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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers based on five-year survival rates. Genes contributing to chemoresistance represent novel therapeutic targets that can improve treatment response. Increased expression of ANGPTL4 in tumors correlates with poor outcomes in pancreatic cancer. Methods: We used statistical analysis of publicly available gene expression data (TCGA-PAAD) to test whether expression of ANGPTL4 and its downstream targets, ITGB4 and APOL1, were correlated with patient survival. We measured the impact of ANGPTL4 overexpression in a common pancreatic cancer cell line, MIA PaCa-2 cells, using CRISPRa for overexpression and DsiRNA for knockdown. We characterized global gene expression changes associated with high levels of ANGPTL4 and response to gemcitabine treatment using RNA-sequencing. Gemcitabine dose response curves were calculated on modified cell lines by measuring cell viability with CellTiter-Glo (Promega). Impacts on cell migration were measured using a time course scratch assay. Results: We show that ANGPTL4 overexpression leads to in vitro resistance to gemcitabine and reduced survival times in patients. Overexpression of ANGPTL4 induces transcriptional signatures of tumor invasion and metastasis, proliferation and differentiation, and inhibition of apoptosis. Analyses revealed an overlapping signature of genes associated with both ANGPTL4 activation and gemcitabine response. Increased expression of the genes in this signature in patient PDAC tissues was significantly associated with shorter patient survival. We identified 42 genes that were both co-regulated with ANGPTL4 and were responsive to gemcitabine treatment. ITGB4 and APOL1 were among these genes. Knockdown of either of these genes in cell lines overexpressing ANGPTL4 reversed the observed gemcitabine resistance and inhibited cellular migration associated with epithelial to mesenchymal transition (EMT) and ANGPTL4 overexpression. Conclusions: These data suggest that ANGPTL4 promotes EMT and regulates the genes APOL1 and ITGB4. Importantly, we show that inhibition of both targets reverses chemoresistance and decreases migratory potential. Our findings have revealed a novel pathway regulating tumor response to treatment and suggest relevant therapeutic targets in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. Methods: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. Results: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. Conclusions: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling. [ABSTRACT FROM AUTHOR]

Background: Current diagnostic tools for prostate cancer lack specificity and sensitivity for detecting very early lesions. DNA methylation is a stable genomic modification that is detectable in peripheral patient fluids such as urine and blood plasma that could serve as a non-invasive diagnostic biomarker for prostate cancer.Methods: We measured genome-wide DNA methylation patterns in 73 clinically annotated fresh-frozen prostate cancers and 63 benign-adjacent prostate tissues using the Illumina Infinium HumanMethylation450 BeadChip array. We overlaid the most significantly differentially methylated sites in the genome with transcription factor binding sites measured by the Encyclopedia of DNA Elements consortium. We used logistic regression and receiver operating characteristic curves to assess the performance of candidate diagnostic models.Results: We identified methylation patterns that have a high predictive power for distinguishing malignant prostate tissue from benign-adjacent prostate tissue, and these methylation signatures were validated using data from The Cancer Genome Atlas Project. Furthermore, by overlaying ENCODE transcription factor binding data, we observed an enrichment of enhancer of zeste homolog 2 binding in gene regulatory regions with higher DNA methylation in malignant prostate tissues.Conclusions: DNA methylation patterns are greatly altered in prostate cancer tissue in comparison to benign-adjacent tissue. We have discovered patterns of DNA methylation marks that can distinguish prostate cancers with high specificity and sensitivity in multiple patient tissue cohorts, and we have identified transcription factors binding in these differentially methylated regions that may play important roles in prostate cancer development. [ABSTRACT FROM AUTHOR]

Background: The liver X receptors (LXRs, NR1H2 and NR1H3) and peroxisome proliferator-activated receptor gamma (PPARG, NR1C3) nuclear receptor transcription factors (TFs) are master regulators of energy homeostasis. Intriguingly, recent studies suggest that these metabolic regulators also impact tumor cell proliferation. However, a comprehensive temporal molecular characterization of the LXR and PPARG gene regulatory responses in tumor cells is still lacking. Methods: To better define the underlying molecular processes governing the genetic control of cellular growth in response to extracellular metabolic signals, we performed a comprehensive, genome-wide characterization of the temporal regulatory cascades mediated by LXR and PPARG signaling in HT29 colorectal cancer cells. For this analysis, we applied a multi-tiered approach that incorporated cellular phenotypic assays, gene expression profiles, chromatin state dynamics, and nuclear receptor binding patterns. Results: Our results illustrate that the activation of both nuclear receptors inhibited cell proliferation and further decreased glutathione levels, consistent with increased cellular oxidative stress. Despite a common metabolic reprogramming, the gene regulatory network programs initiated by these nuclear receptors were widely distinct. PPARG generated a rapid and short-term response while maintaining a gene activator role. By contrast, LXR signaling was prolonged, with initial, predominantly activating functions that transitioned to repressive gene regulatory activities at late time points. Conclusions: Through the use of a multi-tiered strategy that integrated various genomic datasets, our data illustrate that distinct gene regulatory programs elicit common phenotypic effects, highlighting the complexity of the genome. These results further provide a detailed molecular map of metabolic reprogramming in cancer cells through LXR and PPARG activation. As ligand-inducible TFs, these nuclear receptors can potentially serve as attractive therapeutic targets for the treatment of various cancers. [ABSTRACT FROM AUTHOR]

Background: There are few accounts of evidence-based interventions for depression and other common mental disorders (CMDs) in primary care in low-income countries. The Friendship Bench Project is a collaborative care mental health intervention in primary care in Harare for CMDs which began as a pilot in 2006. Case presentation: We employed a mixture of quantitative and qualitative approaches to investigate the project's acceptability and implementation, 4-8 years after the initial pilot study. We carried out basic descriptive analyses of routine data on attendance collected between 2010 and 2014. We also conducted five focus group discussions (FGDs) with LHWs in 2013 and 12 in-depth interviews, six with staff and six with patients, to explore experiences of the intervention, which we analysed using grounded theory. Results show that the intervention appears highly acceptable as evidenced by a consistent number of visits between 2010 and 2014 (mean 505 per year, SD 132); by the finding that the same team of female community LHWs employed as government health promoters continue to deliver assessment and problem-solving therapy, and the perceived positive benefits expressed by those interviewed. Clients described feeling 'relieved and relaxed' after therapy, and having their 'mind opened', and LHWs describing satisfaction from being agents of change. Characteristics of the LHWs (status in the community, maturity, trustworthiness), and of the intervention (use of locally validated symptom screen, perceived relevance of problem-solving therapy) and continuity of the LHW team appeared crucial. Challenges to implementation included the LHWs ongoing need for weekly supervision despite years of experience; the supervisors need for supervision for herself; training needs in managing suicidal and hostile clients; poor documentation; lack of follow-up of depressed clients; and poor access to antidepressants. Conclusions: This case study shows that a collaborative care intervention for CMDs is positively received by patients, rewarding for LHWs to deliver, and can be sustained over time at low cost. Next steps include evaluation of the impact of the intervention through a randomised trial, and testing of a technological platform for supporting supervision and monitoring clients' attendance. [ABSTRACT FROM AUTHOR]

Introduction: Mental health facilities in Uganda remain underutilized, despite efforts to decentralize the services. One of the possible explanations for this is the help-seeking behaviours of people with mental health problems. Unfortunately little is known about the factors that influence the help-seeking behaviours. Delays in seeking proper treatment are known to compromise the outcome of the care. Aim: To examine the help-seeking behaviours of individuals with mental health problems, and the factors that may influence such behaviours in Uganda. Method: Sixty-two interviews and six focus groups were conducted with stakeholders drawn from national and district levels. Thematic analysis of the data was conducted using a framework analysis approach. Results: The findings revealed that in some Ugandan communities, help is mostly sought from traditional healers initially, whereas western form of care is usually considered as a last resort. The factors found to influence helpseeking behaviour within the community include: beliefs about the causes of mental illness, the nature of service delivery, accessibility and cost, stigma. Conclusion: Increasing the uptake of mental health services requires dedicating more human and financial resources to conventional mental health services. Better understanding of socio-cultural factors that may influence accessibility, engagement and collaboration with traditional healers and conventional practitioners is also urgently required. [ABSTRACT FROM AUTHOR]

Background: Despite the 1991 reforms of the health system in Zambia, mental health is still given low priority. This is evident from the fragmented manner in which mental health services are provided in the country and the limited budget allocations, with mental health services receiving 0.4% of the total health budget. Most of the mental health services provided are curative in nature and based in tertiary health institutions. At primary health care level, there is either absence of, or fragmented health services. Aims: The aim of this paper was to explore health providers' views about mental health integration into primary health care. Methods: A mixed methods, structured survey was conducted of 111 health service providers in primary health care centres, drawn from one urban setting (Lusaka) and one rural setting (Mumbwa). Results: There is strong support for integrating mental health into primary health care from care providers, as a way of facilitating early detection and intervention for mental health problems. Participants believed that this would contribute to the reduction of stigma and the promotion of human rights for people with mental health problems. However, health providers felt they require basic training in order to enhance their knowledge and skills in providing health care to people with mental health problems. Recommendations: It is recommended that health care providers should be provided with basic training in mental health in order to enhance their knowledge and skills to enable them provide mental health care to patients seeking help at primary health care level. Conclusion: Integrating mental health services into primary health care is critical to improving and promoting the mental health of the population in Zambia. [ABSTRACT FROM AUTHOR]

Background: The Ugandan government recognizes mental health as a serious public health and development concern, and has of recent implemented a number of reforms aimed at strengthening the country's mental health system. The aim of this study was to provide a profile of the current mental health policy, legislation and services in Uganda. Methods: A survey was conducted of public sector mental health policy and legislation, and service resources and utilisation in Uganda, in the year 2005, using the World Health Organization's Assessment Instrument for Mental Health Systems (WHO-AIMS) Version 2.2. Results: Uganda's draft mental health policy encompasses many positive reforms, including decentralization and integration of mental health services into Primary Health Care (PHC). The mental health legislation is however outdated and offensive. Services are still significantly underfunded (with only 1% of the health expenditure going to mental health), and skewed towards urban areas. Per 100,000 population, there were 1.83 beds in mental hospitals, 1.4 beds in community based psychiatric inpatient units, and 0.42 beds in forensic facilities. The total personnel working in mental health facilities were 310 (1.13 per 100,000 population). Only 0.8% of the medical doctors and 4% of the nurses had specialized in psychiatry. Conclusion: Although there have been important developments in Uganda's mental health policy and services, there remains a number of shortcomings, especially in terms of resources and service delivery. There is an urgent need for more research on the current burden of mental disorders and the functioning of mental health programs and services in Uganda. [ABSTRACT FROM AUTHOR]

There have been dramatic advances in the development of web-based data collection instruments. This paper outlines a systematic web-based approach to facilitate this process through locally developed code and to describe the results of using this process after two years of data collection. We provide a detailed example of a web-based method that we developed for a study in Starr County, Texas, assessing high school students' work and health status. This web-based application includes data instrument design, data entry and management, and data tables needed to store the results that attempt to maximize the advantages of this data collection method. The software also efficiently produces a coding manual, web-based statistical summary and crosstab reports, as well as input templates for use by statistical packages. Overall, web-based data entry using a dynamic approach proved to be a very efficient and effective data collection system. This data collection method expedited data processing and analysis and eliminated the need for cumbersome and expensive transfer and tracking of forms, data entry, and verification. The code has been made available for non-profit use only to the public health research community as a free download [1]. [ABSTRACT FROM AUTHOR]