Citations

Glucagon-like peptide 1 receptor (GLP-1R) agonists were originally developed as treatments for diabetes and subsequently evolved into weight management medications. These drugs have recently been shown to demonstrate remarkable efficacy in cardiovascular disease, kidney disease, and heart failure with preserved ejection fraction (HFpEF). In this review, we focus on the cardiovascular protective effects of GLP-1R agonists identified from basic studies and outcome trials, including a brief description of those forthcoming soon.

Diabetic pregnancy increases the offspring’s risk of neonatal and adult cardiovascular disease (CVD). We previously used a rat model (Sprague–Dawley) to show that diabetic pregnancy impairs mitochondrial bioenergetics, dynamics, mitophagy, and quality control in the offspring’s heart, and we hypothesized that mitochondrial dysfunction during early development influences the adult myocardium structure to confer cardiometabolic disease risk with aging. Here, we used 3D serial block face-scanning electron microscopy (SBF-SEM) to analyze perinuclear (PN) and intrafibrillar (IF) mitochondrial networks in the left ventricular sections from control and pregestational diabetes-exposed newborn (NB) rats that were three-week-old and four-month-old. Diabetes-exposed myocardium had 50% fewer PN and 20% fewer IF mitochondria at birth but counts increased more rapidly, resulting in no difference at three weeks and 35% more PN and 49% more IF mitochondria by four months. Despite rising counts, mitochondria volumes remained significantly lower at every developmental timepoint. This shows that diabetic pregnancy causes maldevelopment of the myocardial mitochondrial reticulum which likely contributes to adult CVD.

This survey study examines whether disparities in risk of burnout and low satisfaction with work-life integration by sex are similar among physicians compared with US workers in other fields.

Abstract Purpose: Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single-arm, open-label phase 2 trial was to determine whether denosumab, a RANKL mAb, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historic Children’s Oncology Group clinical trial data. Patients and Methods: Skeletally mature patients ages 11 to 49 years old with measurable disease were eligible for cohort 1, and those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. Results: Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event-free at 12 months. The predefined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11%, respectively). At steady state, mean serum denosumab trough concentrations were 23.7 to 31 μg/mL in cycles 2 to 7. Serum c-telopeptide and urine n-telopeptide decreased on treatment. Conclusions: Denosumab was well-tolerated with anticipated side effects and pharmacokinetic and pharmacodynamic parameters but had insufficient activity for further development in osteosarcoma.

Complement activation occurs in most glomerular diseases. Complement activation on the kidney biopsy is evidenced by deposition of C3c and C1q on the kidney biopsy. The kidney biopsy provides only limited information as other complement proteins and complement-regulating proteins are not typically studied. Furthermore, kidney biopsy does not distinguish between activated versus inactive complement proteins. Laser microdissection and mass spectrometry (LMD/MS) is a relatively new methodology that can provide an in-depth evaluation of the proteomic profile of complement proteins, complement regulating proteins, complement pathways, and can also determine whether active complement fragments are present in the kidney biopsy sample. A semiquantitative burden of complement can be determined. Furthermore, proteins of a disease can be analyzed using principal component analysis, volcano plots, and heatmaps. In this review, the complement proteomic profile of diseases representing the spectrum of glomerular diseases are shown. The proteomic complement profile of membranous nephropathy associated with various antigens, Ig-associated GN, such as proliferative GN with monoclonal Ig deposits and fibrillary GN, C3 glomerulopathy, and IgA nephropathy, are shown. The findings show important differences in the complement profile including pathways of complement in each disease, and even within the disease, such as altered complement burden and profile between different antigens associated with membranous nephropathy. In conclusion, LMD/MS is a valuable tool for determining the complement proteins, complement-regulating proteins, complement pathways, and determining the burden of complement in each individual case of glomerular disease. In the era of new anticomplement drugs, it will become essential to accurately determine the complement profile in each kidney biopsy for a personalized approach to treating the glomerular disease. LMD/MS is a methodology that can help provide such answers.