Brugia malayi Gene Expression in Response to the Targeting of the Wolbachia Endosymbiont by Tetracycline Treatment

Filarial parasites afflict hundreds of millions of individuals worldwide, and cause significant public health problems in many of the poorest countries in the world. Most of the human filarial parasite species, including Brugia malayi, harbor endosymbiotic bacteria of the genus Wolbachia. Elimination of the endosymbiont leads to sterilization of the adult female worm. The need exists for the development of new chemotherapeutic approaches that can practically exploit the vulnerability of the filaria to the loss of the Wolbachia. In this study we performed ultrastructural and microarray analyses of female worms collected from infected jirds treated with tetracycline. Results suggest that the endosymbiotic bacteria were specifically affected by the antibiotic. Furthermore, in response to the targeting of the endosymbiont, the parasites modulated expression of their genes. When exposed to tetracycline, the parasites over-expressed genes involved in protein synthesis. Expression of genes involved in cuticle biosynthesis and energy metabolism was, on the other hand, limited

Functional Analysis of the Cathepsin-Like Cysteine Protease Genes in Adult Brugia malayi Using RNA Interference

Filarial nematodes are an important group of human pathogens, causing lymphatic filariasis and onchocerciasis, and infecting around 150 million people throughout the tropics with more than 1.5 billion at risk of infection. Control of filariasis currently relies on mass drug administration (MDA) programs using drugs which principally target the microfilarial life-cycle stage. These control programs are facing major challenges, including the absence of a drug with macrofilaricidal or permanent sterilizing activity, and the possibility of the development of drug-resistance against the drugs available. Cysteine proteases are essential enzymes which play important roles in a wide range of cellular processes, and the cathepsin-like cysteine proteases have been identified as potential targets for drug or vaccine development in many parasites. Here we have studied the function of several of the cathepsin-like enzymes in the filarial nematode, B. malayi, and demonstrate that these cysteine proteases are involved in the development of embryos, show similar functions to their counterparts in C. elegans, and therefore, provide an important target for future drug development targeted to eliminate filariasis

Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

A meta-analysis of interventions to increase adherence to medication regimens for pediatric otitis media and streptococcal pharyngitis

Thesis (M.A.)--University of Kansas, Psychology, 2007.Interventions to increase adherence to medication regimens for acute pediatric illnesses are important for both individual and public health outcomes. To date, there has not been a comprehensive, quantitative analysis of the effectiveness of interventions for acute pediatric illnesses. The current study used meta-analysis to quantitatively synthesize the adherence intervention literature for two common acute childhood illnesses and examined the magnitude of change in adherence as indicated by different outcome measures and the relationship between type of intervention and adherence outcome. Combination interventions were more effective than single strategy interventions. However, families receiving educational interventions alone did not demonstrate better adherence than control groups. Indirect measures of adherence showed more change in adherence than direct measures. The results of this meta-analysis suggest that further work is needed to develop effective interventions for improving adherence for the medication regimens required for short term illness and for optimizing health outcomes

Searching the scientific literature: Implications for quantitative and qualitative reviews

Literature reviews are an essential step in the research process and are included in all empirical and review articles. Electronic databases are commonly used to gather this literature. However, several factors can affect the extent to which relevant articles are retrieved, influencing future research and conclusions drawn. The current project examined articles obtained by comparable search strategies in two electronic archives using an exemplar search to illustrate factors that authors should consider when designing their own search strategies. Specifically, literature searches were conducted in PsycINFO and PubMed targeting review articles on two exemplar disorders (bipolar disorder and attention deficit/hyperactivity disorder) and issues of classification and/or differential diagnosis. Articles were coded for relevance and characteristics of article content. The two search engines yielded significantly different proportions of relevant articles overall and by disorder. Keywords differed across search engines for the relevant articles identified. Based on these results. it is recommended that when gathering literature for review papers, multiple search engines should be used, and search syntax and strategies be tailored to the unique capabilities of particular engines. For meta-analyses and systematic reviews, authors may consider reporting the extent to which different archives or sources yielded relevant articles for their particular review. (C) 2012 Elsevier Ltd. All rights reserved

A Pragmatic Guide to Qualitative Analysis for Pediatric Researchers

Objective To describe four approaches to qualitative analysis in order to provide a pragmatic, application-oriented guide to their use in research focused on children and their families. Methods Four commonly used approaches to qualitative analysis—framework analysis, rapid qualitative analysis, content analysis, and reflexive thematic analysis—are described and compared, including their analytic strategies, tips for use, terminology, and application to a hypothetical example. Results A pragmatic guide to each method is provided as well as examples of how each analytic approach could be utilized to analyze the same dataset. Conclusions A variety of approaches to qualitative analysis are available to both novice and experienced qualitative researchers. The approach selected from the options presented in this article will depend on numerous factors, such as the clinical problem being explored, research context, aims, objectives, research questions, and resources available such as time and funds, and the qualitative expertise of the team