tbuckley/cabot-search huggingface dataset:
Metabolic Syndrome Model Definitions Predicting Type 2 Diabetes and Cardiovascular Disease
Authors: Cécile M. Povel, Joline W. Beulens, Yvonne T. van der Schouw, Martijn E.T. Dollé, Annemieke M.W. Spijkerman, W.M. Monique Verschuren, Edith J.M. Feskens, Jolanda M.A. Boer
Journal: Diabetes Care (2012)

Metabolic syndrome (MetS) is a cluster of abdominal obesity, hyperglycemia, hypertension, and dyslipidemia, which increases the risk for type 2 diabetes and cardiovascular diseases (CVDs). Some argue that MetS is not a single disorder because the traditional MetS features do not represent one entity, and they would like to exclude features from MetS. Others would like to add additional features in order to increase predictive ability of MetS. The aim of this study was to identify a MetS model that optimally predicts type 2 diabetes and CVD while still representing a single entity.In a random sample (n = 1,928) of the EPIC-NL cohort and a subset of the EPIC-NL MORGEN study (n = 1,333), we tested the model fit of several one-factor MetS models using confirmatory factor analysis. We compared predictive ability for type 2 diabetes and CVD of these models within the EPIC-NL case-cohort study of 545 incident type 2 diabetic subjects, 1,312 incident CVD case subjects, and the random sample, using survival analyses and reclassification.The standard model, representing the current MetS definition (EPIC-NL comparative fit index [CFI] = 0.95; MORGEN CFI = 0.98); the standard model excluding blood pressure (EPIC-NL CFI = 0.95; MORGEN CFI = 1.00); and the standard model extended with hsCRP (EPIC-NL CFI = 0.95) had an acceptable model fit. The model extended with hsCRP predicted type 2 diabetes (integral discrimination index [IDI]: 0.34) and CVD (IDI: 0.07) slightly better than did the standard model.It seems valid to represent the traditional MetS features by a single entity. Extension of this entity with hsCRP slightly improves predictive ability for type 2 diabetes and CVD.
Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer
Authors: J. A. D. Simpson, A. Al-Attar, N. F. S. Watson, J. H. Scholefield, M. Ilyas, L. G. Durrant
Journal: Gut (2010)

<h3>Objective</h3> To evaluate immunosurveillance/editing in colorectal cancer. <h3>Design</h3> Transformation stimulates the production of interferon γ (IFNγ) which signals via the IFNγ receptor (IFNGR1) on tumours. This results in stimulation of nuclear STAT1 (nSTAT1), inhibition of tumour growth and upregulation of major histocompatibility complex (MHC) while promoting T cell extravasation. In contrast, downregulation of MHC class I by allele loss results in loss of T cell recognition. A tissue microarray of 462 colorectal tumours with mean follow-up of 42 months (range 1–116) was stained by immunohistochemistry for markers which predict immunosurveillance/editing. <h3>Results</h3> The presence of a high level of intratumoral T cells (ITTC) correlated with improved survival compared with a low level of ITTC, with a mean difference in survival of 16.3 months (p=0.006). There was a direct correlation between nSTAT1 expression and ITTC (p&lt;0.001). Patients whose tumours had a high level of ITTC and nSTAT1 survived 20 months longer than those whose tumours had a low level of ITTC and no nSTAT1. A strong correlation was seen between ITTC and MHC class I expression (p=0.0002). A mean survival advantage of 26.1 months was seen in patients whose tumours had strong MHC I expression and high levels of ITTC over those who had weak MHC I and low levels of ITTC (log-rank test=12.023, p=0.034). Both MHC I and ITTC are independent predictors of good survival. <h3>Conclusions</h3> ITTC, nSTAT1 and strong MHC class I expression on tumours identify patients with improved survival and an intact tumour immune system that may benefit from immunotherapy. Conversely, loss of these markers identifies patients whose tumours have escaped immunosurveillance and are unlikely to benefit from immunotherapy.
Cost-Effectiveness of the Children's Oncology Group Long-Term Follow-up Screening Guidelines for Childhood Cancer Survivors at Risk for Treatment-Related Heart Failure
Authors: F. Lennie Wong, Smita Bhatia, Wendy Landier, Liton Francisco, Wendy Leisenring, Melissa M. Hudson, Gregory T. Armstrong, Ann Mertens, Marilyn Stovall, Leslie L. Robison, Gary H. Lyman, Steven E. Lipshultz, Saro H. Armenian
Journal: Annals of Internal Medicine (2014)

Background: Childhood cancer survivors treated with anthracyclines are at high risk for asymptomatic left ventricular dysfunction (ALVD), subsequent heart failure, and death. The consensus-based Children's Oncology Group (COG) Long-Term Follow-up Guidelines recommend lifetime echocardiographic screening for ALVD. Objective: To evaluate the efficacy and cost-effectiveness of the COG guidelines and to identify more cost-effective screening strategies. Design: Simulation of life histories using Markov health states. Data Sources: Childhood Cancer Survivor Study; published literature. Target Population: Childhood cancer survivors. Time Horizon: Lifetime. Perspective: Societal. Intervention: Echocardiographic screening followed by angiotensin-converting enzyme (ACE) inhibitor and β-blocker therapies after ALVD diagnosis. Outcome Measures: Quality-adjusted life-years (QALYs), costs, incremental cost-effectiveness ratios (ICERs) in dollars per QALY, and cumulative incidence of heart failure. Results of Base-Case Analysis: The COG guidelines versus no screening have an ICER of $61 500, extend life expectancy by 6 months and QALYs by 1.6 months, and reduce the cumulative incidence of heart failure by 18% at 30 years after cancer diagnosis. However, less frequent screenings are more cost-effective than the guidelines and maintain 80% of the health benefits. Results of Sensitivity Analysis: The ICER was most sensitive to the magnitude of ALVD treatment efficacy; higher treatment efficacy resulted in lower ICER. Limitation: Lifetime non–heart failure mortality and the cumulative incidence of heart failure more than 20 years after diagnosis were extrapolated; the efficacy of ACE inhibitor and β-blocker therapy in childhood cancer survivors with ALVD is undetermined (or unknown). Conclusion: The COG guidelines could reduce the risk for heart failure in survivors at less than $100 000/QALY. Less frequent screening achieves most of the benefits and would be more cost-effective than the COG guidelines. Primary Funding Source: Lance Armstrong Foundation and National Cancer Institute.
Inhibitory Cardiac Transcription Factor, SRF-N, Is Generated by Caspase 3 Cleavage in Human Heart Failure and Attenuated by Ventricular Unloading
Authors: Jiang Chang, Lei Wei, Takayuki Otani, Keith A. Youker, Mark L. Entman, Robert J. Schwartz
Journal: Circulation (2003)

Knowledge about molecular mechanisms leading to heart failure is still limited, but reduced gene activities and modest activation of caspase 3 are hallmarks of end-stage heart failure. We postulated that serum response factor (SRF), a central cardiac transcription factor, might be a cleavage target for modest activated caspase 3, and this cleavage of SRF may play a dominant inhibitory role in propelling hearts toward failure.We examined SRF protein levels from cardiac samples taken at the time of transplantation in 13 patients with end-stage heart failure and 7 normal hearts. Full-length SRF was markedly reduced and processed into 55- and 32-kDa subfragments in all failing hearts. SRF was intact in normal samples. In contrast, the hearts of 10 patients with left ventricular assist devices showed minimal SRF fragmentation. Specific antibodies to N- and C-terminal SRF sequences and site-directed mutagenesis revealed 2 alternative caspase 3 cleavage sites, so that 2 fragments were detected of each containing either the N- or C-terminal SRF. Expression of SRF-N, the 32-kDa fragment, in myogenic cells inhibited the transcriptional activity of alpha-actin gene promoters by 50% to 60%, which suggests that truncated SRF functioned as a dominant-negative transcription factor.Caspase 3 activation in heart failure sequentially cleaved SRF and generated a dominant-negative transcription factor, which may explain the depression of cardiac-specific genes. Moreover, caspase 3 activation may be reversible in the failing heart with ventricular unloading.
Atopic Allergy: A Failure of Antigen-Presenting Cells to Properly Polarize Helper T Cells?
Authors: MARTIEN L. KAPSENBERG, CATHARIEN M. U. HILKENS, TINEKE C. M. T. van der POUW KRAAN, EDDY A. WIERENGA, PAWEL KALINSKI
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The immunological hallmark of adult atopic allergy is an aberrant production of helper T cell type 2 (Th2) cytokines interleukin 4 (IL-4), IL-5, IL-9, and IL-13 by Th cells reacting to common environmental antigens (1, 2). Mouse model experiments suggest strongly that airway hyperreactivity depends on IL-13 (3) and airway inflammation depends on IL-5 (4). In fact, the bias to type 2 cytokine production in atopic allergy is generalized (5), and an important issue is why these cells have developed in atopic allergic individuals. Th2 cells are effector Th cells that develop from naive Th cells after activation in the presence of certain polarizing signals. A first activation signal (signal 1) is the recognition by the T cell receptor of antigenderived peptides presented in association with MHC molecules expressed by antigen-presenting cells (APCs). An obligatory second signal (signal 2) for these primary T cells is costimulation through the ligation of CD28 by B7.1 or B7.2, expressed by APCs as well. Primary Th cells do produce low levels of Th1 (e.g., interferon g [IFNg ], tumor necrosis factor b [TNFb ]) and Th2 cytokines, but these cytokines will be produced after one or more cell cycles and the concomitant maturation into effector Th cells. Polarization into either Th1 or Th2 cytokine production can be induced by various soluble or membrane-bound molecules, constituting a set of polarizing activities, acting as a third signal (signal 3) during the initial activation of naive Th cells. The process of polarization can occur early, since already within a few days after the initiation of the immune response lymph nodes contain polarized T cells (6). Here we discuss the perspective that the aberrant Th2 cell development in atopic allergy follows from a failure in the Th cell polarization by APCs.
FMN-Coated Fluorescent USPIO for Cell Labeling and Non-Invasive MR Imaging in Tissue Engineering
Authors: Marianne E. Mertens, Julia Frese, Deniz Ali Bölükbas, Ladislav Hrdlicka, Susanne Golombek, Sabine Koch, Petra Mela, Stefan Jockenhövel, Fabian Kiessling, Twan Lammers
Journal: Theranostics (2014)

Non-invasive magnetic resonance imaging (MRI) is gaining significant attention in the field of tissue engineering, since it can provide valuable information on in vitro production parameters and in vivo performance. It can e.g. be used to monitor the morphology, location and function of the regenerated tissue, the integrity, remodeling and resorption of the scaffold, and the fate of the implanted cells. Since cells are not visible using conventional MR techniques, ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are routinely employed to label and monitor the cells embedded in tissue-engineered implants. We here set out to optimize cell labeling procedures with regard to labeling efficiency, biocompatibility and in vitro validation during bioreactor cultivation, using flavin mononucleotide (FMN)-coated fluorescent USPIO (FLUSPIO). Efficient FLUSPIO uptake is demonstrated in three different cell lines, applying relatively short incubation times and low labeling concentrations. FLUSPIO-labeled cells were successfully employed to visualize collagen scaffolds and tissue-engineered vascular grafts. Besides promoting safe and efficient cell uptake, an exquisite property of the non-polymeric FMN-coating is that it renders the USPIO fluorescent, providing a means for in vitro, in vivo and ex vivo validation via fluorescence microscopy and fluorescence reflectance imaging (FRI). FLUSPIO cell labeling is consequently considered to be a suitable tool for theranostic tissue engineering purposes.
The Association Between Diabetes Metabolic Control and Drug Adherence in an Indigent Population
Authors: Joel M. Schectman, Mohan M. Nadkarni, John D. Voss
Journal: Diabetes Care (2002)

OBJECTIVE—Studies of the association between diabetes metabolic control and adherence to drug therapy have yielded conflicting results. Because low socioeconomic and minority populations have poorer diabetes outcomes and greater barriers to adherence, we examined the relationship between adherence and diabetes metabolic control in a large indigent population. RESEARCH DESIGN AND METHODS—The study population consisted of patients receiving medical care from a university-based internal medicine clinic serving a low-income population in rural central Virginia. The sample comprised 810 patients with type 2 diabetes who received oral diabetes medications from the clinic pharmacy and had at least one HbA1c determination during the study period. Multiple linear regression was used to examine the association of HbA1c level as well as change in HbA1c level with medication adherence, demographic, and clinical characteristics. RESULTS—Better metabolic control was independently associated with greater medication adherence, increasing age, white (versus African-American) race, and lower intensity of drug therapy. For each 10% increment in drug adherence, HbA1c decreased by 0.16% (P &amp;lt; 0.0001). Controlling for other demographic and clinical variables, the mean HbA1c of African-Americans was 0.29% higher than that of whites (P = 0.04). Additionally, the intensity of diabetes drug therapy for African-Americans was lower, as was their measured adherence to it. There was no association between metabolic control and gender, income, encounter frequency, frequency of HbA1c testing, or continuity of care. CONCLUSIONS—Adherence to medication regimens for type 2 diabetes is strongly associated with metabolic control in an indigent population; African-Americans have lower adherence and worse metabolic control. Greater efforts are clearly needed to facilitate diabetes self-management behaviors of low-income populations and foster culturally sensitive and appropriate care for minority groups.
Peptide-independent Recognition by Alloreactive Cytotoxic T Lymphocytes (CTL)
Authors: Pamela A. Smith, Anders Brunmark, Michael R. Jackson, Terry A. Potter
Journal: The Journal of Experimental Medicine (1997)

We have isolated several H-2Kb–alloreactive cytotoxic T cell clones and analyzed their reactivity for several forms of H-2Kb. These cytotoxic T lymphocytes (CTL) were elicited by priming with a skin graft followed by in vitro stimulation using stimulator cells that express an H-2Kb molecule unable to bind CD8. In contrast to most alloreactive T cells, these CTL were able to recognize H-2Kb on the surface of the antigen processing defective cell lines RMA-S and T2. Furthermore, this reactivity was not increased by the addition of an extract containing peptides from C57BL/6 (H-2b) spleen cells, nor was the reactivity decreased by treating the target cells with acid to remove peptides bound to MHC molecules. The CTL were also capable of recognizing targets expressing the mutant H-2Kbm8 molecule. These findings suggested that the clones recognized determinants on H-2Kb that were independent of peptide. Further evidence for this hypothesis was provided by experiments in which H-2Kb produced in Drosophila melanogaster cells and immobilized on the surface of a tissue culture plate was able to stimulate hybridomas derived from these alloreactive T cells. Precursor frequency analysis demonstrated that skin graft priming, whether with skin expressing the wild-type or the mutant H-2Kb molecule, is a strong stimulus to elicit peptide-independent CTL. Moreover, reconstitution experiments demonstrated that the peptide-independent CTL clones were capable of mediating rapid and complete rejection of H-2–incompatible skin grafts. These findings provide evidence that not all allorecognition is peptide dependent.
Metastasis-Associated Protein 1 Transgenic Mice: A New Model of Spontaneous B-Cell Lymphomas
Authors: Rozita Bagheri-Yarmand, Seetharaman Balasenthil, Anupama E. Gururaj, Amjad H. Talukder, Yui-Hsi Wang, Ju Han Lee, Young Sik Kim, Xinaglan Zhang, Daniel M. Jones, L. Jeffrey Medeiros, L. Clifton Stephens, Yong-Jun Liu, Norman Lee, Insun Kim, Rakesh Kumar
Journal: Cancer Research (2007)

Abstract Metastasis-associated protein 1 (MTA1), a component of the nuclear remodeling complex and the founding homologue of the MTA family, has been implicated in metastasis, but definitive causative evidence in an animal model system is currently lacking. Here, we show that MTA1 overexpression in transgenic mice is accompanied by a high incidence of spontaneous B cell lymphomas including diffuse large B cell lymphomas (DLBCL). Lymphocytes and lymphoma cells from MTA1-TG mice are hyperproliferative. Lymphomas were transplantable and of clonal origin and were characterized by down-regulation of p27Kip1 as well as up-regulation of Bcl2 and cyclin D1. The significance of these murine studies was established by evidence showing a widespread up-regulation of MTA1 in DLBCL from humans. These findings reveal a previously unrecognized role for the MTA1 pathway in the development of spontaneous B cell lymphomas, and offer a potential therapeutic target in B cell lymphomas. These observations suggest that MTA1-TG mice represent a new model of spontaneous DLBCL associated with high tumor incidence and could be used for therapeutic intervention studies. [Cancer Res 2007;67(15):7062–7]
Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure
Authors: Gopal K.R. Soppa, Joon Lee, Mark A. Stagg, Leanne E. Felkin, Paul J.R. Barton, Urszula Siedlecka, Samuel Youssef, Magdi H. Yacoub, Cesare M.N. Terracciano
Journal: Cardiovascular Research (2008)

Combined left ventricular assist device (LVAD) and pharmacological therapy has been proposed to favour myocardial recovery in patients with end-stage heart failure (HF). Clenbuterol (Clen), a β2-adrenoceptor (β2-AR) agonist, has been used as a part of this strategy. In this study, we investigated the direct effects of clenbuterol on unloaded myocardium in HF. Left coronary artery ligation or sham operation was performed in male Lewis rats. After 4–6 weeks, heterotopic abdominal transplantation of the failing hearts into normal recipients was performed to induce LV unloading (UN). Recipient rats were treated with saline (Sal) or clenbuterol (2 mg/kg/day) via osmotic minipumps (HF + UN + Sal or HF + UN + Clen) for 7 days. Non-transplanted HF animals were treated with Sal (Sham + Sal, HF + Sal) or clenbuterol (HF + Clen). LV myocytes were isolated and studied using optical, fluorescence, and electrophysiological techniques. Clenbuterol treatment improved in vivo LV function measured with echocardiography (LVEF (%): HF 35.9 ± 2 [16], HF + Clen 52.1 ± 1.4 [16]; P < 0.001; mean ± SEM [n]). In combination with unloading, clenbuterol increased sarcomere shortening (amplitude (µm): HF + UN + Clen 0.1 ± 0.01 [50], HF + UN + Sal 0.07 ± 0.01 [38]; P < 0.001) by normalizing the depressed myofilament sensitivity to Ca2+ (slope of the linear relationship between Ca2+ transient and sarcomere shortening hysteresis loop during relaxation (μm/ratio unit): HF + UN + Clen 2.13 ± 0.2 [52], HF + UN + Sal 1.42 ± 0.13 [38]; P < 0.05). Clenbuterol treatment of failing rat hearts, alone or in combination with mechanical unloading, improves LV function at the whole-heart and cellular levels by affecting cell morphology, excitation–contraction coupling, and myofilament sensitivity to calcium. This study supports the use of this drug in the strategy to enhance recovery in HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function.
Overexpressed let-7a inhibits glioma cell malignancy by directly targeting K-ras, independently of PTEN
Authors: X.-R. Wang, H. Luo, H.-L. Li, L. Cao, X.-F. Wang, W. Yan, Y.-Y. Wang, J.-X. Zhang, T. Jiang, C.-S. Kang, N. Liu, Y.-P. You
Journal: Neuro-Oncology (2013)

Altered expression of micro(mi)RNAs has been shown to be associated with tumorigenesis and tumor progression. The expression of phosphatase and tensin homolog (PTEN) plays an important role in glioma and is regarded as a prognostic marker of glioma patients. The goal of this study was to investigate the function of lethal (let)-7a miRNA in glioma cell lines with different PTEN phenotypes.One hundred ninety-eight glioma tissues were used to profile miRNA expression.Let-7a was shown to have lower expression in high-grade glioma than in low-grade glioma. Low expression of let-7a was correlated with poor prognosis of primary glioblastoma patients. We demonstrated that K-ras was a functional target for let-7a to induce cell cycle arrest, apoptosis, and inhibition of cell migration and invasion in vitro. Our further results showed no difference in malignancy inhibition induced by let-7a in 4 glioma cells, including U87 (PTEN null), U251 (PTEN mutant), LN229 (PTEN wild type), and LN229 (PTEN small interfering RNA). The phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were inhibited by let-7a, and the inhibition effects had no difference in 4 glioma cells. We demonstrated that let-7a could induce suppression of glioma in vivo by generating a glioma xenograft model.Our results indicated that let-7a suppresses its target transcript K-ras and inhibits glioma malignancy independent of PTEN expression.
Recent Advances in Public Health Systems Research in the United States
Authors: Timothy W. Van Wave,, F. Douglas Scutchfield, Peggy A. Honoré
Journal: Annual Review of Public Health (2010)

Recognizing the public's health is the outcome of dynamic, adaptive, and complex systems of agencies; infrastructure, relationships, and interactions that dictate how to improve health outcomes; and reducing health risks in a population is based on systems thinking and evidence. New methods such as network analysis and public health practice–based research networks demonstrate the potential for new insight to our understanding of how systems and infrastructure influence population health. We examine advances in public health systems research since 1988 and discuss the relevance of this type of research to public health practice. We assess the current infrastructure for conducting public health systems research, suggest how the research infrastructure can be improved, and conclude with a discussion of how health reform in the United States will require research focused on understanding the adaptive complexity inherent in public health and health care systems and strengthening the systems research infrastructure.
Susceptibility to allergic lung disease regulated by recall responses of dual-receptor memory T cells∗
Authors: Mark A. Aronica, Shadi Swaidani, Yan H. Zhang, Daphne Mitchell, Ana L. Mora, Susan McCarthy, Jamye O'Neal, David Topham, James R. Sheller, Mark Boothby
Journal: Journal of Allergy and Clinical Immunology (2004)
Tissue Clearance as a Measure of Nutritive Blood Flow and the Effect of Lumbar Sympathetic Block upon Such Measures in Calf Muscle
Authors: SAMUEL I. RAPAPORT, ALBERT SAUL, CHESTER HYMAN, M. E. MORTON
Journal: Circulation (1952)

This paper reports the effect of procedures known to alter local blood flow upon the rate of removal of locally injected Na 24 and I 131 . An evaluation of this clearance method as a measure of nutritive blood flow is made. A second purpose is to report the lack of effect upon clearance from calf muscle of lumbar sympathetic block, and to discuss its therapeutic implications.