tbuckley/cabot-search huggingface dataset:
Subclass-Specific Nuclear Localization of a Novel Cd4 Silencer Binding Factor
Authors: William W.S. Kim, Gerald Siu
Journal: The Journal of Experimental Medicine (1999)

The control of CD4 expression is essential for proper T lymphocyte development. We have previously described a cis-acting silencer element required for repressing transcription of the CD4 gene. Here we report the cloning and characterization of a novel factor that binds to a critical functional site in the CD4 silencer. This factor, referred to as silencer-associated factor (SAF), is a member of the helix-turn-helix factor family and shares sequence similarity with the homeodomain class of transcriptional regulators. Introduction of a specific mutation into the SAF binding site in the CD4 silencer abrogates silencer activity in transgenic mice, supporting the hypothesis that SAF is important in mediating silencer function. Although SAF is expressed in all lymphocytes, immunofluorescence studies indicate that SAF is present primarily in the cytoplasm in T cells in which the endogenous silencer is nonfunctional, whereas it is present primarily in the nucleus in T cells in which the silencer is functional. We thus hypothesize that the subclass-specific subcellular compartmentalization of SAF plays an important role in mediating the specificity of function of the CD4 silencer during T cell development.
Comment on “Multidimensional Results Reporting to Participants in Genomic Studies: Getting It Right”
Authors: Ebony B. Bookman, Aleisha A. Langehorne, John H. Eckfeldt, Kathleen C. Glass, Gail P. Jarvik, Michael Klag, Greg Koski, Arno Motulsky, Benjamin Wilfond, Teri A. Manolio, Richard R. Fabsitz, Russell V. Luepker
Journal: Science Translational Medicine (2011)

The Commentary by Kohane and Taylor published on 23 June 2010, mistakenly indicates that the NHLBI Working Group advocated that researchers keep genetic information from research subjects if an intervention is not available for the disease.
Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting
Authors: Vasileios Karantalis, Darcy L. DiFede, Gary Gerstenblith, Si Pham, James Symes, Juan Pablo Zambrano, Joel Fishman, Pradip Pattany, Ian McNiece, John Conte, Steven Schulman, Katherine Wu, Ashish Shah, Elayne Breton, Janice Davis-Sproul, Richard Schwarz, Gary Feigenbaum, Muzammil Mushtaq, Viky Y. Suncion, Albert C. Lardo, Ivan Borrello, Adam Mendizabal, Tomer Z. Karas, John Byrnes, Maureen Lowery, Alan W. Heldman, Joshua M. Hare
Journal: Circulation Research (2014)

Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 ± 1.7%, P=0.0002) and decreased scar mass (-47.5 ± 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 ± 0.07), whereas revascularized (0.5 ± 0.21) and nontreated segments (-0.07 ± 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.
Differential Contributions of STAT5A and STAT5B to Stress Protection and Tyrosine Kinase Inhibitor Resistance of Chronic Myeloid Leukemia Stem/Progenitor Cells
Authors: Luana Casetti, Séverine Martin-Lannerée, Imen Najjar, Isabelle Plo, Sylvie Augé, Lydia Roy, Jean-Claude Chomel, Evelyne Lauret, Ali G. Turhan, Isabelle Dusanter-Fourt
Journal: Cancer Research (2013)

STAT5 fulfills essential roles in hematopoietic stem cell (HSC) self-renewal and chronic myeloid leukemia (CML), a prototypical stem cell malignancy. However, the specific contributions of the two related genes STAT5A and STAT5B have not been determined. In this study, we used a RNAi-based strategy to establish participation of these genes to CML disease and persistence following targeted therapy. We showed that STAT5A/STAT5B double-knockdown triggers CML cell apoptosis and suppresses both normal and CML HSC long-term clonogenic potential. STAT5A and STAT5B exhibited similar prosurvival activity, but STAT5A attenuation alone was ineffective at impairing growth of normal and CML CD34(+) cells isolated at diagnosis. In contrast, STAT5A attenuation was sufficient to enhance basal oxidative stress and DNA damage of normal CD34(+) and CML cells. Furthermore, it weakened the ability to manage exogenous oxidative stress, increased p53 (TRP53)/CHK-2 (CHEK2) stress pathway activation, and enhanced prolyl hydroxylase domain (PHD)-3 (EGLN3) mRNA expression. Only STAT5A and its transactivation domain-deficient mutant STAT5AΔ749 specifically rescued these activities. STAT5A attenuation was also active at inhibiting growth of CML CD34(+) cells from patients with acquired resistance to imatinib. Our findings show that STAT5A has a selective role in contributing to stress resistance through unconventional mechanisms, offering new opportunities to eradicate the most primitive and tyrosine kinase inhibitor-resistant CML cells with an additional potential to eradicate persistent stem cell populations.
Large variation between hospitals and pathology laboratories in lymph node evaluation in colon cancer and its impact on survival, a nationwide population-based study in The Netherlands
Authors: M.A.G. Elferink, S. Siesling, O. Visser, H.J. Rutten, J.H.J.M. van Krieken, R.A.E.M. Tollenaar, V.E.P.P. Lemmens
Journal: Annals of Oncology (2010)
Negative life events and quality of life in adults with asthma
Authors: C Archea, I H Yen, H Chen, M D Eisner, P P Katz, U Masharani, E H Yelin, G Earnest, P D Blanc
Journal: Thorax (2006)

Background: The relationship between stress and quality of life in adults with asthma has not been well studied. Stress, quantified by negative life events, may be linked to quality of life in asthma through multiple pathways, including increase in disease severity and adverse effects on socioeconomic status (SES). Methods: The responses to a self-completed questionnaire assessing negative life events (NLEs) in the previous 12 months (from a 24-item checklist) among 189 adults with asthma from a well-characterised cohort were analysed. The relationship between the number of NLEs reported and asthma-specific quality of life (AQOL) was measured with the Marks instrument. General linear modelling was used to test the conjoint effects of NLEs, SES and disease severity based on the Severity of Asthma Score, a validated acute and chronic disease measure. Results: Those with annual family incomes <$60 000 reported significantly more NLEs than those with higher incomes (p = 0.03). The number of NLEs did not differ significantly between those with forced expiratory volume in 1 s <80% predicted and those with >80% predicted, nor among those with lower compared with higher Severity of Asthma Score. The frequency of NLEs was associated with poorer (higher numerical score) AQOL (p = 0.002). When studied together in the same model, combinations of income level and asthma severity (greater or lesser Severity of Asthma Score; p<0.001) and number of NLEs (p = 0.03) were both significantly associated with AQOL. Conclusion: NLEs are associated with quality of life among adults with asthma, especially among those of lower SES. Clinicians should be aware of this relationship, especially in vulnerable patient subsets.
Multifaceted end points in brain tumor clinical trials: Cognitive deterioration precedes MRI progression
Authors: Christina A. Meyers, Kenneth R. Hess
Journal: Neuro-Oncology (2003)

Current treatments for brain cancer have, for the most part, equivocal survival benefit. However, clinical trials of new anticancer agents do not adequately assess potential clinical benefits for patient function other than survival and time to tumor progression. We evaluated 56 patients with recurrent brain tumors who were recruited on phase 1 and phase 2 clinical trials and given assessments of cognitive function, quality of life (QOL), and ability to perform activities of daily living (ADL) prior to receiving treatment and at intervals coinciding with MRI scans, generally monthly. Meaningful change on the cognitive and functional assessments was determined by the reliable change index. Cognitive or functional deterioration was then used as a time-dependent covariate in a Cox proportional hazards regression model with tumor progression, as defined by standard criteria, as the end point. Cognitive deterioration occurred 6 weeks prior to radiographic failure (median 7.4 weeks vs. 13.4 weeks). In contrast, median time for QOL to deteriorate was not achieved. Median time for instrumental ADL to decline was 43 weeks, long after tumor progression. For patients with brain cancer, brain function began to worsen before MRI evidence of tumor progression. QOL and ADL function were not strongly tied to cognitive decline or to time to tumor progression, suggesting that these measures may not be sufficiently sensitive to change in clinical trials of new anticancer agents, although they are important measures in terms of patient care. This study also demonstrates the feasibility of performing neurocognitive testing in this patient population. New drugs that slow the cognitive decline of brain tumor patients may be of clinical benefit regardless of the impact on overall survival.
THE COW AS A MODEL TO STUDY FOOD INTAKE REGULATION
Authors: Michael S. Allen, Barry J. Bradford, Kevin J. Harvatine
Journal: Annual Review of Nutrition (2005)

Animal models have been invaluable for studying aspects of food intake regulation that for various reasons cannot be observed in humans. The dairy cow is a unique animal model because of an unrivaled energy requirement; its great drive to eat results in feeding behavior responses to treatments within the physiological range. Cows' docile nature and large size make them ideal for measuring temporal treatment effects because digestion and absorption kinetics and responses in endocrine systems, gene expression, metabolite pools and fluxes, and feeding behavior can be measured simultaneously. Thus, cows are important models to investigate interactions of short-term signals regulating food intake. Furthermore, different physiological states throughout the lactation cycle provide powerful models to study how short- and long-term signals interact to affect long-term energy status. The use of the cow as a model can lead to breakthroughs in understanding the complex interactions of signals regulating food intake.
Self H-2 antigens influence the specificity of alloreactive cells.
Authors: T Hünig, M J Bevan
Journal: The Journal of Experimental Medicine (1980)

We have tested Jerne's hypothesis (9) that the phenomenon alloreactivity is explained by the existence of T cells that express germline-encoded receptors specific for major histocompatibility complex antigens and that these cells undergo no change in specificity during thymic differentiation. T cells from [F1 leads to Parent] bone marrow radiation chimeras reactive to conventional antigens are known to have a self preference, i.e., [A X B leads to A] chimeras respond better to H-2A-plus-antigen than to H-2B-plus-antigen. We show here that alloreactive cells from such chimeras also have a self preference. Thus, H-2k-specific alloreactive T cells from [H-2b X H-2d leads to H-2b] and [H-2b X H-2d leads to H-2d] chimeras cross-react more on TNP-modified H-2b or H-2d targets, respectively. In contrast to Jerne's prediction, the results suggest that the receptor repertoire of alloreactive F1 cells is influenced by H-2 antigens on radiation-resistant cells present during T cell ontogeny. By this criterion of having a self preference in H-2 restriction, alloreactive T cells appear to be similar to T cells that respond to conventional antigens.
On the origin of genomes and cells within inorganic compartments
Authors: Eugene V. Koonin, William Martin
Journal: Trends in Genetics (2005)

Building on the model of Russell and Hall for the emergence of life at a warm submarine hydrothermal vent, we suggest that, within a hydrothermally formed system of contiguous iron-sulfide (FeS) compartments, populations of virus-like RNA molecules, which eventually encoded one or a few proteins each, became the agents of both variation and selection. The initial darwinian selection was for molecular self-replication. Combinatorial sorting of genetic elements among compartments would have resulted in preferred proliferation and selection of increasingly complex molecular ensembles--those compartment contents that achieved replication advantages. The last universal common ancestor (LUCA) we propose was not free-living but an inorganically housed assemblage of expressed and replicable genetic elements. The evolution of the enzymatic systems for (i) DNA replication; and (ii) membrane and cell wall biosynthesis, enabled independent escape of the first archaebacterial and eubacterial cells from their hydrothermal hatchery, within which the LUCA itself remained confined.
Inhibition of T1/St2 during Respiratory Syncytial Virus Infection Prevents T Helper Cell Type 2 (Th2)- but Not Th1-Driven Immunopathology
Authors: Gerhard Walzl, Stephen Matthews, Sharon Kendall, Jose Carlos Gutierrez-Ramos, Anthony J. Coyle, Peter J.M. Openshaw, Tracy Hussell
Journal: The Journal of Experimental Medicine (2001)

T cells secreting interleukin (IL)-4 and IL-5 (T helper cell type 2 [Th2] cells) play a detrimental role in a variety of diseases, but specific methods of regulating their activity remain elusive. T1/ST2 is a surface ligand of the IL-1 receptor family, expressed on Th2- but not on interferon (IFN)-γ–producing Th1 cells. Prior exposure of BALB/c mice to the attachment (G) or fusion (F) protein of respiratory syncytial virus (RSV) increases illness severity during intranasal RSV challenge, due to Th2-driven lung eosinophilia and exuberant Th1-driven pulmonary infiltration, respectively. We used these polar models of viral illness to study the recruitment of T1/ST2 cells to the lung and to test the effects of anti-T1/ST2 treatment in vivo. T1/ST2 was present on a subset of CD4+ cells from mice with eosinophilic lung disease. Monoclonal anti-T1/ST2 treatment reduced lung inflammation and the severity of illness in mice with Th2 (but not Th1) immunopathology. These results show that inhibition of T1/ST2 has a specific effect on virally induced Th2 responses and suggests that therapy targeted at this receptor might be of value in treating Th2-driven illness.
Comparison of Outcomes of Synthetic Mesh vs Suture Repair of Elective Primary Ventral Herniorrhaphy
Authors: Mylan T. Nguyen, Rachel L. Berger, Stephanie C. Hicks, Jessica A. Davila, Linda T. Li, Lillian S. Kao, Mike K. Liang
Journal: JAMA Surgery (2014)

More than 350,000 ventral hernias are repaired in the United States annually, of which 75% are primary ventral hernias (eg, umbilical or epigastric hernias). Despite the volume, there is insufficient evidence to support the use of sutures vs mesh for primary ventral hernia repairs.To compare suture vs mesh repairs for 3 outcomes: hernia recurrence, surgical site infection (SSI), and seromas.Randomized controlled trials, case-control, and cohort studies were identified from OVID, PubMed, and reference lists from January 1, 1980, through June 1, 2012.English-language studies with adult patients were eligible for review if there was mention of both suture and mesh techniques used during elective repair of a primary ventral hernia. Two study authors independently reviewed the 1492 articles originally identified and selected 9 for analysis. The Downs and Black 26-item checklist was used to critically assess the risk of bias.Year of publication, study design, inclusion and exclusion criteria, number of patients, follow-up duration, use of preoperative antibiotics, size of hernias repaired, age, body mass index (calculated as weight in kilograms divided by height in meters squared), American Society of Anesthesiologists grade, repair techniques, incidence of hernia recurrence, seroma, and SSI.Three separate univariate meta-analyses for each end point followed by a multivariate meta-analysis were performed. Across all 9 studies, there were 637 mesh repairs and 1145 suture repairs. The pooled mesh repairs demonstrated a 2.7% recurrence rate, 7.7% seroma rate, and 7.3% SSI rate The pooled suture repairs demonstrated an 8.2% recurrence rate, 3.8% seroma rate, and 6.6% SSI rate. On the basis of results from the multivariate meta-analysis, recurrences (log odds ratio , −1.04; 95% CI, −1.58 to −0.52) were more common with suture repair, whereas seromas (0.84; 0.27-1.41) and SSIs (0.65; 0.12-1.18) were more common with mesh repair.Mesh repair has a small reduction in recurrence rates compared with suture repairs for primary ventral hernias, but an increased risk of seroma and SSI was observed. Further high-quality studies are necessary to determine whether suture or mesh repair leads to improved outcomes for primary ventral hernias.
Enzyme deficiency in cholesteryl ester storage disease
Authors: Howard R. Sloan, Donald S. Fredrickson
Journal: Journal of Clinical Investigation (1972)

Cholesteryl ester storage disease has been shown to involve severe deficiency of acid cholesteryl ester hydrolase and triglyceride lipase activity in liver, spleen, and lymph node. The cholesteryl ester hydrolase was also deficient in aorta. Tissue storage of both cholesteryl esters and triglycerides is generalized. Both the lipid and enzymatic changes are very similar to those in Wolman's disease.
DERMATOMYOSITIS PRESENTING AS APLASTIC ANAEMIA.
Authors: P. R. DUNCAN, P. W. HARVEY, R. H. SEVILLE
Journal: British Journal of Dermatology (1959)

Journal Article DERMATOMYOSITIS PRESENTING AS APLASTIC ANAEMIA. Get access P. R. DUNCAN, M.D., M.R.C.P., P. R. DUNCAN, M.D., M.R.C.P. Consultant Physician, The Victoria Hospital, Blackpool Search for other works by this author on: Oxford Academic Google Scholar P. W. HARVEY, M.B., Ch. B., D. Path., P. W. HARVEY, M.B., Ch. B., D. Path. Consultant Pathologist, The Victoria Hospital, Blackpool Search for other works by this author on: Oxford Academic Google Scholar R. H. SEVILLE, M.D., M R.C.P. R. H. SEVILLE, M.D., M R.C.P. Consultant Dermatologist, The Victoria Hospital, Blackpool Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 71, Issue 10, 1 October 1959, Pages 344–346, https://doi.org/10.1111/j.1365-2133.1959.tb13360.x Published: 01 October 1959
Adverse effects of salmeterol in asthma: a neuronal perspective
Authors: M Lommatzsch, Y Lindner, A Edner, K Bratke, M Kuepper, J C Virchow
Journal: Thorax (2009)

<h3>Background:</h3> Regular use of inhaled β<sub>2</sub>-agonists has been associated with a paradoxical loss of asthma control and a deterioration of airway hyper-responsiveness, but the underlying mechanism is unknown. The neurotrophin brain-derived neurotrophic factor (BDNF) has recently been identified as a mediator of airway hyper-responsiveness in asthma. <h3>Methods:</h3> Eighteen patients with mild allergic asthma who did not use any regular antiasthmatic therapy inhaled the long-acting β<sub>2</sub>-agonist salmeterol for 2 weeks followed by 2 weeks of combination therapy with salmeterol and the corticosteroid fluticasone. Airway responsiveness to histamine and BDNF concentrations in blood were assessed prior to entry, after 14 days of salmeterol therapy and after 14 days of combination therapy. In a separate experiment, salmeterol effects on BDNF release by human peripheral blood mononuclear cells were assessed. <h3>Results:</h3> Monotherapy with salmeterol significantly increased BDNF concentrations in serum and platelets. This increase was abolished by the addition of fluticasone to the treatment. The findings were confirmed in vitro: salmeterol increased the release of BDNF by mononuclear cells, and this was inhibited by co-incubation with fluticasone. Increased BDNF concentrations in serum and platelets correlated with the deterioration of airway hyper-responsiveness following salmeterol monotherapy. In contrast, there was no association between β<sub>2</sub>-receptor polymorphisms and changes in airway responsiveness. <h3>Conclusion:</h3> Increased BDNF concentrations may underly the adverse effects of salmeterol monotherapy on airway responsiveness in asthma. <h3>Trial registration number:</h3> NCT00736801.
European and North American populations should be screened for coeliac disease
Authors: A Fasano
Journal: Gut (2003)

Coeliac disease (CD) is an immune mediated enteropathy triggered by ingestion of gluten containing grains in genetically susceptible individuals.1 CD is associated with HLA alleles DQ2 and/or DQ8, and in the continued presence of gluten the disease is self perpetuating.1,2 To sustain the position that active screening in search of CD cases is a justified policy, we will review the WHO guidelines for disease mass screening recommendations to establish whether CD satisfies these criteria.3



1.  Early detection of the disease could be difficult on a clinical basis.

2.  The disease must be a common disorder causing significant morbidity in the general population.

3.  The screening tests must be highly sensitive and specific for the target disease.

4.  A treatment for the disease must be available.

5.  If not recognised, the disease could result in severe complications difficult to manage.



CD can manifest with a previously unsuspected range of clinical presentations, including the typical malabsorption syndrome (chronic diarrhoea, weight loss, abdominal distension) and a spectrum of symptoms …