tbuckley/cabot-search huggingface dataset:
Prenatal Tobacco Smoke Exposure Affects Global and Gene-specific DNA Methylation
Authors: Carrie V. Breton, Hyang-Min Byun, Made Wenten, Fei Pan, Allen Yang, Frank D. Gilliland
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation.Objectives: To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations.Methods: Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Children's Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Children's Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results.Measurements and Main Results: DNA methylation patterns were associated with in utero exposure to maternal smoking. Exposed children had significantly lower methylation of AluYb8 (β, −0.31; P = 0.03). Differences in smoking-related effects on LINE1 methylation were observed in children with the common GSTM1 null genotype. Differential methylation of CpG loci in eight genes was identified through the screen. Two genes, AXL and PTPRO, were validated by pyrosequencing and showed significant increases in methylation of 0.37 (P = 0.005) and 0.34 (P = 0.02) in exposed children. The associations with maternal smoking varied by a common GSTP1 haplotype.Conclusions: Life-long effects of in utero exposures may be mediated through alterations in DNA methylation. Variants in detoxification genes may modulate the effects of in utero exposure through epigenetic mechanisms.
Heat stroke and 10K "fun runs": new safety measures are called for
Authors: A J Sanders, J Redhead
Journal: British Journal of Sports Medicine (2006)

On Sunday 11 June 2006, 8000 people undertook a “fun run” in Hyde Park, the BUPA Capital 10K. During the course of the afternoon, St Mary’s Hospital emergency department received four, and another local hospital received three, collapsed adult runners.

All collapsed at 7–10 km, were confused, and showed signs of severe heat stroke (with core temperatures of 40–41°C). Three patients required intubation, and three required sedation and high dependency unit care. One patient was admitted to the intensive care unit for 72 hours. Happily all survived, but there are some important lessons to be learnt for future similar events.

No official temperatures were recorded at …
NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression
Authors: Margit A. Huber, Ninel Azoitei, Bernd Baumann, Stefan Grünert, Andreas Sommer, Hubert Pehamberger, Norbert Kraut, Hartmut Beug, Thomas Wirth
Journal: Journal of Clinical Investigation (2004)

The transcription factor NF-κB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-κB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-β. We show here that the IKK-2/IκBα/NF-κB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-κB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-β. Furthermore, inhibition of NF-κB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-κB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-κB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-κB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-β–dependent signaling pathways in late-stage tumorigenesis depends critically on NF-κB activity.
Treating Patients as Persons: A Capabilities Approach to Support Delivery of Person-Centered Care
Authors: Vikki A. Entwistle, Ian S. Watt
Journal: The American Journal of Bioethics (2013)

Health services internationally struggle to ensure health care is "person-centered" (or similar). In part, this is because there are many interpretations of "person-centered care" (and near synonyms), some of which seem unrealistic for some patients or situations and obscure the intrinsic value of patients' experiences of health care delivery. The general concern behind calls for person-centered care is an ethical one: Patients should be "treated as persons." We made novel use of insights from the capabilities approach to characterize person-centered care as care that recognizes and cultivates the capabilities associated with the concept of persons. This characterization unifies key features from previous characterisations and can render person-centered care applicable to diverse patients and situations. By tying person-centered care to intrinsically valuable capability outcomes, it incorporates a requirement for responsiveness to individuals and explains why person-centered care is required independently of any contribution it may make to health gain.
Cyclosporin trough levels: is monitoring necessary during short-term treatment in psoriasis? A systematic review and clinical data on trough levels
Authors: V.M.R. Heydendael, P.I. Spuls, I.J.M. Ten Berge, B.C. Opmeer, J.D. Bos, M.A. De Rie
Journal: British Journal of Dermatology (2002)

Cyclosporin is an effective treatment for severe plaque psoriasis. Unfortunately, its use may be limited by time- and dose-related nephrotoxicity. Serum trough levels may be useful for monitoring the risk of nephrotoxicity.To determine whether monitoring of trough levels is necessary in psoriasis patients undergoing short-term treatment with cyclosporin.A computerized and manual literature search identified studies on adults with plaque-type psoriasis treated with cyclosporin < or = 5 mg kg-1 daily, in which trough levels were measured in whole blood. Number of patients, treatment duration, formulation and dosage, renal function tests and trough levels were extracted. The association between renal function and trough levels was investigated. Additionally, in a randomized controlled trial on cyclosporin vs. methotrexate in moderate to severe psoriasis, cyclosporin trough levels were measured frequently in 20 patients during 12 weeks of treatment. The Pearson correlation coefficient between serum creatinine and cyclosporin trough levels was calculated.Fifty-six articles were found concerning cyclosporin trough level measurements in psoriasis patients, of which eight were analysed. Many studies were excluded due to inappropriate cyclosporin dosages used. As data were heterogeneous and lacked various key parameters, a correlation study and a meta-analysis could not be performed. Instead, a quantitative description of the literature was given. No high mean trough levels or elevations of serum creatinine were described. In our clinical study, all the mean trough levels in 17 patients treated with cyclosporin 3 mg kg-1 daily were within the therapeutic range (< 200 ng mL-1). Elevated trough levels were found in two of three patients treated with cyclosporin 3-5 mg kg-1 daily. No signs of renal dysfunction were seen.The literature does not provide a definitive answer on whether monitoring cyclosporin trough levels in patients with psoriasis should be standard practice. Our own data show no need for cyclosporin trough level monitoring during short-term treatment with cyclosporin 3 mg kg-1 daily. However, when cyclosporin doses are > 3 mg kg-1 daily, monitoring may be indicated.
PED Mediates AKT-Dependent Chemoresistance in Human Breast Cancer Cells
Authors: Giorgio Stassi, Michela Garofalo, Monica Zerilli, Lucia Ricci-Vitiani, Ciro Zanca, Matilde Todaro, Federico Aragona, Gennaro Limite, Giuseppe Petrella, Gerolama Condorelli
Journal: Cancer Research (2005)

Abstract Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs–induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.
Effects of Exercise Training Intensity on Pancreatic β-Cell Function
Authors: Cris A. Slentz, Charles J. Tanner, Lori A. Bateman, Michael T. Durheim, Kim M. Huffman, Joseph A. Houmard, William E. Kraus
Journal: Diabetes Care (2009)

Insulin resistance and beta-cell dysfunction both are important contributors to the pathogenesis of type 2 diabetes. Exercise training improves insulin sensitivity, but its effects on beta-cell function are less well studied.Sedentary, overweight adults were randomized to control or one of three 8-month exercise programs: 1) low amount/moderate intensity, 2) low amount/vigorous intensity, or 3) high amount/vigorous intensity. Of 387 randomized, 260 completed the study and 237 had complete data. Insulin sensitivity (S(i)), acute insulin response to glucose (AIRg), and the disposition index (DI = S(i) x AIRg) were modeled from an intravenous glucose tolerance test.Compared with control subjects, all three training programs led to increases in DI. However, the moderate-intensity group experienced a significantly larger increase in DI than either of the vigorous-intensity groups and through a different mechanism. The high-amount/vigorous-intensity group improved S(i) and had a compensatory reduction in AIRg, whereas the moderate-intensity group had a similar improvement in S(i) but almost no reduction in AIRg. Importantly, the inactive control group experienced a significant increase in fasting glucose.To the extent that the DI accurately reflects beta-cell function, we observed that both moderate- and vigorous-intensity exercise training improved beta-cell function, albeit through distinct mechanisms. It is not clear which of these mechanisms is preferable for maintenance of metabolic health. While moderate-intensity exercise led to a larger improvement in DI, which may reflect a transition toward a more normal DI, longer-term investigations would be necessary to determine which was more effective at reducing diabetes risk.
Pharmacologic Lipid-Lowering Therapy in Type 2 Diabetes Mellitus: Background Paper for the American College of Physicians
Authors: Sandeep Vijan
Journal: Annals of Internal Medicine (2004)

Background: Cardiovascular disease is the primary complication and cause of death in patients with type 2 diabetes mellitus. Modification of cardiovascular risk factors may improve patient outcomes. Purpose: To evaluate the effectiveness of pharmacologic lipid-lowering therapy on outcomes in type 2 diabetes mellitus. Data Sources: Review of the literature. Study Selection: Randomized trials evaluating clinical outcomes of lipid-lowering treatment in patients with diabetes. Data Extraction: Studies were identified by searching the Cochrane Library, MEDLINE, meta-analyses, review articles, and inquiries to experts. The Cochrane Library and MEDLINE searches were done in September 2002. Data were abstracted onto standardized forms by a single reviewer and were confirmed by a second reviewer. Data Synthesis: Meta-analysis of 6 primary prevention studies showed that lipid-lowering medications reduced risks for cardiovascular outcomes (relative risk, 0.78 [95% CI, 0.67 to 0.89]; absolute risk reduction, 0.03 [CI, 0.01 to 0.04] in 4.3 years of treatment); 1 major cardiovascular event was prevented by treating 34 to 35 patients. Meta-analysis of 8 studies of secondary prevention showed a similar relative risk (0.76 [CI, 0.59 to 0.93]) but more than twice the absolute risk reduction (0.07 [CI, 0.03 to 0.12] in 4.9 years of treatment) and a number needed to treat for benefit of 13 to 14. Most studies compared a lipid-lowering drug with placebo but did not evaluate the effect of reaching specific cholesterol levels. The benefit of lipid lowering with a fixed dose of a statin appeared to be similar regardless of starting cholesterol levels. Limitations: Target cholesterol levels and the effectiveness of dose titration (or the use of multiple agents) have not been rigorously examined. Conclusions: In patients with type 2 diabetes, treatment with lipid-lowering agents reduces cardiovascular risk. Most patients, including those whose baseline low-density lipoprotein cholesterol levels are below 2.97 mmol/L (<115 mg/dL), and possibly below 2.59 mmol/L (<100 mg/dL), benefit from statins. Moderate doses of these drugs suffice in most patients with diabetes.
Interferon γ Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy
Authors: Ali A. Ashkar, James P. Di Santo, B. Anne Croy
Journal: The Journal of Experimental Medicine (2000)

The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-γ. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2−/− common cytokine receptor chain γ [γc]−/−) or IFN-γ signaling (IFN-γ−/− or IFN-γRα−/−) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell–derived IFN-γ during pregnancy, RAG-2−/−γc−/− females were engrafted with bone marrow from IFN-γ−/− mice, IFN-γ signal-disrupted mice (IFN-γRα−/− or signal transducer and activator of transcription [Stat]-1−/−), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-γ−/− mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-γRα−/− or Stat-1−/− mice overproduced uNK cells, all of which were immature. Grafts from IFN-γ−/−, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-γ to pregnant RAG-2−/−γc−/− mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell–derived IFN-γ modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.
Use of a Pump Oxygenator in Clinical Cardiac Failure
Authors: John H. Kennedy
Journal: JAMA (1966)

Heart failure in some patients, in spite of optimal medical therapy, remains refractory to treatment and they die of loss of effective action of the heart as a pump. Six patients thought to be in medically intractable heart failure were treated by partial perfusion by use of a disc oxygenator. All patients had temporary improvement, and two became long-term survivors. Case selection for assisted circulation is of importance, and for this, progressive fall in the central venous oxygen saturation as measured in the superior vena cava is a clinically useful estimate of the existing cardiac output failing to meet the oxygen requirements of the tissues.
Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart
Authors: U Ravens
Journal: Cardiovascular Research (2000)

The mammalian organism responds to chronic pressure and volume overload of the heart with a plethora of adaptive changes that consist of resetting of the neurohumoral homeostasis on a more general level and of structural remodeling and functional alterations on the cellular level. These latter changes include electrophysiological properties as exemplified by prolongation in action potential duration and rhythm disturbances considered responsible for sudden cardiac death as well as depression in contractile function of individual myocytes. Since calcium ions (Ca2+) play a pivotal role in cardiac excitation–contraction coupling, contractile dysfunction has been interpreted as a defect in Ca2+-handling proteins of the sarcoplasmic reticulum (SR) at the subcellular level.

This survey begins with a brief outline of cardiac excitation–contraction coupling and the functional role of the SR Ca2+-ATPase and its regulatory protein phospholamban. It continues with a summary of a frequently cited paper on the modulatory changes in these two Ca2+ homeostasis regulating proteins in human heart failure [1] and it will then discuss the confirmatory and controversial issues published since that seminal work appeared. The review will conclude with recently defined deficiencies at other subcellular sites. In its course, the reader is frequently referred to the excellent reviews of our current knowledge on the topic, which were compiled in the 1998 focused issue of this journal [2–7].

Contraction of heart muscle is initiated by electrical excitation of the plasmalemma followed by the typical long lasting cardiac action potential. Calcium entering the myocytes during the plateau phase of the action potential mainly via voltage sensitive L-type Ca2+ channels serves as a trigger for further release of Ca2+ from the major intracellular store, the SR. The free cytosolic Ca2+ concentration ([Ca2+]i) determines the extent of activation of contractile proteins …
1B50-1, a mAb Raised against Recurrent Tumor Cells, Targets Liver Tumor-Initiating Cells by Binding to the Calcium Channel α2δ1 Subunit
Authors: Wei Zhao, Limin Wang, Haibo Han, Kemin Jin, Na Lin, Ting Guo, Yangde Chen, Heping Cheng, Fengmin Lu, Weigang Fang, Yu Wang, Baocai Xing, Zhiqian Zhang
Journal: Cancer Cell (2013)
Maintenance Dialysis Population Dynamics
Authors: Michael J. Lysaght
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Despite a general recognition that treatment of end-stage renal disease (ESRD) has become a large-scale undertaking, the size of the treated population and the associated costs are not well quantified. This report combines data available from a variety of sources and places the current (midyear 2001) estimated global maintenance dialysis population at just over 1.1 million patients. The size of this population has been expanding at a rate of 7% per year. Total therapy cost per patient per year in the United States is approximately $66,000. Assuming that this figure is a reasonable global average, the annual worldwide cost of maintenance ESRD therapy in the year 2001, excluding renal transplantation, will be between $70 and $75 billion US dollars. If current trends in ESRD prevalence continue, as seems probable, the ESRD population will exceed 2 million patients by the year 2010. The care of this group represents a major societal commitment: the aggregate cost of treating ESRD during the coming decade will exceed $1 trillion, a thought-provoking sum by any economic metric.
Toward interoperable bioscience data
Authors: Susanna-Assunta Sansone, Philippe Rocca-Serra, Dawn Field, Eamonn Maguire, Chris Taylor, Oliver Hofmann, Hong Fang, Steffen Neumann, Weida Tong, Linda Amaral-Zettler, Kimberly Begley, Tim Booth, Lydie Bougueleret, Gully Burns, Brad Chapman, Tim Clark, Lee-Ann Coleman, Jay Copeland, Sudeshna Das, Antoine de Daruvar, Paula de Matos, Ian Dix, Scott Edmunds, Chris T Evelo, Mark J Forster, Pascale Gaudet, Jack Gilbert, Carole Goble, Julian L Griffin, Daniel Jacob, Jos Kleinjans, Lee Harland, Kenneth Haug, Henning Hermjakob, Shannan J Ho Sui, Alain Laederach, Shaoguang Liang, Stephen Marshall, Annette McGrath, Emily Merrill, Dorothy Reilly, Magali Roux, Caroline E Shamu, Catherine A Shang, Christoph Steinbeck, Anne Trefethen, Bryn Williams-Jones, Katherine Wolstencroft, Ioannis Xenarios, Winston Hide
Journal: Nature Genetics (2012)

To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.
Abstract 3310: Human Peripheral Blood-derived CD31 <sup>+</sup> Cells Have Robust Angio-vasculogenic Properties And Enhance Recovery Following Hindlimb Ischemia
Authors: Sung-Whan Kim, Hyun-Jai Cho, Ji Yoon Lee, Yong Jin Choi, Young-sup Yoon
Journal: Circulation (2007)

Background: Recently, we reported that murine bone marrow derived CD31 + cells have hemangioblastic activities. In this study, we hypothesized that human peripheral blood derived CD31 + cells (hCD31 + ) have robust angio-vasculogenic potential and can induce therapeutic neovascularization in hindlimb ischemia. Methods and Results: hCD31 + cells were isolated using a magnetic bead separation technique. By FACS analysis, we confirmed that more than 98% of hCD31 + cells are positive for CD45, suggesting that hCD31 + cells are not circulating endothelial cells. In endothelial progenitor cell (EPC) culture assay, hCD31 + cells almost exclusively gave rise to EPCs and produced significantly higher colony forming activity than hCD31 - cells (n=5, each) (25.2 ± 2.2 vs. 3.6 ± 0.5/mm 2 , P&lt;0.01). In the matrigel tube formation assay, coculturing HUVEC with hCD31 + cells revealed that hCD31 + cells robustly contributed to network formation with HUVECs suggestive of angio-vasculogenic activity. Real-time PCR showed that hCD31 + cells express higher levels of angiogenic genes (fold increase: angiopoietin-1, 5.6 ± 0.8; HGF, 2.7 ± 0.6; VEGF-A, 3.8 ± 0.5; FGF-2, 2.0 ± 0.5) and lower levels of inflammatory genes (fold decrease: Interferonγ, 13.2 ± 2.5; TNFα, 2.3 ± 0.9) than hCD31 − cells. To investigate therapeutic potential, we surgically induced hindlimb ischemia in athymic nude mice, and injected hCD31 + cells, hCD31 − cells and PBS into the ischemic limbs (n=9, each). The hCD31 + treated group showed a higher limb salvage rate than other groups [total salvage/tip necrosis/amputation; hCD31 + cells 5/4/0, hCD31 − cells 2/5/2, PBS control 0/5/4] (P&lt;0.01). At 14 days, perfusion ratio and capillary density were significantly higher in the hCD31 + treated group compared to the hCD31 − and PBS treated groups. Histologic analysis demonstrated that a fraction of injected DiI-labeled hCD31 + cells exhibit endothelial phenotypes during the follow-up period of 8 weeks. Conclusion: The present study demonstrated that hCD31 + cells have robust angio-vasculogenic potential with low inflammatory activity, and enhanced post-ischemia recovery. These data suggested that hCD31 + cell transplantation may represent a novel therapeutic option for treating ischemic cardiovascular diseases.