13 results on '"Houstis N"'
Search Results
2. Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.
- Author
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Perry AS, Farber-Eger E, Gonzales T, Tanaka T, Robbins JM, Murthy VL, Stolze LK, Zhao S, Huang S, Colangelo LA, Deng S, Hou L, Lloyd-Jones DM, Walker KA, Ferrucci L, Watts EL, Barber JL, Rao P, Mi MY, Gabriel KP, Hornikel B, Sidney S, Houstis N, Lewis GD, Liu GY, Thyagarajan B, Khan SS, Choi B, Washko G, Kalhan R, Wareham N, Bouchard C, Sarzynski MA, Gerszten RE, Brage S, Wells QS, Nayor M, and Shah RV
- Subjects
- Humans, Male, Female, Middle Aged, Risk Factors, Adult, Aged, Cohort Studies, Exercise physiology, Cardiorespiratory Fitness, Proteomics methods
- Abstract
Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable., (© 2024. The Author(s).)
- Published
- 2024
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3. Cardioprotective and Anti-Inflammatory Effects of FAM3D in Myocardial Ischemia-Reperfusion Injury.
- Author
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Rhee J, Freeman R, Roh K, Lyons M, Xiao C, Zlotoff D, Yeri A, Li H, Guerra J, Guseh JS, Kuznetsov A, Houstis N, Roh J, Damilano F, Liu X, Silverman M, Kwong R, Das S, and Rosenzweig A
- Subjects
- Humans, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Cytokines, Myocardial Reperfusion Injury prevention & control
- Abstract
Competing Interests: Disclosures None.
- Published
- 2023
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4. Tissue perfusion pressure enables continuous hemodynamic evaluation and risk prediction in the intensive care unit.
- Author
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Chandrasekhar A, Padrós-Valls R, Pallarès-López R, Palanques-Tost E, Houstis N, Sundt TM, Lee HS, Sodini CG, and Aguirre AD
- Subjects
- Humans, Hemodynamics, Blood Pressure, Perfusion, Intensive Care Units, Shock
- Abstract
Treatment of circulatory shock in critically ill patients requires management of blood pressure using invasive monitoring, but uncertainty remains as to optimal individual blood pressure targets. Critical closing pressure, which refers to the arterial pressure when blood flow stops, can provide a fundamental measure of vascular tone in response to disease and therapy, but it has not previously been possible to measure this parameter routinely in clinical care. Here we describe a method to continuously measure critical closing pressure in the systemic circulation using readily available blood pressure monitors and then show that tissue perfusion pressure (TPP), defined as the difference between mean arterial pressure and critical closing pressure, provides unique information compared to other hemodynamic parameters. Using analyses of 5,988 admissions to a modern cardiac intensive care unit, and externally validated with 864 admissions to another institution, we show that TPP can predict the risk of mortality, length of hospital stay and peak blood lactate levels. These results indicate that TPP may provide an additional target for blood pressure optimization in patients with circulatory shock., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
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5. Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium.
- Author
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Rhee J, Kuznetsov A, McKay T, Lyons M, Houstis N, Mekkonen J, Ethridge B, Ibala R, Hahm E, Gitlin J, Guseh JS, Kitchen R, Rosenzweig A, Shaefi S, Flaczyk A, Qu J, and Akeju O
- Abstract
Background: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD., Methods: Serum and whole blood samples were collected before CPB ( n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay., Results: Cardiac surgery with CPB resulted in a significant ( p
adj < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A)., Conclusions: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rhee, Kuznetsov, McKay, Lyons, Houstis, Mekkonen, Ethridge, Ibala, Hahm, Gitlin, Guseh, Kitchen, Rosenzweig, Shaefi, Flaczyk, Qu and Akeju.)- Published
- 2021
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6. Metabolic Cost of Exercise Initiation in Patients With Heart Failure With Preserved Ejection Fraction vs Community-Dwelling Adults.
- Author
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Shah RV, Schoenike MW, Armengol de la Hoz MÁ, Cunningham TF, Blodgett JB, Tanguay M, Sbarbaro JA, Nayor M, Rouvina J, Kowal A, Houstis N, Baggish AL, Ho JE, Hardin C, Malhotra R, Larson MG, Vasan RS, and Lewis GD
- Subjects
- Aged, Body Mass Index, Cohort Studies, Exercise Test, Female, Humans, Male, Middle Aged, Obesity physiopathology, Heart Failure physiopathology, Oxygen Consumption physiology
- Abstract
Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions., Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences., Design, Setting, and Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020., Exposures: Internal work (IW), a measure of work equivalents required to initiate movement., Main Outcomes and Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures., Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW., Conclusions and Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.
- Published
- 2021
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7. Exercise training reverses cardiac aging phenotypes associated with heart failure with preserved ejection fraction in male mice.
- Author
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Roh JD, Houstis N, Yu A, Chang B, Yeri A, Li H, Hobson R, Lerchenmüller C, Vujic A, Chaudhari V, Damilano F, Platt C, Zlotoff D, Lee RT, Shah R, Jerosch-Herold M, and Rosenzweig A
- Subjects
- Animals, Humans, Male, Mice, Phenotype, Aging genetics, Echocardiography, Doppler methods, Exercise physiology, Heart Failure physiopathology, Stroke Volume physiology
- Abstract
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age-related disease. The molecular mechanisms by which ExT induces its beneficial effects in HFpEF, however, remain largely unknown. Given the strong association between aging and HFpEF, we hypothesized that ExT might reverse cardiac aging phenotypes that contribute to HFpEF pathophysiology and additionally provide a platform for novel mechanistic and therapeutic discovery. Here, we show that aged (24-30 months) C57BL/6 male mice recapitulate many of the hallmark features of HFpEF, including preserved left ventricular ejection fraction, subclinical systolic dysfunction, diastolic dysfunction, impaired cardiac reserves, exercise intolerance, and pathologic cardiac hypertrophy. Similar to older humans, ExT in old mice improved exercise capacity, diastolic function, and contractile reserves, while reducing pulmonary congestion. Interestingly, RNAseq of explanted hearts showed that ExT did not significantly modulate biological pathways targeted by conventional HF medications. However, it reversed multiple age-related pathways, including the global downregulation of cell cycle pathways seen in aged hearts, which was associated with increased capillary density, but no effects on cardiac mass or fibrosis. Taken together, these data demonstrate that the aged C57BL/6 male mouse is a valuable model for studying the role of aging biology in HFpEF pathophysiology, and provide a molecular framework for how ExT potentially reverses cardiac aging phenotypes in HFpEF., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2020
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8. IMP2 Increases Mouse Skeletal Muscle Mass and Voluntary Activity by Enhancing Autocrine Insulin-Like Growth Factor 2 Production and Optimizing Muscle Metabolism.
- Author
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Regué L, Ji F, Flicker D, Kramer D, Pierce W, Davidoff T, Widrick JJ, Houstis N, Minichiello L, Dai N, and Avruch J
- Subjects
- Animals, Autocrine Communication, Fatty Acids metabolism, Female, Glucose metabolism, Glycogen Synthase Kinase 3 metabolism, Insulin metabolism, Insulin-Like Growth Factor II metabolism, Male, Mice, Mice, Inbred C57BL, Muscle Fibers, Skeletal metabolism, PPAR alpha metabolism, Phosphorylation, Physical Exertion physiology, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Motor Activity physiology, Muscle, Skeletal metabolism, RNA-Binding Proteins metabolism
- Abstract
Insulin-like growth factor 2 (IGF2) mRNA binding protein 2 (IMP2) was selectively deleted from adult mouse muscle; two phenotypes were observed: decreased accrual of skeletal muscle mass after weaning and reduced wheel-running activity but normal forced treadmill performance. Reduced wheel running occurs when mice are fed a high-fat diet but is normalized when mice consume standard chow. The two phenotypes are due to altered output from different IMP2 client mRNAs. The reduced fiber size of IMP2-deficient muscle is attributable, in part, to diminished autocrine Igf2 production; basal tyrosine phosphorylation of the insulin and IGF1 receptors is diminished, and Akt1 activation is selectively reduced. Gsk3α is disinhibited, and S536-phosphorylated ε subunit of eukaryotic initiation factor 2B [eIF2Bε(S536)] is hyperphosphorylated. Protein synthesis is reduced despite unaltered mTOR complex 1 activity. The diet-dependent reduction in voluntary exercise is likely due to altered muscle metabolism, as contractile function is normal. IMP2-deficient muscle exhibits reduced fatty acid oxidation, due to a reduced abundance of mRNA of peroxisome proliferator-activated receptor α (PPARα), an IMP2 client, and PPARα protein. IMP2-deficient muscle fibers treated with a mitochondrial uncoupler to increase electron flux, as occurs with exercise, exhibit reduced oxygen consumption from fatty acids, with higher oxygen consumption from glucose. The greater dependence on muscle glucose metabolism during increased oxygen demand may promote central fatigue and thereby diminish voluntary activity., (Copyright © 2019 American Society for Microbiology.)
- Published
- 2019
- Full Text
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9. Activin type II receptor signaling in cardiac aging and heart failure.
- Author
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Roh JD, Hobson R, Chaudhari V, Quintero P, Yeri A, Benson M, Xiao C, Zlotoff D, Bezzerides V, Houstis N, Platt C, Damilano F, Lindman BR, Elmariah S, Biersmith M, Lee SJ, Seidman CE, Seidman JG, Gerszten RE, Lach-Trifilieff E, Glass DJ, and Rosenzweig A
- Subjects
- Activins blood, Adult, Aged, Aged, 80 and over, Aging blood, Animals, Constriction, Pathologic, Disease Models, Animal, Follistatin-Related Proteins metabolism, Frailty, Heart Failure blood, Heart Failure pathology, Heart Failure physiopathology, Heart Ventricles pathology, Heart Ventricles physiopathology, Humans, Ligands, Male, Mice, Inbred C57BL, Middle Aged, Myocytes, Cardiac metabolism, Pressure, Proteasome Endopeptidase Complex metabolism, Proteolysis, Rats, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Severity of Illness Index, Systole, Activin Receptors, Type II metabolism, Aging metabolism, Heart Failure metabolism, Myocardium metabolism, Myocardium pathology, Signal Transduction
- Abstract
Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca
2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
- Full Text
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10. Why Don't We Have Proven Treatments for HFpEF?
- Author
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Roh J, Houstis N, and Rosenzweig A
- Subjects
- Animals, Heart Failure diagnostic imaging, Humans, Treatment Outcome, Heart Failure physiopathology, Heart Failure therapy, Stroke Volume physiology
- Published
- 2017
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11. Using exercise to measure and modify cardiac function.
- Author
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Platt C, Houstis N, and Rosenzweig A
- Subjects
- Animals, Cardiovascular System metabolism, Humans, Cardiovascular Physiological Phenomena, Exercise physiology
- Abstract
Exercise is the archetype of physiologic demands placed on the cardiovascular system. Acute responses provide an informative assessment of cardiovascular function and fitness, while repeated exercise promotes cardiovascular health and evokes important molecular, structural, and functional changes contributing to its effects in primary and secondary prevention. Here we examine the use of exercise in murine models, both as a phenotypic assay and as a provocative intervention. We first review the advantages and limitations of exercise testing for assessing cardiac function, then highlight the cardiac structural and cellular changes elicited by chronic exercise and key molecular pathways that mediate these effects., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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12. Reactive oxygen species have a causal role in multiple forms of insulin resistance.
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Houstis N, Rosen ED, and Lander ES
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- 3T3-L1 Cells, Animals, Antioxidants metabolism, Antioxidants pharmacology, Body Weight drug effects, Catalase genetics, Catalase metabolism, Glucose Tolerance Test, Male, Metalloporphyrins pharmacology, Mice, Mice, Obese, Obesity genetics, Oxidation-Reduction, Rosiglitazone, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Thiazolidinediones pharmacology, Transgenes genetics, Insulin Resistance physiology, Reactive Oxygen Species metabolism
- Abstract
Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-alpha and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.
- Published
- 2006
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13. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
- Author
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Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, and Groop LC
- Subjects
- Animals, Cells, Cultured, Down-Regulation, Gene Expression Profiling, Glucose metabolism, Glucose Tolerance Test, Humans, Insulin physiology, Male, Mice, Myoblasts physiology, Oligonucleotide Array Sequence Analysis, RNA, Messenger metabolism, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Muscle, Skeletal drug effects, Oxidative Phosphorylation, Transcription Factors pharmacology
- 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-1alpha 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.
- Published
- 2003
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