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

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