69 research outputs found
PtdIns(3,4,5)P₃-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling
Novel Association Strategy with Copy Number Variation for Identifying New Risk Loci of Human Diseases
Copy number variations (CNV) are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP) signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases
Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer
In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer
An approach to addressing governance from a health system framework perspective
As countries strive to strengthen their health systems in resource constrained contexts, policy makers need to know how best to improve the performance of their health systems. To aid these decisions, health system stewards should have a good understanding of how health systems operate in order to govern them appropriately. While a number of frameworks for assessing governance in the health sector have been proposed, their application is often hindered by unrealistic indicators or they are overly complex resulting in limited empirical work on governance in health systems. This paper reviews contemporary health sector frameworks which have focused on defining and developing indicators to assess governance in the health sector. Based on these, we propose a simplified approach to look at governance within a common health system framework which encourages stewards to take a systematic perspective when assessing governance. Although systems thinking is not unique to health, examples of its application within health systems has been limited. We also provide an example of how this approach could be applied to illuminate areas of governance weaknesses which are potentially addressable by targeted interventions and policies. This approach is built largely on prior literature, but is original in that it is problem-driven and promotes an outward application taking into consideration the major health system building blocks at various levels in order to ensure a more complete assessment of a governance issue rather than a simple input-output approach. Based on an assessment of contemporary literature we propose a practical approach which we believe will facilitate a more comprehensive assessment of governance in health systems leading to the development of governance interventions to strengthen system performance and improve health as a basic human right
Development and clinical application of an integrative genomic approach to personalized cancer therapy
A Mutation in Synaptojanin 2 Causes Progressive Hearing Loss in the ENU-Mutagenised Mouse Strain Mozart
C - Journal ArticlesBACKGROUND: Hearing impairment is the most common sensory impairment in humans, affecting 1:1,000 births. We have identified an ENU generated mouse mutant, Mozart, with recessively inherited, non-syndromic progressive hearing loss caused by a mutation in the synaptojanin 2 (Synj2), a central regulatory enzyme in the phosphoinositide-signaling cascade. METHODOLOGY/PRINCIPAL FINDINGS: The hearing loss in Mozart is caused by a p.Asn538Lys mutation in the catalytic domain of the inositol polyphosphate 5-phosphatase synaptojanin 2. Within the cochlea, Synj2 mRNA expression was detected in the inner and outer hair cells but not in the spiral ganglion. Synj2(N538K) mutant protein showed loss of lipid phosphatase activity, and was unable to degrade phosphoinositide signaling molecules. Mutant Mozart mice (Synj2(N538K/N538K)) exhibited progressive hearing loss and showed signs of hair cell degeneration as early as two weeks of age, with fusion of stereocilia followed by complete loss of hair bundles and ultimately loss of hair cells. No changes in vestibular or neurological function, or other clinical or behavioral manifestations were apparent. CONCLUSIONS/SIGNIFICANCE: Phosphoinositides are membrane associated signaling molecules that regulate many cellular processes including cell death, proliferation, actin polymerization and ion channel activity. These results reveal Synj2 as a critical regulator of hair cell survival that is essential for hair cell maintenance and hearing function
The Inositol Polyphosphate 5-Phosphatase PIPP Regulates AKT1-Dependent Breast Cancer Growth and Metastasis
SummaryMetastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer
Suspected caffeine and ephedrine toxicosis resulting from ingestion of an herbal supplement containing guarana and ma huang in dogs: 47 cases (1997-1999)
Function of heterologous and pseudo border repeats in T region transfer via the octopine virulence system of Agrobacterium tumefaciens
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