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. (ClinicalTrials.gov 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. (ClinicalTrials.gov 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 ClinicalTrials.gov, 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. (ClinicalTrials.gov 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. (ClinicalTrials.gov 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 (http://www.genome.jp/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. (ClinicalTrials.gov 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

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