Translational research : the journal of laboratory and clinical medicine
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Invasive aspergillosis (IA) is a major cause of critical illness in immunocompromised (IC) patients. However, current fungal tests are limited. Disease-specific gene expression patterns in circulating host cells show promise as novel diagnostics, however it is unknown whether such a 'signature' exists for IA and the effect of iatrogenic immunosuppression on any such biomarkers. ⋯ The host transcriptomic response to IA is robust and conserved. Pharmacologic perturbation of the host immune response has powerful effects on classifier performance and must be considered when developing such novel diagnostics. When appropriately designed, host-derived peripheral blood transcriptomic responses demonstrate the ability to accurately diagnose Aspergillus infection, even in the presence of immunosuppression.
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Deposition of hydroxyapatite (HAP) basal to the retinal pigment epithelium (RPE) is linked to the progression of age-related macular degeneration (AMD). Serum-deprivation of RPE cells in culture mimics some features of AMD. We now show that serum-deprivation also leads to the induction of amelotin (AMTN), a protein involved in hydroxyapatite mineralization in enamel. ⋯ In situ hybridization and immunofluorescence imaging of human eye tissue show that AMTN is expressed in RPE of donor eyes with geographic atrophy ("dry" AMD) in regions with soft drusen containing HAP spherules or nodules. AMTN is not found in hard drusen, normal RPE, or donor eyes diagnosed with wet AMD. These findings suggest that AMTN is involved in formation of HAP spherules or nodules in AMD, and as such provides a new therapeutic target for slowing disease progression.
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Accurately prognostic evaluation of patients with stage I-II pancreatic ductal adenocarcinoma (PDAC) is of importance to treatment decision and patient management. Most previously reported prognostic signatures were based on risk scores summarized from quantitative expression measurements of signature genes, which are susceptible to experimental batch effects and impractical for clinical applications. Based on the within-sample relative expression orderings of genes, we developed a robust qualitative transcriptional prognostic signature, consisting of 64 gene pairs (64-GPS), to predict the overall survival (OS) of 161 stage I-II PDAC patients in the training dataset who were treated with surgery only. ⋯ The epigenomic analysis showed that the epigenetic alternations may cause consistently transcriptional changes between the 2 different prognostic groups. The genomic analysis revealed that mutation‑induced disturbances in several key genes, such as LRMDA, MAPK10, and CREBBP, might lead to poor prognosis for PDAC patients. Conclusively, the 64-GPS can robustly predict the prognosis of patients with stage I-II PDAC, which provides theoretical basis for clinical individualized treatment.
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The mechanisms underlying metabolic and reproductive dysfunction caused by arrhythmic circadian clock and their involvement in polycystic ovary syndrome (PCOS) are not understood. Here, we addressed this issue using rats with constant light or darkness exposure for 8 weeks and human leukocytes and serum of PCOS and non-PCOS patients. Additionally, we utilized HepG2 cells and KGN cells to verify the molecular mechanisms. ⋯ Furthermore, melatonin treatment relieved the hyperinsulinemia and hyperandrogenism of darkness-treated rats via BMAL1, PER1, and PER2. Restoring normal light/dark exposure for 2 weeks reversed these conditions via BMAL1. In conclusion, our findings elucidated the critical function of circadian clock genes, especially BMAL1, PER1, and PER2 in PCOS, which might aid the development of feasible preventive and therapeutic strategies for PCOS in women with biorhythm disorder.
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Multicenter Study Observational Study
Peripheral microRNA panels to guide the diagnosis of familial cardiomyopathy.
Etiology-based diagnosis of dilated cardiomyopathy (DCM) is challenging. We evaluated whether peripheral microRNAs (miRNAs) could be used to characterize the DCM etiology. We investigated the miRNA plasma profiles of 254 subjects that comprised 5 groups: Healthy subjects (n = 70), idiopathic DCM patients (n = 55), ischemic DCM patients (n = 60) and 2 groups of patients with pathogenic variants responsible for familial DCM in the LMNA (LMNAMUT, n = 37) and BAG3 (BAG3MUT, n = 32) genes. ⋯ The 5-miRNA panel discriminated between carriers and healthy controls with AUCs ranging from 83.2 to 90.8. Again, only 1 to 10 of the subjects in the lowest tertiles of the 5-miRNA panel were carriers of pathogenic variants. In conclusion, miRNA signatures could be used to rule out patients with pathogenic variants responsible for DCM.