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First report of a bla metallo-β-lactamase-possessing Klebsiella michiganensis.

J Glob Antimicrob Resist 2021 May 3. Epub 2021 May 3.

Institute for Infectious Diseases (IFIK), University of Bern. Electronic address:

Background: Klebsiella michiganensis is an emerging pathogen. As for Klebsiella pneumoniae, this species is able to acquire antibiotic resistance genes (ARGs) via mobile genetic elements. In this context, K. Read More

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Synthase-Selective Exploration of a Tunicate Microbiome by Activity-Guided Single-Cell Genomics.

ACS Chem Biol 2021 May 6. Epub 2021 May 6.

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.

While thousands of environmental metagenomes have been mined for the presence of novel biosynthetic gene clusters, such computational predictions do not provide evidence of their biosynthetic functionality. Using fluorescent enzyme assay targeting carrier proteins common to polyketide (PKS) and nonribosomal peptide synthetases (NRPS), we applied fluorescence-activated cell sorting to tunicate microbiome to enrich for microbes with active secondary metabolic capabilities. Single-cell genomics uncovered the genetic basis for a wide biosynthetic diversity in the enzyme-active cells and revealed a member of marine harboring a novel NRPS gene cluster with high similarity to phylogenetically distant marine and terrestrial bacteria. Read More

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Novel Neuroprotective Loci Modulating Ischemic Stroke Volume in Wild-Derived Inbred Mouse Strains.

Genetics 2019 Nov;213(3):1079-1092

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.

To identify genes involved in cerebral infarction, we have employed a forward genetic approach in inbred mouse strains, using quantitative trait loci (QTL) mapping for cerebral infarct volume after middle cerebral artery occlusion. We had previously observed that infarct volume is inversely correlated with cerebral collateral vessel density in most strains. In this study, we expanded the pool of allelic variation among classical inbred mouse strains by utilizing the eight founder strains of the Collaborative Cross and found a wild-derived strain, WSB/EiJ, that breaks this general rule that collateral vessel density inversely correlates with infarct volume. Read More

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November 2019

Novel Neuroprotective Loci Modulating Ischemic Stroke Volume in Wild-Derived Inbred Mouse Strains.

Genetics 2019 Nov;213(3):1079-1092

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.

To identify genes involved in cerebral infarction, we have employed a forward genetic approach in inbred mouse strains, using quantitative trait loci (QTL) mapping for cerebral infarct volume after middle cerebral artery occlusion. We had previously observed that infarct volume is inversely correlated with cerebral collateral vessel density in most strains. In this study, we expanded the pool of allelic variation among classical inbred mouse strains by utilizing the eight founder strains of the Collaborative Cross and found a wild-derived strain, WSB/EiJ, that breaks this general rule that collateral vessel density inversely correlates with infarct volume. Read More

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November 2019

Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals.

JAMA Cardiol 2021 May 5. Epub 2021 May 5.

Department of Medicine, University of Illinois at Chicago.

Importance: Although rare variants in cardiac ion channels, transcription factors, and myocardial structural proteins are associated with early-onset atrial fibrillation (AF) in White individuals of European descent, it remains unclear whether genetic variation also contributes to the cause of AF in those of minority ethnicity.

Objectives: To assess the prevalence of rare and novel pathogenic variants in candidate genes in ethnic minority probands with early-onset AF and determine genotype-phenotype associations.

Design, Setting, And Participants: In this cohort, family-based study, probands of African and Hispanic descent with early-onset AF (defined as AF occurring in individuals aged ≤66 years) prospectively enrolled in a clinical and genetic biorepository underwent sequencing of 60 candidate genes. Read More

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The Role of Left-Atrial Mechanics Assessed by Two-Dimensional Speckle-Tracking Echocardiography to Differentiate Hypertrophic Cardiomyopathy from Hypertensive Left-Ventricular Hypertrophy.

Diagnostics (Basel) 2021 Apr 30;11(5). Epub 2021 Apr 30.

Cardio-thoracic Department, University of Medicine and Pharmacy Carol Davila, Eroii Sanitari Bvd. 8, 050474 Bucharest, Romania.

Hypertrophic cardiomyopathy (HCM) and arterial hypertension (HTN) are conditions with different pathophysiology, but both can result in left-ventricular hypertrophy (LVH). The role of left-atrial (LA) functional changes detected by two-dimensional speckle-tracking echocardiography (STE) in indicating LVH etiology is unknown.

Methods: We aimed to characterize LA mechanics using STE in LVH patients with HCM and HTN. Read More

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Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature.

Invest Ophthalmol Vis Sci 2021 May;62(6)

Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.

Purpose: The purpose of this study was to report retinal dystrophy as a novel clinical feature and expand the ocular phenotype in patients harboring biallelic candidate FDXR variants.

Methods: Patients carrying biallelic candidate FDXR variants were identified by whole genome sequencing (WGS) as part of the National Institute for Health Research BioResource rare-disease and the UK's 100,000 Genomes Project (100KGP) with an additional case identified by exome sequencing. Retrospective clinical data were collected from the medical records. Read More

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iTIME.219: An Immortalized KSHV Infected Endothelial Cell Line Inducible by a KSHV-Specific Stimulus to Transition From Latency to Lytic Replication and Infectious Virus Release.

Front Cell Infect Microbiol 2021 14;11:654396. Epub 2021 Apr 14.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) is the causative agent of Kaposi's sarcoma and two B cell lymphoproliferative disorders: primary effusion lymphoma and KSHV-associated multicentric Castleman's disease. These distinct pathologies involve different infected cell types. In Kaposi's sarcoma, the virus is harbored in spindle-like tumor cells of endothelial origin, in contrast with the two pathologies of B cells. Read More

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Case Report: Dacomitinib May Not Benefit Patients Who Develop Rare Compound Mutations After Later-Line Osimertinib Treatment.

Front Oncol 2021 15;11:649843. Epub 2021 Apr 15.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The acquired C797X mutation has been identified as the most notable resistance to osimertinib, and novel secondary mutations of L718 and L792 residues have also been demonstrated to confer osimertinib resistance, making the choice of medication after osimertinib treatment a quandary. Dacomitinib has been reported to have potential impact on patients acquiring rare compound mutations after osimertinib resistance; however, little evidence is available to date. In five lung adenocarcinoma patients resistant to later-line osimertinib, recurrent mutations at L792 and/or L718 were identified using targeted next-generation sequencing of tissue or cell-free DNA from plasma or pleural effusion. Read More

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Split Cord Malformation Type 1 (Bony Spur) Excision Using Microrongeur.

J Pediatr Neurosci 2020 Oct-Dec;15(4):349-351. Epub 2021 Jan 19.

Department of Neurosurgery, Seth GS Medical College and King Edward VII Memorial Hospital, Parel, Mumbai 400012, India.

Split cord malformation is well documented and reported in various case series and reports in the literature. The excision of bony spur in type 1 split cord malformation is challenging due to the intricate pathologic anatomy. The standard method advocated is to excise the bony spur with the help of a high-speed microdrill and a forward cutting punch. Read More

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January 2021

An Integrated Genomic, Proteomic, and Immunopeptidomic Approach to Discover Treatment-Induced Neoantigens.

Front Immunol 2021 15;12:662443. Epub 2021 Apr 15.

Mass Spectrometry Platform, Chan Zuckerberg Biohub, Stanford, CA, United States.

All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) are necessary for directing T-cell responses against cells harboring non-self antigens derived from pathogens or from somatic mutations. Alterations in tumor-specific antigen repertoires - particularly novel MHC presentation of mutation-bearing peptides (neoantigens) - can be potent targets of anti-tumor immune responses. Read More

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Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome.

Front Immunol 2021 14;12:586320. Epub 2021 Apr 14.

Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil.

Since the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. Read More

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Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer.

Clin Transl Med 2021 Apr;11(4):e401

McGill University-Segal Cancer Centre, Jewish General Hospital, 3755 Côte Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada.

Background: Therapeutic resistance is the main cause of death in metastatic colorectal cancer. To investigate genomic plasticity, most specifically of metastatic lesions, associated with response to first-line systemic therapy, we collected longitudinal liver metastatic samples and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome.

Methods: Liver metastatic biopsies were collected prior to treatment (pre, n = 97) and when clinical imaging demonstrated therapeutic resistance (post, n = 43). Read More

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MGA Mutation as a Novel Biomarker for Immune Checkpoint Therapies in Non-Squamous Non-Small Cell Lung Cancer.

Front Pharmacol 2021 13;12:625593. Epub 2021 Apr 13.

Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Immune checkpoint inhibitors have changed the treatment landscape for advanced non-small cell lung cancer. However, only a small proportion of patients experience clinical benefit from ICIs. Thus, the discovery of predictive biomarkers is urgently warranted. Read More

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Five-year microevolution of a multidrug-resistant Mycobacterium tuberculosis strain within a patient with inadequate compliance to treatment.

BMC Infect Dis 2021 Apr 29;21(1):394. Epub 2021 Apr 29.

Instituto Nacional de Enfermedades Infecciosas-ANLIS Carlos Malbrán, Buenos Aires, Argentina.

Background: Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution -the genetic variability of M. Read More

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Loss-of-Function Mutations of Are an Independent Marker of Adverse Outcomes in Intensively Treated Patients with Acute Myeloid Leukemia.

Cancers (Basel) 2021 Apr 26;13(9). Epub 2021 Apr 26.

Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital, 60177 Brno, Czech Republic.

Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The corepressor and its homolog, the , have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Read More

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Transient and Efficient Vascular Permeability Window for Adjuvant Drug Delivery Triggered by Microbeam Radiation.

Cancers (Basel) 2021 Apr 27;13(9). Epub 2021 Apr 27.

Institute of Anatomy, University of Bern, 3012 Bern, Switzerland.

Background: Microbeam Radiation Therapy (MRT) induces a transient vascular permeability window, which offers a novel drug-delivery system for the preferential accumulation of therapeutic compounds in tumors. MRT is a preclinical cancer treatment modality that spatially fractionates synchrotron X-rays into micrometer-wide planar microbeams which can induce transient vascular permeability, especially in the immature tumor vessels, without compromising vascular perfusion. Here, we characterized this phenomenon using Chicken Chorioallantoic Membrane (CAM) and demonstrated its therapeutic potential in human glioblastoma xenografts in mice. Read More

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Acute Pulmonary Histoplasmosis Following COVID-19: Novel Laboratorial Methods Aiding Diagnosis.

J Fungi (Basel) 2021 Apr 28;7(5). Epub 2021 Apr 28.

Evandro Chagas National Institute of Infectious Diseases, Fiocruz, Rio de Janeiro 21040-900, Brazil.

The acute form of histoplasmosis usually occurs after the exposition of more than one individual to a common environmental source harboring . Here, we present two cases of acute pulmonary histoplasmosis seen within two weeks at a reference center for infectious diseases at Rio de Janeiro, Brazil. The patients did not present a common epidemiologic history for histoplasmosis, however both presented COVID-19 before the onset of histoplasmosis symptoms. Read More

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Identification and Characterization of a Novel Genomic Island Harboring Cadmium and Arsenic Resistance Genes in .

Biomolecules 2021 Apr 11;11(4). Epub 2021 Apr 11.

Department of Food, Bioprocessing and Nutrition Sciences, North Carolina State University, Raleigh, NC 27695-7624, USA.

the bacterial foodborne pathogen responsible for the severe disease listeriosis, frequently exhibits heavy metal resistance. Concurrent resistance to cadmium and arsenic in is strongly associated with the 35-kb chromosomal island LGI2. LGI2 has been encountered repeatedly among serotype 4b hypervirulent clones but, surprisingly, not among non-pathogenic spp. Read More

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Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes.

Int J Mol Sci 2021 Apr 10;22(8). Epub 2021 Apr 10.

Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. Read More

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Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance.

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.

Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. Read More

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A Novel Structure Harboring on IncF Plasmids in Isolated from Swine in China.

Antibiotics (Basel) 2021 Apr 4;10(4). Epub 2021 Apr 4.

Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.

The aim of this study was to elucidate the prevalence of -producing and transmission mechanisms of from swine farms in China. A total of 333 isolates were collected from two farms from 2013 to 2016. Thirty-two CTX-M-27-positive were obtained, and all were multidrug-resistant. Read More

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Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis.

J Bone Miner Res 2021 Apr 27. Epub 2021 Apr 27.

BIH Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Human induced pluripotent stem cells (hiPSCs) hold great potential for modelling human diseases and the development of innovative therapeutic approaches. Here, we report on a novel, simplified differentiation method for forming functional osteoclasts from hiPSCs. The three-step protocol starts with embryoid body formation, followed by hematopoietic specification, and finally osteoclast differentiation. Read More

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Exposure to diverse Plasmodium falciparum genotypes shapes the risk of symptomatic malaria in incident and persistent infections: A longitudinal molecular epidemiologic study in Kenya.

Clin Infect Dis 2021 Apr 27. Epub 2021 Apr 27.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill NC, USA.

Background: Repeated exposure to malaria infections could protect against symptomatic progression, as people develop adaptive immunity to infections acquired over time.

Methods: We investigated how new, recurrent, and persistent Plasmodium falciparum infections were associated with the odds of developing symptomatic compared to asymptomatic malaria. Using a 14-month longitudinal cohort in Western Kenya, we used amplicon deep sequencing of two polymorphic genes (pfama1 and pfcsp) to assess overlap of parasite genotypes (represented by haplotypes) acquired within an individual's successive infections. Read More

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Discovery of 2-(3-(3-Carbamoylpiperidin-1-yl)phenoxy)acetic Acid Derivatives as Novel Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

J Med Chem 2021 Apr 26. Epub 2021 Apr 26.

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.

The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we describe the medicinal chemistry optimization of a screening hit to yield novel small-molecule inhibitors of the β-catenin/BCL9 interaction. The best compound can disrupt the β-catenin/BCL9 interaction with a of 3. Read More

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Farnesyl pyrophosphate is a new danger signal inducing acute cell death.

PLoS Biol 2021 Apr 26;19(4):e3001134. Epub 2021 Apr 26.

School of Life Sciences, Institute for Immunology, Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China.

Cell death is a vital event in life. Infections and injuries cause lytic cell death, which gives rise to danger signals that can further induce cell death, inflammation, and tissue damage. The mevalonate (MVA) pathway is an essential, highly conserved and dynamic metabolic pathway. Read More

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Metabolic Scar Assessment with F-FDG -PET: Correlation to Ischemic VT Substrate and Successful Ablation Sites.

J Nucl Med 2021 Apr 23. Epub 2021 Apr 23.

University of Maryland medical center, United States.

Functional/molecular imaging characteristics of ischemic ventricular tachycardia (VT) substrate are incompletely understood. Objective: Compare regional F-FDG - PET tracer uptake with detailed electroanatomic maps (EAM) in a more extensive series of post-infarction VT patients to define metabolic properties of the VT substrate/successful ablation sites. 3D metabolic left ventricular (LV) reconstructions were created from perfusion-normalized F-FDG images in consecutive patients undergoing VT ablation. Read More

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Concomitant mutation status of -rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib.

Transl Lung Cancer Res 2021 Mar;10(3):1525-1535

Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China.

Background: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase () rearrangement characterizes a subgroup of patients who show sensitivity to tyrosine kinase inhibitors (TKIs). However, the prognoses of these patients are heterogeneous. A better understanding of the genomic alterations occurring in these tumors could explain the prognostic heterogeneity observed in these patients. Read More

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Expanding the Genotypic Spectrum of Congenital Sensory and Autonomic Neuropathies Using Whole-Exome Sequencing.

Neurol Genet 2021 Apr 3;7(2):e568. Epub 2021 Mar 3.

New York University School of Medicine (J.-A.P., L.N.-K., H.K.), New York, NY; and Massachusetts General Hospital Research Institute (R.Y., D.G., S.S), Boston.

Objective: To test the hypothesis that many patients presenting with congenital insensitivity to pain have lesser known or unidentified mutations not captured by conventional genetic panels, we performed whole-exome sequencing in a cohort of well-characterized patients with a clinical diagnosis of congenital hereditary sensory and autonomic neuropathy with unrevealing conventional genetic testing.

Methods: We performed whole-exome sequencing (WES) in 13 patients with congenital impaired or absent sensation to pain and temperature with no identified molecular diagnosis from a conventional genetic panel. Patients underwent a comprehensive phenotypic assessment including autonomic function testing, and neurologic and ophthalmologic examinations. Read More

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