Breakthroughs of the year 2006

1. Control of developmental regulator’s by polycomb in human embryonic stem cells

T. I. Lee, R. G. Jenner, L. A. Boyer, M. G. Guenther, S. S. Levine, R. M. Kumar, B. Chevalier, S. E. Johnstone, M. F. Cole, K. Isono, H. Koseki, T. Fuchikami, K. Abe, H. L. Murray, J. P. Zucker, B. B. Yuan, G. W. Bell, E. Herbolsheimer, N. M. Hannett, K. M. Sun, D. T. Odom, A. P. Otte, T. L. Volkert, D. P. Bartel, D. A. Melton, D. K. Gifford, R. Jaenisch and R. A. Young

Cell.2006 Apr;125(2):301-313.

Abstract: Polycomb group proteins are essential for early development in metazoans, but their contributions to human development are not well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit SUZ12 across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells. We found that SUZ12 is distributed across large portions of over two hundred genes encoding key developmental regulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved noncoding elements in the genome. We found that PRC2 target genes are preferentially activated during ES cell differentiation and that the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes. These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.

Keywords: histone methyltransferase activity, early mouse development, hox, gene-expression, drosophila-melanogaster, monoclonal-antibodies, human, blastocysts, response element, group-complexes, group proteins, gaga, factor

*Times Cited: 1058

PMID: 16630818


2. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 alpha

M. Lagouge, C. Argmann, Z. Gerhart-Hines, H. Meziane, C. Lerin, F. Daussin, N. Messadeq, J. Milne, P. Lambert, P. Elliott, B. Geny, M. Laakso, P. Puigserver and J. Auwerx

Cell.2006 Dec;127(6):1109-1122.

Abstract: Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV’s effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1 alpha acetylation and an increase in PGC-1 alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

Keywords: transcriptional coactivator pgc-1-alpha, messenger-rna expression, cerevisiae life-span, alpha err-alpha, skeletal-muscle, calorie, restriction, receptor-alpha, saccharomyces-cerevisiae, oxidative-phosphorylation, adaptive thermogenesis

*Times Cited: 1002

PMID: 17112576


3. TGF beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells

M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley and B. Stockinger

Immunity.2006 Feb;24(2):179-189.

Abstract: We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4(+) CD25(+) T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGF beta 1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1 beta and TNF alpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGF beta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGF beta 1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.

Keywords: growth-factor-beta, experimental autoimmune encephalomyelitis, myelin, oligodendrocyte glycoprotein, transcription factor foxp3, synovial, inflammation, dendritic cells, il-6-deficient mice, gata-3 expression, induced arthritis, gene-expression

*Times Cited: 1580

PMID: 16473830


4. The orphan nuclear receptor ROR gamma t directs the differentiation program of proinflammatory IL-17(+) T helper cells

Ivanov, II, B. S. McKenzie, L. Zhou, C. E. Tadokoro, A. Lepelley, J. J. Lafaille, D. J. Cua and D. R. Littman

Cell.2006 Sep;126(6):1121-1133.

Abstract: IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor ROR gamma t is the key transcription factor that orchestrates the differentiation of this effector cell lineage. ROR gamma t induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naive CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express ROR gamma t, and are absent in mice deficient for ROR gamma t or IL-6. Mice with ROR gamma t-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that ROR gamma t is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.

Keywords: isolated lymphoid follicles, autoimmune encephalomyelitis, transcription, factor, tgf-beta, lineage commitment, interleukin-17, inflammation, il-23, immune, induction

*Times Cited: 1375

PMID: 16990136


5. A bivalent chromatin structure marks key developmental genes in embryonic stem cells

B. E. Bernstein, T. S. Mikkelsen, X. H. Xie, M. Kamal, D. J. Huebert, J. Cuff, B. Fry, A. Meissner, M. Wernig, K. Plath, R. Jaenisch, A. Wagschal, R. Feil, S. L. Schreiber and E. S. Lander

Cell.2006 Apr;125(2):315-326.

Abstract: The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed “bivalent domains,” consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.

Keywords: polycomb group-complexes, histone code, human genome, transposable, elements, epigenetic regulation, x-inactivation, methylation, mouse, binding, methyltransferase

*Times Cited: 1561

PMID: 16630819


6. An intervention to decrease catheter-related bloodstream infections in the ICU

P. Pronovost, D. Needham, S. Berenholtz, D. Sinopoli, H. T. Chu, S. Cosgrove, B. Sexton, R. Hyzy, R. Welsh, G. Roth, J. Bander, J. Kepros and C. Goeschel

N Engl J Med.2006 Dec;355(26):2725-2732.

Abstract: BACKGROUND: Catheter-related bloodstream infections occurring in the intensive care unit (ICU) are common, costly, and potentially lethal. METHODS: We conducted a collaborative cohort study predominantly in ICUs in Michigan. An evidence-based intervention was used to reduce the incidence of catheter-related bloodstream infections. Multilevel Poisson regression modeling was used to compare infection rates before, during, and up to 18 months after implementation of the study intervention. Rates of infection per 1000 catheter-days were measured at 3-month intervals, according to the guidelines of the National Nosocomial Infections Surveillance System. RESULTS: A total of 108 ICUs agreed to participate in the study, and 103 reported data. The analysis included 1981 ICU-months of data and 375,757 catheter-days. The median rate of catheter-related bloodstream infection per 1000 catheter-days decreased from 2.7 infections at baseline to 0 at 3 months after implementation of the study intervention (P <= 0.002), and the mean rate per 1000 catheter-days decreased from 7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002). The regression model showed a significant decrease in infection rates from baseline, with incidence-rate ratios continuously decreasing from 0.62 (95% confidence interval [CI], 0.47 to 0.81) at 0 to 3 months after implementation of the intervention to 0.34 (95% CI, 0.23 to 0.50) at 16 to 18 months. CONCLUSIONS: An evidence-based intervention resulted in a large and sustained reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study period.

Keywords: intensive-care, education-program, patient safety, surveillance, prevention

*Times Cited: 936

PMID: 17192537


7. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4(+) T reg cells

W. H. Liu, A. L. Putnam, Z. Xu-Yu, G. L. Szot, M. R. Lee, S. Zhu, P. A. Gottlieb, P. Kapranov, T. R. Gingeras, B. Fazekas de St Groth, C. Clayberger, D. M. Soper, S. F. Ziegler and J. A. Bluestone

Journal of Experimental Medicine.2006 Jul;203(7):1701-1711.

Abstract: Regulatory T (T reg)cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4(+) T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3(+), including those that express low levels or no CD25. A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers. These cells were highly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25(+) CD4(+) and CD25(-) CD4(+) T cell subsets), were as suppressive as the “classic” CD4(+) CD25(hi) T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.

Keywords: immunological self-tolerance, transcription factor foxp3, tgf-beta, multiple-sclerosis, regulatory cells, tnf receptor, autoimmunity, transplantation, mechanisms, ctla-4

*Times Cited: 967

PMID: 16818678


8. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events

D. L. Bhatt, K. A. A. Fox, W. Hacke, P. B. Berger, H. R. Black, W. E. Boden, P. Cacoub, E. A. Cohen, M. A. Creager, J. D. Easton, M. D. Flather, S. M. Haffner, C. W. Hamm, G. J. Hankey, S. C. Johnston, K. H. Mak, J. L. Mas, G. Montalescot, T. A. Pearson, P. G. Steg, S. R. Steinhubl, M. A. Weber, D. M. Brennan, L. Fabry-Ribaudo, J. Booth, E. J. Topol and C. Investigators

N Engl J Med.2006 Apr;354(16):1706-1717.

Abstract: BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes.

Keywords: acute myocardial-infarction, st-segment elevation, antiplatelet therapy, controlled trial, risk

*Times Cited: 931

PMID: 16531616


9. From genomics to chemical genomics: new developments in KEGG

M. Kanehisa, S. Goto, M. Hattori, K. F. Aoki-Kinoshita, M. Itoh, S. Kawashima, T. Katayama, M. Araki and M. Hirakawa

Nucleic acids research.2006 Jan;34:D354-D357.

Abstract: The increasing amount of genomic and molecular information is the basis for understanding higher-order biological systems, such as the cell and the organism, and their interactions with the environment, as well as for medical, industrial and other practical applications. The KEGG resource ( provides a reference knowledge base for linking genomes to biological systems, categorized as building blocks in the genomic space (KEGG GENES) and the chemical space (KEGG LIGAND), and wiring diagrams of interaction networks and reaction networks (KEGG PATHWAY). A fourth component, KEGG BRITE, has been formally added to the KEGG suite of databases. This reflects our attempt to computerize functional interpretations as part of the pathway reconstruction process based on the hierarchically structured knowledge about the genomic, chemical and network spaces. In accordance with the new chemical genomics initiatives, the scope of KEGG LIGAND has been significantly expanded to cover both endogenous and exogenous molecules. Specifically, RPAIR contains curated chemical structure transformation patterns extracted from known enzymatic reactions, which would enable analysis of genome-environment interactions, such as the prediction of new reactions and new enzyme genes that would degrade new environmental compounds. Additionally, drug information is now stored separately and linked to new KEGG DRUG structure maps.

Keywords: database, proteins

*Times Cited: 1015

PMID: 16381885


10. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks

J. V. Olsen, B. Blagoev, F. Gnad, B. Macek, C. Kumar, P. Mortensen and M. Mann

Cell.2006 Nov;127(3):635-648.

Abstract: Cell signaling mechanisms often transmit information via posttranslational protein modifications, most importantly reversible protein phosphorylation. Here we develop and apply a general mass spectrometric technology for identification and quantitation of phosphorylation sites as a function of stimulus, time, and subcellular location. We have detected 6,600 phosphorylation sites on 2,244 proteins and have determined their temporal dynamics after stimulating HeLa cells with epidermal growth factor (EGF) and recorded them in the Phosida database. Fourteen percent of phosphorylation sites are modulated at least 2-fold by EGF, and these were classified by their temporal profiles. Surprisingly, a majority of proteins contain multiple phosphorylation sites showing different kinetics, suggesting that they serve as platforms for integrating signals. In addition to protein kinase cascades, the targets of reversible phosphorylation include ubiquitin ligases, guanine nucleotide exchange factors, and at least 46 different transcriptional regulators. The dynamic phosphoproteorne provides a missing link in a global, integrative view of cellular regulation.

Keywords: growth-factor receptor, mass-spectrometry, tyrosine phosphorylation, protein-phosphorylation, phosphoproteome analysis, quantitative, proteomics, transcriptional control, cell-culture, amino-acids, kinase

*Times Cited: 1205

PMID: 17081983


11. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy

S. E. Kahn, S. M. Haffner, M. A. Heise, W. H. Herman, R. R. Holman, N. P. Jones, B. G. Kravitz, J. M. Lachin, M. C. O’Neill, B. Zinman, G. Viberti and A. S. Grp

N Engl J Med.2006 Dec;355(23):2427-2443.

Abstract: BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and (beta)-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes.

Keywords: type-2 diabetes-mellitus, beta-cell function, randomized, controlled-trial, blood-glucose control, insulin-resistance, consensus, statement, complications, risk, sulfonylurea, association

*Times Cited: 968

PMID: 17145742


12. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

K. Takahashi and S. Yamanaka

Cell.2006 Aug;126(4):663-676.

Abstract: Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.

Keywords: transcription factor klf4, self-renewal, c-myc, somatic-cells, es cells, tumor-suppressor, beta-catenin, differentiation, expression, nanog

*Times Cited: 4730

PMID: 16904174


13. Intensive insulin therapy in the medical ICU

G. Van den Berghe, A. Wilmer, G. Hermans, W. Meersseman, P. J. Wouters, I. Milants, E. Van Wijngaerden, H. Bobbaers and R. Bouillon

N Engl J Med.2006 Feb;354(5):449-461.

Abstract: BACKGROUND: Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown. METHODS: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients. RESULTS: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced. CONCLUSIONS: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data.

Keywords: critically-ill patients, blood-glucose control, intervention scoring, system, myocardial-infarction, stress hyperglycemia, diabetes-mellitus, critical illness, mortality, complications, protects

*Times Cited: 1348

PMID: 16452557


14. Lapatinib plus capecitabine for HER2-positive advanced breast cancer

C. E. Geyer, J. Forster, D. Lindquist, S. Chan, C. G. Romieu, T. Pienkowski, A. Jagiello-Gruszfeld, J. Crown, A. Chan, B. Kaufman, D. Skarlos, M. Campone, N. Davidson, M. Berger, C. Oliva, S. D. Rubin, S. Stein and D. Cameron

N Engl J Med.2006 Dec;355(26):2733-2743.

Abstract: BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab.

Keywords: adjuvant chemotherapy, monoclonal-antibody, kinase inhibitor, trastuzumab, growth, safety, metastases, survival, efficacy, gw572016

*Times Cited: 1031

PMID: 17192538


15. Matrix elasticity directs stem cell lineage specification

A. J. Engler, S. Sen, H. L. Sweeney and D. E. Discher

Cell.2006 Aug;126(4):677-689.

Abstract: Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown hereto specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.

Keywords: marrow stromal cells, bone-marrow, myosin-ii, in-vitro, osteoblast, differentiation, substrate stiffness, focal adhesions, tissue, fibroblasts, expression

*Times Cited: 2236

PMID: 16923388


16. Microbial translocation is a cause of systemic immune activation in chronic HIV infection

J. M. Brenchley, D. A. Price, T. W. Schacker, T. E. Asher, G. Silvestri, S. Rao, Z. Kazzaz, E. Bornstein, O. Lambotte, D. Altmann, B. R. Blazar, B. Rodriguez, L. Teixeira-Johnson, A. Landay, J. N. Martin, F. M. Hecht, L. J. Picker, M. M. Lederman, S. G. Deeks and D. C. Douek

Nature Medicine.2006 Dec;12(12):1365-1371.

Abstract: Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

Keywords: immunodeficiency-virus-infection, t-cell depletion, combination, antiretroviral therapy, inflammatory-bowel-disease, versus-host-disease, toll-like receptors, gastrointestinal-tract, type-1 infection, siv, infection, intestinal permeability

*Times Cited: 913

PMID: 17115046


*Updated on 03/15/2013

Breakthroughs of the year 2007

1. A chromatin landmark and transcription initiation at most promoters in human cells

M. G. Guenther, S. S. Levine, L. A. Boyer, R. Jaenisch and R. A. Young

Cell.2007 Jul;130(1):77-88.

Abstract: We describe the results of a genome- wide analysis of human cells that suggests that most protein- coding genes, including most genes thought to be transcriptionally inactive, experience transcription initiation. We found that nucleosomes with H3K4me3 and H3K9,14Ac modifications, together with RNA polymerase II, occupy the promoters of most protein- coding genes in human embryonic stem cells. Only a subset of these genes produce detectable full- length transcripts and are occupied by nucleosomes with H3K36me3 modifications, a hallmark of elongation. The other genes experience transcription initiation but show no evidence of elongation, suggesting that they are predominantly regulated at post-initiation steps. Genes encoding most developmental regulators fall into this group. Our results also identify a class of genes that are excluded from experiencing transcription initiation, at which mechanisms that prevent initiation must predominate. These observations extend to differentiated cells, suggesting that transcription initiation at most genes is a general phenomenon in human cells.

Keywords: rna-polymerase-ii, embryonic stem-cells, histone h3, active genes, saccharomyces-cerevisiae, human genome, hiv-1 tat, in-vivo, methylation, elongation

*Times Cited: 732

PMID: 17632057


2. A mammalian microRNA expression atlas based on small RNA library sequencing

P. Landgraf, M. Rusu, R. Sheridan, A. Sewer, N. Iovino, A. Aravin, S. Pfeffer, A. Rice, A. O. Kamphorst, M. Landthaler, C. Lin, N. D. Socci, L. Hermida, V. Fulci, S. Chiaretti, R. Foa, J. Schliwka, U. Fuchs, A. Novosel, R. U. Muller, B. Schermer, U. Bissels, J. Inman, Q. Phan, M. C. Chien, D. B. Weir, R. Choksi, G. De Vita, D. Frezzetti, H. I. Trompeter, V. Hornung, G. Teng, G. Hartmann, M. Palkovits, R. Di Lauro, P. Wernet, G. Macino, C. E. Rogler, J. W. Nagle, J. Y. Ju, F. N. Papavasiliou, T. Benzing, P. Lichter, W. Tam, M. J. Brownstein, A. Bosio, A. Borkhardt, J. J. Russo, C. Sander, M. Zavolan and T. Tuschl

Cell.2007 Jun;129(7):1401-1414.

Abstract: MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. In order to identify miRNAs and to assess their expression patterns, we sequenced over 250 small RNA libraries from 26 different organ systems and cell types of human and rodents that were enriched in neuronal as well as normal and malignant hematopoietic cells and tissues. We present expression profiles derived from clone count data and provide computational tools for their analysis. Unexpectedly, a relatively small set of miRNAs, many of which are ubiquitously expressed, account for most of the differences in miRNA profiles between cell lineages and tissues. This broad survey also provides detailed and accurate information about mature sequences, precursors, genome locations, maturation processes, inferred transcriptional units, and conservation patterns. We also propose a subclassification scheme for miRNAs for assisting future experimental and computational functional analyses.

Keywords: mental-retardation protein, posttranscriptional regulation, c-elegans, caenorhabditis-elegans/, animal development, gene-expression, identification, targets, mirnas, zebrafish

*Times Cited: 1102

PMID: 17604727


3. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

R. L. Mehta, J. A. Kellum, S. V. Shah, B. A. Molitoris, C. Ronco, D. G. Warnock, A. Levin and N. Acute Kidney Injury

Crit Care.2007 11(2

Abstract: Introduction Acute kidney injury ( AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from preclinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Methods Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group’s discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. Results The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. Conclusion We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Keywords: acute-renal-failure, critically-ill patients, international consensus, conference, hospitalized-patients, serum creatinine, replacement, therapy, rifle criteria, mortality, care, icu

*Times Cited: 959

PMID: 17331245


4. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome

C. Ginestier, M. H. Hur, E. Charafe-Jauffret, F. Monville, J. Dutcher, M. Brown, J. Jacquemier, P. Viens, C. G. Kleer, S. L. Liu, A. Schott, D. Hayes, D. Birnbaum, M. S. Wicha and G. Dontu

Cell Stem Cell.2007 Nov;1(5):555-567.

Abstract: Application of stem cell biology to breast cancer research has been limited by the lack of simple methods for identification and isolation of normal and malignant stem cells. Utilizing in vitro and in vivo experimental systems, we show that normal and cancer human mammary epithelial cells with increased aldehyde dehydrogenase activity (ALDH) have stem/progenitor properties. These cells contain the subpopulation of normal breast epithelium with the broadest lineage differentiation potential and greatest growth capacity in a xenotransplant model. In breast carcinomas, high ALDH activity identifies the tumorigenic cell fraction, capable of self-renewal and of generating tumors that recapitulate the heterogeneity of the parental tumor. In a series of 577 breast carcinomas, expression of ALDH1 detected by immunostaining correlated with poor prognosis. These findings offer an important new tool for the study of normal and malignant breast stem cells and facilitate the clinical application of stem cell concepts.

Keywords: aldehyde dehydrogenase-activity, acute myeloid-leukemia, adult human, breast, functional-characterization, prospective identification, in-vitro, cancer, progenitor, transformation, subpopulation

*Times Cited: 776

PMID: 18371393


5. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial

B. Escudier, A. Pluzanska, P. Koralewski, A. Ravaud, S. Bracarda, C. Szczylik, C. Chevreau, M. Filipek, B. Melichar, E. Bajetta, V. Gorbunova, J. O. Bay, I. Bodrogi, A. Jagiello-Gruszfeld, N. Moore and A. T. Investigators

Lancet.2007 Dec-Jan;370(9605):2103-2111.

Abstract: Background Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted. Methods In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-fine therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. Ibis trial is registered with, number BO017705E. Findings 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10 . 2 months vs 5.4 months; HR 0.63, 95% Cl 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]). Interpretation The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.

Keywords: endothelial growth-factor, tumor-suppressor gene, colorectal-cancer, therapy, alpha, erlotinib, combination, paclitaxel, guidelines, sorafenib

*Times Cited: 832

PMID: 18156031


6. Current concepts in the management of Helicobacter pylori infection: the maastricht III consensus report

P. Malfertheiner, F. Megraud, C. O’Morain, F. Bazzoli, E. El-Omar, D. Graham, R. Hunt, T. Rokkas, N. Vakil, E. J. Kuipers and E. S. Grp

Gut.2007 Jun;56(6):772-781.

Abstract: Background: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. Aims: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. Results: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a “test and treat” strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naive users of non-steroidal antiinflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. Conclusion: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

Keywords: gastroesophageal-reflux disease, randomized controlled-trial, c-13-urea, breath test, nonsteroidal antiinflammatory drugs, idiopathic, thrombocytopenic purpura, prevent gastric-cancer, iron-deficiency, anemia, proton pump inhibitors, low-dose aspirin, b-c

*Times Cited: 795

PMID: 17170018


7. Development, cytokine profile and function of human interleukin 17-producing helper T cells

N. J. Wilson, K. Boniface, J. R. Chan, B. S. McKenzie, W. M. Blumenschein, J. D. Mattson, B. Basham, K. Smith, T. Chen, F. Morel, J. C. Lecron, R. A. Kastelein, D. J. Cua, T. K. McClanahan, E. P. Bowman and R. D. Malefyt

Nat Immunol.2007 Sep;8(9):950-957.

Abstract: T-H-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the T-H-17 lineage is dependent on transforming growth factor-beta and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1 beta induced the development of human T-H-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-gamma, the chemokine CCL20 and transcription factor ROR gamma t. In situ, T-H-17 cells were identified by expression of the IL-23 receptor and the memory T cell marker CD45RO. Psoriatic skin lesions contained IL-23-producing dendritic cells and were enriched in the cytokines produced by human T-H-17 cells that promote the production of antimicrobial peptides in human keratinocytes. Our data collectively indicate that human and mouse T-H-17 cells require distinct factors during differentiation and that human T-H-17 cells may regulate innate immunity in epithelial cells.

Keywords: autoimmune inflammation, antimicrobial peptides, human keratinocytes, beta-defensins, host-defense, il-23, expression, psoriasis, distinct, differentiation

*Times Cited: 751

PMID: 17676044


8. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution

N. Maherali, R. Sridharan, W. Xie, J. Utikal, S. Eminli, K. Arnold, M. Stadtfeld, R. Yachechko, J. Tchieu, R. Jaenisch, K. Plath and K. Hochedlinger

Cell Stem Cell.2007 Jul;1(1):55-70.

Abstract: Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (PS) cells. It remains unknown if nuclear reprogramming induced by these four factors globally resets epigenetic differences between differentiated and pluripotent cells. Here, using novel selection approaches, we have generated PS cells from fibroblasts to characterize their epigenetic state. Female PS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation. Genome-wide analysis of two key histone modifications indicated that PS cells are highly similar to ES cells. Consistent with these observations, PS cells gave rise to viable high-degree chimeras with contribution to the germline. These data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state. Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming does not pose a problem for the potential therapeutic applications of PS cells.

Keywords: embryonic stem-cells, inactive x-chromosome, developmental regulators, somatic-cells, es cells, mouse, pluripotency, methylation, nanog, polycomb

*Times Cited: 741

PMID: 18371336


9. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes

S. E. Nissen and K. Wolski

N Engl J Med.2007 Jun;356(24):2457-2471.

Abstract: BACKGROUND: Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. METHODS: We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes. RESULTS: Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). CONCLUSIONS: Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.

Keywords: type-2 diabetes-mellitus, randomized controlled-trial, improves glycemic, control, combination therapy, metformin, sulfonylurea, events, pioglitazone, monotherapy, glyburide

*Times Cited: 1619

PMID: 17517853


10. Effects of bariatric surgery on mortality in Swedish obese subjects

L. Sjostrom, K. Narbro, D. Sjostrom, K. Karason, B. Larsson, H. Wedel, T. Lystig, M. Sullivan, C. Bouchard, B. Carlsson, C. Bengtsson, S. Dahlgren, A. Gummesson, P. Jacobson, J. Karlsson, A. K. Lindroos, H. Lonroth, I. Naslund, T. Olbers, K. Stenlof, J. Torgerson, G. Agren, L. M. S. Carlsson and S. Swedish Obese Subjects

N Engl J Med.2007 Aug;357(8):741-752.

Abstract: Background: Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality. Methods: The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%). Results: The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). Conclusions: Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.

Keywords: body-mass index, intentional weight-loss, aged 40-64 years, united-states, subjects sos, older persons, follow-up, overweight, cohort, intervention

*Times Cited: 1055

PMID: 17715408


11. Effects of torcetrapib in patients at high risk for coronary events

P. J. Barter, M. Caulfield, M. Eriksson, S. M. Grundy, J. J. P. Kastelein, M. Komajda, J. Lopez-Sendon, L. Mosca, J. Tardif, D. D. Waters, C. L. Shear, J. H. Revkin, K. A. Buhr, M. R. Fisher, A. R. Tall, B. Brewer and I. Investigators

N Engl J Med.2007 Nov;357(21):2109-2122.

Abstract: Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina. Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and a decrease of 24.9% in low-density lipoprotein cholesterol, as compared with baseline (P<0.001 for both comparisons), in addition to an increase of 5.4 mm Hg in systolic blood pressure, a decrease in serum potassium, and increases in serum sodium, bicarbonate, and aldosterone (P<0.001 for all comparisons). There was also an increased risk of cardiovascular events (hazard ratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001) and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change. Conclusions Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. ( number, NCT00134264.).

Keywords: ester transfer protein, high-density-lipoprotein, cardiovascular-disease, hdl-cholesterol, atherosclerosis, target, inhibitor

*Times Cited: 767

PMID: 17984165


12. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada clinical trials group

M. J. Moore, D. Goldstein, J. Hamm, A. Figer, J. R. Hecht, S. Gallinger, H. J. Au, P. Murawa, D. Walde, R. A. Wolff, D. Campos, R. Lim, K. Ding, G. Clark, T. Voskoglou-Nomikos, M. Ptasynski and W. Parulekar

Journal of Clinical Oncology.2007 May;25(15):1960-1966.

Abstract: Purpose Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival. Results A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% Cl, 0.69 to 0.99; P=.038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P =.023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% Cl, 0.64 to 0.92; P =.004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2. Conclusion To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.

Keywords: growth-factor receptor, tyrosine kinase inhibitor, cell lung-cancer, randomized-trial, therapy, chemotherapy, combination, osi-774, adenocarcinoma, expression

*Times Cited: 1010

PMID: 17452677


13. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells

H. Valadi, K. Ekstrom, A. Bossios, M. Sjostrand, J. J. Lee and J. O. Lotvall

Nat Cell Biol.2007 Jun;9(6):654-U672.

Abstract: Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called “exosomal shuttle RNA” (esRNA).

Keywords: mast-cell, proteomic analysis, dendritic cells, animal development, microvesicles, vesicles, accumulation, activation, complex, surface

*Times Cited: 727

PMID: 17486113


14. EzTaxon: a web-based tool for the identification of prokaryotes based on 16S ribosomal RNA gene sequences

J. Chun, J. H. Lee, Y. Jung, M. Kim, S. Kim, B. K. Kim and Y. W. Lim

Int J Syst Evol Microbiol.2007 Oct;57:2259-2261.

Abstract: 16S rRNA gene sequences have been widely used for the identification of prokaryotes. However, the flood of sequences of non-type strains and the lack of a peer-reviewed database for 16S rRNA gene sequences of type strains have made routine identification of isolates difficult and labour-intensive. In the present study, we generated a database containing 16S rRNA gene sequences of all prokaryotic type strains. In addition, a web-based tool, named EzTaxon, for analysis of 16S rRNA gene sequences was constructed to achieve identification of isolates based on pairwise nucleoticle similarity values and phylogenetic inference methods. The system developed provides users with a similarity-based search, multiple sequence alignment and various phylogenetic analyses. All of these functions together with the 16S rRNA gene sequence database of type strains can be successfully used for automated and reliable identification of prokaryotic isolates.

Keywords: alignment, trees

*Times Cited: 964

PMID: 17911292


15. Genomewide association analysis of coronary artery disease

N. J. Samani, J. Erdmann, A. S. Hall, C. Hengstenberg, M. Mangino, B. Mayer, R. J. Dixon, T. Meitinger, P. Braund, H. E. Wichmann, J. H. Barrett, I. R. Konig, S. E. Stevens, S. Szymczak, D. Tregouet, M. M. Iles, F. Pahlke, H. Pollard, W. Lieb, F. Cambien, M. Fischer, W. Ouwehand, S. Blankenberg, A. J. Balmforth, A. Baessler, S. G. Ball, T. M. Strom, I. Braenne, C. Gieger, P. Deloukas, M. D. Tobin, A. Ziegler, J. R. Thompson, H. Schunkert, Wtccc and C. Cardiogenics

N Engl J Med.2007 Aug;357(5):443-453.

Abstract: Background Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of TRUE association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80×10(-14) and P=3.40×10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2×10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3×10(-6)) and a high probability(>80%) of a TRUE association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

Keywords: mitochondrial c-1-tetrahydrofolate synthase, wide association, risk-factors, myocardial-infarction, gene, susceptibility, replication, expression, families, linkage

*Times Cited: 802

PMID: 17634449


16. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

J. D. Rioux, R. J. Xavier, K. D. Taylor, M. S. Silverberg, P. Goyette, A. Huett, T. Green, P. Kuballa, M. M. Barmada, L. W. Datta, Y. Y. Shugart, A. M. Griffiths, S. R. Targan, A. F. Ippoliti, E. J. Bernard, L. Mei, D. L. Nicolae, M. Regueiro, L. P. Schumm, A. H. Steinhart, J. I. Rotter, R. H. Duerr, J. H. Cho, M. J. Daly and S. R. Brant

Nature Genetics.2007 May;39(5):596-604.

Abstract: We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations ( combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.

Keywords: inflammatory-bowel-disease, dendritic cells, nadph oxidase, gene, complex, antigen, localization, concordance, expression, variants

*Times Cited: 729

PMID: 17435756


17. High-resolution profiling of histone methylations in the human genome

A. Barski, S. Cuddapah, K. R. Cui, T. Y. Roh, D. E. Schones, Z. B. Wang, G. Wei, I. Chepelev and K. J. Zhao

Cell.2007 May;129(4):823-837.

Abstract: Histone modifications are implicated in influencing gene expression. We have generated high-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology. Typical patterns of histone methylations exhibited at promoters, insulators, enhancers, and transcribed regions are identified. The monomethylations of H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations of H3K27, H3K9, and H3K79 are linked to repression. H2A.Z associates with functional regulatory elements, and CTCF marks boundaries of histone methylation domains. Chromosome banding patterns are correlated with unique patterns of histone modifications. Chromosome breakpoints detected in T cell cancers frequently reside in chromatin regions associated with H3K4 methylations. Our data provide new insights into the function of histone methylation and chromatin organization in genome function.

Keywords: embryonic stem-cells, active genes, t-cells, developmental regulators, saccharomyces-cerevisiae, mammalian chromatin, coding regions, wide, h2a.z, h3

*Times Cited: 1895

PMID: 17512414


18. Identification of pancreatic cancer stem cells

C. W. Li, D. G. Heidt, P. Dalerba, C. F. Burant, L. J. Zhang, V. Adsay, M. Wicha, M. F. Clarke and D. M. Simeone

Cancer research.2007 Feb;67(3):1030-1037.

Abstract: Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.

Keywords: acute myeloid-leukemia, initiating cells, progenitor cells, brain-tumors, hedgehog, adenocarcinoma, apoptosis, survival, growth

*Times Cited: 992

PMID: 17283135


19. Induction of pluripotent stem cells from adult human fibroblasts by defined factors

K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda and S. Yamanaka

Cell.2007 Nov;131(5):861-872.

Abstract: Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.

Keywords: self-renewal, human blastocysts, mouse embryos, es cells, lines, differentiation, activation, stat3, generation, maintain

*Times Cited: 3800

PMID: 18035408


*Updated on 03/15/2013

Breakthroughs of the year 2008

1. GENEPOP ‘ 007: a complete re-implementation of the GENEPOP software for Windows and Linux

F. Rousset

Mol Ecol Resour.2008 Jan;8(1):103-106.

Abstract: This note summarizes developments of the GENEPOP software since its first description in 1995, and in particular those new to version 4.0: an extended input format, several estimators of neighbourhood size under isolation by distance, new estimators and confidence intervals for null allele frequency, and less important extensions to previous options. GENEPOP now runs under Linux as well as under Windows, and can be entirely controlled by batch calls.

Keywords: exact tests, isolation by distance, maximum likelihood, null alleles, partial mantel tests, genetic differentiation, maximum-likelihood, permutation tests, f-statistics, population, frequency, alleles

*Times Cited: 1342

PMID: 21585727


2. A perivascular origin for mesenchymal stem cells in multiple human organs

M. Crisan, S. Yap, L. Casteilla, C. W. Chen, M. Corselli, T. S. Park, G. Andriolo, B. Sun, B. Zheng, L. Zhang, C. Norotte, P. N. Teng, J. Traas, R. Schugar, B. M. Deasy, S. Badylak, H. J. Buhring, J. P. Giacobino, L. Lazzari, J. Huard and B. Peault

Cell Stem Cell.2008 Sep;3(3):301-313.

Abstract: Mesenchymal stem cells (MSCs), the archetypal multipotent progenitor cells derived in cultures of developed organs, are of unknown identity and native distribution. We have prospectively identified perivascular cells, principally pericytes, in multiple human organs including skeletal muscle, pancreas, adipose tissue, and placenta, on CD146, NG2, and PDGF-R beta expression and absence of hematopoietic, endothelial, and myogenic cell markers. Perivascular cells purified from skeletal muscle or nonmuscle tissues were myogenic in culture and in vivo. Irrespective of their tissue origin, long-term cultured perivascular cells retained myogenicity; exhibited at the clonal level osteogenic, chondrogenic, and adipogenic potentials; expressed MSC markers; and migrated in a culture model of chemotaxis. Expression of MSC markers was also detected at the surface of native, noncultured perivascular cells. Thus, blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSCs and other related adult stem cells.

Keywords: human skeletal-muscle, human adipose-tissue, endothelial-cells, bone-marrow, microvascular pericytes, differential expression, myogenic, progenitors, satellite cells, alpha-actin, markers

*Times Cited: 690

PMID: 18786417


3. A quantitative analysis of kinase inhibitor selectivity

M. W. Karaman, S. Herrgard, D. K. Treiber, P. Gallant, C. E. Atteridge, B. T. Campbell, K. W. Chan, P. Ciceri, M. I. Davis, P. T. Edeen, R. Faraoni, M. Floyd, J. P. Hunt, D. J. Lockhart, Z. V. Milanov, M. J. Morrison, G. Pallares, H. K. Patel, S. Pritchard, L. M. Wodicka and P. P. Zarrinkar

Nature Biotechnology.2008 Jan;26(1):127-132.

Abstract: Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets(1,2). The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome(2-4). We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Keywords: receptor tyrosine kinase, renal-cell carcinoma, antitumor-activity, c-kit, targets, discovery, cancer, tumor, drug, abl

*Times Cited: 745

PMID: 18183025


4. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory

G. M. Shankar, S. M. Li, T. H. Mehta, A. Garcia-Munoz, N. E. Shepardson, I. Smith, F. M. Brett, M. A. Farrell, M. J. Rowan, C. A. Lemere, C. M. Regan, D. M. Walsh, B. L. Sabatini and D. J. Selkoe

Nature Medicine.2008 Aug;14(8):837-842.

Abstract: Alzheimer’s disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer’s disease has not been achieved. We extracted soluble amyloid-beta protein (Ab) oligomers directly from the cerebral cortex of subjects with Alzheimer’s disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Ab from Alzheimer’s disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Ab dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Ab N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer’s disease cortex did not impair LTP unless they were first solubilized to release Ab dimers, suggesting that plaque cores are largely inactive but sequester Ab dimers that are synaptotoxic. We conclude that soluble Ab oligomers extracted from Alzheimer’s disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.

Keywords: long-term potentiation, a-beta, natural oligomers, transgenic mice, area, ca1, disease, depression, hippocampus, expression, a-beta(1-42)

*Times Cited: 943

PMID: 18568035


5. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models

K. J. Preacher and A. F. Hayes

Behav Res Methods.2008 Aug;40(3):879-891.

Abstract: Hypotheses involving mediation are common in the behavioral sciences. Mediation exists when a predictor affects a dependent variable indirectly through at least one intervening variable, or mediator. Methods to assess mediation involving multiple simultaneous mediators have received little attention in the methodological literature despite a clear need. We provide an overview of simple and multiple mediation and explore three approaches that can be used to investigate indirect processes, as well as methods for contrasting two or more mediators within a single model. We present an illustrative example, assessing and contrasting potential mediators of the relationship between the helpfulness of socialization agents and job satisfaction. We also provide SAS and SPSS macros, as well as Mplus and LISREL syntax, to facilitate the use of these methods in applications.

Keywords: structural-equation models, confidence-intervals, product, socialization, intervention, performance, program, limits

*Times Cited: 1927

PMID: 18697684


6. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study

L. B. Saltz, S. Clarke, E. Diaz-Rubio, W. Scheithauer, A. Figer, R. Wong, S. Koski, M. Lichinitser, T. S. Yang, F. Rivera, F. Couture, F. Sirzen and J. Cassidy

Journal of Clinical Oncology.2008 Apr;26(12):2013-2019.

Abstract: Purpose To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients and Methods Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). Results A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P =. 077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. Conclusion The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

Keywords: cell lung-cancer, fluorouracil, leucovorin, trial, capecitabine, carboplatin, paclitaxel, efficacy, safety

*Times Cited: 672

PMID: 18421054


7. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies

A. G. Renehan, M. Tyson, M. Egger, R. F. Heller and M. Zwahlen

Lancet.2008 Feb;371(9612):569-578.

Abstract: Background Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. Methods We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m(2) increase in BMI. Findings We analysed 221 datasets (141 articles), including 282137 incident cases. In men, a 5 kg/m(2) increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1.52, p<0.0001) and with thyroid (1.33, p=0. 02), colon (1 . 24, p< 0.0001), and renal (1.34, p <0 .0001) cancers. In women, we recorded strong associations between a 5 kg/m(2) increase in BMI and endometrial (1 . 59, p<0.0001), gallbladder (1 .59, p=0.04), oesophageal adenocarcinoma (1 . 51, p<0. 0001), and renal (1. 34, p<0.0001) cancers. We noted weaker positive associations (RR <1 .20) between increased BMI and rectal cancer and malignant melanoma in men; postmenopausal breast, pancreatic, thyroid, and colon cancers in women; and leukaemia, multiple myeloma, and non-Hodgkin lymphoma in both sexes. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia-Pacific region, but we recorded stronger associations in Asia-Pacific populations between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. Interpretation Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.

Keywords: renal-cell carcinoma, epithelial ovarian-cancer, meta-regression, analysis, million norwegian men, self-reported height, to-hip ratio, breast-cancer, multiethnic cohort, pancreatic-cancer, fat distribution

*Times Cited: 636

PMID: 18280327


8. Disease-specific induced pluripotent stem cells

I. H. Park, N. Arora, H. Huo, N. Maherali, T. Ahfeldt, A. Shimamura, M. W. Lensch, C. Cowan, K. Hochedlinger and G. Q. Daley

Cell.2008 Sep;134(5):877-886.

Abstract: Tissue culture of immortal cell strains from diseased patients is an invaluable resource for medical research but is largely limited to tumor cell lines or transformed derivatives of native tissues. Here we describe the generation of induced pluripotent stem (iPS) cells from patients with a variety of genetic diseases with either Mendelian or complex inheritance; these diseases include adenosine deaminase deficiency-related severe combined immunodeficiency (ADA-SCID), Shwachman-Bodian-Diamond syndrome (SBDS), Gaucher disease (GD) type III, Duchenne (DMD) and Becker muscular dystrophy (BMD), Parkinson disease (PD), Huntington disease (HD), juvenile-onset, type 1 diabetes mellitus (JDM), Down syndrome (DS)/trisomy 21, and the carrier state of Lesch-Nyhan syndrome. Such disease-specific stem cells offer an unprecedented opportunity to recapitulate both normal and pathologic human tissue formation in vitro, thereby enabling disease investigation and drug development.

Keywords: duchenne muscular-dystrophy, human somatic-cells, down-syndrome, defined, factors, critical region, hprt gene, mouse, mutation, locus, chromosome-21

*Times Cited: 698

PMID: 18691744


9. Effect of a multifactorial intervention on mortality in type 2 diabetes

P. Gaede, H. Lund-Andersen, H. H. Parving and O. Pedersen

N Engl J Med.2008 Feb;358(6):580-591.

Abstract: Background: Intensified multifactorial intervention — with tight glucose regulation and the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes. Methods: In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause. Results: Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported. Conclusions: In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. ( number, NCT00320008.).

Keywords: coronary heart-disease, placebo-controlled trial, blood-glucose control, cardiovascular-disease, vascular-disease, follow-up, complications, risk, pressure, mellitus

*Times Cited: 756

PMID: 18256393


10. Effects of intensive glucose lowering in type 2 diabetes

H. C. Gerstein, M. E. Miller, R. P. Byington, D. C. Goff, J. T. Bigger, J. B. Buse, W. C. Cushman, S. Genuth, F. Ismail-Beigi, R. H. Grimm, J. L. Probstfield, D. G. Simons-Morton, W. T. Friedewald and D. Act Control Cardiovasc Risk

N Engl J Med.2008 Jun;358(24):2545-2559.

Abstract: Background: Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. Methods: In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. Results: At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). Conclusions: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. ( number, NCT00000620.).

Keywords: control cardiovascular risk, accord trial, glycemic control, mellitus, design, complications, disease, rationale, association, prevention

*Times Cited: 1795

PMID: 18539917


11. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial

R. J. Motzer, B. Escudier, S. Oudard, T. E. Hutson, C. Porta, S. Bracarda, V. Grunwald, J. A. Thompson, R. A. Figlin, N. Hollaender, G. Urbanowitz, W. J. Berg, A. Kay, D. Lebwohl, A. Ravaud and R.-S. Grp

Lancet.2008 Aug;372(9637):449-456.

Abstract: Background Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We dida phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. Methods Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with, number NCT00410124. Findings All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0 – 30, 95% CI 0.22-0.40, p < 0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity Interpretation Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

Keywords: advanced solid tumors, mammalian target, clinical-trials, interferon-alpha, kidney cancer, inhibitor, pathways, oncology, mtor

*Times Cited: 851

PMID: 18653228


12. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts

M. Nakagawa, M. Koyanagi, K. Tanabe, K. Takahashi, T. Ichisaka, T. Aoi, K. Okita, Y. Mochiduki, N. Takizawa and S. Yamanaka

Nature Biotechnology.2008 Jan;26(1):101-106.

Abstract: Direct reprogramming of somatic cells provides an opportunity to generate patient- or disease-specific pluripotent stem cells. Such induced pluripotent stem (iPS) cells were generated from mouse fibroblasts by retroviral transduction of four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc(1). Mouse iPS cells are indistinguishable from embryonic stem (ES) cells in many respects and produce germline- competent chimeras(2-4). Reactivation of the c-Myc retrovirus, however, increases tumorigenicity in the chimeras and progeny mice, hindering clinical applications(3). Here we describe a modified protocol for the generation of iPS cells that does not require the Myc retrovirus. With this protocol, we obtained significantly fewer non-iPS background cells, and the iPS cells generated were consistently of high quality. Mice derived from Myc-iPS cells did not develop tumors during the study period. The protocol also enabled efficient isolation of iPS cells without drug selection. Furthermore, we generated human iPS cells from adult dermal fibroblasts without MYC.

Keywords: es cells, expression, family, nanog, gene

*Times Cited: 959

PMID: 18059259


13. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease

J. C. Barrett, S. Hansoul, D. L. Nicolae, J. H. Cho, R. H. Duerr, J. D. Rioux, S. R. Brant, M. S. Silverberg, K. D. Taylor, M. M. Barmada, A. Bitton, T. Dassopoulos, L. W. Datta, T. Green, A. M. Griffiths, E. O. Kistner, M. T. Murtha, M. D. Regueiro, J. I. Rotter, L. P. Schumm, A. H. Steinhart, S. R. Targan, R. J. Xavier, C. Libioulle, C. Sandor, M. Lathrop, J. Belaiche, O. Dewit, I. Gut, S. Heath, D. Laukens, M. Mni, P. Rutgeerts, A. Van Gossum, D. Zelenika, D. Franchimont, J. P. Hugot, M. de Vos, S. Vermeire, E. Louis, L. R. Cardon, C. A. Anderson, H. Drummond, E. Nimmo, T. Ahmad, N. J. Prescott, C. M. Onnie, S. A. Fisher, J. Marchini, J. Ghori, S. Bumpstead, R. Gwilliam, M. Tremelling, P. Deloukas, J. Mansfield, D. Jewell, J. Satsangi, C. G. Mathew, M. Parkes, M. Georges, M. J. Daly, N. I. G. Consortium, I. B. D. C. Belgian-French and C. Wellcome Trust Case

Nature Genetics.2008 Aug;40(8):955-962.

Abstract: Several risk factors for Crohn’s disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn’s disease ( a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Keywords: large-scale, nonsynonymous snps, genetic-variation, variants, cells, expression, il-23, multiple, colitis, risk

*Times Cited: 952

PMID: 18587394


14. High body mass index for age among US children and adolescents, 2003-2006

C. L. Ogden, M. D. Carroll and K. M. Flegal

Jama-Journal of the American Medical Association.2008 May;299(20):2401-2405.

Abstract: Context The prevalence of overweight among US children and adolescents increased between 1980 and 2004. Objectives To estimate the prevalence of 3 measures of high body mass index ( BMI) for age ( calculated as weight in kilograms divided by height in meters squared) and to examine recent trends for US children and adolescents using national data with measured heights and weights. Design, Setting, and Participants Height and weight measurements were obtained from 8165 children and adolescents as part of the 2003- 2004 and 2005- 2006 National Health and Nutrition Examination Survey ( NHANES), nationally representative surveys of the US civilian, noninstitutionalized population. Main Outcome Measures Prevalence of BMI for age at or above the 97th percentile, at or above the 95th percentile, and at or above the 85th percentile of the 2000 sex- specific Centers for Disease Control and Prevention ( CDC) BMI- for- age growth charts among US children by age, sex, and racial/ ethnic group. Results Because no statistically significant differences in the prevalence of high BMI for age were found between estimates for 2003- 2004 and 2005- 2006, data for the 4 years were combined to provide more stable estimates for the most recent time period. Overall, in 2003- 2006, 11.3% ( 95% confidence interval [ CI], 9.7%- 12.9%) of children and adolescents aged 2 through 19 years were at or above the 97th percentile of the 2000 BMI- for- age growth charts, 16.3% ( 95% CI, 14.5%- 18.1%) were at or above the 95th percentile, and 31.9% ( 95% CI, 29.4%- 34.4%) were at or above the 85th percentile. Prevalence estimates varied by age and by racial/ ethnic group. Analyses of the trends in high BMI for age showed no statistically significant trend over the 4 time periods ( 1999- 2000, 2001- 2002, 2003- 2004, and 2005- 2006) for either boys or girls ( P values between .07 and .41). Conclusion The prevalence of high BMI for age among children and adolescents showed no significant changes between 2003- 2004 and 2005- 2006 and no significant trends between 1999 and 2006.

Keywords: expert committee, overweight, obesity, recommendations, prevalence

*Times Cited: 878

PMID: 18505949


15. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags

X. M. Qian, X. H. Peng, D. O. Ansari, Q. Yin-Goen, G. Z. Chen, D. M. Shin, L. Yang, A. N. Young, M. D. Wang and S. M. Nie

Nature Biotechnology.2008 Jan;26(1):83-90.

Abstract: We describe biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on pegylated gold nanoparticles and surface-enhanced Raman scattering (SERS). Colloidal gold has been safely used to treat rheumatoid arthritis for 50 years, and has recently been found to amplify the efficiency of Raman scattering by 14-15 orders of magnitude. Here we show that large optical enhancements can be achieved under in vivo conditions for tumor detection in live animals. An important finding is that small-molecule Raman reporters such as organic dyes were not displaced but were stabilized by thiolmodified polyethylene glycols. These pegylated SERS nanoparticles were considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor-targeting ligands such as single-chain variable fragment (ScFv) antibodies, the conjugated nanoparticles were able to target tumor biomarkers such as epidermal growth factor receptors on human cancer cells and in xenograft tumor models.

Keywords: semiconductor quantum dots, gold nanoparticles, colloidal gold, cancer-therapy, drug-delivery, lung-cancer, scattering, molecules, nanotechnology, nanocrystals

*Times Cited: 607

PMID: 18157119


16. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells

X. Chen, H. Xu, P. Yuan, F. Fang, M. Huss, V. B. Vega, E. Wong, Y. L. Orlov, W. W. Zhang, J. M. Jiang, Y. H. Loh, H. C. Yeo, Z. X. Yeo, V. Narang, K. R. Govindarajan, B. Leong, A. Shahab, Y. J. Ruan, G. Bourque, W. K. Sung, N. D. Clarke, C. L. Wei and H. H. Ng

Cell.2008 Jun;133(6):1106-1117.

Abstract: Transcription factors (TFs) and their specific interactions with targets are crucial for specifying gene-expression programs. To gain insights into the transcriptional regulatory networks in embryonic stem (ES) cells, we use chromatin immunoprecipitation coupled with ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of 13 sequence-specific TFs (Nanog, Oct4, STAT3, Smad1, Sox2, Zfx, c-Myc, n-Myc, Klf4, Esrrb, Tcfcp2l1, E2f1, and CTCF) and 2 transcription regulators (p300 and Suz12). These factors are known to play different roles in ES-cell biology as components of the LIF and BMP signaling pathways, self-renewal regulators, and key reprogramming factors. Our study provides insights into the integration of the signaling pathways into the ES-cell-specific transcription circuitries. Intriguingly, we find specific genomic regions extensively targeted by different TFs. Collectively, the comprehensive mapping of TF-binding sites identifies important features of the transcriptional regulatory networks that define ES-cell identity.

Keywords: self-renewal, human genome, binding-sites, developmental regulators, beta enhanceosome, in-vivo, c-myc, pluripotent, gene, induction

*Times Cited: 675

PMID: 18555785


17. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes

A. Patel, S. MacMahon, J. Chalmers, B. Neal, L. Billot, M. Woodward, M. Marre, M. Cooper, P. Glasziou, D. Grobbee, P. Hamet, S. Harrap, S. Heller, L. S. Liu, G. Mancia, C. E. Mogensen, C. Y. Pan, N. Poulter, A. Rodgers, B. Williams, S. Bompoint, B. E. de Galan, R. Joshi, F. Travert and A. C. Grp

N Engl J Med.2008 Jun;358(24):2560-2572.

Abstract: Background: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. Methods: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. Results: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). Conclusions: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. ( number, NCT00145925.).

Keywords: randomized controlled-trial, cause-specific mortality, cardiovascular, events, microvascular outcomes, glycemic control, mellitus, complications, disease, metaanalysis, gliclazide

*Times Cited: 1535

PMID: 18539916


18. Intensive insulin therapy and pentastarch resuscitation in severe sepsis

F. M. Brunkhorst, C. Engel, F. Bloos, A. Meier-Hellmann, M. Ragaller, N. Weiler, O. Moerer, M. Gruendling, M. Oppert, S. Grond, D. Olthoff, U. Jaschinski, S. John, R. Rossaint, T. Welte, M. Schaefer, P. Kern, E. Kuhnt, M. Kiehntopf, C. Hartog, C. Natanson, M. Loeffler, K. Reinhart and S. German Competence Network

N Engl J Med.2008 Jan;358(2):125-139.

Abstract: Background: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. Methods: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer’s lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. Results: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, <= 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer’s lactate. Conclusions: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. ( number, NCT00135473.).

Keywords: critically-ill patients, hydroxyethyl starch, renal-function, critical-care, failure, surgery, transplantation, replacement, multicenter, gelatin

*Times Cited: 907

PMID: 18184958


19. KEGG for linking genomes to life and the environment

M. Kanehisa, M. Araki, S. Goto, M. Hattori, M. Hirakawa, M. Itoh, T. Katayama, S. Kawashima, S. Okuda, T. Tokimatsu and Y. Yamanishi

Nucleic acids research.2008 Jan;36:D480-D484.

Abstract: KEGG ( is a database of biological systems that integrates genomic, chemical and systemic functional information. KEGG provides a reference knowledge base for linking genomes to life through the process of PATHWAY mapping, which is to map, for example, a genomic or transcriptomic content of genes to KEGG reference pathways to infer systemic behaviors of the cell or the organism. In addition, KEGG provides a reference knowledge base for linking genomes to the environment, such as for the analysis of drug-target relationships, through the process of BRITE mapping. KEGG BRITE is an ontology database representing functional hierarchies of various biological objects, including molecules, cells, organisms, diseases and drugs, as well as relationships among them. KEGG PATHWAY is now supplemented with a new global map of metabolic pathways, which is essentially a combined map of about 120 existing pathway maps. In addition, smaller pathway modules are defined and stored in KEGG MODULE that also contains other functional units and complexes. The KEGG resource is being expanded to suit the needs for practical applications. KEGG DRUG contains all approved drugs in the US and Japan, and KEGG DISEASE is a new database linking disease genes, pathways, drugs and diagnostic markers.

Keywords: prediction

*Times Cited: 827

PMID: 18077471


20. K-ras mutations and benefit from cetuximab in advanced colorectal cancer

C. S. Karapetis, S. Khambata-Ford, D. J. Jonker, C. J. O’Callaghan, D. Tu, N. C. Tebbutt, R. J. Simes, H. Chalchal, J. D. Shapiro, S. Robitaille, T. J. Price, L. Shepherd, H. J. Au, C. Langer, M. J. Moore and J. R. Zalcberg

N Engl J Med.2008 Oct;359(17):1757-1765.

Abstract: Background: Treatment with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor, improves overall and progression-free survival and preserves the quality of life in patients with colorectal cancer that has not responded to chemotherapy. The mutation status of the K-ras gene in the tumor may affect the response to cetuximab and have treatment-independent prognostic value. Methods: We analyzed tumor samples, obtained from 394 of 572 patients (68.9%) with colorectal cancer who were randomly assigned to receive cetuximab plus best supportive care or best supportive care alone, to look for activating mutations in exon 2 of the K-ras gene. We assessed whether the mutation status of the K-ras gene was associated with survival in the cetuximab and supportive-care groups. Results: Of the tumors evaluated for K-ras mutations, 42.3% had at least one mutation in exon 2 of the gene. The effectiveness of cetuximab was significantly associated with K-ras mutation status (P=0.01 and P<0.001 for the interaction of K-ras mutation status with overall survival and progression-free survival, respectively). In patients with wild-type K-ras tumors, treatment with cetuximab as compared with supportive care alone significantly improved overall survival (median, 9.5 vs. 4.8 months; hazard ratio for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001) and progression-free survival (median, 3.7 months vs. 1.9 months; hazard ratio for progression or death, 0.40; 95% CI, 0.30 to 0.54; P<0.001). Among patients with mutated K-ras tumors, there was no significant difference between those who were treated with cetuximab and those who received supportive care alone with respect to overall survival (hazard ratio, 0.98; P=0.89) or progression-free survival (hazard ratio, 0.99; P=0.96). In the group of patients receiving best supportive care alone, the mutation status of the K-ras gene was not significantly associated with overall survival (hazard ratio for death, 1.01; P=0.97). Conclusions: Patients with a colorectal tumor bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor bearing wild-type K-ras did benefit from cetuximab. The mutation status of the K-ras gene had no influence on survival among patients treated with best supportive care alone. ( number, NCT00079066.).

Keywords: growth-factor receptor, tyrosine kinase inhibitors, cell lung-cancer, kras mutation, phase-ii, survival, therapy, egfr, adenocarcinomas, expression

*Times Cited: 968

PMID: 18946061


*Updated on 03/15/2013

Breakthroughs of the year 2009

1. Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team

F. S. Dawood, S. Jain, L. Finelli, M. W. Shaw, S. Lindstrom, R. J. Garten, L. V. Gubareva, X. Y. Xu, C. B. Bridges and T. M. Uyeki

N Engl J Med.2009 Jun;360(25):2605-2615.

Abstract: BACKGROUND On April 15 and April 17, 2009, novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in specimens obtained from two epidemiologically unlinked patients in the United States. The same strain of the virus was identified in Mexico, Canada, and elsewhere. We describe 642 confirmed cases of human S-OIV infection identified from the rapidly evolving U. S. outbreak. METHODS Enhanced surveillance was implemented in the United States for human infection with influenza A viruses that could not be subtyped. Specimens were sent to the Centers for Disease Control and Prevention for real-time reverse-transcriptase-polymerasechain-reaction confirmatory testing for S-OIV. RESULTS From April 15 through May 5, a total of 642 confirmed cases of S-OIV infection were identified in 41 states. The ages of patients ranged from 3 months to 81 years; 60% of patients were 18 years of age or younger. Of patients with available data, 18% had recently traveled to Mexico, and 16% were identified from school outbreaks of S-OIV infection. The most common presenting symptoms were fever (94% of patients), cough (92%), and sore throat (66%); 25% of patients had diarrhea, and 25% had vomiting. Of the 399 patients for whom hospitalization status was known, 36 (9%) required hospitalization. Of 22 hospitalized patients with available data, 12 had characteristics that conferred an increased risk of severe seasonal influenza, 11 had pneumonia, 8 required admission to an intensive care unit, 4 had respiratory failure, and 2 died. The S-OIV was determined to have a unique genome composition that had not been identified previously. CONCLUSIONS A novel swine-origin influenza A virus was identified as the cause of outbreaks of febrile respiratory infection ranging from self-limited to severe illness. It is likely that the number of confirmed cases underestimates the number of cases that have occurred.

Keywords: infection, vaccines, adults

*Times Cited: 1347

PMID: 19423869


2. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers

P. C. Fong, D. S. Boss, T. A. Yap, A. Tutt, P. J. Wu, M. Mergui-Roelvink, P. Mortimer, H. Swaisland, A. Lau, M. J. O’Connor, A. Ashworth, J. Carmichael, S. B. Kaye, J. H. M. Schellens and J. S. de Bono

N Engl J Med.2009 Jul;361(2):123-134.

Abstract: Background: The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods: This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results: We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. Conclusions: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. ( number, NCT00516373.) N Engl J Med 2009;361:123-34.

Keywords: dna-repair defect, ovarian-cancer, prostate-cancer, clinical-trials, mutant-cells, solid tumors, guidelines, maintenance, resistance, cisplatin

*Times Cited: 825

PMID: 19553641


3. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes

D. M. Nathan, J. B. Buse, M. B. Davidson, E. Ferrannini, R. R. Holman, R. Sherwin and B. Zinman

Diabetes Care.2009 Jan;32(1):193-203.

Abstract: The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues Surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Keywords: blood-glucose control, dipeptidyl peptidase-4 inhibitor, randomized, controlled-trial, intensive insulin therapy, improved glycemic control, disease risk-factors, cardiovascular-disease, microvascular, complications, exenatide exendin-4, life-style

*Times Cited: 905

PMID: 18945920


4. STRING 8-a global view on proteins and their functional interactions in 630 organisms

L. J. Jensen, M. Kuhn, M. Stark, S. Chaffron, C. Creevey, J. Muller, T. Doerks, P. Julien, A. Roth, M. Simonovic, P. Bork and C. von Mering

Nucleic acids research.2009 Jan;37:D412-D416.

Abstract: Functional partnerships between proteins are at the core of complex cellular phenotypes, and the networks formed by interacting proteins provide researchers with crucial scaffolds for modeling, data reduction and annotation. STRING is a database and web resource dedicated to protein-protein interactions, including both physical and functional interactions. It weights and integrates information from numerous sources, including experimental repositories, computational prediction methods and public text collections, thus acting as a meta-database that maps all interaction evidence onto a common set of genomes and proteins. The most important new developments in STRING 8 over previous releases include a URL-based programming interface, which can be used to query STRING from other resources, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures. Version 8.0 of STRING covers about 2.5 million proteins from 630 organisms, providing the most comprehensive view on protein-protein interactions currently available. STRING can be reached at

Keywords: interaction networks, interaction database, biological networks, genomic, data, update, prediction, associations, environment, software, resource

*Times Cited: 573

PMID: 18940858


5. A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population

A. B. Haynes, T. G. Weiser, W. R. Berry, S. R. Lipsitz, A. H. S. Breizat, E. P. Dellinger, T. Herbosa, S. Joseph, P. L. Kibatala, M. C. M. Lapitan, A. F. Merry, K. Moorthy, R. K. Reznick, B. Taylor, A. A. Gawande and G. Safe Surgery Saves Lives Study

N Engl J Med.2009 Jan;360(5):491-499.

Abstract: Background: Surgery has become an integral part of global health care, with an estimated 234 million operations performed yearly. Surgical complications are common and often preventable. We hypothesized that a program to implement a 19-item surgical safety checklist designed to improve team communication and consistency of care would reduce complications and deaths associated with surgery. Methods: Between October 2007 and September 2008, eight hospitals in eight cities (Toronto, Canada; New Delhi, India; Amman, Jordan; Auckland, New Zealand; Manila, Philippines; Ifakara, Tanzania; London, England; and Seattle, WA) representing a variety of economic circumstances and diverse populations of patients participated in the World Health Organization’s Safe Surgery Saves Lives program. We prospectively collected data on clinical processes and outcomes from 3733 consecutively enrolled patients 16 years of age or older who were undergoing noncardiac surgery. We subsequently collected data on 3955 consecutively enrolled patients after the introduction of the Surgical Safety Checklist. The primary end point was the rate of complications, including death, during hospitalization within the first 30 days after the operation. Results: The rate of death was 1.5% before the checklist was introduced and declined to 0.8% afterward (P=0.003). Inpatient complications occurred in 11.0% of patients at baseline and in 7.0% after introduction of the checklist (P<0.001). Conclusions: Implementation of the checklist was associated with concomitant reductions in the rates of death and complications among patients at least 16 years of age who were undergoing noncardiac surgery in a diverse group of hospitals. N Engl J Med 2009;360:491-9.

Keywords: antibiotic-prophylaxis, operating-room, surgery, risk, infections, anesthesia, hospitals, australia, teamwork, nurses

*Times Cited: 710

PMID: 19144931


6. Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

J. M. L. Ebos, C. R. Lee, W. Cruz-Munoz, G. A. Bjarnason, J. G. Christensen and R. S. Kerbel

Cancer Cell.2009 Mar;15(3):232-239.

Abstract: Herein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments.

Keywords: endothelial progenitor cells, sunitinib malate, kinase inhibitor, cancer, therapy, models, cyclophosphamide, selectivity, progression, disease

*Times Cited: 586

PMID: 19249681


7. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

M. Paez-Ribes, E. Allen, J. Hudock, T. Takeda, H. Okuyama, F. Vinals, M. Inoue, G. Bergers, D. Hanahan and O. Casanovas

Cancer Cell.2009 Mar;15(3):220-231.

Abstract: Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies.

Keywords: endothelial growth-factor, central-nervous-system, carcinoma-cell, invasion, high-grade glioma, breast-cancer, mouse model, in-vivo, angiogenesis, vegf, tumorigenesis

*Times Cited: 703

PMID: 19249680


8. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

E. Van Cutsem, C. H. Kohne, E. Hitre, J. Zaluski, C. R. C. Chien, A. Makhson, G. D’Haens, T. Pinter, R. Lim, G. Bodoky, J. K. Roh, G. Folprecht, P. Ruff, C. Stroh, S. Tejpar, M. Schlichting, J. Nippgen and P. Rougier

N Engl J Med.2009 Apr;360(14):1408-1417.

Abstract: Background We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. Methods We randomly assigned patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival. Results A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab-FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P = 0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P = 0.31). There was a significant interaction between treatment group and KRAS mutation status for tumor response (P = 0.03) but not for progression-free survival (P = 0.07) or overall survival (P = 0.44). The hazard ratio for progression-free survival among patients with wild-type-KRAS tumors was 0.68 (95% CI, 0.50 to 0.94), in favor of the cetuximab-FOLFIRI group. The following grade 3 or 4 adverse events were more frequent with cetuximab plus FOLFIRI than with FOLFIRI alone: skin reactions (which were grade 3 only) (in 19.7% vs. 0.2% of patients, P<0.001), infusion-related reactions (in 2.5% vs. 0%, P<0.001), and diarrhea (in 15.7% vs. 10.5%, P = 0.008). Conclusions First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. ( number, NCT00154102.)

Keywords: k-ras mutations, 1st-line treatment, plus irinotecan, phase-iii, fluorouracil, oxaliplatin, leucovorin, kras, combination, trial

*Times Cited: 811

PMID: 19339720


9. Cytochrome P-450 Polymorphisms and Response to Clopidogrel

J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, R. D. Hockett, J. T. Brandt, J. R. Walker, E. M. Antman, W. Macias, E. Braunwald and M. S. Sabatine

N Engl J Med.2009 Jan;360(4):354-362.

Abstract: Background: Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods: We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. Results: In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02). Conclusions: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers. N Engl J Med 2009;360:354-62.

Keywords: acute coronary syndromes, st-segment elevation, platelet inhibition, individual responsiveness, atherothrombotic events, myocardial-infarction, stent thrombosis, healthy-subjects, increased, risk, prasugrel

*Times Cited: 784

PMID: 19106084


10. Dabigatran versus Warfarin in Patients with Atrial Fibrillation

S. J. Connolly, M. D. Ezekowitz, S. Yusuf, J. Eikelboom, J. Oldgren, A. Parekh, J. Pogue, P. A. Reilly, E. Themeles, J. Varrone, S. Wang, M. Alings, D. Xavier, J. Zhu, R. Diaz, B. S. Lewis, H. Darius, H. C. Diener, C. D. Joyner, L. Wallentin, R.-L. S. Comm and Investigator

N Engl J Med.2009 Sep;361(12):1139-1151.

Abstract: Background: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Methods: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Results: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). Conclusions: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. ( number, NCT00262600.) N Engl J Med 2009;361:1139-51.

Keywords: non-inferiority trial, antithrombotic therapy, anticoagulant-therapy, oral anticoagulant, prevent stroke, aspirin, thromboembolism, metaanalysis, clopidogrel, etexilate

*Times Cited: 1312

PMID: 19717844


11. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

R. Stupp, M. E. Hegi, W. P. Mason, M. J. van den Bent, M. J. B. Taphoorn, R. C. Janzer, S. K. Ludwin, A. Allgeier, B. Fisher, K. Belanger, P. Hau, A. A. Brandes, J. Gijtenbeek, C. Marosi, C. J. Vecht, K. Mokhtari, P. Wesseling, S. Villa, E. Eisenhauer, T. Gorlia, M. Weller, D. Lacombe, J. G. Cairncross, R. O. Mirimanoff, R. European Org, Treatment, G. Canc Brain Tumour, G. Radiat Oncol and T. Natl Canc Inst Canada Clin

Lancet Oncology.2009 May;10(5):459-466.

Abstract: Background In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with, number NCT00006353. Findings Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide.

Keywords: newly-diagnosed glioblastoma, recursive partitioning analysis, mgmt, promoter methylation, controlled clinical-trial, aspartic acid peptide, malignant glioma, prognostic-factors, accelerated radiotherapy, oncology-group, multiforme

*Times Cited: 703

PMID: 19269895


12. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

A. L. Cheng, Y. K. Kang, Z. D. Chen, C. J. Tsao, S. K. Qin, J. S. Kim, R. C. Luo, J. F. Feng, S. L. Ye, T. S. Yang, J. M. Xu, Y. Sun, H. J. Liang, J. W. Liu, J. J. Wang, W. Y. Tak, H. M. Pan, K. Burock, J. Zou, D. Voliotis and Z. Z. Guan

Lancet Oncology.2009 Jan;10(1):25-34.

Abstract: Background Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase 111, randomised, double-blind, placebo. controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods Between Sept 20, 2005, and Jan 31, 2007, patients with hepatorcellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with, number NCT00492752. Findings 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% Cl 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.791; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. Interpretation Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Keywords: over-expression, natural-history, cancer, epidemiology, guidelines, therapies, prognosis, cirrhosis, tumors, japan

*Times Cited: 653

PMID: 19095497


13. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

P. O. McGowan, A. Sasaki, A. C. D’Alessio, S. Dymov, B. Labonte, M. Szyf, G. Turecki and M. J. Meaney

Nat Neurosci.2009 Mar;12(3):342-348.

Abstract: Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1(F) splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.

Keywords: major depression, maternal-care, stress responses, genetic-analysis, mood disorders, messenger-rna, young-adults, schizophrenia, methylation, suicide

*Times Cited: 583

PMID: 19234457


14. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma

T. S. Mok, Y. L. Wu, S. Thongprasert, C. H. Yang, D. T. Chu, N. Saijo, P. Sunpaweravong, B. H. Han, B. Margono, Y. Ichinose, Y. Nishiwaki, Y. Ohe, J. J. Yang, B. Chewaskulyong, H. Y. Jiang, E. L. Duffield, C. L. Watkins, A. A. Armour and M. Fukuoka

N Engl J Med.2009 Sep;361(10):947-957.

Abstract: Background: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. Methods: In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. Results: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Conclusions: Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. ( number, NCT00322452.) N Engl J Med 2009;361:947-57.

Keywords: cell lung-cancer, receptor gene-mutations, prospective phase-ii, egfr, mutations, functional assessment, 1st-line gefitinib, treated patients, never-smokers, therapy, erlotinib

*Times Cited: 1293

PMID: 19692680


15. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events

T. Simon, C. Verstuyft, M. Mary-Krause, L. Quteineh, E. Drouet, N. Meneveau, P. G. Steg, J. Ferrieres, N. Danchin, L. Becquemont and S. T. E. French Registry Acute

N Engl J Med.2009 Jan;360(4):363-375.

Abstract: Background: Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. Methods: We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Results: Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Conclusions: Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. ( number, NCT00673036.) N Engl J Med 2009;360:363-75.

Keywords: st-segment elevation, percutaneous coronary intervention, healthy, japanese subjects, of-function polymorphism, sequence variations, myocardial-infarction, p-glycoprotein, duodenal enterocytes, controlled, trial, drug response

*Times Cited: 603

PMID: 19106083


16. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C

Y. Tanaka, N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, M. Nakagawa, M. Korenaga, K. Hino, S. Hige, Y. Ito, E. Mita, E. Tanaka, S. Mochida, Y. Murawaki, M. Honda, A. Sakai, Y. Hiasa, S. Nishiguchi, A. Koike, I. Sakaida, M. Imamura, K. Ito, K. Yano, N. Masaki, F. Sugauchi, N. Izumi, K. Tokunaga and M. Mizokami

Nature Genetics.2009 Oct;41(10):1105-U1181.

Abstract: The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

Keywords: plus ribavirin, combination therapy, virological response, host factors, virus, genotype-1, trial, 1b

*Times Cited: 731

PMID: 19749757


17. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

W. Duckworth, C. Abraira, T. Moritz, D. Reda, N. Emanuele, P. D. Reaven, F. J. Zieve, J. Marks, S. N. Davis, R. Hayward, S. R. Warren, S. Goldman, M. McCarren, M. E. Vitek, W. G. Henderson, G. D. Huang and V. Investigators

N Engl J Med.2009 Jan;360(2):129-U162.

Abstract: Background The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. Methods We randomly assigned 1791 military veterans ( mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive- therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard- therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. Results The median follow- up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard- therapy group and 6.9% in the intensive- therapy group. The primary outcome occurred in 264 patients in the standard- therapy group and 235 patients in the intensive- therapy group (hazard ratio in the intensive- therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P = 0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause ( hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P = 0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard- therapy group and 24.1% in the intensive- therapy group. Conclusions Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications. (ClinicalTrials. gov number, NCT00032487.).

Keywords: microvascular complications, macrovascular disease, glycemic control, mellitus, trial, association, progression, retinopathy, risk

*Times Cited: 929

PMID: 19092145


18. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy

V. Suppiah, M. Moldovan, G. Ahlenstiel, T. Berg, M. Weltman, M. L. Abate, M. Bassendine, U. Spengler, G. J. Dore, E. Powell, S. Riordan, D. Sheridan, A. Smedile, V. Fragomeli, T. Muller, M. Bahlo, G. J. Stewart, D. R. Booth, J. George and C. S. Hepatitis

Nature Genetics.2009 Oct;41(10):1100-U1174.

Abstract: Hepatitis C virus (HCV) infects 3% of the world’s population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFN lambda 3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.

Keywords: genome-wide association, gene-expression, antiviral activity, virus-replication, randomized-trial, plus ribavirin, ifn-lambda, iii, ifn, infection, opinion

*Times Cited: 667

PMID: 19749758


*Updated on 03/26/2013

Breakthroughs of the year 2010

1. Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer

E. L. Kwak, Y. J. Bang, D. R. Camidge, A. T. Shaw, B. Solomon, R. G. Maki, S. H. I. Ou, B. J. Dezube, P. A. Janne, D. B. Costa, M. Varella-Garcia, W. H. Kim, T. J. Lynch, P. Fidias, H. Stubbs, J. A. Engelman, L. V. Sequist, W. W. Tan, L. Gandhi, M. Mino-Kenudson, G. C. Wei, S. M. Shreeve, M. J. Ratain, J. Settleman, J. G. Christensen, D. A. Haber, K. Wilner, R. Salgia, G. I. Shapiro, J. W. Clark and A. J. Iafrate

N Engl J Med.2010 Oct;363(18):1693-1703.

Abstract: BACKGROUND Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients.

Keywords: eml4-alk fusion gene, activating mutations, 2nd-line treatment, egfr, mutations, phase-ii, gefitinib, alk, identification, tumors, immunohistochemistry

*Times Cited: 634

PMID: 20979469


2. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

K. Matsushita, M. van der Velde, B. C. Astor, M. Woodward, A. S. Levey, P. E. de Jong, J. Coresh, R. T. Gansevoort and C. Chronic Kidney Dis Prognosis

Lancet.2010 Jun;375(9731):2073-2081.

Abstract: Background Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. Methods In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. Findings The analysis included 105 872 participants (730 577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1128 310 participants (4 732110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1. 73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. Interpretation eGFR less than 60 mi./min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease.

Keywords: chronic kidney-disease, risk-factor, cystatin-c, serum creatinine, pooled analysis, renal-disease, older-adults, prevalence, equation, outcomes

*Times Cited: 391

PMID: 20483451


3. Common SNPs explain a large proportion of the heritability for human height

J. A. Yang, B. Benyamin, B. P. McEvoy, S. Gordon, A. K. Henders, D. R. Nyholt, P. A. Madden, A. C. Heath, N. G. Martin, G. W. Montgomery, M. E. Goddard and P. M. Visscher

Nature Genetics.2010 Jul;42(7):565-U131.

Abstract: SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.

Keywords: genome-wide association, missing heritability, artificial selection, complex diseases, traits, loci, populations, prediction

*Times Cited: 389

PMID: 20562875


4. Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer

J. S. Temel, J. A. Greer, A. Muzikansky, E. R. Gallagher, S. Admane, V. A. Jackson, C. M. Dahlin, C. D. Blinderman, J. Jacobsen, W. F. Pirl, J. A. Billings and T. J. Lynch

N Engl J Med.2010 Aug;363(8):733-742.

Abstract: BACKGROUND Patients with metastatic non-small-cell lung cancer have a substantial symptom burden and may receive aggressive care at the end of life. We examined the effect of introducing palliative care early after diagnosis on patient-reported outcomes and end-of-life care among ambulatory patients with newly diagnosed disease. METHODS We randomly assigned patients with newly diagnosed metastatic non-small-cell lung cancer to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. Quality of life and mood were assessed at baseline and at 12 weeks with the use of the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale, respectively. The primary outcome was the change in the quality of life at 12 weeks. Data on end-of-life care were collected from electronic medical records. RESULTS Of the 151 patients who underwent randomization, 27 died by 12 weeks and 107 (86% of the remaining patients) completed assessments. Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (mean score on the FACT-L scale [in which scores range from 0 to 136, with higher scores indicating better quality of life], 98.0 vs. 91.5; P = 0.03). In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms (16% vs. 38%, P = 0.01). Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02). CONCLUSIONS Among patients with metastatic non-small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival. (Funded by an American Society of Clinical Oncology Career Development Award and philanthropic gifts; number, NCT01038271.)

Keywords: quality-of-life, cooperative-oncology-group, randomized, controlled-trial, functional assessment, elderly-patients, supportive, care, therapy-lung, depression, survival, chemotherapy

*Times Cited: 421

PMID: 20818875


5. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

H. N. Ginsberg, M. B. Elam, L. C. Lovato, J. R. Crouse, L. A. Leiter, P. Linz, W. T. Friedewald, J. B. Buse, H. C. Gerstein, J. Probstfield, R. H. Grimm, F. Ismail-Beigi, J. T. Bigger, D. C. Goff, W. C. Cushman, D. G. Simons-Morton, R. P. Byington and A. S. Grp

N Engl J Med.2010 Apr;362(17):1563-1574.

Abstract: BACKGROUND We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. METHODS We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P = 0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P = 0.057 for interaction). CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. ( number, NCT00000620.)

Keywords: coronary-heart-disease, placebo-controlled trial, treatment panel-iii, cardiovascular-disease, artery-disease, risk-factors, myocardial-infarction, secondary prevention, intervention trial, ldl, cholesterol

*Times Cited: 396

PMID: 20228404


6. Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus

W. C. Cushman, G. W. Evans, R. P. Byington, D. C. Goff, R. H. Grimm, J. A. Cutler, D. G. Simons-Morton, J. N. Basile, M. A. Corson, J. L. Probstfield, L. Katz, K. A. Peterson, W. T. Friedewald, J. B. Buse, J. T. Bigger, H. C. Gerstein and F. Ismail-Beigi

N Engl J Med.2010 Apr;362(17):1575-1585.

Abstract: BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., < 120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P = 0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P = 0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P = 0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. ( number, NCT00000620.)

Keywords: microvascular complications, risk, disease, trial, prevention, hot

*Times Cited: 463

PMID: 20228401


7. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

K. K. Kumarasamy, M. A. Toleman, T. R. Walsh, J. Bagaria, F. Butt, R. Balakrishnan, U. Chaudhary, M. Doumith, C. G. Giske, S. Irfan, P. Krishnan, A. V. Kumar, S. Maharjan, S. Mushtaq, T. Noorie, D. L. Paterson, A. Pearson, C. Perry, R. Pike, B. Rao, U. Ray, J. B. Sarma, M. Sharma, E. Sheridan, M. A. Thirunarayan, J. Turton, S. Upadhyay, M. Warner, W. Welfare, D. M. Livermore and N. Woodford

Lancet Infect Dis.2010 Sep;10(9):597-602.

Abstract: Background Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-beta-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK. Methods Enterobacteriaceae isolates were studied from two major centres in India-Chennai (south India), Haryana (north India)-and those referred to the UK’s national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene bla(NDM 1) was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by Si nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan Findings We identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries. Interpretation The potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.

Keywords: klebsiella-pneumoniae carbapenemase, ctx-m, beta-lactamases, enterobacteriaceae, infections, prevalence, hospitals, threat

*Times Cited: 482

PMID: 20705517


8. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

J. Ferlay, H. R. Shin, F. Bray, D. Forman, C. Mathers and D. M. Parkin

Int J Cancer.2010 Dec;127(12):2893-2917.

Abstract: Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.

Keywords: incidence, mortality, cancer, global estimates, 18 major cancers, mortality, population, prediction, frequency, survival

*Times Cited: 1185

PMID: 21351269


9. Exome sequencing identifies the cause of a mendelian disorder

S. B. Ng, K. J. Buckingham, C. Lee, A. W. Bigham, H. K. Tabor, K. M. Dent, C. D. Huff, P. T. Shannon, E. W. Jabs, D. A. Nickerson, J. Shendure and M. J. Bamshad

Nature Genetics.2010 Jan;42(1):30-U41.

Abstract: We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40x and sufficient depth to call variants at similar to 97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.

Keywords: postaxial acrofacial dysostosis, ultraconserved elements, drosophila-melanogaster, rheumatoid-arthritis, kappa-b, leflunomide, mice, inhibition, mutations, capture

*Times Cited: 466

PMID: 19915526


10. Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR

M. Maemondo, A. Inoue, K. Kobayashi, S. Sugawara, S. Oizumi, H. Isobe, A. Gemma, M. Harada, H. Yoshizawa, I. Kinoshita, Y. Fujita, S. Okinaga, H. Hirano, K. Yoshimori, T. Harada, T. Ogura, M. Ando, H. Miyazawa, T. Tanaka, Y. Saijo, K. Hagiwara, S. Morita, T. Nukiwa and N. E. J. S. Grp

N Engl J Med.2010 Jun;362(25):2380-2388.

Abstract: Background: Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. Methods: We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. Results: In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. Conclusions: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.) N Engl J Med 2010;362:2380-8.

Keywords: growth-factor-receptor, previously treated patients, randomized, phase-iii, acid pcr clamp, japanese patients, gene-mutations, survival, trial, adenocarcinoma, paclitaxel

*Times Cited: 555

PMID: 20573926


11. Genetic Variation in IL28B Is Associated With Chronic Hepatitis C and Treatment Failure: A Genome-Wide Association Study

A. Rauch, Z. Kutalik, P. Descombes, T. Cai, J. Di Iulio, T. Mueller, M. Bochud, M. Battegay, E. Bernasconi, J. Borovicka, S. Colombo, A. Cerny, J. F. Dufour, H. Furrer, H. F. Gunthard, M. Heim, B. Hirschel, R. Malinverni, D. Moradpour, B. Mullhaupt, A. Witteck, J. S. Beckmann, T. Berg, S. Bergmann, F. Negro, A. Telenti, P. Y. Bochud, C. Swiss Hepatitis and S. Hiv Cohort

Gastroenterology.2010 Apr;138(4):1338-U1173.

Abstract: BACKGROUND & AIMS: Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy. METHODS: The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression. RESULTS: Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype. CONCLUSIONS: The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.

Keywords: Hepatitis C, Genetics, Interferon, Interleukin-28, alpha-2a plus ribavirin, virus-infection, peginterferon alpha-2a, natural-history, interferon-lambda, immune-responses, ifn-lambda, replication, host, polymorphisms

*Times Cited: 384

PMID: 20060832


*Updated on 04/10/2013

Breakthroughs of the year 2011

1. Guidelines for the Prevention of Stroke in Patients With Stroke or Transient Ischemic Attack A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

K. L. Furie, S. E. Kasner, R. J. Adams, G. W. Albers, R. L. Bush, S. C. Fagan, J. L. Halperin, S. C. Johnston, I. Katzan, W. N. Kernan, P. H. Mitchell, B. Ovbiagele, Y. Y. Palesch, R. L. Sacco, L. H. Schwamm, S. Wassertheil-Smoller, T. N. Turan, D. Wentworth, C. Amer Heart Assoc Stroke, N. Council Cardiovasc, C. Council Clin and Q. Interdisciplinary Council

Stroke.2011 Jan;42(1):227-276.

Abstract: The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches to the implementation of guidelines and their use in high-risk populations. (Stroke. 2011;42:227-276.)

Keywords: AHA Scientific Statements, ischemia, transient ischemic attack, stroke, stroke prevention, patent foramen ovale, sickle-cell-disease, high-risk patients, randomized controlled-trial, carotid-artery dissection, activated, protein-c, factor-v-leiden, densit

*Times Cited: 228

PMID: 20966421


2. Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration The CATT Research Group

D. F. Martin, M. G. Maguire, G. S. Ying, J. E. Grunwald, S. L. Fine, G. J. Jaffe and C. R. Grp

N Engl J Med.2011 May;364(20):1897-1908.

Abstract: Background Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. Methods In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Results Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 mu m) than in the other groups (152 to 168 mu m, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. Conclusions At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials. gov number, NCT00593450.)

Keywords: myocardial-infarction, stroke

*Times Cited: 239

PMID: 21526923


3. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

A. E. Renton, E. Majounie, A. Waite, J. Simon-Sanchez, S. Rollinson, J. R. Gibbs, J. C. Schymick, H. Laaksovirta, J. C. van Swieten, L. Myllykangas, H. Kalimo, A. Paetau, Y. Abramzon, A. M. Remes, A. Kaganovich, S. W. Scholz, J. Duckworth, J. H. Ding, D. W. Harmer, D. G. Hernandez, J. O. Johnson, K. Mok, M. Ryten, D. Trabzuni, R. J. Guerreiro, R. W. Orrell, J. Neal, A. Murray, J. Pearson, I. E. Jansen, D. Sondervan, H. Seelaar, D. Blake, K. Young, N. Halliwell, J. B. Callister, G. Toulson, A. Richardson, A. Gerhard, J. Snowden, D. Mann, D. Neary, M. A. Nalls, T. Peuralinna, L. Jansson, V. M. Isoviita, A. L. Kaivorinne, M. Holtta-Vuori, E. Ikonen, R. Sulkava, M. Benatar, J. Wuu, A. Chio, G. Restagno, G. Borghero, M. Sabatelli, D. Heckerman, E. Rogaeva, L. Zinman, J. D. Rothstein, M. Sendtner, C. Drepper, E. E. Eichler, C. Alkan, Z. Abdullaev, S. D. Pack, A. Dutra, E. Pak, J. Hardy, A. Singleton, N. M. Williams, P. Heutink, S. Pickering-Brown, H. R. Morris, P. J. Tienari, B. J. Traynor and I. Consortium

Neuron.2011 Oct;72(2):257-268.

Abstract: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Keywords: amyotrophic-lateral-sclerosis, frontotemporal lobar degeneration, human, genome, mutations, tdp-43, dementia, susceptibility, association, population, common

*Times Cited: 270

PMID: 21944779


4. A Prospective Natural-History Study of Coronary Atherosclerosis

G. W. Stone, A. Maehara, A. J. Lansky, B. de Bruyne, E. Cristea, G. S. Mintz, R. Mehran, J. McPherson, N. Farhat, S. P. Marso, H. Parise, B. Templin, R. White, Z. Zhang, P. W. Serruys and P. Investigators

N Engl J Med.2011 Jan;364(3):226-235.

Abstract: Background: Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. Methods: In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. Results: The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [+/-SD] diameter stenosis, 32.3+/-20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(sup 2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). Conclusions: In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; number, NCT00180466.) N Engl J Med 2011;364:226-35.

Keywords: intravascular ultrasound assessment, risk-assessment strategies, vulnerable plaque, artery-disease, regression-analysis, definitions, progression, patient, lesions, call

*Times Cited: 215

PMID: 21247313


5. Abiraterone and Increased Survival in Metastatic Prostate Cancer

J. S. De Bono, C. J. Logothetis, A. Molina, K. Fizazi, S. North, L. Chu, K. N. Chi, R. J. Jones, O. B. Goodman, F. Saad, J. N. Staffurth, P. Mainwaring, S. Harland, T. W. Flaig, T. E. Hutson, T. Cheng, H. Patterson, J. D. Hainsworth, C. J. Ryan, C. N. Sternberg, S. L. Ellard, A. Flechon, M. Saleh, M. Scholz, E. Efstathiou, A. Zivi, D. Bianchini, Y. Loriot, N. Chieffo, T. Kheoh, C. M. Haqq, H. I. Scher and C.-A.-. Investigators

N Engl J Med.2011 May;364(21):1995-2005.

Abstract: BACKGROUND Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS We randomly assigned, in a 2: 1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the pre-planned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. CONCLUSIONS The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 number, NCT00638690.)

Keywords: androgen-deprivation therapy, human cytochrome p450(17-alpha), i, clinical-trial, hormonal-therapy, steroidal inhibitors, plus prednisone, working group, castration, acetate, cyp17

*Times Cited: 346

PMID: 21612468


6. Apixaban in Patients with Atrial Fibrillation

S. J. Connolly, J. Eikelboom, C. Joyner, H. C. Diener, R. Hart, S. Golitsyn, G. Flaker, A. Avezum, S. H. Hohnloser, R. Diaz, M. Talajic, J. Zhu, P. Pais, A. Budaj, A. Parkhomenko, P. Jansky, P. Commerford, R. S. Tan, K. H. Sim, B. S. Lewis, W. Van Mieghem, G. Y. H. Lip, J. H. Kim, F. Lanas-Zanetti, A. Gonzalez-Hermosillo, A. L. Dans, M. Munawar, M. O’Donnell, J. Lawrence, G. Lewis, R. Afzal and S. Yusuf

N Engl J Med.2011 Mar;364(9):806-817.

Abstract: BACKGROUND Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P = 0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P = 0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.

Keywords: antithrombotic therapy, knee replacement, prevent stroke, warfarin, aspirin, trial, thromboprophylaxis, anticoagulation, metaanalysis, clopidogrel

*Times Cited: 277

PMID: 21309657


7. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection

B. R. Bacon, S. C. Gordon, E. Lawitz, P. Marcellin, J. M. Vierling, S. Zeuzem, F. Poordad, Z. D. Goodman, H. L. Sings, F. Poordad, Z. D. Goodman, H. L. Sings, N. Boparai, M. Burroughs, C. A. Brass, J. K. Albrecht, R. Esteban and H. R. Investigators

N Engl J Med.2011 Mar;364(13):1207-1217.

Abstract: BACKGROUND In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment. METHODS To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1: 2: 2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. RESULTS A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10) IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls. CONCLUSIONS The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone.

Keywords: chronic hepatitis-c, peginterferon alpha-2b, protease inhibitor, ribavirin, interferon, therapy

*Times Cited: 329

PMID: 21449784


8. Boceprevir for Untreated Chronic HCV Genotype 1 Infection

F. Poordad, J. McCone, B. R. Bacon, S. Bruno, M. P. Manns, M. S. Sulkowski, I. M. Jacobson, K. R. Reddy, Z. D. Goodman, N. Boparai, M. J. DiNubile, V. Sniukiene, C. A. Brass, J. K. Albrecht, J. P. Bronowicki and S. Investigators

N Engl J Med.2011 Mar;364(13):1195-1206.

Abstract: BACKGROUND Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P = 0.04), and in 29 of the 55 patients (53%) in group 3 (P = 0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

Keywords: chronic hepatitis-c, alpha-2a plus ribavirin, peginterferon alpha-2a, randomized-trial, virus-infection, telaprevir, interferon-alpha-2b, sch-503034, inhibitor

*Times Cited: 471

PMID: 21449783


9. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

K. Fizazi, M. Carducci, M. Smith, R. Damiao, J. Brown, L. Karsh, P. Milecki, N. Shore, M. Rader, H. I. Wang, Q. Jiang, S. Tadros, R. Dansey and C. Goessl

Lancet.2011 Mar;377(9768):813-822.

Abstract: Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal. related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12.2 months (IQR 5.9-18.5) for patients on denosumab and 11.2 months (IQR 5.6-17.4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8-24.9) with denosumab compared with 17.1 months (15-0-19.4) with zoledronic acid (hazard ratio 0.82, 95% CI 0.71-0.95; p=0.0002 for non-inferiority; p=0.008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0.0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0.09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.

Keywords: controlled phase-ii, breast-cancer, skeletal complications, controlled-trials, long-term, therapy, multicenter, prevention, carcinoma, survival

*Times Cited: 218

PMID: 21353695


10. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms

F. Zannad, J. J. V. McMurray, H. Krum, D. J. van Veldhuisen, K. Swedberg, H. Shi, J. Vincent, S. J. Pocock, B. Pitt and E.-H. S. Grp

N Engl J Med.2011 Jan;364(1):11-21.

Abstract: Background: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. Methods: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. Results: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). Conclusions: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; number, NCT00232180.) N Engl J Med 2011;364:11-21.

Keywords: left-ventricular dysfunction, acute myocardial-infarction, mineralocorticoid receptor, cardiac fibrosis, task-force, aldosterone, spironolactone, association, survival, trial

*Times Cited: 244

PMID: 21073363


11. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline

M. F. Holick, N. C. Binkley, H. A. Bischoff-Ferrari, C. M. Gordon, D. A. Hanley, R. P. Heaney, M. H. Murad and C. M. Weaver

J Clin Endocrinol Metab.2011 Jul;96(7):1911-1930.

Abstract: Objective: The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. Participants: The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society’s Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society website for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. Conclusions: Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxy vitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D(2) or vitamin D(3) was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection. (J Clin Endocrinol Metab 96: 1911-1930, 2011)

Keywords: serum 25-hydroxyvitamin d, breast-fed infants, randomized-controlled-trials, healthy postmenopausal women, nursing-home, residents, bone-mineral density, d supplementation, hypovitaminosis-d, d, insufficiency, calcium supplementation

*Times Cited: 291

PMID: 21646368


12. Everolimus for Advanced Pancreatic Neuroendocrine Tumors

J. C. Yao, M. H. Shah, T. Ito, C. L. Bohas, E. M. Wolin, E. Van Cutsem, T. J. Hobday, T. Okusaka, J. Capdevila, E. G. E. de Vries, P. Tomassetti, M. E. Pavel, S. Hoosen, T. Haas, J. Lincy, D. Lebwohl, K. Oberg and R. A. D. A. N. T. T

N Engl J Med.2011 Feb;364(6):514-523.

Abstract: Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. Results: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). Conclusions: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 number, NCT00510068.) N Engl J Med 2011;364:514-23.

Keywords: islet-cell-carcinoma, antitumor-activity, endocrine tumors, solid, tumors, phase-ii, streptozocin, doxorubicin, fluorouracil, combination, efficacy

*Times Cited: 284

PMID: 21306238


*Updated on 04/10/2013

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