Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation.

Genomic imprinting is an epigenetic mechanism resulting in parental allele-specific gene expression. Defects in normal imprinting are found in cancer, assisted reproductive technologies, and several human syndromes. In mouse models, germline-derived DNA methylation is shown to regulate imprinting. Though imprinting is largely conserved between mammals, species- and tissue-specific domains of imprinted expression exist. Using the cynomolgus macaque (Macaca fascicularis) to assess primate-specific imprinting, we present a comprehensive view of tissue-specific imprinted expression and DNA methylation at established imprinted gene clusters. For example, like mouse and unlike human, macaque IGF2R is consistently imprinted, and the PLAGL1, INPP5F transcript variant 2, and PEG3 imprinting control regions are not methylated in the macaque germline but acquire this post-fertilization. Methylome data from human early embryos appear to support this finding. These suggest fundamental differences in imprinting control mechanisms between primate species and rodents at some imprinted domains, with implications for our understanding of the epigenetic programming process in humans and its influence on disease.This study was conducted by all authors while at the Singapore Institute for Clinical Research and was fully supported by funding from the Agency for Science, Technology and Research, Singapore.This is the author accepted manuscript. The final version is available from Cold Spring Harbor Laboratory Press at http://genome.cshlp.org/content/early/2015/04/10/gr.183301.114.abstract

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

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

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors JACC State-of-the-Art Review

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed

Downscaling SMAP Brightness Temperatures to 3 km Using CYGNSS Reflectivity Observations: Factors That Affect Spatial Heterogeneity

NASA’s Soil Moisture Active Passive (SMAP) mission only retrieved ~2.5 months of 3 km near surface soil moisture (NSSM) before its radar transmitter malfunctioned. NSSM remains an important area of study, and multiple applications would benefit from 3 km NSSM data. With the goal of creating a 3 km NSSM product, we developed an algorithm to downscale SMAP brightness temperatures (TBs) using Cyclone Global Navigation Satellite System (CYGNSS) reflectivity data. The purpose of downscaling SMAP TB is to represent the spatial heterogeneity of TB at a finer scale than possible via passive microwave data alone. Our SMAP/CYGNSS TB downscaling algorithm uses β as a scaling factor that adjusts TB based on variations in CYGNSS reflectivity. β is the spatially varying slope of the negative linear relationship between SMAP emissivity (TB divided by surface temperature) and CYGNSS reflectivity. In this paper, we describe the SMAP/CYGNSS TB downscaling algorithm and its uncertainties and we analyze the factors that affect the spatial patterns of SMAP/CYGNSS β. 3 km SMAP/CYGNSS TBs are more spatially heterogeneous than 9 km SMAP enhanced TBs. The median root mean square difference (RMSD) between 3 km SMAP/CYGNSS TBs and 9 km SMAP TBs is 3.03 K. Additionally, 3 km SMAP/CYGNSS TBs capture expected NSSM patterns on the landscape. Lower (more negative) β values yield greater spatial heterogeneity in SMAP/CYGNSS TBs and are generally found in areas with low topographic roughness (<350 m), moderate NSSM variance (~0.01–0.0325), low-to-moderate mean annual precipitation (~0.25–1.5 m), and moderate mean Normalized Difference Vegetation Indices (~0.2–0.6). β values are lowest in croplands and grasslands and highest in forested and barren lands

Downscaling SMAP Brightness Temperatures to 3 km Using CYGNSS Reflectivity Observations: Factors That Affect Spatial Heterogeneity

NASA&rsquo;s Soil Moisture Active Passive (SMAP) mission only retrieved ~2.5 months of 3 km near surface soil moisture (NSSM) before its radar transmitter malfunctioned. NSSM remains an important area of study, and multiple applications would benefit from 3 km NSSM data. With the goal of creating a 3 km NSSM product, we developed an algorithm to downscale SMAP brightness temperatures (TBs) using Cyclone Global Navigation Satellite System (CYGNSS) reflectivity data. The purpose of downscaling SMAP TB is to represent the spatial heterogeneity of TB at a finer scale than possible via passive microwave data alone. Our SMAP/CYGNSS TB downscaling algorithm uses &beta; as a scaling factor that adjusts TB based on variations in CYGNSS reflectivity. &beta; is the spatially varying slope of the negative linear relationship between SMAP emissivity (TB divided by surface temperature) and CYGNSS reflectivity. In this paper, we describe the SMAP/CYGNSS TB downscaling algorithm and its uncertainties and we analyze the factors that affect the spatial patterns of SMAP/CYGNSS &beta;. 3 km SMAP/CYGNSS TBs are more spatially heterogeneous than 9 km SMAP enhanced TBs. The median root mean square difference (RMSD) between 3 km SMAP/CYGNSS TBs and 9 km SMAP TBs is 3.03 K. Additionally, 3 km SMAP/CYGNSS TBs capture expected NSSM patterns on the landscape. Lower (more negative) &beta; values yield greater spatial heterogeneity in SMAP/CYGNSS TBs and are generally found in areas with low topographic roughness (&lt;350 m), moderate NSSM variance (~0.01&ndash;0.0325), low-to-moderate mean annual precipitation (~0.25&ndash;1.5 m), and moderate mean Normalized Difference Vegetation Indices (~0.2&ndash;0.6). &beta; values are lowest in croplands and grasslands and highest in forested and barren lands