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Examination of the allostatic load develop and its longitudinal association with well being outcomes inside the Celtics Puerto Rican Wellness Examine.
A similar behavior was observed in patients with macroalbuminuria or normoalbuminuria (p = 0.219, and 0.109, respectively), with a significant trend in those with microalbuminuria (p = 0.019). Even in patients with HbA1c  less then  7, high HbA1c_CV also predicts rapid eGFR decline. Before macroalbuminuria, minimizing HbA1c_CV also has renal benefit. Conclusions HbA1c variability is an independent risk factor for deterioration of renal function. Even with well-controlled HbA1c levels ( less then 7%), patients with high HbA1c_CV still experienced faster eGFR decline. Early minimization of glycemic variability (before macroalbuminuira) can curb deterioration of renal function. Monitoring and lowering of HbA1c_CV is highly recommended for diabetic care. © The Author(s), 2020.Background Asthma is a common chronic airway disease associated with hyperresponsiveness and airway inflammation. Anti-inflammatory medication especially inhaled corticosteroids are important for control of airway inflammation, decrease of airway hyperresponsiveness and lung function variability, reduce asthma symptoms, and improve lung function as well as quality of life. Most studies investigating the influence of complementary and alternative medicine (CAM) in asthma measure clinical effectiveness, but only few evaluate the impact on markers of airway inflammation. Objective The aim of this study was to investigate the effect of reflexology and homeopathy added to conventional treatment on different markers of airway inflammation in asthma. Methods Eighty-four patients with asthma were randomized to receive conventional treatment alone or conventional treatment with addition of homeopathy or reflexology in a single center, investigator blinded, controlled, one-year trial. During the study period, patients regularly consulted their general practitioner for evaluation and asthma treatment. At randomization, and after 6 and 12 months, methacholine challenge test and measurement of exhaled nitric oxide were performed. Blood samples were collected for eosinophil count and measurement of serum eosinophil cationic protein. Results No significant differences between groups for any of the inflammatory markers were demonstrated. Methacholine responsiveness improved in all three groups but improvements were not statistically significant within and between groups. Conclusions This randomized controlled study of reflexology and homeopathy failed to show significant improvement on selected markers of inflammation and airway hyperresponsiveness in asthma. GNE-049 manufacturer © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.[This corrects the article DOI 10.18632/oncotarget.19404.]. Copyright © 2020 Pudelko et al.[This corrects the article DOI 10.18632/oncotarget.5358.]. Copyright © 2020 Hou et al.Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Especially for early stage CRC, prognostic molecular markers are needed to guide therapy. In this study, we first extracted total proteomes from matched pairs of fresh cancer and benign mucosal tissues from 22 CRC patients. Global proteomic profiling with Fourier transform liquid chromatography-mass spectrometry sequencing and label free quantitation uncovered that P4HA1 (prolyl 4-hydroxylase alpha 1) was overexpressed in CRC relative to benign colonic mucosa. We then investigated expression by immunohistochemical staining with P4HA1-specific antibodies using CRC tissue microarrays. Independent validation cohorts of 599 cases of early stage CRC and 91 cases of late stage CRC were examined. Multivariate and univariate survival analyses revealed that high expression of P4HA1 protein was an independent poor prognostic marker for patients with early stage CRC, especially of the microsatellite stable subtype. Our study provides strong support for P4HA1 as a predictive protein marker for precision diagnostics, therapeutic decision-making, and drug development for early stage colorectal cancer and demonstrates the utility of proteomic profiling to identify novel protein biomarkers. Copyright © 2020 Tanaka et al.SLC25A32 is a member of the solute carrier 25 family of mitochondrial transporters. SLC25A32 transports tetrahydrofolate (THF) as well as FAD into mitochondria and regulates mitochondrial one-carbon metabolism and redox balance. While it is known that cancer cells require one-carbon and FAD-dependent mitochondrial metabolism to sustain cell proliferation, the role of SLC25A32 in cancer cell growth remains unexplored. Our results indicate that the SLC25A32 gene is highly amplified in different tumors and that amplification correlates with increased mRNA expression and reduced patients´ survival. siRNA-mediated knock-down and CRISPR-mediated knock-out of SLC25A32 in cancer cells of different origins, resulted in the identification of cell lines sensitive and resistant to SLC25A32 inhibition. Mechanistically, tracing of deuterated serine revealed that SLC25A32 knock-down does not affect the mitochondrial/cytosolic folate flux as measured by Liquid Chromatography coupled Mass Spectrometry (LC-MS). Instead, SLC25A32 inhibition results in a respiratory chain dysfunction at the FAD-dependent complex II enzyme, induction of Reactive Oxygen Species (ROS) and depletion of reduced glutathione (GSH), which impairs cancer cell proliferation. Moreover, buthionine sulfoximine (BSO) treatment further sensitizes cells to ROS-mediated inhibition of cell proliferation upon SLC25A32 knock-down. Treatment of cells with the FAD precursor riboflavin and with GSH rescues cancer cell proliferation upon SLC25A32 down-regulation. Our results indicate that the reduction of mitochondrial FAD concentrations by targeting SLC25A32 has potential clinical applications as a single agent or in combination with approved cancer drugs that lead to increased oxidative stress and reduced tumor growth. Copyright © 2020 Santoro et al.Triple-negative breast cancer (TNBC) shows limited therapeutic efficacy. PARP inhibitor has been approved to treat advanced BRCA-mutant breast cancer but shows high resistance. Therefore, the development of new therapeutics that sensitize TNBC irrespective of BRCA status is urgently needed. The neddylation pathway plays a critical role in many physiological processes by regulating the degradation of proteins. MLN4924, a selective inhibitor of the key neddylation enzyme NEDD8 Activation Enzyme (NAE1), shows higher sensitivity to both BRCA1-wild type and -mutant TNBCs compared to other breast cancer subtypes. MLN4924 induced re-replication with >4N DNA content leading to robust DNA damage. Accumulation of unrepaired DNA damage resulted in S and G2/M arrest causing apoptosis and senescence, due to the stabilization of the replication initiation protein CDT1 and the accumulation of cell cycle proteins upon MLN4924 treatment. Moreover, adding MLN4924 to the standard TNBC chemotherapeutic agent cisplatin increased the DNA damage level, further enhancing the sensitivity.
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