Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.

Aberrant activation of the RAS family of guanosine triphosphatases (GTPases) is prevalent in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. We previously identified somatic mutations and amplifications of the gene encoding RAS family GTPase RIT1 in lung adenocarcinomas. To explore the biological pathways regulated by RIT1 and how they relate to the oncogenic KRAS network, we performed quantitative proteomic, phosphoproteomic, and transcriptomic profiling of isogenic lung epithelial cells in which we ectopically expressed wild-type or cancer-associated variants of RIT1 and KRAS. We found that both mutant KRAS and mutant RIT1 promoted canonical RAS signaling and that overexpression of wild-type RIT1 partially phenocopied oncogenic RIT1 and KRAS, including induction of epithelial-to-mesenchymal transition. Our findings suggest that RIT1 protein abundance is a factor in its pathogenic function. Therefore, chromosomal amplification of wild-type RIT1 in lung and other cancers may be tumorigenic.

Factors Associated with Pregnancy among Incarcerated African American Adolescent Girls.

The purpose of this study was to examine the social and behavioral factors associated with pregnancy history among a sample of African American adolescent girls recruited from a short-term juvenile detention center in order to better understand the needs of this vulnerable population. Data were collected from a sample of 188 detained African American, 13-17-year-old girls in Atlanta, Georgia, who participated in a larger HIV prevention study. An audio computer-assisted self-interviewing survey was completed by participants to obtain information on socioecological factors to include individual, parental/familial, sexual risk, psychosocial, and substance use factors. Among the 188 participants, 25.5 % reported a history of pregnancy. A multivariable logistic regression model showed that girls with a history of pregnancy were more likely to live in a household receiving government aid, use hormonal contraceptives at last sex, participate in sex trading, have casual sex partners, have condomless sex in the past 90 days, and have a history of physical abuse. Girls with no history of pregnancy were more likely to have been incarcerated at least twice and to have previously used alcohol. Detention-based interventions and pregnancy prevention programs for this vulnerable population may benefit by addressing factors related to sexual behavior and development, substance use, individual background, and psychosocial health.

CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs.

Developing technologies for efficient and scalable disruption of gene expression will provide powerful tools for studying gene function, developmental pathways, and disease mechanisms. Here, we develop clustered regularly interspaced short palindromic repeat interference (CRISPRi) to repress gene expression in human induced pluripotent stem cells (iPSCs). CRISPRi, in which a doxycycline-inducible deactivated Cas9 is fused to a KRAB repression domain, can specifically and reversibly inhibit gene expression in iPSCs and iPSC-derived cardiac progenitors, cardiomyocytes, and T lymphocytes. This gene repression system is tunable and has the potential to silence single alleles. Compared with CRISPR nuclease (CRISPRn), CRISPRi gene repression is more efficient and homogenous across cell populations. The CRISPRi system in iPSCs provides a powerful platform to perform genome-scale screens in a wide range of iPSC-derived cell types, dissect developmental pathways, and model disease.

Differences in Physicians' and Nurses' Recent Suicide Attempts: An Exploratory Study.

The aim of this study was to examine the characteristics of physicians' and nurses' suicide attempts (SA). A retrospective review of 493 medical records of physicians and nurses admitted to an inpatient unit for health professionals; 36 patients had a recent SA. Depression, cluster B and C personality disorders, and a history of previous SA were more prevalent in patients with a recent SA compared to those without it. Both professional groups preferred drug overdose as a suicide method. Physicians made more lethal attempts and had a history of more previous stressors than nurses. Depression, cluster B and C personality disorders, and previous SA should be appropriately screened and treated in order to prevent SA amongst physicians and nurses.

Dating violence and suicidal behavior in adolescents.

The aim of this paper is to assess the possible consequences of adolescent physical, emotional and sexual dating violence through a review of the literature on the topic. An electronic search of major biomedical bibliographic databases (Pubmed, ISI, PsycINFO) was used to retrieve articles providing information on the prevalence rates, risk factors, associated consequences and possible preventive measures for adolescent dating violence across different populations. Currently, there have been few longitudinal studies conducted to identify potential risk factors for entering a violent dating relationship in adolescence. Risky behaviors such as early sexual intercourse may predispose someone for victimization. Dating violence itself is also a predictor of future dating violence. Adolescent dating violence was associated with an increase in other violence-related behaviors, substance use, depression, poorer educational outcomes, posttraumatic stress, unhealthy weight control and risky sexual behavior. The association between adolescent dating violence and an increase in suicidal behavior is a major public health concern. Future research should focus on longitudinal studies so that a causal relationship between dating violence and suicidality may be better understood.

Oscillatory shear stress induces mitochondrial superoxide production: implication of NADPH oxidase and c-Jun NH2-terminal kinase signaling.

Fluid shear stress is intimately linked with vascular oxidative stress and atherosclerosis. We posited that atherogenic oscillatory shear stress (OSS) induced mitochondrial superoxide (mtO2•-) production via NADPH oxidase and c-Jun NH(2)-terminal kinase (JNK-1 and JNK-2) signaling. In bovine aortic endothelial cells, OSS (±3 dyn/cm2) induced JNK activation, which peaked at 1 h, accompanied by an increase in fluorescein isothiocyanate-conjugated JNK fluorescent and MitoSOX Red (specific for mtO2•- production) intensities. Pretreatment with apocynin (NADPH oxidase inhibitor) or N-acetyl cysteine (antioxidant) significantly attenuated OSS-induced JNK activation. Apocynin further reduced OSS-mediated dihydroethidium and MitoSOX Red intensities specific for cytosolic O2•- and mtO2•- production, respectively. As a corollary, transfecting bovine aortic endothelial cells with JNK siRNA (siJNK) and pretreating with SP600125 (JNK inhibitor) significantly attenuated OSS-mediated mtO2•- production. Immunohistochemistry on explants of human coronary arteries further revealed prominent phosphorylated JNK staining in OSS-exposed regions. These findings indicate that OSS induces mtO2•- production via NADPH oxidase and JNK activation relevant for vascular oxidative stress.