Stokholmlanier1349

nternational Society for Autism Research, Wiley Periodicals, Inc.Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. Simnotrelvir supplier All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients. © 2020 Wiley Periodicals, Inc.The investigation of cell cycle stage-dependent processes in a population of cells is often performed using flow cytometry. While this approach is high-throughput, it is relatively low in resolution and unable to measure phenotypic changes or processes occurring in subcellular compartments. We integrated automated microscopy with newly developed informatics workflow that enabled the quantitation of multiple fluorescent markers from specific subnuclear regions throughout a population of cells. Telomeres protect chromosome termini and prevent cellular aging. Cancer cells lengthen telomeres by synthesizing new TTAGGG repeats by the enzyme telomerase, while others activate recombination-dependent alternative lengthening of telomeres (ALT). A key feature of the ALT pathway is the specific clustering of promyelocytic leukemia (PML) nuclear bodies at telomeres. These ALT-associated PML bodies (APBs) common in tumors of mesenchymal origin have gained in diagnostic use in the past decade. Here we applied recent improvements in automated microscopy and developed novel informatics workflows for quantitation of multiple fluorescent markers from specific subnuclear regions at the single cell level. Key to this workflow are customized machine learning algorithms within HCS Studio™ Cell Analysis which automatically identify and segment cells into defined regions of interest based on fluorescent markers, measure marker intensities and compute marker colocalizations in specific segmented regions. These multiparametric cellular assays assess cell cycle dynamics as well as the interactome of APBs, are amenable to adherent cells and histological sections, and are adaptable for use with additional markers. In the future we anticipate exploiting these algorithms for a wide range of research questions related to telomere biology with potential to facilitate clinical development of ALT detection assays to benefit patients with these often-poor prognosis tumors. © 2020 International Society for Advancement of Cytometry.BACKGROUND Cardiac amyloidosis (CA) is characterized by left ventricular hypertrophy (LVH) and autonomic nervous imbalance due to amyloid infiltration. However, autonomic dysfunction is often seen in heart failure (HF) with LVH from other etiologies. We aimed to characterize autonomic dysfunction in CA from other etiologies of LVH. METHODS Fifty-five HF patients with LVH (35 males, mean age 65 ± 16 years) were enrolled. LVH was defined as left ventricular mass index measured by echocardiography >95 g/m2 in women and 115 g/m2 in men. The etiology was as follows amyloid light chain (AL)-CA, n = 14; hypertrophic cardiomyopathy, n = 21; and aortic stenosis (AS), n = 20. With the patient in a clinically stable condition, heart rate variability (HRV) and heart rate turbulence (HRT), which reflect autonomic dysfunction, were measured using Holter monitoring and compared among the three groups. RESULTS Brain natriuretic peptide levels, LVH severity, left ventricular ejection fraction, and tissue Doppler index E/e' did not differ among the three groups. However, severe abnormalities of HRV and HRT were obtained in AL-CA. In the ROC analysis to identify AL-CA in HF with LVH, the best cutoff value for standard deviation of all R-R intervals, standard deviation of the 5-min mean R-R intervals, turbulence onset, and turbulence slope were 68.5 ms (AUC 0.865), 58.5 ms (AUC 0.834), 0.25% (AUC 0.813), and 1.00 ms/RR (AUC 0.736), respectively. CONCLUSION Autonomic dysfunction is a hallmark of AL-CA, and its noninvasive assessment by Holter monitoring may be a useful tool for differential diagnosis of HF with LVH. © 2020 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals, Inc.Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.