Changes in Apoptotic Mechanisms Following Penetrating Ballistic-Like Brain Injury

We investigated apoptotic pathways in a model of severe traumatic brain injury, penetrating ballistic-like brain injury (PBBI). TUNEL staining identified increasing apoptosis within 24 h. From targeted arrays, 11 genes were identified for temporal mRNA evaluation. In addition, mRNA levels and enzyme activity for caspases 3, 8, and 9 were examined. In the death receptor-mediated apoptosis pathway, the relative quantities (RQs) of mRNA for tnfr1, fas, and tnf were upregulated while trail mRNA was downregulated. In the anti-apoptotic TNF-R2 pathway, tnfr2 and flip were upregulated while xiap was downregulated. These findings indicate that increases in tnf levels following injury are not only pro-apoptotic but may also signal competing anti-apoptotic mechanisms. For the mitochondria-mediated apoptosis pathway, RQs of anti-apoptotic factors bcl2a1d and birc3 were upregulated while both bcl2 and bax were downregulated. RQs for casp 3 and casp 8 increased while casp9 decreased. Enzymatic activity increased for caspases 3, 8, and 9. While multiple mechanisms promoting and inhibiting apoptosis are at play during the first week after a PBBI, the cumulative result remains increased apoptosis. The ability to understand and dissect these events will assist in the development and evaluation of treatments targeting apoptosis following severe brain injury.     

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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Approaches to the prevention of postnatal depression and anxiety – a review of the literature

Introduction: Poor maternal mental health during the perinatal period has been shown to have potentially long-lasting effects for mother and child. In recognition of this, maternal mental health is receiving increased attention from political and healthcare organizations, with a growing focus on preventing the onset of common mental health disorders.

Objective: The objective for this review is to provide an update of randomized controlled trials examining the use of interventions targeted to prevent the onset of postnatal depression and anxiety in nondiagnostic populations with universal or selected samples.

Methods: A total of four databases, EBSCO Host, Science Direct, Scopus, and Web of Science, incorporating PsychINFO were searched and papers selected according to clearly specified inclusion criteria. A large Health Technology review was published in 2016, for which the final search was conducted in December 2012. Therefore inclusion criteria were studies published from January 2013 onwards, available in English language, had a focus on prevention of postnatal maternal depression and anxiety, and used psychological interventions. Drug intervention trials were excluded.

Findings: 12 studies were identified as examining antenatal or postnatal intervention trials with an aim of preventing maternal postnatal depression and/or anxiety. There continues to be limited evidence to recommend specific prevention strategies for universal samples without further testing. There is evidence to suggest the use of rational-emotive behavioral therapy in an antenatal sample may have some utility, and the use of psychotherapy-based interventions in a postnatal setting is also supported although both require further investigation. Additionally, there is a need to gather information on acceptability, as many trials were hindered by poor adherence to interventions and high attrition that were otherwise unexplained.     

Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.     

Extreme chromosome 17 copy number instability is a prognostic factor in patients with gastroesophageal adenocarcinoma: A retrospective cohort study

Gastric and esophageal cancers frequently show genomic instability and aneuploidy. Chromosomal copy number instability (CIN) is a form of genomic instability that exerts pleiotropic effects on cellular biology and is a source of genetic heterogeneity in a population of cells. CIN results in cell‐to‐cell variation in chromosome copy number which can be detected and quantified by fluorescence in situ hybridization (FISH). CIN is a biomarker associated with differential response to a number of chemotherapy compounds. We quantified chromosome 17 copy number instability (CIN‐17) in 348 gastroesophageal adenocarcinomas by centromeric FISH in cases that were tested for HER2 amplification. We evaluated the association between CIN‐17 and clinical outcome after surgical and nonsurgical treatment. CIN‐17 was detected in 45.4% (158/348) and extreme CIN‐17 in 28.4% (99/348). Extreme CIN‐17 had no association with outcome in surgically treated patients. However, in patients treated with conventional radiation and/or chemotherapy, extreme CIN‐17 was associated with 55% reduction in overall mortality (hazard ratio, 0.448; 95% confidence interval, 0.263–0.763) after adjusting for age and clinical stage at diagnosis. Extreme CIN‐17 is detected in over a quarter of gastroesophageal adenocarcinomas and is a favorable prognostic marker in patients treated nonoperatively.