribute to higher hospital safety risk for patients with limited English proficiency. Dedicated efforts to improve communication with patients and families with limited English proficiency are necessary to improve hospital safety and reduce disparities.

Aims Wernicke–Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. Methods Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. Results Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case–control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10−11). Conclusion This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.

Introduction Cancer cachexia is associated with poor surgical outcomes, including increased length of stay, morbidity and mortality. Cachexia is a complex multi-faceted pathological process consistently associated with energy imbalance via hypermetabolism. Beyond this, pre-clinical animal models suggest mitochondrial dysfunction to be an important component of cachexia, although this is unconfirmed in humans. This study aimed to investigate the mitochondrial function of pre-surgical cancer patients, and the impact of exercise prehabilitation on this. Methods This study was approved by an NHS research ethics committee (IRAS: 275264). Male patients awaiting surgery with curative intent for colorectal and prostate cancer were eligible, with healthy volunteers recruited for comparison. Muscle biopsies of vastus lateralis were taken before and after 4-weeks home-based exercise (3x/wk). Mitochondrial oxidative phosphorylation (OXPHOS) was analysed using high-resolution respirometry (Oroboros Instruments). Results Eleven cancer patients and 6 healthy volunteers were recruited. Cancer patients had significantly lower maximal coupled (44.49pmol/(s*mg) vs. 74.81pmol/(s*mg), p=0.004) and uncoupled (55.82pmol/(s*mg) vs. 100.00pmol/(s*mg), p Conclusion Declines in mitochondrial function appear to play a role in cancer cachexia. Short-term exercise training, in keeping with target timeframes for surgery (i.e.

Figure S1 shows sensitivity of NCI-H2077 cells to FGFR inhibition

Spearman rank-correlation coefficient (r) between the densities of T-cells

Supplementary Tables 1 and 2 PDF file 91K, Table 1 contains clinical and genotypic data from the patient cohort referred to in Fig. 6. Table 2 contains shRNA target sequences

Supplementary Figure Legends 1-7 from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

Supplementary Figures and Legends

Supplementary Figure S3 PDF file 66K,Additional data related to the proliferative and apoptotic phenotypes of CRC cells expressing mutant Ras

MIR21 expression after adjusting for cellularity in colorectal cancer tissue and statistical analysis

Supplementary Fig. 1: Mutation rate and ploidy for each individual patient's primary and metastatic sample (cohort 1);Supplementary Fig. 2: Validation of genomic heterogeneity within primary tumor and between primary tumor and lymph node (LN) metastases detected by next generation sequencing (NGS) with fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC);Supplementary Fig. 3: PANGEA: Platform clinical trial of molecularly driven therapies in patients with previously untreated GEA;Supplementary Fig. 4: Biomarker profiling of PANGEA where the biomarker profiling of the metastatic tumor did not lead to treatment reassignment relative to treatments assigned based upon the primary tumor

Ordinal logistic regression analysis to assess the association of tumor PDCD1LG2 (PD-L2) expression (predictor) with the overall lymphocytic reaction score (outcome)

Supplementary Figure Legend

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR.See related commentary by Sundar and Tan, p. 14.See related article by Janjigian et al., p. 49.This article is highlighted in the In This Issue feature, p. 1

Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOAY42C, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOAY42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOAY42C exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. RHOAY42C mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP–TAZ, PI3K–AKT, and β-catenin. RHOAY42C murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled with sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers.Significance:The functional significance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOAY42C mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and define how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors.See related commentary by Benton and Chernoff, p. 182.This article is highlighted in the In This Issue feature, p. 161

Supplementary Fig. S2. Histone mark profiles in known menin targets

Supplementary Methods

List of Models

PDF - 36KB, Sensitivity of NCI-H2286 and NCI-H2286-DR to MEK inhibitor is unchanged in the presence or absence of dasatinib.