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  • 1
  • 2
    Keywords: PROSTATE-CANCER ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; SQUAMOUS-CELL CARCINOMA ; LUNG ADENOCARCINOMA ; ACUTE MYELOID-LEUKEMIA ; SOMATIC MUTATIONS ; GENETIC LANDSCAPE ; 21 BREAST CANCERS ; RECURRENT MUTATIONS ; FREQUENT MUTATION
    Abstract: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
    Type of Publication: Journal article published
    PubMed ID: 23945592
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  • 3
    Publication Date: 2018-11-02
    Description: The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic cells in systemic mastocytosis (SM). We found that clonal CD34 + /CD38 – stem cells, CD34 + /CD38 + progenitor cells, and CD117 ++ /CD34 – MCs invariably express CD44 in patients with indolent SM (ISM), SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia (MCL). In addition, all human MCL-like cell lines examined (HMC-1, ROSA, and MCPV-1) displayed cytoplasmic and cell-surface CD44. We also found that expression of CD44 in neoplastic MCs depends on RAS-MEK and STAT5 signaling and increases with the aggressiveness of SM. Correspondingly, higher levels of soluble CD44 were measured in the sera of patients with advanced SM compared with ISM or cutaneous mastocytosis and were found to correlate with overall and progression-free survival. To investigate the functional role of CD44, a xenotransplantation model was employed using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and a short hairpin RNA (shRNA) against CD44. In this model, the shRNA-mediated knockdown of CD44 resulted in reduced MC expansion and tumor formation and prolonged survival in SCID mice compared with HMC-1.2 cells transduced with control shRNA. Together, our data show that CD44 is a RAS-MEK/STAT5-driven MC invasion receptor that correlates with the aggressiveness of SM. Whether CD44 can serve as therapeutic target in advanced SM remains to be determined in forthcoming studies.
    Keywords: Myeloid Neoplasia
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-11-20
    Description: T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide–MHC complexes T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide–MHC complexes, Published online: 19 November 2018; doi:10.1038/nbt.4303 The relative affinity of T cell receptors for different peptide–MHCs is measured at high throughput, revealing T cell cross-reactivity.
    Print ISSN: 1087-0156
    Electronic ISSN: 1546-1696
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
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  • 5
    Publication Date: 2018-03-21
    Description: Aims Genetic abnormalities, including copy number variants (CNV), copy number neutral loss of heterozygosity (CN-LOH) and gene mutations, underlie the pathogenesis of myeloid malignancies and serve as important diagnostic, prognostic and/or therapeutic markers. Currently, multiple testing strategies are required for comprehensive genetic testing in myeloid malignancies. The aim of this proof-of-principle study was to investigate the feasibility of combining detection of genome-wide large CNVs, CN-LOH and targeted gene mutations into a single assay using next-generation sequencing (NGS). Methods For genome-wide CNV detection, we designed a single nucleotide polymorphism (SNP) sequencing backbone with 22 762 SNP regions evenly distributed across the entire genome. For targeted mutation detection, 62 frequently mutated genes in myeloid malignancies were targeted. We combined this SNP sequencing backbone with a targeted mutation panel, and sequenced 9 healthy individuals and 16 patients with myeloid malignancies using NGS. Results We detected 52 somatic CNVs, 11 instances of CN-LOH and 39 oncogenic mutations in the 16 patients with myeloid malignancies, and none in the 9 healthy individuals. All CNVs and CN-LOH were confirmed by SNP microarray analysis. Conclusions We describe a genome-wide SNP sequencing backbone which allows for sensitive detection of genome-wide CNVs and CN-LOH using NGS. This proof-of-principle study has demonstrated that this strategy can provide more comprehensive genetic profiling for patients with myeloid malignancies using a single assay.
    Print ISSN: 0021-9746
    Electronic ISSN: 1472-4146
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 6
    Publication Date: 2018-01-06
    Description: UBIAD1 (UbiA prenyltransferase domain–containing protein-1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize vitamin K2. We previously reported that sterols stimulate binding of UBIAD1 to endoplasmic reticulum (ER)–localized 3-hydroxy-3-methylglutaryl (HMG) CoA reductase. UBIAD1 binding inhibits sterol-accelerated, ER-associated degradation (ERAD) of reductase, one of several mechanisms for feedback control of this rate-limiting enzyme in the branched pathway that produces cholesterol and nonsterol isoprenoids such as GGpp. Accumulation of GGpp in ER membranes triggers release of UBIAD1 from reductase, permitting its maximal ERAD and ER-to-Golgi transport of UBIAD1. Mutant UBIAD1 variants associated with Schnyder corneal dystrophy (SCD), a human disorder characterized by corneal accumulation of cholesterol, resist GGpp-induced release from reductase and remain sequestered in the ER to block reductase ERAD. Using lines of genetically manipulated cells, we now examine consequences of UBIAD1 deficiency and SCD-associated UBIAD1 on reductase ERAD and cholesterol synthesis. Our results indicated that reductase becomes destabilized in the absence of UBIAD1, resulting in reduced cholesterol synthesis and intracellular accumulation. In contrast, an SCD-associated UBIAD1 variant inhibited reductase ERAD, thereby stabilizing the enzyme and contributing to enhanced synthesis and intracellular accumulation of cholesterol. Finally, we present evidence that GGpp-regulated, ER-to-Golgi transport enables UBIAD1 to modulate reductase ERAD such that synthesis of nonsterol isoprenoids is maintained in sterol-replete cells. These findings further establish UBIAD1 as a central player in the reductase ERAD pathway and regulation of isoprenoid synthesis. They also indicate that UBIAD1-mediated inhibition of reductase ERAD underlies cholesterol accumulation associated with SCD.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
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  • 7
    Publication Date: 2018-02-27
    Description: Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy, Published online: 26 February 2018; doi:10.1038/s41588-018-0063-6 Biallelic loss-of-function mutations in TGFB1 are reported in three individuals with severe infantile inflammatory bowel disease and neurodevelopmental delay. These findings highlight a critical role for TGF-β1 in human intestinal homeostasis and central nervous system development.
    Print ISSN: 1061-4036
    Electronic ISSN: 1546-1718
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2014-11-05
    Description: Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world's population and are largely due to chronic Helicobacter pylori infection. Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis, and there is no experimental model of normal human gastric mucosa. Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells. We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs). Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach. Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells. We used hGO cultures to identify novel signalling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3. Using hGOs to model pathogenesis of human disease, we found that H. pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signalling and induction of epithelial proliferation. Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270898/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McCracken, Kyle W -- Cata, Emily M -- Crawford, Calyn M -- Sinagoga, Katie L -- Schumacher, Michael -- Rockich, Briana E -- Tsai, Yu-Hwai -- Mayhew, Christopher N -- Spence, Jason R -- Zavros, Yana -- Wells, James M -- 5P30DK034933/DK/NIDDK NIH HHS/ -- K01 DK091415/DK/NIDDK NIH HHS/ -- K01DK091415/DK/NIDDK NIH HHS/ -- P30 DK078392/DK/NIDDK NIH HHS/ -- P30 DK0789392/DK/NIDDK NIH HHS/ -- R01 DK080823/DK/NIDDK NIH HHS/ -- R01 DK092456/DK/NIDDK NIH HHS/ -- R01 DK098350/DK/NIDDK NIH HHS/ -- R01 GM072915/GM/NIGMS NIH HHS/ -- R01DK080823/DK/NIDDK NIH HHS/ -- R01DK092456/DK/NIDDK NIH HHS/ -- T32 GM063483/GM/NIGMS NIH HHS/ -- U54 RR025216/RR/NCRR NIH HHS/ -- UL1 RR026314/RR/NCRR NIH HHS/ -- UL1 TR000077/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):400-4. doi: 10.1038/nature13863. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA. ; Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267, USA. ; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA. ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA. ; 1] Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA [2] Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA. ; 1] Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA [2] Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363776" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Differentiation ; Helicobacter Infections/*physiopathology ; Helicobacter pylori ; Humans ; *Models, Biological ; *Organogenesis ; Organoids/*cytology/microbiology ; Pluripotent Stem Cells/*cytology ; Signal Transduction ; Stomach/*cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2011-09-03
    Description: The corticotropin-releasing hormone receptor 1 (CRHR1) critically controls behavioral adaptation to stress and is causally linked to emotional disorders. Using neurochemical and genetic tools, we determined that CRHR1 is expressed in forebrain glutamatergic and gamma-aminobutyric acid-containing (GABAergic) neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, we found that the lack of CRHR1 in forebrain glutamatergic circuits reduces anxiety and impairs neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increases anxiety-like behavior and reduces dopamine release in the prefrontal cortex. These results define a bidirectional model for the role of CRHR1 in anxiety and suggest that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems might lead to emotional disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Refojo, Damian -- Schweizer, Martin -- Kuehne, Claudia -- Ehrenberg, Stefanie -- Thoeringer, Christoph -- Vogl, Annette M -- Dedic, Nina -- Schumacher, Marion -- von Wolff, Gregor -- Avrabos, Charilaos -- Touma, Chadi -- Engblom, David -- Schutz, Gunther -- Nave, Klaus-Armin -- Eder, Matthias -- Wotjak, Carsten T -- Sillaber, Inge -- Holsboer, Florian -- Wurst, Wolfgang -- Deussing, Jan M -- New York, N.Y. -- Science. 2011 Sep 30;333(6051):1903-7. doi: 10.1126/science.1202107. Epub 2011 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Psychiatry, Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21885734" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; *Anxiety ; Behavior, Animal ; Corticotropin-Releasing Hormone/metabolism ; Dopamine/*metabolism ; Fear ; Glutamic Acid/*metabolism ; Hippocampus/metabolism ; Male ; Memory ; Mesencephalon ; Mice ; Mice, Knockout ; Motor Activity ; Neurons/*metabolism ; Prefrontal Cortex/metabolism ; Prosencephalon/cytology/metabolism ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/genetics/*metabolism ; Synaptic Transmission ; Ventral Tegmental Area/metabolism ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  54. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds); 20090907-20090910; Essen; DOC09gmds103 /20090831/
    Publication Date: 2009-08-31
    Keywords: propensity score methods ; estimation of treatment effect ; ddc: 610
    Language: English
    Type: conferenceObject
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