Clinical, Radiographic, Histopathologic, and Serologic Features and their Differentiation from Wegener Granulomatosis

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PREDICTORS OF SUBSEQUENT INTERVENTION AFTER INITIAL TREATMENT FOR ACUTE AORTIC DISSECTION

none15siopenLettinga, Mark; Patel, Himanshu; Peterson, Mark; Ehrlich, Marek; Myrmel, Truls; Conklin, Lori; Mussa, Firas; Bavaria, Joseph; Gleason, Thomas; Di Eusanio, Marco; Montgomery, Daniel; Eagle, Kim; Isselbacher, Eric; Nienaber, Christoph; Trimarchi, SantiLettinga, Mark; Patel, Himanshu; Peterson, Mark; Ehrlich, Marek; Myrmel, Truls; Conklin, Lori; Mussa, Firas; Bavaria, Joseph; Gleason, Thomas; Di Eusanio, Marco; Montgomery, Daniel; Eagle, Kim; Isselbacher, Eric; Nienaber, Christoph; Trimarchi, Sant

Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a

Pluripotent embryonic stem cells (ESCs) self-renew or differentiate into all tissues of the developing embryo and cell-specification factors are necessary to balance gene expression. Here we delineate the function of the PHD-finger protein 5a (Phf5a) in ESC self-renewal and ascribe its role in regulating pluripotency, cellular reprogramming, and myoblast specification. We demonstrate that Phf5a is essential for maintaining pluripotency, since depleted ESCs exhibit hallmarks of differentiation. Mechanistically, we attribute Phf5a function to the stabilization of the Paf1 transcriptional complex and control of RNA polymerase II elongation on pluripotency loci. Apart from an ESC-specific factor, we demonstrate that Phf5a controls differentiation of adult myoblasts. Our findings suggest a potent mode of regulation by the Phf5a in stem cells, which directs their transcriptional program ultimately regulating maintenance of pluripotency and cellular reprogramming

STUDY OF ACUTE TYPE A AORTIC DISSECTION PATIENTS WITH UNDILATED AORTAS

none15siopenFroehlich, Benjamin; Trimarchi, Santi; Bossone, Eduardo; Suzuki, Toru; Braverman, Alan; Kline-Rogers, Eva; Appoo, Jehangir; Di Eusanio, Marco; Gleason, Thomas; Abdul-Nour, Khaled; Lee, Teng; Montgomery, Daniel; Isselbacher, Eric; Nienaber, Christoph; Eagle, KimFroehlich, Benjamin; Trimarchi, Santi; Bossone, Eduardo; Suzuki, Toru; Braverman, Alan; Kline-Rogers, Eva; Appoo, Jehangir; Di Eusanio, Marco; Gleason, Thomas; Abdul-Nour, Khaled; Lee, Teng; Montgomery, Daniel; Isselbacher, Eric; Nienaber, Christoph; Eagle, Ki

Fabry disease and COVID-19: International expert recommendations for management based on real-world experience

The rapid spread of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has raised questions about Fabry disease (FD) as an independent risk factor for severe COVID-19 symptoms. Available real-world data on 22 patients from an international group of healthcare providers reveals that most patients with FD experience mild-to-moderate COVID-19 symptoms with an additional complication of Fabry pain crises and transient worsening of kidney function in some cases; however, two patients over the age of 55 years with renal or cardiac disease experienced critical COVID-19 complications. These outcomes support the theory that pre-existent tissue injury and inflammation may predispose patients with more advanced FD to a more severe course of COVID-19, while less advanced FD patients do not appear to be more susceptible than the general population. Given these observed risk factors, it is best to reinforce all recommended safety precautions for individuals with advanced FD. Diagnosis of FD should not preclude providing full therapeutic and organ support as needed for patients with FD and severe or critical COVID-19, although a FD-specific safety profile review should always be conducted prior to initiating COVID-19-specific therapies. Continued specific FD therapy with enzyme replacement therapy, chaperone therapy, dialysis, renin–angiotensin blockers or participation to clinical trials during the pandemic is recommended as FD progression will only increase susceptibility to infection. In order to compile outcome data and inform best practices, an international registry for patients affected by Fabry and infected by COVID-19 should be established

Responses of Drosophila giant descending neurons to visual and mechanical stimuli

In Drosophila, the paired giant descending neurons (GDNs), also known as giant fibers, and the paired giant antennal mechanosensory descending neurons (GAMDNs), are supplied by visual and mechanosensory inputs. Both neurons have the largest cell bodies in the brain and both supply slender axons to the neck connective. The GDN axon thereafter widens to become the largest axon in the thoracic ganglia, supplying information to leg extensor and wing depressor muscles. The GAMDN axon remains slender, interacting with other descending neuron axons medially. GDN and GAMDN dendrites are partitioned to receive inputs from antennal mechanosensory afferents and inputs from the optic lobes. Although GDN anatomy has been well studied in Musca domestica, less is known about the Drosophila homolog, including electrophysiological responses to sensory stimuli. Here we provide detailed anatomical comparisons of the GDN and the GAMDN, characterizing their sensory inputs. The GDN showed responses to light-on and light-off stimuli, expanding stimuli that result in luminance decrease, mechanical stimulation of the antennae, and combined mechanical and visual stimulation. We show that ensembles of lobula columnar neurons (type Col A) and mechanosensory antennal afferents are likely responsible for these responses. The reluctance of the GDN to spike in response to stimulation confirms observations of the Musca GDN. That this reluctance may be a unique property of the GDN is suggested by comparisons with the GAMDN, in which action potentials are readily elicited by mechanical and visual stimuli. The results are discussed in the context of descending pathways involved in multimodal integration and escape responses

Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

Analysis of 3D chromatin architecture in T-ALL identifies differences in intra-TAD interactions and TAD boundary insulation. Inhibition of oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions. Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer-promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP-seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD 'fusion' event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.We thank Drs. Susan Schwab, Dan Littman, Sherif Ibrahim, Angel Pellicer, Susanne Tranguch and Adolfo Ferrando for helpful discussions and/or critically comments on the manuscript. Elisabetta Andermarcher professionally edited the manuscript. We are indebted to Dr. M. Yan (Genentech) for the anti-DLL4 antibody for cytometry. We are also in debt with Christopher Murriel from Oncomed who provided the therapeutic murine anti-DLL4 antibody and demcizumab (anti-human DLL4 antibody). We thank the NYU School of Medicine Flow Cytometry Core facility, particularly Dr. Peter Lopez, Keith Kobylarz and Michael Gregory, and also the NYU School of Medicine Confocal imaging facility, particularly Yan Deng. We also thank Henry Alexandre Michaud for his great help with the FACS analysis of PDTALL cells. We thank Nelly Pirot and the rest of members of the IRCM IHC platform for their fantastic work. M.M. is supported by a contract from Fondation ARC. The NYU Cancer Institute Center Support Grant partially funded this core through grant NIH/NCI 5 P30CA16087-31. Work in JJL's laboratory is supported by the NIH/NIAID, National Multiple Sclerosis Society, and the Helmsley Charitable Trust. Work in AM's laboratory is supported by the Fondation ARC (PJA 20131200405), the European Commission (CIG631431), the Institute de Cancer de Montpellier Fondation, and the Institut National du Cancer (INCa_9257 and INCa-DGOS-Inserm 12553).S

The Nicotinic Acetylcholine Receptor Dα7 Is Required for an Escape Behavior inDrosophila

Acetylcholine is the major excitatory neurotransmitter in the central nervous system of insects. Mutant analysis of the Dα7 nicotinic acetylcholine receptor (nAChR) ofDrosophila shows that it is required for the giant fiber-mediated escape behavior. The Dα7 protein is enriched in the dendrites of the giant fiber, and electrophysiological analysis of the giant fiber circuit showed that sensory input to the giant fiber is disrupted, as is transmission at an identified cholinergic synapse between the peripherally synapsing interneuron and the dorsal lateral muscle motor neuron. Moreover, we found thatgfA(1), a mutation identified in a screen for giant fiber defects more than twenty years ago, is an allele ofDα7. Therefore, a combination of behavioral, electrophysiological, anatomical, and genetic data indicate an essential role for the Dα7 nAChR in giant fiber-mediated escape inDrosophila

Corrigendum to "European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. [Eur J Vasc Endovasc Surg (2022) 63, 184-267]"

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