Lorenzenaarup8240

© Georg Thieme Verlag KG Stuttgart · New York.Due to the current development around the COVID-19 pandemic, palliative ch has created a Task Force to provide recommendations for health professionals on the treatment of palliative care patients in the various settings ‒ inpatient and outpatient.Fossils are the only remaining evidence of the majority of species that have ever existed, providing a direct window into events in evolutionary history that shaped the diversification of life on Earth. Phylogenies underpin our ability to make sense of evolution but are routinely inferred using only data available from living organisms. Although extinct taxa have been shown to add crucial information for inferring macroevolutionary patterns and processes (such as ancestral states, paleobiogeography and diversification dynamics), the role fossils play in reconstructing phylogeny is controversial. Since the early years of phylogenetic systematics, different studies have dismissed the impact of fossils due to their incompleteness, championed their ability to overturn phylogenetic hypotheses or concluded that their behavior is indistinguishable from that of extant taxa. Based on taxon addition experiments on empirical data matrices, we show that the inclusion of paleontological data has a remarkable effect in phyor the design of taxon sampling in both morphological and total-evidence analyses. © The Author(s) 2020. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For permissions, please email journals.permissions@oup.com.Since the discovery of FMS-like tyrosine kinase-3 (FLT3)-activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug's rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors. © 2020 by The American Society of Hematology.RUNX1 is frequently mutated in myeloid and lymphoid malignancies. It has been shown to negatively regulate Toll-like receptor 4 (TLR4) signaling through nuclear factor κB (NF-κB) in lung epithelial cells. Here we show that RUNX1 regulates TLR1/2 and TLR4 signaling and inflammatory cytokine production by neutrophils. Hematopoietic-specific RUNX1 loss increased the production of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), by bone marrow neutrophils in response to TLR1/2 and TLR4 agonists. Hematopoietic RUNX1 loss also resulted in profound damage to the lung parenchyma following inhalation of the TLR4 ligand lipopolysaccharide (LPS). However, neutrophils with neutrophil-specific RUNX1 loss lacked the inflammatory phenotype caused by pan-hematopoietic RUNX1 loss, indicating that dysregulated TLR4 signaling is not due to loss of RUNX1 in neutrophils per se. Rather, single-cell RNA sequencing indicates the dysregulation originates in a neutrophil precursor. Enhanced inflammatory cytokine production by neutrophils following pan-hematopoietic RUNX1 loss correlated with increased degradation of the inhibitor of NF-κB signaling, and RUNX1-deficient neutrophils displayed broad transcriptional upregulation of many of the core components of the TLR4 signaling pathway. Hence, early, pan-hematopoietic RUNX1 loss de-represses an innate immune signaling transcriptional program that is maintained in terminally differentiated neutrophils, resulting in their hyperinflammatory state. We hypothesize that inflammatory cytokine production by neutrophils may contribute to leukemia associated with inherited RUNX1 mutations. © 2020 by The American Society of Hematology.First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM. CIL56 mw © 2020 by The American Society of Hematology.Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA.