Translational research : the journal of laboratory and clinical medicine
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Obesity and hyperinsulinemia are known risk factors for endometrial cancer, yet the biological pathways underlying this relationship are incompletely understood. This study investigated protein expression in endometrial cancer and benign tissue and its correlation with obesity and insulin resistance. One hundred and seven women undergoing hysterectomy for endometrial cancer or benign conditions provided a fasting blood sample and endometrial tissue. ⋯ Obese women without cancer had increased mitogenic and antiapoptotic signaling by way of upregulation of Mcl-1, DUSP4, and Insulin Receptor-b. This exploratory study identified a number of candidate proteins specific to endometrioid endometrial cancer and benign endometrial tissues. Obesity and insulin resistance in women with benign endometrium leads to specific upregulation of proteins involved in insulin and driver oncogenic signaling pathways such as the PI3K-AKT-mTOR and growth factor signaling pathways which are mitogenic and also disruptive to metabolism.
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In view of the increasing prevalence of gestational diabetes mellitus (GDM) and the increased risks of delivering a macrosomic infant, developing preeclampsia, and suffering a perinatal death due to GDM, GDM has emerged as a growing public health problem. Although the placenta was suggested to play a crucial role in the pathology of GDM, the mechanisms that induce the development of GDM are still obscure. Fibrinogen-like protein (FGL)-1 is a hepatokine that plays an important role in hepatogenesis, as well as in nonalcoholic fatty liver disease and diabetes. ⋯ In addition, plasma concentrations of FGL-1 were higher in subjects with GDM, and the increased circulating FGL-1 might contribute to systemic insulin resistance. FGL-1 disrupted the gluconeogenic action of insulin in HepG2 cells, and decreased insulin-induced glucose uptake by L6 myotubes. Taken together, placental FGL-1 possibly plays a role in the impairment of insulin function in the development of GDM, and it might be a novel biomarker for diagnosing GDM.
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Comparative Study
The embedded researcher model in Australian healthcare settings: comparison by degree of "embeddedness".
The embedded researcher model is a health-academic partnership where researchers are core members of a healthcare organization, with an aim to support evidence translation. The purpose of this study was to describe the characteristics and experiences of embedded researchers in Australian healthcare settings, and investigate how the model is experienced differently based on the level of "embeddedness." This exploratory study utilized a purpose-designed online survey. Responses were described using Word and Excel and analyzed using SPSS. ⋯ Of those with a formal dual affiliation over a quarter reported conflict between expectations of the healthcare and academic organizations. Respondents with a primary academic affiliation were older, more qualified, had more research experience, had been in the role longer, and had more positive perceptions of the research culture of healthcare organizations. This study provides a starting point for healthcare organizations and academic institutions to partner in the further development and implementation of this model.
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Cardiac alterations (hypertrophic/dilated cardiomyopathy, and rhythm alterations) are one of the major causes of mortality and morbidity in propionic acidemia (PA), caused by the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC), involved in the catabolism of branched-chain amino acids, cholesterol, and odd-chain fatty acids. Impaired mitochondrial oxidative phosphorylation has been documented in heart biopsies of PA patients, as well as in the hypomorphic Pcca-/-(A138T) mouse model, in the latter correlating with increased oxidative damage and elevated expression of cardiac dysfunction biomarkers atrial and brain natriuretic peptides (ANP and BNP) and beta-myosin heavy chain (β-MHC). ⋯ In vitro studies in HL-1 cardiomyocytes indicate that propionate, the major toxic metabolite accumulating in the disease, triggers the increase in expression levels of miRNAs, BNP, and β-MHC, concomitant with an increase in reactive oxygen species. Our results highlight miRNAs and signaling alterations in the PCC-deficient heart which may contribute to the development of PA-associated cardiomyopathy and provide a basis to identify new targets for therapeutic intervention.
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Seasonal influenza viruses cause major morbidity and mortality worldwide, threatening in particular older adults and the immunocompromised. Two classes of influenza therapeutics dominate current disease management, but both are compromised by pre-existing or rapidly emerging viral resistance. We have recently reported a novel ribonucleoside analog clinical candidate, EIDD-2801, that combines potent antiviral efficacy in ferrets and human airway epithelium cultures with a high barrier against viral escape. ⋯ Administered in 12-hour intervals, three 7 mg/kg doses of EIDD-2801 were sufficient for maximal therapeutic benefit against a pandemic IAV and significantly shortened the time to resolution of clinical signs. Ferrets infected with pandemic IAV and treated following the minimally efficacious EIDD-2801 regimen demonstrated significantly less shed virus and inflammatory cellular infiltrates in nasal lavages, but mounted a robust humoral antiviral response after recovery that was indistinguishable from that of vehicle-treated animals. These results provide an experimental basis in a human disease-relevant influenza animal model for clinical testing of EIDD-2801.