9 research outputs found
Aerobic exercise in obese diabetic patients with chronic kidney disease: a randomized and controlled pilot study
<p>Abstract</p> <p>Background</p> <p>Patients with obesity, diabetes, and chronic kidney disease (CKD) are generally physically inactive, have a high mortality rate, and may benefit from an exercise program.</p> <p>Methods</p> <p>We performed a 24-week randomized controlled feasibility study comparing aerobic exercise plus optimal medical management to medical management alone in patients with type 2 diabetes, obesity (body mass index [BMI] > 30 kg/m<sup>2</sup>), and stage 2-4 CKD (estimated glomerular filtration rate [eGFR] 15-90 mL/min/1.73 m<sup>2 </sup>with persistent proteinuria). Subjects randomized to exercise underwent thrice weekly aerobic training for 6 followed by 18 weeks of supervised home exercise. The primary outcome variable was change in proteinuria.</p> <p>Results</p> <p>Seven subjects randomized to exercise and 4 control subjects completed the study. Exercise training resulted in an increase in exercise duration during treadmill testing, which was accompanied by slight but insignificant decreases in resting systolic blood pressure and 24-hour proteinuria. Exercise did not alter GFR, hemoglobin, glycated hemoglobin, serum lipids, or C-reactive protein (CRP). Caloric intake and body weight and composition also did not change with exercise training.</p> <p>Conclusion</p> <p>Exercise training in obese diabetic patients with CKD is feasible and may have clinical benefits. A large-scale randomized controlled trial to determine the effects of exercise on renal functions, cardiovascular fitness, inflammation, and oxidative stress in diabetic patients with CKD is planned.</p
Activating Mutations in <i>PIK3CA</i> Lead to Widespread Modulation of the Tyrosine Phosphoproteome
The
human oncogene <i>PIK3CA</i> is frequently mutated
in human cancers. Two hotspot mutations in <i>PIK3CA</i>, E545K and H1047R, have been shown to regulate widespread signaling
events downstream of AKT, leading to increased cell proliferation,
growth, survival, and motility. We used quantitative mass spectrometry
to profile the global phosphotyrosine proteome of isogenic knock-in
cell lines containing these activating mutations, where we identified
824 unique phosphopeptides. Although it is well understood that these
mutations result in hyperactivation of the serine/threonine kinase
AKT, we found a surprisingly widespread modulation of tyrosine phosphorylation
levels of proteins in the mutant cells. In the tyrosine kinome alone,
29 tyrosine kinases were altered in their phosphorylation status.
Many of the regulated phosphosites that we identified were located
in the kinase domain or the canonical activation sites, indicating
that these kinases and their downstream signaling pathways were activated.
Our study demonstrates that there is frequent and unexpected cross-talk
that occurs between tyrosine signaling pathways and serine/threonine
signaling pathways activated by the canonical PI3K-AKT axis
Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: Updated results of the E1912 trial
Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients with CLL age \u3c70 years. Patients were randomly assigned (2:1 ratio) to receive ibrutinib and rituximab (IR) or six cycles of FCR. With a median follow-up of 5.8 years, median PFS is superior for IR (hazard ratio [HR], 0.37; P \u3c .001). IR improved PFS relative to FCR in both IGHV mutated (HR: 0.27; P \u3c 0.001) and IGHV unmutated patients (HR: 0.27; P \u3c 0.001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events/complication, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. Median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in OS was observed for patients on the IR arm (HR=0.47; p=0.018). In conclusion, Ibrutinib-rituximab therapy offers superior PFS relative to FCR in both IGHV mutated and unmutated CLL patients as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. Clinical trial at NCT02048813
14-3-3 Coordinates Microtubules, Rac, and Myosin II to Control Cell Mechanics and Cytokinesis
The Impact of Nurse Turnover on Patient, Nurse, and System Outcomes: A Pilot Study and Focus for a Multicenter International Study
Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.
Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease