Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Myxine insulin : amino-acid sequence, three dimensional structure, biosynthesis, release, physiological role, receptor binding affinity, and biological activity

The Atlantic hagfish, Myxlne. glutinosa,is the most primitive vertebrate extant, and it diverged from the main vertebrate evolutionary chain some 500 mi 11 ion years ago. The primary sequence of hagfish insulin shows that it contains the residues implemented for expression of activity and the residues stabi­lizing the insulin monomer and dimer, but not the hexamer. The primary sequence of hagfish preproinsulin, deduced from the mRNA-cDNA sequence shows little homology in sequence of the precursor parts of the molecule. However, the sequence contains the structural requirements for the tenta­tive functions, jL.z. vectorial discharge of the prohormone and a minimum over-all size of the precursor. The proinsulin converting enzyme(s) seems to have a specificity similar to that of all other vertebrates studied. The tertiary structure of hagfish insulin in the crystal is almost super­imposable on pig insulin's structure. The biological  activity of hagfish insulin is 5%   of that  of piginsulin and its receptor binding affinity   is 23% in isolated   rat fat  cells.Hagfish insulin was the first partial insulin antagonist on the rat fat cell insulin receptor. The change(s) in structure responsible for the reduction of acti­vity and binding are not known. Biosynthesis of hagfish insulin, In vXJyto, follows the pattern observed in higher vertebrates, although at a much slower rate. Unlike the situation in mammals, hagfish insulin biosynthesis is not stimulated by glucose. A radioimmunoassay for hagfish insulin was developed and the antiserum cross-reacted with       bovine insulin to only 0.01%. Theassay was used to study insulin release in vitro. Glucose  stimulates insulin release but, unlike the situation in higher vertebrates, amino acids do not. In vivo, hagfish insulin stimulated the incorporation of 14C-glucose and 14C-leucine into hagfish skeletal muscle glycogen and protein. The observed similari ties,between hagfish and higher vertebrates,with regards to insulin's structure, biosynthesis, release, receptor binding, and biological activity support the conclusion that, insulin and its processing and effector machineries were structurally and biologically well defined some 500 million years ago.S. 1-32: sammanfattning, s. 33-160: 8 uppsatserdigitalisering@um

Intratumoral variations in DNA ploidy and s-phase fraction in human breast cancer

To study intratumoral DNA ploidy heterogeneity and Sphase fraction (SPF) variability, we prospectively collected five different samples from 48 breast carcinomas and each sample was analysed separately by flow cytometry. Aneuploidy rate was 89.6% after analysis of four or five samples. DNA ploidy heterogeneity, i.e., different samples classified as either DNA euploid or DNA aneuploid in the same tumor was seen in 17%, and DNA index heterogeneity, i.e., tumor populations with different DNA indices (DIs) seen in different samples was 44%. A statistical model defining SPF heterogeneity is proposed. SPF heterogeneity as defined by us was 71%, and as expected the SPF heterogeneity rate increased significantly with increasing number of analysed samples. Four or more samples are needed to detect the most deviant (highest) SPF values. An unrecognized intratumor heterogeneity of DNA ploidy and SPF may partly explain the conflicting results reported in the literature on the above prognostic indicators