tbuckley/cabot-search huggingface dataset:
FOXP3 Controls an miR-146/NF-κB Negative Feedback Loop That Inhibits Apoptosis in Breast Cancer Cells
Authors: Runhua Liu, Cong Liu, Dongquan Chen, Wei-Hsiung Yang, Xiuping Liu, Chang-Gong Liu, Courtney M. Dugas, Fei Tang, Pan Zheng, Yang Liu, Lizhong Wang
Journal: Cancer Research (2015)

Abstract FOXP3 functions not only as the master regulator in regulatory T cells, but also as an X-linked tumor suppressor. The tumor-suppressive activity of FOXP3 has been observed in tumor initiation, but its role during tumor progression remains controversial. Moreover, the mechanism of FOXP3-mediated tumor-suppressive activity remains largely unknown. Using chromatin immunoprecipitation (ChIP) sequencing, we identified a series of potential FOXP3-targeted miRNAs in MCF7 cells. Notably, FOXP3 significantly induced the expression of miR-146a/b. In vitro, FOXP3-induced miR-146a/b prevented tumor cell proliferation and enhanced apoptosis. Functional analyses in vitro and in vivo revealed that FOXP3-induced miR-146a/b negatively regulates NF-κB activation by inhibiting the expression of IRAK1 and TRAF6. In ChIP assays, FOXP3 directly bound the promoter region of miR-146a but not of miR-146b, and FOXP3 interacted directly with NF-κB p65 to regulate an miR-146–NF-κB negative feedback regulation loop in normal breast epithelial and tumor cells, as demonstrated with luciferase reporter assays. Although FOXP3 significantly inhibited breast tumor growth and migration in vitro and metastasis in vivo, FOXP3-induced miR-146a/b contributed only to the inhibition of breast tumor growth. These data suggest that miR-146a/b contributes to FOXP3-mediated tumor suppression during tumor growth by triggering apoptosis. The identification of a FOXP3–miR-146–NF-κB axis provides an underlying mechanism for disruption of miR-146 family member expression and constitutive NF-κB activation in breast cancer cells. Linking the tumor suppressor function of FOXP3 to NF-κB activation reveals a potential therapeutic approach for cancers with FOXP3 defects. Cancer Res; 75(8); 1703–13. ©2015 AACR.
Topoisomerase IIα Expression as an Independent Prognostic Factor in Hodgkin's Lymphoma
Authors: Ipatia A. Doussis-Anagnostopoulou, Theodoros P. Vassilakopoulos, Irini Thymara, Penelope Korkolopoulou, Maria K. Angelopoulou, Marina P. Siakantaris, Styliani I. Kokoris, Evangelia M. Dimitriadou, Christina Kalpadakis, Marina Matzouranis, Loukas Kaklamanis, Panayiotis Panayiotidis, Marie-Christine Kyrtsonis, Athina Androulaki, Efstratios Patsouris, Christos Kittas, Gerassimos A. Pangalis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To correlate the immunohistochemical expression of topoisomerase IIα (topoIIα) in Hodgkin's lymphoma (HL) with clinicopathological parameters, the expression of Ki-67 and the outcome of patients, who had been homogenously treated with ABVD or equivalent regimens. Experimental Design: Immunohistochemistry using the monoclonal antibody Ki-S1 (topoIIα) was performed in 238 HL patients. MiB1 (Ki-67) expression was evaluated in 211/238. Results: The mean ± SD percentage of topoIIα- and Ki-67–positive Hodgkin-Reed-Sternberg (HRS) cells was 63 ± 19% (5%-98%) and 73 ± 19% (8%-99%), respectively. The median percentage of topoIIα-positive HRS cells was 64% (interquartile range, 51-78%). There was no correlation between topoIIα expression and patient characteristics. TopoIIα and Ki-67 expression were correlated (Spearman's Rho 0.255, P &amp;lt; 0.001). TopoIlα expression within the highest quartile of this patient population was predictive of failure free survival (FFS) (10-year rates 82 ± 3% vs 68 ± 7%, P = 0.02 for patients falling into the quartiles 1-3 and 4 respectively). In multivariate analysis topoIIα expression was independently predictive of FFS. Conclusion: TopoIIα was expressed in all cases of HL showing a correlation with Ki-67 expression. Under current standard therapy including drugs inhibiting its activity, topoIIα was an independent adverse predictor of FFS with no statistically significant correlation with other established prognostic factors.
Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial
Authors: Rovina Ruslami, A Rizal Ganiem, Sofiati Dian, Lika Apriani, Tri Hanggono Achmad, Andre J van der Ven, George Borm, Rob E Aarnoutse, Reinout van Crevel
Journal: The Lancet Infectious Diseases (2012)
Biologic Determinants of Tumor Recurrence in Stage II Colon Cancer: Validation Study of the 12-Gene Recurrence Score in Cancer and Leukemia Group B (CALGB) 9581
Authors: Alan P. Venook, Donna Niedzwiecki, Margarita Lopatin, Xing Ye, Mark Lee, Paula N. Friedman, Wendy Frankel, Kim Clark-Langone, Carl Millward, Steven Shak, Richard M. Goldberg, Najjia N. Mahmoud, Robert S. Warren, Richard L. Schilsky, Monica M. Bertagnolli
Journal: Journal of Clinical Oncology (2013)

Purpose A greater understanding of the biology of tumor recurrence should improve adjuvant treatment decision making. We conducted a validation study of the 12-gene recurrence score (RS), a quantitative assay integrating stromal response and cell cycle gene expression, in tumor specimens from patients enrolled onto Cancer and Leukemia Group B (CALGB) 9581. Patients and Methods CALGB 9581 randomly assigned 1,713 patients with stage II colon cancer to treatment with edrecolomab or observation and found no survival difference. The analysis reported here included all patients with available tissue and recurrence (n = 162) and a random (approximately 1:3) selection of nonrecurring patients. RS was assessed in 690 formalin-fixed paraffin-embedded tumor samples with quantitative reverse transcriptase polymerase chain reaction by using prespecified genes and a previously validated algorithm. Association of RS and recurrence was analyzed by weighted Cox proportional hazards regression. Results Continuous RS was significantly associated with risk of recurrence (P = .013) as was mismatch repair (MMR) gene deficiency (P = .044). In multivariate analyses, RS was the strongest predictor of recurrence (P = .004), independent of T stage, MMR, number of nodes examined, grade, and lymphovascular invasion. In T3 MMR-intact (MMR-I) patients, prespecified low and high RS groups had average 5-year recurrence risks of 13% (95% CI, 10% to 16%) and 21% (95% CI, 16% to 26%), respectively. Conclusion The 12-gene RS predicts recurrence in stage II colon cancer in CALGB 9581. This is consistent with the importance of stromal response and cell cycle gene expression in colon tumor recurrence. RS appears to be most discerning for patients with T3 MMR-I tumors, although markers such as grade and lymphovascular invasion did not add value in this subset of patients.
Risk Factors for Suicide in Blacks and Whites: An Analysis of Data From the 1993 National Mortality Followback Survey
Authors: Kathryn Castle, Paul R. Duberstein, Sean Meldrum, Kenneth R. Conner, Yeates Conwell
Journal: American Journal of Psychiatry (2004)

Data on risk factors for suicide in blacks in the United States are needed, given the dramatic increase in the black suicide rate from 1980 to 1997. The 1993 National Mortality Followback Survey represented an unprecedented opportunity to identify risk factors for suicide in blacks and to determine whether race differences (black versus white) in risk factors exist.
Overview of molecular typing methods for outbreak detection and epidemiological surveillance
Authors: A J Sabat, A Budimir, D Nashev, R Sá-Leão, J M van Dijl, F Laurent, H Grundmann, A W Friedrich, None on behalf of the ESCMID Study Group
Journal: Eurosurveillance (2013)

Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage-type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages.
The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa
Authors: Brian G Williams, James O Lloyd-Smith, Eleanor Gouws, Catherine Hankins, Wayne M Getz, John Hargrove, Isabelle de Zoysa, Christopher Dye, Bertran Auvert
Journal: PLoS Medicine (2006)

Background A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60% (32%−76%; 95% CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. Methods and Findings Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC, we estimate the impact of increasing MC coverage on HIV incidence, HIV prevalence, and HIV-related deaths over the next ten, twenty, and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years, we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95% confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1−3.8) million new HIV infections and 0.3 (0.1−0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that, it could avert a further 3.7 (1.9−7.5) million new HIV infections and 2.7 (1.5−5.3) million deaths, with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52% to 58%; b) where there is homogenous mixing but not all men are circumcised, the prevalence of infection in circumcised men is likely to be about 80% of that in uncircumcised men; c) MC is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%. Conclusions This analysis is based on the result of just one RCT, but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa, especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate, the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years.
Neutrophils and the increased risk of cardiovascular events in severe COPD
Authors: Kenji Yazaki, Naoko Kamada, Yoshimi Fujibe, Masayuki Kashima, Kenichi Asakura, Mituko Sato, Tazuko Sato, Kenji Kikuchi
Journal: European Respiratory Journal (2012)

Introduction:

Inflammatory cells and mediators that may lead to destructive changes in airways, pulmonary vasculature, and lung parenchyma may be associated with an increased risk of cardiovascular events in patients with chronic obstructive pulmonary disease (COPD).

Aims:

We tested the hypothesis that neutrophils in venous blood have a relationship with serum human atrial natriuretic peptide (hANP) and brachial-ankle pulse wave velocity (baPWV) in COPD.

Methods:

Five male outpatients with COPD (83±4 age, forced expiratory volume in 1 second (FEV1 ) 39.1±7 % predicted), all ex-smokers and undergoing long-term oxygen therapy, were included.

Measurements were obtained monthly for the ratio of circulating neutrophil cell count to peripheral white blood cell count (neutrophil%), FEV1, forced vital capacity (FVC), hANP, and baPWV from July 1,2011, to December 15, 2011.

Results:

Neutrophil% (67.4±11.1%) was significantly correlated with BaPWV (2465.8± 652.7cm/s) (rs =0.480702, p<0.05) and hANP (27.6±8.7 pg/ml)(rs=0.471491, p<0.05). However, BaPWV was not correlated with FEV1 or FVC.

Conclusions:

This report suggests that neutrophils might be involved in the increased risk of cardiovascular events in sever COPD.
Interleukin-27 Receptor Limits Atherosclerosis in <i>Ldlr</i> <sup>−/−</sup> Mice
Authors: Ekaterina K. Koltsova, Gisen Kim, Kathleen M. Lloyd, Christiaan J.M. Saris, Sibylle von Vietinghoff, Mitchell Kronenberg, Klaus Ley
Journal: Circulation Research (2012)

Atherosclerosis is a chronic inflammatory disease of the arterial wall. Several proinflammatory cytokines are known to promote atherosclerosis, but less is known about the physiological role of anti-inflammatory cytokines. Interleukin (IL)-27 is a recently discovered member of the IL-6/IL-12 family. The IL-27 receptor is composed of IL-27 receptor A (WSX-1) and gp130 and is required for all established IL-27 signaling pathways. The expression of the IL-27 subunit Ebi3 is elevated in human atheromas, yet its function in atherosclerosis remains unknown.The aim of this study was to test the role of IL-27 receptor signaling in immune cells in atherosclerosis development.Atherosclerosis-prone Ldlr(-/-) mice transplanted with Il27ra(-/-) bone marrow and fed Western diet for 16 weeks developed significantly larger atherosclerotic lesions in aortic roots, aortic arches, and abdominal aortas. Augmented disease correlated with increased accumulation of CD45(+) leukocytes and CD4(+) T cells in the aorta, which produced increased amounts of IL-17A and tumor necrosis factor. Several chemokines, including CCL2, were upregulated in the aortas of Ldlr(-/-) mice receiving Il27ra(-/-) bone marrow, resulting in accumulation of CD11b(+) and CD11c(+) macrophages and dendritic cells in atherosclerotic aortas.The absence of anti-inflammatory IL-27 signaling skews immune responses toward T-helper 17, resulting in increased production of IL-17A and tumor necrosis factor, which in turn enhances chemokine expression and drives the accumulation of proatherogenic myeloid cells in atherosclerotic aortas. These findings establish a novel antiatherogenic role for IL-27 receptor signaling, which acts to suppress the production of proinflammatory cytokines and chemokines and to curb the recruitment of inflammatory myeloid cells into atherosclerotic aortas.
Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice
Authors: Jin Chu, Phillip F Giannopoulos, Carolina Ceballos-Diaz, Todd E Golde, Domenico Pratico
Journal: Molecular Neurodegeneration (2012)

Abstract Background The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice. Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology. Results Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2. Conclusions These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.
Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete Remission
Authors: Michael G. Kiehl, Ludwig Kraut, Rainer Schwerdtfeger, Bernd Hertenstein, Mats Remberger, Nicolaus Kroeger, Mathias Stelljes, Martin Bornhaeuser, Hans Martin, Christoph Scheid, Arnold Ganser, Axel R. Zander, Joachim Kienast, Gerhard Ehninger, Dieter Hoelzer, Volker Diehl, Axel A. Fauser, Olle Ringden
Journal: Journal of Clinical Oncology (2004)

The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors.The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor.Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041).Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.
Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study
Authors: Werner Hacke, Anthony J Furlan, Yasir Al-Rawi, Antoni Davalos, Jochen B Fiebach, Franz Gruber, Markku Kaste, Leslie J Lipka, Salvador Pedraza, Peter A Ringleb, Howard A Rowley, Dietmar Schneider, Lee H Schwamm, Joaquin Serena Leal, Mariola Söhngen, Phil A Teal, Karin Wilhelm-Ogunbiyi, Max Wintermark, Steven Warach
Journal: The Lancet Neurology (2008)
<scp>PI</scp>3K, <scp>ERK</scp>, p38 <scp>MAPK</scp> and integrins regulate <scp>CCR</scp>3‐mediated secretion of mouse and human eosinophil‐associated <scp>RN</scp>ases
Authors: R. Shamri, K. M. Young, P. F. Weller
Journal: Allergy (2013)

Abstract Background Eosinophils have the capacity to secrete varied cytotoxic proteins. Among the proteins are the eosinophil‐associated RN ases ( EAR s): the human eosinophil‐derived neurotoxin and eosinophilic cationic protein, and their murine ortholog EAR s, which have been shown to be involved in host defense, tissue remodeling, and immunity regulation. However, the signal transduction that regulates EAR s secretion in response to physiological stimuli, such as chemokines, has been little studied in human and scarcely in mouse eosinophils, the foremost animal model for eosinophil‐associated human diseases. Objective In this study, we aimed to understand the signal transduction involved in the secretion of enzymatically active EAR s following chemokine stimulation. Methods Fresh mouse and human eosinophils were stimulated with CCL 11 and CCL 24, and the secretion of enzymatically active EAR s was detected using an RN ase activity assay. The involvement of signaling factors or integrins was probed using specific inhibitors and blocking antibodies. Adhesion was evaluated by microscopy. Results We found that secretion of mouse EAR s in response to CCL 11 and CCL 24 was G αi ‐dependent. Both mouse and human eosinophils required the activation of PI 3 K , ERK , and p38 MAPK . In addition, the adhesion molecules β1 and β2 integrins were found to be crucial for EAR secretion, and we suggest a mechanism in which spreading is obligatory for EAR secretion. Conclusions Collectively, these data suggest a common CCR 3‐mediated signaling pathway that leads to EAR secretion in both mouse and human eosinophils. These findings are applicable for eosinophil‐mediated host defense and eosinophil‐associated diseases.
Genetics of Longevity and Aging
Authors: Jan Vijg, Yousin Suh
Journal: Annual Review of Medicine (2005)

Longevity, i.e., the property of being long-lived, has its natural limitation in the aging process. Longevity has a strong genetic component, as has become apparent from studies with a variety of organisms, from yeast to humans. Genetic screening efforts with invertebrates have unraveled multiple genetic pathways that suggest longevity is promoted through the manipulation of metabolism and the resistance to oxidative stress. To some extent, these same mechanisms appear to act in mammals also, despite considerable divergence during evolution. Thus far, evidence from population-based studies with humans suggests the importance of genes involved in cardiovascular disease as important determinants of longevity. The challenge is to test if the candidate longevity genes that have emerged from studies with model organisms exhibit genetic variation for life span in human populations. Future investigations are likely to involve large-scale case-control studies, in which large numbers of genes, corresponding to entire gene functional modules, will be assessed for all possible sequence variation and associated with detailed phenotypic information on each individual over extended periods of time. This should eventually unravel the genetic factors that contribute to each particular aging phenotype.