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 (http://www.genome.jp/kegg/) 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

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