Institution
Novartis Foundation
Nonprofit•Basel, Switzerland•
About: Novartis Foundation is a nonprofit organization based out in Basel, Switzerland. It is known for research contribution in the topics: Health care & Leprosy. The organization has 99 authors who have published 85 publications receiving 3993 citations.
Topics: Health care, Leprosy, Population, Phosphorylation, Gene
Papers published on a yearly basis
Papers
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TL;DR: It is shown that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues, which suggest a role for the dem methylated form in maintenance of enzyme function and phosphorylation networks in vivo.
Abstract: Background
Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo.
Methodology/Principal Findings
Here, we show that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in PME-1(−/−) tissues, which also displayed alterations in phosphoproteome content.
Conclusions
These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo.
53 citations
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TL;DR: Findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which m TORC1 inhibition is perturbing age- related phenotypes.
Abstract: Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes.
52 citations
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TL;DR: Post-exposure prophylaxis with SDR is safe; can be integrated into different leprosy control programmes with minimal additional efforts once contact tracing has been established; and is generally well accepted by index patients, their contacts, and health-care workers.
52 citations
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TL;DR: LGX818 is a potent and selective RAF kinase inhibitor with unique biochemical properties that contribute to an excellent pharmacological profile and a Phase I clinical trial in patients with BRAF mutant tumors is ongoing.
Abstract: Selective RAF inhibitors have significant activity in patients with metastatic melanoma whose tumors express BRAFV600E. However, not all patients respond equally well to treatment and the duration of response is often limited to less than 6 months. LGX818 was developed with the hypothesis that a more potent inhibitor with excellent pharmacological properties would maximize the degree and duration of patient response. LGX818 is a highly potent RAF inhibitor with selective anti-proliferative and apoptotic activity in cells expressing BRAFV600E. In the A375 (BRAFV600E) human melanoma cell line LGX818 suppresses phospho-ERK (EC50 = 3 nM) leading to potent inhibition of proliferation (EC50 = 4 nM). No significant activity was observed against a panel of 100 kinases (IC50 > 900 nM) and LGX818 did not inhibit proliferation of > 400 cell lines expressing wild-type BRAF. Contributing to the high potency of LGX818 is the extremely slow off-rate from BRAFV600E which is not observed with other RAF inhibitors. In biochemical assays the dissociation half-life was >24 hours which translated into sustained target inhibition in cells following drug wash-out. Single dose PK/PD studies in human melanoma xenograft models (BRAFV600E) indicated that LGX818 treatment at oral doses as low as 6 mg/kg resulted in strong (75%) and sustained (>24 hours) decrease in phospho-MEK, even following clearance of drug from circulation. Decreases in phospho-ERK were consistent with phospho-MEK but markers of downstream transcriptional output (DUSP6 and SPRY4) appeared to provide a more sensitive measure of pathway activation. LGX818 induced tumor regression in multiple BRAF mutant human tumor xenograft models grown in immune compromised mice and rats at doses as low as 1 mg/kg. Consistent with the in vitro data, LGX818 was inactive against BRAF wild-type tumors at doses up to 300 mg/kg bid, with good tolerability and linear increase in exposure. Efficacy was also achieved in a more disease-relevant spontaneous metastatic melanoma and a model of melanoma brain metastasis. LGX818 is a potent and selective RAF kinase inhibitor with unique biochemical properties that contribute to an excellent pharmacological profile. A Phase I clinical trial in patients with BRAF mutant tumors is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3790. doi:1538-7445.AM2012-3790
47 citations
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TL;DR: Data show that Dd-STATc functions as a transcriptional activator in a stress-response pathway and the pharmacological evidence, at least, is consistent with cGMP acting as a second messenger.
Abstract: The Dictyostelium stalk cell inducer differentiation-inducing
factor (DIF) directs tyrosine phosphorylation and nuclear accumulation of the
STAT (signal transducer and activator of transcription) protein Dd-STATc. We
show that hyperosmotic stress, heat shock and oxidative stress also activate
Dd-STATc. Hyperosmotic stress is known to elevate intracellular cGMP and cAMP
levels, and the membrane-permeant analogue 8-bromo-cGMP rapidly activates
Dd-STATc, whereas 8-bromo-cAMP is a much less effective inducer. Surprisingly,
however, Dd-STATc remains stress activatable in null mutants for components of
the known cGMP-mediated and cAMP-mediated stress-response pathways and in a
double mutant affecting both pathways. Also, Dd-STATc null cells are not
abnormally sensitive to hyperosmotic stress. Microarray analysis identified
two genes, gapA and rtoA , that are induced by hyperosmotic
stress. Osmotic stress induction of gapA and rtoA is
entirely dependent on Dd-STATc. Neither gene is inducible by DIF but both are
rapidly inducible with 8-bromo-cGMP. Again, 8-bromo-cAMP is a much less potent
inducer than 8-bromo-cGMP. These data show that Dd-STATc functions as a
transcriptional activator in a stress-response pathway and the pharmacological
evidence, at least, is consistent with cGMP acting as a second messenger.
46 citations
Authors
Showing all 100 results
Name | H-index | Papers | Citations |
---|---|---|---|
Peter G. Schultz | 156 | 893 | 89716 |
Elizabeth A. Winzeler | 69 | 243 | 30083 |
Andrew I. Su | 58 | 202 | 20263 |
Diego H. Castrillon | 54 | 108 | 15087 |
Scott B. Ficarro | 54 | 134 | 11374 |
Eric C. Peters | 50 | 82 | 11393 |
Kavita Shah | 46 | 107 | 6741 |
Scott A. Lesley | 46 | 227 | 10590 |
Xu Wu | 42 | 70 | 6929 |
Tim Wiltshire | 39 | 112 | 11960 |
Glen Spraggon | 37 | 129 | 5172 |
Richard Glynne | 37 | 70 | 6087 |
Claudio A. P. Joazeiro | 34 | 48 | 10941 |
Mathew T. Pletcher | 30 | 53 | 4704 |
Arnab K. Chatterjee | 28 | 71 | 3251 |