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Identification of novel Topoisomerase II alpha inhibitors by virtual screening, molecular docking and bioassay.

Chem Biol Drug Des 2021 Jul 26. Epub 2021 Jul 26.

Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.

Breast cancer is one of the most common tumors and its treatment still leaves room for improvement. Topoisomerase II alpha is a potential target for the treatment of human diseases such as breast cancer. In this article, we attempted to discover a novel anti-cancer drug. Read More

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Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Adv Sci (Weinh) 2021 07 13;8(14):2100626. Epub 2021 May 13.

Department of Internal Medicine I University Hospital Ulm Albert-Einstein Allee 23 89081 Ulm Germany.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. Read More

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Nicotinamide phosphoribosyltransferase inhibitors selectively induce apoptosis of AML stem cells by disrupting lipid homeostasis.

Cell Stem Cell 2021 Jul 12. Epub 2021 Jul 12.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medicine, University of Toronto, ON, Canada; Division of Medical Oncology and Hematology, Department of Medicine, University Health Network, Toronto, ON, Canada. Electronic address:

Current treatments for acute myeloid leukemia (AML) are often ineffective in eliminating leukemic stem cells (LSCs), which perpetuate the disease. Here, we performed a metabolic drug screen to identify LSC-specific vulnerabilities and found that nicotinamide phosphoribosyltransferase (NAMPT) inhibitors selectively killed LSCs, while sparing normal hematopoietic stem and progenitor cells. Treatment with KPT-9274, a NAMPT inhibitor, suppressed the conversion of saturated fatty acids to monounsaturated fatty acids, a reaction catalyzed by the stearoyl-CoA desaturase (SCD) enzyme, resulting in apoptosis of AML cells. Read More

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Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.

Nature 2021 Jul 21. Epub 2021 Jul 21.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

The classic mode of STING activation is through binding the cyclic dinucleotide 2'3'-cyclic GMP-AMP (cGAMP), produced by the DNA sensor cyclic GMP-AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann-Pick type C1 (NPC1) as a cofactor in the trafficking of STING. Read More

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Massively parallel in vivo CRISPR screening identifies RNF20/40 as epigenetic regulators of cardiomyocyte maturation.

Nat Commun 2021 07 21;12(1):4442. Epub 2021 Jul 21.

Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

The forward genetic screen is a powerful, unbiased method to gain insights into biological processes, yet this approach has infrequently been used in vivo in mammals because of high resource demands. Here, we use in vivo somatic Cas9 mutagenesis to perform an in vivo forward genetic screen in mice to identify regulators of cardiomyocyte (CM) maturation, the coordinated changes in phenotype and gene expression that occur in neonatal CMs. We discover and validate a number of transcriptional regulators of this process. Read More

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A Simple RT-PCR Melting temperature Assay to Rapidly Screen for Widely Circulating SARS-CoV-2 Variants.

J Clin Microbiol 2021 Jul 21:JCM0084521. Epub 2021 Jul 21.

Public Health Research Institute; Center for Emerging Pathogens, Rutgers New Jersey Medical School; Institute of Genomic Medicine, Rutgers New Jersey Medical School, Newark, NJ.

. The increased transmission of SARS-CoV-2 variants of concern (VOC) which originated in the United Kingdom (B.1. Read More

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High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma.

Sci Rep 2021 Jul 20;11(1):14755. Epub 2021 Jul 20.

Department of Oral and Maxillofacial Diseases, University of Helsinki, 00014, Helsinki, Finland.

Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. Read More

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Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma.

Sci Rep 2021 Jul 20;11(1):14814. Epub 2021 Jul 20.

Institute for Clinical Research, Veterans Affairs Medical Center, Washington, DC, USA.

Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S. Read More

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Chemical screen identifies diverse and novel HDAC inhibitors as repressors of NUT function: implications for NUT carcinoma pathogenesis and treatment.

Mol Cancer Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School

NUT carcinoma (NC), characterized most commonly by the BRD4-NUTM1 fusion, is a rare, aggressive variant of squamous carcinoma with no effective treatment. BRD4-NUT drives growth and maintains the poorly differentiated state of NC by activating pro-growth genes such as MYC, through the formation of massive, hyperacetylated, super-enhancer-like domains termed megadomains. BRD4-NUT-mediated hyperacetylation of chromatin is facilitated by the chromatin-targeting tandem bromodomains of BRD4, combined with NUT, which recruits the histone acetyltransferase, p300. Read More

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Establishment of a plasticity-associated risk model based on a SOX2- and SOX9-related gene set in head and neck squamous cell carcinoma.

Mol Cancer Res 2021 Jul 20. Epub 2021 Jul 20.

Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg

Recent studies highlighted SOX2 and SOX9 as key determinants for cancer cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related genetic programs with risk factors and genetic or epigenetic alterations in primary head and neck squamous cell carcinoma (HNSCC), and their prognostic value is largely unknown. Here, we identified differentially expressed genes (DEGs) related to SOX2 and SOX9 transcription in TCGA-HNSC, which enable clustering of patients into groups with distinct clinical features and survival. Read More

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Weighted gene co-expression network analysis identifies specific modules and hub genes related to Parkinson's disease.

Neuroreport 2021 Jul 19. Epub 2021 Jul 19.

Changchun University of Chinese Medicine College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University Affiliated Hospital of Changchun University of Chinese Medicine College of Chinese Medicinal Materials, Jilin Agricultural University, Jilin, China.

Objective: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. This study aims to screen specific modules and key genes related to PD.

Methods: Gene expression profile data GSE6613 and GSE22491 were downloaded from the Gene Expression Omnibus database. Read More

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Bacterial Cytological Profiling Identifies Rhodanine-containing PAINS Analogs as Specific Inhibitors of Thymidylate Kinase .

J Bacteriol 2021 Jul 19:JB0010521. Epub 2021 Jul 19.

Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

In this study, we sought to determine if an assay for studying antibiotic mechanisms of action could provide insight into the activity of compounds that may inhibit multiple targets. Thus, we conducted an activity screen of 31 structural analogs of rhodanine-containing pan-assay interference compounds (PAINS). We identified nine active molecules against and classified them according to their mechanisms of action. Read More

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Screening for intrinsic capacity impairments as markers of increased risk of frailty and disability in the context of integrated care for older people: Secondary analysis of MAPT.

Maturitas 2021 Aug 4;150:1-6. Epub 2021 Jun 4.

Gerontopole of Toulouse, Institute of Aging, Toulouse University Hospital (CHU Toulouse), Toulouse, France; UPS/Inserm UMR1027, University of Toulouse III, Toulouse, France. Electronic address:

Aim: This longitudinal secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) aimed to test whether the Integrated Care for Older People (ICOPE) Step 1 screening tool is able to identify people at risk of developing frailty and disability in basic (ADL) and instrumental (IADL) activities of daily living among community-dwelling older adults.

Participants And Setting: Seven hundred and fifty-nine (n = 759) non-demented participants of the MAPT aged 70-89 years were assessed in memory clinics in France between 2008 and 2013.

Methods: We measured six intrinsic capacity (IC) impairments, adapted from the ICOPE screening tool. Read More

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The BTB-domain transcription factor ZBTB2 recruits chromatin remodelers and a histone chaperone during the exit from pluripotency.

J Biol Chem 2021 Jul 13:100947. Epub 2021 Jul 13.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. Electronic address:

Transcription factors (TFs) harboring BTB (Broad-Complex, Tramtrack, and Bric a brac) domains play important roles in development and disease. These BTB domains are thought to recruit transcriptional modulators to target DNA regions. However, a systematic molecular understanding of the mechanism of action of this TF family is lacking. Read More

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Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections.

J Clin Invest 2021 Jul;131(14)

Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden.

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort. Read More

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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling.

Nat Commun 2021 07 14;12(1):4308. Epub 2021 Jul 14.

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA, USA.

Hypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. Read More

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HLA-DR cancer cells expression correlates with T cell infiltration and is enriched in lung adenocarcinoma with indolent behavior.

Sci Rep 2021 Jul 13;11(1):14424. Epub 2021 Jul 13.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Lung adenocarcinoma (ADC) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate whether CyTOF identifies cellular and molecular predictors of tumor behavior. We developed and validated a CyTOF panel of 34 antibodies in four ADC cell lines and PBMC. Read More

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Barcode sequencing and a high-throughput assay for chronological lifespan uncover ageing-associated genes in fission yeast.

Microb Cell 2021 Jul 10;8(7):146-160. Epub 2021 May 10.

Institute of Healthy Ageing and Department of Genetics, Evolution & Environment, University College London, London WC1E 6BT, UK.

Ageing-related processes are largely conserved, with simple organisms remaining the main platform to discover and dissect new ageing-associated genes. Yeasts provide potent model systems to study cellular ageing owing their amenability to systematic functional assays under controlled conditions. Even with yeast cells, however, ageing assays can be laborious and resource-intensive. Read More

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Fast Mek1 Hit Identification with TRIC Technology Correlates Well with Other Biophysical Methods.

SLAS Discov 2021 Jul 8:24725552211026267. Epub 2021 Jul 8.

Application Team, NanoTemper Technologies GmbH, Munich, Germany.

The variety and complexity of drug targets are expanding rapidly. At the same time, there is significant interest in exploring a larger chemical space to identify new candidates. Fragment-based screening (FBS) has emerged as a popular alternative to traditional high-throughput screening campaigns to identify such drug candidates. Read More

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Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Nat Commun 2021 07 7;12(1):4198. Epub 2021 Jul 7.

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

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. Read More

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Genome-wide CRISPR/Cas9 screening in human iPS derived cardiomyocytes uncovers novel mediators of doxorubicin cardiotoxicity.

Sci Rep 2021 Jul 6;11(1):13866. Epub 2021 Jul 6.

Department of Medicine, University of California, San Diego, San Diego, CA, USA.

Human induced pluripotent stem (iPS) cell technologies coupled with genetic engineering now facilitate the study of the molecular underpinnings of disease in relevant human cell types. Application of CRISPR/Cas9-based approaches for genome-scale functional screening in iPS-derived cells, however, has been limited by technical constraints, including inefficient transduction in pooled format, loss of library representation, and poor cellular differentiation. Herein, we present optimized approaches for whole-genome CRISPR/Cas9 based screening in human iPS derived cardiomyocytes with near genome-wide representation at both the iPS and differentiated cell stages. Read More

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14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

Ann Rheum Dis 2021 Jul 5. Epub 2021 Jul 5.

Department of Orthopaedic Surgery, NYU Grossman School of Medicine, New York, New York, USA

Objectives: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. Read More

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Single Cell Proteomics Reveals Circulating Tumor Cell Heterogeneity during Treatment.

ACS Nano 2021 Jul 6. Epub 2021 Jul 6.

Centre for Personalised Nanomedicine, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Corner College and Cooper Roads (Bldg 75), Brisbane, Queensland 4072, Australia.

Cancer is a dynamic disease with heterogenic molecular signatures and constantly evolves during the course of the disease. Single cell proteomic analysis could offer a suitable pathway to monitor cancer cell heterogeneity and deliver critical information for the diagnosis, recurrence, and drug-resistant mechanisms in cancer. Current standard techniques for proteomic analysis such as ELISA, mass spectrometry, and Western blots are time-consuming, expensive, and often require fluorescence labeling that fails to provide accurate information about the multiple protein expression changes at the single cell level. Read More

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A new high-content screening assay of the entire hepatitis B virus life cycle identifies novel antivirals.

JHEP Rep 2021 Aug 30;3(4):100296. Epub 2021 Apr 30.

Applied Molecular Virology Laboratory, Institut Pasteur Korea, Seongnam-si, South Korea.

Background & Aims: Chronic hepatitis B is an incurable disease. Addressing the unmet medical need for therapies has been hampered by a lack of suitable cell culture models to investigate the HBV life cycle in a single experimental setup. We sought to develop a platform suitable to investigate all aspects of the entire HBV life cycle. Read More

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Identification of Early Diagnostic and Prognostic Biomarkers WGCNA in Stomach Adenocarcinoma.

Front Oncol 2021 18;11:636461. Epub 2021 Jun 18.

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China.

Stomach adenocarcinoma (STAD) is a leading cause of cancer deaths, and the outcome of the patients remains dismal for the lack of effective biomarkers of early detection. Recent studies have elucidated the landscape of genomic alterations of gastric cancer and reveal some biomarkers of advanced-stage gastric cancer, however, information about early-stage biomarkers is limited. Here, we adopt Weighted Gene Co-expression Network Analysis (WGCNA) to screen potential biomarkers for early-stage STAD using RNA-Seq and clinical data from TCGA database. Read More

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Medullary Thyroid Cancer - Feature Review and Update on Systemic Treatment.

Acta Clin Croat 2020 Jun;59(Suppl 1):50-59

1Department of Oncology and Nuclear Medicine, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia; 2University of Zagreb, School of Medicine; 3University of Zagreb, School of Dental Medicine.

Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic mutations and, less frequently, mutations, have been described in tumor tissues of sporadic MTC. Read More

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The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis.

Intensive Care Med Exp 2021 Jul 2;9(1):34. Epub 2021 Jul 2.

Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, USA.

Objective: To identify priorities for administrative, epidemiologic and diagnostic research in sepsis.

Design: As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis.

Methods: Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. Read More

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Conditional cash transfers to incentivize tuberculosis screening: Description of a novel strategy for contact investigation in rural South Africa.

Clin Infect Dis 2021 Jul 2. Epub 2021 Jul 2.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

Background: Providing incentives to screen close contacts for tuberculosis (TB) is an alternative to traditional household-based contact investigation. We aimed to characterize patients and contexts for which this incentive-based strategy might be preferred.

Methods: This is a secondary analysis of a cluster randomized trial of TB contact investigation in Limpopo District, South Africa, conducted between 2016-2020. Read More

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A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer.

Sci Rep 2021 Jul 1;11(1):13683. Epub 2021 Jul 1.

Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Resistance to drugs targeting the androgen receptor (AR) signaling axis remains an important challenge in the treatment of prostate cancer patients. Activation of alternative growth pathways is one mechanism used by cancer cells to proliferate despite treatment, conferring drug resistance. Through a kinome-centered CRISPR-Cas9 screen in CWR-R1 prostate cancer cells, we identified activated BRAF signaling as a determinant for enzalutamide resistance. Read More

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Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening.

BMC Pediatr 2021 Jul 1;21(1):296. Epub 2021 Jul 1.

Newborn Screening Ontario, Ottawa, Ontario, Canada.

Background: Newborn screening (NBS) for sickle cell disease incidentally identifies heterozygous carriers of hemoglobinopathy mutations. In Ontario, Canada, these carrier results are not routinely disclosed, presenting an opportunity to investigate the potential health implications of carrier status. We aimed to compare rates of health services use among children identified as carriers of hemoglobinopathy mutations and those who received negative NBS results. Read More

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