Journal ArticleDOI
PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Vamsi K. Mootha,Cecilia M. Lindgren,Cecilia M. Lindgren,Karl-Fredrik Eriksson,Aravind Subramanian,Smita Sihag,J. Lehar,Pere Puigserver,Emma Carlsson,Martin Ridderstråle,Esa Laurila,Nicholas E. Houstis,Mark J. Daly,Nick Patterson,Jill P. Mesirov,Todd R. Golub,Todd R. Golub,Pablo Tamayo,Bruce M. Spiegelman,Eric S. Lander,Joel N. Hirschhorn,Joel N. Hirschhorn,Joel N. Hirschhorn,David Altshuler,Leif Groop +24 more
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TLDR
An analytical strategy is introduced, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes, which identifies a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle.Abstract:
DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.read more
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High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO
TL;DR: High-resolution time series of transcript abundance data implicate dFOXO as a major coordinator of the transcriptional response to nutrients downstream of insulin and suggest that mitochondria biogenesis is linked to insulin signaling via d FOXO-mediated repression of a PGC-1 homolog.
Journal ArticleDOI
Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator–Activated Receptor (PPAR)-δ and Is of Metabolic Relevance in Humans
Harald Staiger,Carina Haas,Jiirgen Machann,Roman Werner,Melanie Weisser,Fritz Schick,Fausto Machicao,Norbert Stefan,Andreas Fritsche,Hans-Ulrich Häring +9 more
TL;DR: It is shown here that ANGPTL4 (encoding angiopoietin-like protein 4) represents a prominent LCFA-responsive gene in human myotubes and seems to be of systemic relevance in humans.
Journal ArticleDOI
Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes
Subir K. Roy Chowdhury,Darrell R. Smith,Ali Saleh,Jason Schapansky,Alexandra Marquez,Suzanne Gomes,Eli Akude,Dwane Morrow,Nigel A. Calcutt,Paul Fernyhough +9 more
TL;DR: The data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.
Journal ArticleDOI
Type 2 Diabetes Mellitus and Skeletal Muscle Metabolic Function
Esther Phielix,Marco Mensink +1 more
TL;DR: Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function is related to the development of insulin resistance and type 2 diabetes mellitus, and a likely candidate is an impaired mitochondrial function underlying metabolic defects.
Journal ArticleDOI
Neoadjuvant Docetaxel before Radical Prostatectomy in Patients with High-Risk Localized Prostate Cancer
Phillip G. Febbo,Jerome P. Richie,Daniel J. George,Massimo Loda,Judith Manola,Sridhar Shankar,Agnieska Szot Barnes,Clare M. Tempany,William J. Catalona,Philip W. Kantoff,William Oh +10 more
TL;DR: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI.
References
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Journal ArticleDOI
Cluster analysis and display of genome-wide expression patterns
TL;DR: A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression, finding in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function.
Journal ArticleDOI
Molecular classification of cancer: class discovery and class prediction by gene expression monitoring.
Todd R. Golub,Todd R. Golub,Donna K. Slonim,Pablo Tamayo,Christine Huard,Michelle Gaasenbeek,Jill P. Mesirov,Hilary A. Coller,Mignon L. Loh,James R. Downing,Michael A. Caligiuri,Clara D. Bloomfield,Eric S. Lander +12 more
TL;DR: A generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case and suggests a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.
Journal ArticleDOI
Significance analysis of microarrays applied to the ionizing radiation response
TL;DR: A method that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements is described, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.
Journal ArticleDOI
A direct approach to false discovery rates
TL;DR: The calculation of the q‐value is discussed, the pFDR analogue of the p‐value, which eliminates the need to set the error rate beforehand as is traditionally done, and can yield an increase of over eight times in power compared with the Benjamini–Hochberg FDR method.
Journal ArticleDOI
Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1
Zhidan Wu,Pere Puigserver,Ulf Andersson,Chen-Yu Zhang,Guillaume Adelmant,Vamsi K. Mootha,Amy E Troy,Saverio Cinti,Bradford B. Lowell,Richard C. Scarpulla,Bruce M. Spiegelman +10 more
TL;DR: PGC-1, a cold-inducible coactivator of nuclear receptors, stimulates mitochondrial biogenesis and respiration in muscle cells through an induction of uncoupling protein 2 (UCP-2) and through regulation of the nuclear respiratory factors (NRFs).
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