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Genomic characterization of hepatoid tumors: context matters.

Hum Pathol 2021 Sep 22. Epub 2021 Sep 22.

Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Bearsden, G61 1QH Glasgow; Sanger Institute, Wellcome Trust Genome Campus, CB10 1SA Cambridge.

Hepatoid tumors (HT) are rare neoplasms, morphologically resembling hepatocellular carcinoma, which arise in several organs other than the liver. A comprehensive molecular profile of this group of neoplasms is still lacking. Genomic characterization of 19 HT from different organs (3 colon, 4 esophagogastric, 4 biliary, 6 genitourinary, 2 lung) was performed using a multigene next-generation sequencing panel. Read More

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September 2021

Analysis of Dispatched Protein Processing and Sonic Hedgehog Ligand Release.

Methods Mol Biol 2022 ;2374:95-106

Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.

The 12-pass transmembrane protein Dispatched (DISP) is essential for Sonic Hedgehog (SHH) release from ligand-producing cells and is indispensable for establishment of the SHH morphogen gradient during tissue patterning. Regulatory events controlling DISP release of SHH are not yet fully characterized. We recently demonstrated that DISP is cleaved by FURIN proprotein convertase at a conserved site in its first extracellular loop. Read More

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January 2022

The Prognostic Significance of Pleomorphism in Gastrointestinal Stromal Tumors.

Histopathology 2021 Sep 25. Epub 2021 Sep 25.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Gastrointestinal stromal tumors (GISTs) typically show uniform nuclear morphology, with spindle cell, epithelioid, or mixed histology. Risk of progression in GIST is estimated based on anatomic site, tumor size, and mitotic index. Pleomorphic GISTs are rare and have not been systemically investigated. Read More

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September 2021

Proteolytic activation of SARS-CoV-2 spike protein.

Authors:
Makoto Takeda

Microbiol Immunol 2021 Sep 25. Epub 2021 Sep 25.

Department of Virology 3, National Institute of Infectious Diseases, Tokyo, Japan.

Spike (S) protein cleavage is a crucial step in coronavirus infection. In this review, we discuss this process, with particular focus on the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with influenza virus and paramyxovirus membrane fusion proteins, the cleavage activation mechanism of coronavirus S protein is much more complex. Read More

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September 2021

Naturally-Occurring Mutations to Muscle-type Creatine Kinase Impact its Canonical and Pharmacological Activities in a Substrate-dependent Manner in vitro.

Mol Pharmacol 2021 Sep 24. Epub 2021 Sep 24.

Medicine, Johns Hopkins University School of Medicine, United States

Tenofovir (TFV) is a key component of HIV pre-exposure prophylaxis (PrEP). TFV is a nucleotide analog reverse transcriptase inhibitor prodrug that requires two separate phosphorylation reactions by intracellular kinases in order to form the active metabolite, tenofovir-diphosphate (TFV-DP). Muscle-type creatine kinase (CKM) has previously been demonstrated to be the kinase most responsible for the phosphorylation of tenofovir-monophosphate (TFV-MP) to the active metabolite in colon tissue. Read More

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September 2021

Rational enzyme design for controlled functionalization of acetylated xylan for cell-free polymer biosynthesis.

Carbohydr Polym 2021 Dec 19;273:118564. Epub 2021 Aug 19.

Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA; Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA. Electronic address:

Xylan O-acetyltransferase 1 (XOAT1) is involved in O-acetylating the backbone of hemicellulose xylan. Recent structural analysis of XOAT1 showed two unequal lobes forming a cleft that is predicted to accommodate and position xylan acceptors into proximity with the catalytic triad. Here, we used docking and molecular dynamics simulations to investigate the optimal orientation of xylan in the binding cleft of XOAT1 and identify putative key residues (Gln445 and Arg444 on Minor lobe & Asn312, Met311 and Asp403 on Major lobe) involved in substrate interactions. Read More

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December 2021

Optimization strategies for expression of a novel bifunctional anti-PD-L1/TGFBR2-ECD fusion protein.

Protein Expr Purif 2021 Sep 21:105973. Epub 2021 Sep 21.

Hisun Biopharmaceutical Co., Ltd., Hangzhou, Zhejiang, 311404, China. Electronic address:

The novel anti-PD-L1/TGFBR2-ECD fusion protein (BR102) comprises an anti-PD-L1 antibody (HS636) which is fused at the C terminus of the heavy chain to a TGF-β1 receptor Ⅱ ectodomain (TGFBR2-ECD), and which can sequester the PD-1/PD-L1 pathway and TGF-β bioactivity in the immunosuppressive tumor microenvironment. In the expression of TGFBR2-ECD wild-type fused protein (BR102-WT), a 50 kDa clipped species was confirmed to be induced by proteolytic cleavage at a "QKS" site located in the N-terminus of the ectodomain, which resulted in the formation of IgG-like clipping. The matrix metalloproteinase-9 was determined to be associated with BR102-WT digestion. Read More

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September 2021

Exact site frequency spectra of neutrally evolving tumors: A transition between power laws reveals a signature of cell viability.

Theor Popul Biol 2021 Sep 21. Epub 2021 Sep 21.

School of Mathematics, University of Minnesota, Twin Cities, MN 55455, USA. Electronic address:

The site frequency spectrum (SFS) is a popular summary statistic of genomic data. While the SFS of a constant-sized population undergoing neutral mutations has been extensively studied in population genetics, the rapidly growing amount of cancer genomic data has attracted interest in the spectrum of an exponentially growing population. Recent theoretical results have generally dealt with special or limiting cases, such as considering only cells with an infinite line of descent, assuming deterministic tumor growth, or taking large-time or large-population limits. Read More

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September 2021

Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC).

Biochem Pharmacol 2021 Sep 21:114781. Epub 2021 Sep 21.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen Ø, Denmark. Electronic address:

The molecular basis for the signal transduction through the classical Cys-loop receptors (CLRs) has been delineated in great detail. The Zinc-Activated Channel (ZAC) constitutes a so far poorly elucidated fifth branch of the CLR superfamily, and in this study we explore the molecular mechanisms underlying ZAC signaling in Xenopus oocytes by two-electrode voltage clamp electrophysiology. In studies of chimeric receptors fusing either the extracellular domain (ECD) or the transmembrane/intracellular domain (TMD-ICD) of ZAC with the complementary domains of 5-HTA serotonin or α glycine receptors, serotonin and Zn/H evoked robust concentration-dependent currents in 5-HTA/ZAC- and ZAC/α-Gly-expressing oocytes, respectively, suggesting that Zn and protons activate ZAC predominantly through its ECD. Read More

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September 2021

A case of CADASIL caused by NOTCH3 c.512_605delinsA heterozygous mutation.

J Clin Lab Anal 2021 Sep 24:e24027. Epub 2021 Sep 24.

Department of Neurology, First Affiliated Hospital of Dalian Medical University, Dalian, China.

Background: Autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebrovascular disease closely related to the NOTCH3 gene. More than 200 mutations in this gene have been reported to be associated with this disease.

Methods: The NOTCH3 gene from CADASIL patient was screened for mutations by whole-exome sequencing (WES). Read More

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September 2021

Amino acid substitution (Gly-654-Tyr) in acetolactate synthase (ALS) confers broad spectrum resistance to ALS-inhibiting herbicides.

Pest Manag Sci 2021 Sep 24. Epub 2021 Sep 24.

Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.

Background: Amaranthus retroflexus L. is a problematic weed in agricultural fields. In China, the repeated use of acetolactate synthase (ALS) inhibiting herbicides has led to the evolution of many A. Read More

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September 2021

The Predictive Value of Clinical and Molecular Characteristics or Immunotherapy in Non-Small Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

Front Oncol 2021 7;11:732214. Epub 2021 Sep 7.

Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, China.

Background: This meta-analysis aimed to investigate the efficacy of immune checkpoint inhibitor (ICI)-based therapy in non-small cell lung cancer (NSCLC) patients with different clinical and molecular characteristics such as age, sex, histological type, performance status (PS), smoking status, driver mutations, metastatic site, region and number of prior systemic regimens.

Methods: A systematic literature search was conducted in PubMed, Embase, and the Cochrane library databases to identify qualified randomized controlled trials (RCTs). The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Read More

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September 2021

Growth hormone promotes hepatic gluconeogenesis by enhancing BTG2-YY1 signaling pathway.

Sci Rep 2021 Sep 23;11(1):18999. Epub 2021 Sep 23.

Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, Republic of Korea.

Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2-YY1 signaling pathway in glucose metabolism. Read More

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September 2021

Estimating evolutionary changes between highly passaged and original parental lumpy skin disease virus strains.

Transbound Emerg Dis 2021 Sep 23. Epub 2021 Sep 23.

Federal Center for Animal Health, Vladimir, 600901, Russia.

Research into the phylogenetic relationships of lumpy skin disease virus (LSDV) strains was long overlooked, partially due to its original restricted distribution to sub-Saharan Africa. However, recent incursions into northern latitudes, and a rapid spread causing major economic losses worldwide, have intensified additional research on the disease and the causative virus. This study delineates the phylogeny of LSDV in the context of full genome sequences of strains recovered in the field, as well as strains highly passaged in cell culture. Read More

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September 2021

Expanding the target range of base editing in plants without loss of efficiency by blocking RNA-silencing.

Plant Biotechnol J 2021 Sep 23. Epub 2021 Sep 23.

Shanghai Center for Plant Stress Biology and Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China.

Bacterial-derived CRISPR/Cas systems are versatile platforms to engineer site-specific gene editing tools. Compared to the canonical Cas9-mediated DNA cleavage systems, which induce a high-proportion of frame-shift mutations, the recently developed base editing (BE) tools allow more precise and predictable base substitutions within a CRISPR/Cas9-defined editing window. Initially, such tools made use of engineered cytosine deaminases or evolved adenine deaminases to catalyze base deamination when fused to a Cas9 nickase (nCas9) (Rees and Liu, 2018). Read More

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September 2021

Improved functionality and potency of next generation BinMLV viral vectors toward safer gene therapy.

Mol Ther Methods Clin Dev 2021 Dec 21;23:51-67. Epub 2021 Jul 21.

Laboratory for Viral Vector Technology and Gene Therapy, Department of Pharmacological and Pharmaceutical Sciences, KU Leuven, 3000 Leuven, Belgium.

To develop safer retroviral murine leukemia virus (MLV)-based vectors, we previously mutated and re-engineered the MLV integrase: the W390A mutation abolished the interaction with its cellular tethering factors, BET proteins, and a retargeting peptide (the chromodomain of the CBX1 protein) was fused C-terminally. The resulting BET-independent MLV was shown to integrate efficiently and more randomly, away from typical retroviral markers. In this study, we assessed the functionality and stability of expression of the redistributed MLV vector in more depth, and evaluated safety using a clinically more relevant vector design encompassing a self-inactivated (SIN) LTR and a weak internal elongation factor 1α short (EFS) promoter. Read More

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December 2021

Emerging SARS-CoV-2 variants follow a historical pattern recorded in outgroups infecting non-human hosts.

Commun Biol 2021 Sep 22;4(1):1134. Epub 2021 Sep 22.

Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, 565-0871, Japan.

The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. We estimated diversity of each site on a multiple sequence alignment (MSA) of the Spike (S) proteins from close relatives of SARS-CoV-2 that infected bat and pangolin before the pandemic. Then we compared the locations of high diversity sites in this MSA and those of mutations found in multiple emerging lineages of human-infecting SARS-CoV-2. Read More

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September 2021

An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins.

Cell Rep 2021 Sep;36(12):109735

Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany. Electronic address:

Subtype C is the most prevalent clade of human immunodeficiency virus type 1 (HIV-1) worldwide. The reasons for this are poorly understood. Here, we demonstrate that a characteristic additional third nuclear factor κB (NF-κB) binding site in the long terminal repeat (LTR) promoter allows subtype C HIV-1 strains to evade restriction by nuclear PYHIN proteins, which sequester the transcription factor Sp1. Read More

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September 2021

Canakinumab is effective in patients with familial Mediterranean fever resistant and intolerant to the colchicine and/or anakinra treatment.

Rheumatol Int 2021 Sep 22. Epub 2021 Sep 22.

Division of Rheumatology, Department of Physical Medicine and Rehabilitation, Marmara University School of Medicine, İstanbul, Turkey.

As an autosomal recessive autoinflammatory disease, treatment of Familial Mediterranean fever (FMF) has still gaps. Clinical studies are proving the safety and efficacy of colchicine in patients with FMF. However, there are very limited data on colchicine-resistant patients treated with canakinumab. Read More

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September 2021

A study on catalytic and non-catalytic sites of H5N1 and H1N1 neuraminidase as the target for chalcone inhibitors.

Appl Biol Chem 2021 17;64(1):69. Epub 2021 Sep 17.

Faculty of Pharmacy, Sanata Dharma University, Campus III, Paingan, Maguwoharjo, Depok, Sleman, 55282 Yogyakarta Indonesia.

The H1N1 pandemic in 2009 and the H5N1 outbreak in 2005 have shocked the world as millions of people were infected and hundreds of thousands died due to the infections by the influenza virus. Oseltamivir, the most common drug to block the viral life cycle by inhibiting neuraminidase (NA) enzyme, has been less effective in some resistant cases due to the virus mutation. Presently, the binding of 10 chalcone derivatives towards H5N1 and H1N1 NAs in the non-catalytic and catalytic sites was studied using molecular docking. Read More

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September 2021

The R140H mutation alters tRNA metabolism and mRNA 3' processing in mouse models of pontocerebellar hypoplasia.

Proc Natl Acad Sci U S A 2021 09;118(39)

Department of Cellular and Molecular Medicine, Division of Biological Sciences, Section of Neurobiology, University of California San Diego, La Jolla, CA 92093;

Homozygous mutation of the RNA kinase (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated mutation, R140H, and one heterozygous for this mutation and a null allele. Read More

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September 2021

A molecular sensor determines the ubiquitin substrate specificity of SARS-CoV-2 papain-like protease.

Cell Rep 2021 Sep 8:109754. Epub 2021 Sep 8.

Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

The SARS-CoV-2 papain-like protease (PLpro) is a target for antiviral drug development. It is essential for processing viral polyproteins for replication and functions in host immune evasion by cleaving ubiquitin (Ub) and ubiquitin-like protein (Ubl) conjugates. While highly conserved, SARS-CoV-2 and SARS-CoV PLpro have contrasting Ub/Ubl substrate preferences. Read More

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September 2021

O-GlcNAcylation of High Mobility Group Box 1 (HMGB1) Alters Its DNA Binding and DNA Damage Processing Activities.

J Am Chem Soc 2021 Sep 21. Epub 2021 Sep 21.

Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, Texas 78723, United States.

Protein O-GlcNAcylation is an essential and dynamic regulator of myriad cellular processes, including DNA replication and repair. Proteomic studies have identified the multifunctional nuclear protein HMGB1 as O-GlcNAcylated, providing a potential link between this modification and DNA damage responses. Here, we verify the protein's endogenous modification at S100 and S107 and found that the major modification site is S100, a residue that can potentially influence HMGB1-DNA interactions. Read More

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September 2021

Glucosinolate Biosynthesis: Role Of MAM Synthase And Its Perspectives.

Authors:
Bidyadhar Das

Biosci Rep 2021 Sep 21. Epub 2021 Sep 21.

North Eastern Hill University, Shillong, India.

Glucosinolates, synthesized by the glucosinolate biosynthesis pathway, are the secondary metabolites used as a defence mechanism in the Brassicaceae plants, including Arabidopsis thaliana. The first committed step in the pathway, catalysed by  methylthioalkylmalate (MAM) synthase (EC: 2.3. Read More

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September 2021

Biallelic variants in YRDC cause a developmental disorder with progeroid features.

Hum Genet 2021 Sep 20. Epub 2021 Sep 20.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. Read More

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September 2021

Two adjacent C-terminal mutations enable expression of aryl-alcohol oxidase from Pleurotus eryngii in Pichia pastoris.

Appl Microbiol Biotechnol 2021 Sep 21. Epub 2021 Sep 21.

Institute of Biochemistry, Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.

Fungal aryl-alcohol oxidases (AAOs) are attractive biocatalysts because they selectively oxidize a broad range of aromatic and aliphatic allylic primary alcohols while yielding hydrogen peroxide as the only by-product. However, their use is hampered by challenging and often unsuccessful heterologous expression. Production of PeAAO1 from Pleurotus eryngii ATCC 90787 in Pichia pastoris failed, while PeAAO2 from P. Read More

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September 2021

Loss of Function Variants in the XPC Causes Severe Xeroderma Pigmentosum in Three Large Consanguineous Families.

Klin Padiatr 2021 Sep 20. Epub 2021 Sep 20.

Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.

Background: Xeroderma pigmentosum (XP) is a rare recessively inherited disorder that presents clinical and genetic heterogeneity. Mutations in eight genes, of which seven are involved in nucleotide excision repair (NER) pathway have been reported to cause the XP.

Methods And Results: Three large consanguineous families of Pakistani origin displaying typical clinical hallmarks of XP were evaluated at clinical and molecular level. Read More

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September 2021

Evidence for a force favoring GC over AT at short intronic sites in Drosophila simulans and Drosophila melanogaster.

G3 (Bethesda) 2021 Sep;11(9)

School of Biological Sciences, Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3FL, UK.

Population genetics studies often make use of a class of nucleotide site free from selective pressures, in order to make inferences about population size changes or natural selection at other sites. If such neutral sites can be identified, they offer the opportunity to avoid any confounding effects of selection. Here, we investigate evolution at putatively neutrally evolving short intronic sites in natural populations of Drosophila melanogaster and Drosophila simulans, in order to understand the properties of spontaneous mutations and the extent of GC-biased gene conversion in these species. Read More

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September 2021

Quantification of NADH:ubiquinone oxidoreductase (complex I) content in biological samples.

J Biol Chem 2021 Sep 17:101204. Epub 2021 Sep 17.

Department of Pediatrics, Division of Neonatology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address:

Impairments in mitochondrial energy metabolism have been implicated in human genetic diseases associated with mitochondrial and nuclear DNA mutations, neurodegenerative and cardiovascular disorders, diabetes, and aging. Alteration in mitochondrial complex I structure and activity has been shown to play a key role in Parkinson's disease and ischemia/reperfusion tissue injury, but significant difficulty remains in assessing the content of this enzyme complex in a given sample. The present study introduces a new method utilizing native polyacrylamide gel electrophoresis in combination with flavin fluorescence scanning to measure the absolute content of complex I, as well as α-ketoglutarate dehydrogenase complex (KGDHC), in any preparation. Read More

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September 2021

Dystrophic epidermolysis bullosa pruriginosa: a new case series of a rare phenotype unveils skewed Th2 immunity.

J Eur Acad Dermatol Venereol 2021 Sep 20. Epub 2021 Sep 20.

Department of Dermatology, Hôpital Saint Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.

Importance: Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr) is a rare subtype of hereditary epidermolysis bullosa, with a poorly understood pathogenesis and no satisfactory treatment.

Objective: To assess the clinical and biological features, genetic basis and therapeutic management in order to better characterize this rare genodermatosis.

Design: We have conducted a retrospective study, reviewing the clinical presentation, genetic diagnosis, biological analyses and management of patients with dystrophic epidermolysis bullosa pruriginosa. Read More

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September 2021