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Institution

Johns Hopkins University School of Medicine

HealthcareBaltimore, Maryland, United States
About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.


Papers
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Journal ArticleDOI
TL;DR: Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging is traced.
Abstract: Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging

822 citations

Journal ArticleDOI
10 Jan 2008-Nature
TL;DR: It is shown that many TSGs have nearby antisense RNAs, and an inverse relation between p15 antisense (p15AS) and p15 sense expression in leukaemia is found, which suggests natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis.
Abstract: Tumour suppressor genes (TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer DNA methylation is commonly associated with TSG silencing, yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown An intriguing possible mechanism for gene regulation involves widespread non-coding RNAs such as microRNA, Piwi-interacting RNA and antisense RNAs Widespread sense-antisense transcripts have been systematically identified in mammalian cells, and global transcriptome analysis shows that up to 70% of transcripts have antisense partners and that perturbation of antisense RNA can alter the expression of the sense gene For example, it has been shown that an antisense transcript not naturally occurring but induced by genetic mutation leads to gene silencing and DNA methylation, causing thalassaemia in a patient Here we show that many TSGs have nearby antisense RNAs, and we focus on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukaemia We found an inverse relation between p15 antisense (p15AS) and p15 sense expression in leukaemia A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process The p15AS-induced silencing was Dicer-independent Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells Thus, natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis

822 citations

Journal ArticleDOI
12 Mar 2015-Nature
TL;DR: In this paper, a mouse model was introduced to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
Abstract: Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

821 citations

Journal ArticleDOI
16 Feb 2018-Science
TL;DR: Clinical benefit was associated with loss-of-function mutations in the PBRM1 gene, which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, and may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
Abstract: Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti–PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene ( P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti–CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1 -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase–signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

821 citations

Journal ArticleDOI
TL;DR: D-Serine appears to be the endogenous ligand for the glycine site of NMDA receptors, suggesting a mechanism by which astrocyte-derived D-serine could modulate neurotransmission.
Abstract: Using an antibody highly specific for D-serine conjugated to glutaraldehyde, we have localized endogenous D-serine in rat brain. Highest levels of D-serine immunoreactivity occur in the gray matter of the cerebral cortex, hippocampus, anterior olfactory nucleus, olfactory tubercle, and amygdala. Localizations of D-serine immunoreactivity correlate closely with those of D-serine binding to the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor as visualized by autoradiography and are inversely correlated to the presence of D-amino acid oxidase. D-Serine is enriched in process-bearing glial cells in neuropil with the morphology of protoplasmic astrocytes. In glial cultures of rat cerebral cortex, D-serine is enriched in type 2 astrocytes. The release of D-serine from these cultures is stimulated by agonists of non-NMDA glutamate receptors, suggesting a mechanism by which astrocyte-derived D-serine could modulate neurotransmission. D-Serine appears to be the endogenous ligand for the glycine site of NMDA receptors.

820 citations


Authors

Showing all 44754 results

NameH-indexPapersCitations
Robert Langer2812324326306
Bert Vogelstein247757332094
Solomon H. Snyder2321222200444
Steven A. Rosenberg2181204199262
Kenneth W. Kinzler215640243944
Hagop M. Kantarjian2043708210208
Mark P. Mattson200980138033
Stuart H. Orkin186715112182
Paul G. Richardson1831533155912
Aaron R. Folsom1811118134044
Gonçalo R. Abecasis179595230323
Jie Zhang1784857221720
Daniel R. Weinberger177879128450
David Baker1731226109377
Eliezer Masliah170982127818
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
2023149
2022622
20216,078
20205,107
20194,444
20183,848