tbuckley/cabot-search huggingface dataset:
A controlled trial of 6-weeks' treatment with a novel inhaled phosphodiesterase type-4 inhibitor in COPD
Authors: J. Vestbo, L. Tan, G. Atkinson, J. Ward
Journal: European Respiratory Journal (2009)

Anti-inflammatory drugs are lacking in chronic obstructive pulmonary disease (COPD) and inhibitors of the phosphodiesterase type-4 (PDE4) enzyme have been suggested to be an interesting class of drugs to treat inflammation in COPD. The present authors report the findings of a phase II trial of a novel inhaled PDE4 inhibitor. Three doses, 0.1, 0.4 and 1.0 mg b.i.d. , of the compound UK-500,001 were tested in a double-blind, placebo-controlled, 6-week trial in 209 patients with moderate-to-severe COPD. The primary efficacy parameter was trough forced expiratory volume in one second after 6 weeks of treatment, and secondary end-points included other lung function end-points and symptom scores assessed at 2-week intervals. The present study was stopped following a planned interim analysis for futility. No effect on the primary efficacy parameter, other measures of lung function or symptom scores was observed at any dose of UK-500,001 after 6 weeks of treatment. However, after the first 2 weeks of treatment, an improvement in a number of outcome measures in the 1.0 mg b.i.d. dose group was observed compared with placebo. The drug was well tolerated, although PDE4 inhibitor-related side-effects were observed, especially in the highest dose group. The findings of the present study question the role of inhaled phosphodiesterase type-4 inhibitors in chronic obstructive pulmonary disease.
Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women
Authors: Paul M. Ridker
Journal: JAMA (1999)

Individuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease. However, prospective studies of homocysteine are inconsistent and data among women are limited.To determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease.Prospective, nested case-control study with a mean 3-year follow-up.The Women's Health Study, an ongoing US primary prevention trial initiated in 1993.From a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline, 122 women who subsequently experienced cardiovascular events were defined as cases, and 244 age- and smoking status-matched women who remained free of disease during follow-up were defined as controls.Incidence of death due to cardiovascular disease, nonfatal myocardial infarction (MI), stroke, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft by baseline homocysteine level.Of the 122 cases, there were 85 events of MI or stroke and 37 coronary revascularizations. Case subjects had significantly higher baseline homocysteine levels than controls (14.1 vs 12.4 micromol/L; P = .02). Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event (relative risk [RR], 2.0; 95% confidence interval [CI], 1.1-3.8). This effect was largely due to an excess of cases with high levels of homocysteine; the RR for those with homocysteine levels at or higher than the 95th percentile (20.7 micromol/L) was 2.6 (95% CI, 1.1-5.7). Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke (RR for those with baseline homocysteine levels in the top quartile, 2.2; 95% CI, 1.1-4.6). Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine (P<.001). However, the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use (P = .003 for trend), and subgroup analyses limited to women who were (P = .02 for trend) or were not (P = .04 for trend) taking multivitamin supplements.Among healthy postmenopausal US women, elevated levels of homocysteine moderately increased the risk of future cardiovascular disease. Whether lowering the homocysteine level reduces risk of cardiovascular events requires testing in randomized controlled trials.
Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program
Authors: E Beillard, N Pallisgaard, V H J van der Velden, W Bi, R Dee, E van der Schoot, E Delabesse, E Macintyre, E Gottardi, G Saglio, F Watzinger, T Lion, J J M van Dongen, P Hokland, J Gabert
Journal: Leukemia (2003)
A novel 80-kD cell surface structure identifies human circulating lymphocytes with natural killer activity.
Authors: H Maïza, G Leca, I G Mansur, V Schiavon, L Boumsell, A Bensussan
Journal: The Journal of Experimental Medicine (1993)

Human lymphocytes with natural killer (NK) activity, including most activated gamma/delta+ T lymphocytes, recognize and lyse tumor target cells without requiring recognition of major histocompatibility complex antigen. However, unlike gamma/delta+ T lymphocytes, NK cells do not express CD3/T cell receptor (TCR) molecules, and the receptors involved in cell-mediated cytotoxicity are unknown. To further delineate circulating NK cells, we developed monoclonal antibodies (mAbs) against the human NK leukemia YT2C2. We report the isolation of a mAb termed BY55, recognizing at the cell surface a novel 80-kD protein with restricted expression. In addition to the immunizing cell line, this mAb binds to circulating NK cells, gamma/delta+ cells, and a minor subset of alpha/beta+ T lymphocytes. Expression of the BY55 mAb-reactive epitope/molecule is regulated by activation, as short-term culture of peripheral blood lymphocytes (PBL) with phorbol ester induced its downmodulation. Furthermore, BY55 mAb reactivity was found neither with the NK nor with the TCR alpha/beta+ gamma/delta+ clones tested. Biochemical studies as well as phenotypic analysis revealed that this structure is different from all previously identified molecules on the lymphocyte cell surface. Interestingly, we found that BY55+ cells exert most NK activity obtained with fresh circulating lymphocytes. We report that within fresh E rosette-positive PBL only a subset of the CD16+, CD56+, and CD57+ cells coexpressed BY55 molecule, indicating that BY55 mAb defines a unique subset mediating NK activity of circulating PBL.
Establishment in Severe Combined Immunodeficiency Mice of Subrenal Capsule Xenografts and Transplantable Tumor Lines from a Variety of Primary Human Lung Cancers: Potential Models for Studying Tumor Progression–Related Changes
Authors: Jean-Claude Cutz, Jun Guan, Jane Bayani, Maisa Yoshimoto, Hui Xue, Margaret Sutcliffe, John English, Julia Flint, Jean LeRiche, John Yee, Jeremy A. Squire, Peter W. Gout, Stephen Lam, Yu-Zhuo Wang
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Lung cancer is a biologically diverse disease and relevant models reflecting its diversity would facilitate the improvement of existing therapies. With a view to establishing such models, we developed and evaluated xenografts of a variety of human lung cancers. Experimental Design: Using nonobese diabetic/severe combined immunodeficiency mice, subrenal capsule xenografts were generated from primary lung cancer tissue, including moderately and poorly differentiated squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, large cell undifferentiated carcinoma, and carcinosarcoma. After 4 to 12 weeks, xenografts were harvested for serial transplantation and comparison with the original tissue via histologic, chromosomal, and cytogenetic analyses. Results: Xenografts were successfully established. H&amp;E staining showed that xenografts retained major histologic features of the original cancers. Immunohistochemistry and fluorescence in situ hybridization confirmed the human origin of the tumor cells and development in xenografts of murine supportive stroma. Four transplantable lines were developed from rapidly growing tumors (&amp;gt;5 generations), i.e., a small cell lung carcinoma, large cell undifferentiated carcinoma, pulmonary carcinosarcoma, and squamous cell carcinoma. Analyses including spectral karyotyping, comparative genomic hybridization, and fluorescence in situ hybridization, revealed that the xenografts were genetically similar to the original tumors, showing chromosomal abnormalities consistent with karyotypic changes reported for lung cancer. Conclusions: The subrenal capsule xenograft approach essentially provides a living tumor bank derived from patient material and a means for isolating and expanding specific cell populations. The transplantable tumor lines seem to provide good models for studying various aspects of tumor progression and a platform for developing novel therapeutic regimens, with the possibility of patient-tailored therapies.
Whole genome sequencing of SIV-infected macaques identifies candidate loci that may contribute to host control of virus replication
Authors: Adam J Ericsen, Gabriel J Starrett, Justin M Greene, Michael Lauck, Muthuswamy Raveendran, David Rio Deiros, Mariel S Mohns, Nicolas Vince, Brian T Cain, Ngoc H Pham, Jason T Weinfurter, Adam L Bailey, Melisa L Budde, Roger W Wiseman, Richard Gibbs, Donna Muzny, Thomas C Friedrich, Jeffrey Rogers, David H O’Connor
Journal: Genome biology (2014)

A small percentage of human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected macaques control virus replication without antiretroviral treatment. The major determinant of this control is host expression of certain major histocompatibility complex alleles. However, this association is incompletely penetrant, suggesting that additional loci modify the major histocompatibility complex's protective effect. Here, to identify candidate control-modifying loci, we sequence the genomes of 12 SIV-infected Mauritian cynomolgus macaques that experienced divergent viral load set points despite sharing the protective M1 major histocompatibility complex haplotype. Our genome-wide analysis of haplotype-level variation identifies seven candidate control-modifying loci on chromosomes 2, 3, 7, 8, 9, 10, and 14. The highest variant density marks the candidate on chromosome 7, which is the only control-modifying locus to comprise genes with known immunological function. Upon closer inspection, we found an allele for one of these genes, granzyme B, to be enriched in M1(+) controllers. Given its established role as a cytotoxic effector molecule that participates in CD8-mediated killing of virus-infected cells, we test the role of variation within gzmb in modifying SIV control by prospectively challenging M1(+) granzyme B-defined macaques. Our study establishes a framework for using whole genome sequencing to identify haplotypes that may contribute to complex clinical phenotypes. Further investigation into the immunogenetics underlying spontaneous HIV control may contribute to the rational design of a vaccine that prevents acquired immune deficiency syndrome.
Passive acquired mucosal immunity to group A streptococci by secretory immunoglobulin A.
Authors: D Bessen, V A Fischetti
Journal: The Journal of Experimental Medicine (1988)

We present a model in which animals are passively immunized at a mucosal site, allowing one to evaluate immunological protection at the mucosal level only. Affinity-purified, anti-M protein sIgA administered intranasally protected mice against systemic infection after intranasal challenge with group A streptococci. In contrast, anti-M protein serum Ig administered intranasally was not protective at this site, although it neutralized the antiphagocytic property of M protein and promoted phagocytosis. Protection by sIgA occurred despite the lower immunoreactivity of sIgA to purified M protein compared with serum Ig. The data suggest that sIgA can protect at the mucosa and may preclude the need for opsonic IgG in preventing streptococcal infection.
Canadians want national medical standards to prevent inequalities
Authors: B. Kermode-Scott
Journal: BMJ (2012)

Canada’s doctors and nurses have become strong allies as they push jointly for national standards of care for all patients in Canada, regardless of where they live. Canadians fear that national standards are being eroded as government leaders squabble over healthcare.

Because of its size the federation of Canada is administered by not one but 14 governments: one federal, 10 provincial, and three territorial. The federal government is responsible for setting national principles for healthcare through the Canada Health Act, which gives Canadians access to “universal, comprehensive coverage for medically necessary hospital and physician services” through Medicare, the nation’s publicly funded healthcare system. 

But there are inequalities in care and costs, as each government decides what is “medically necessary.” Also, Medicare does not cover the cost of outpatient prescription drugs ( BMJ 2012;344:e514, doi:10.1136/bmj.e514), dental care, or home care. …
Epstein-Barr Virus: An Important Vaccine Target for Cancer Prevention
Authors: Jeffrey I. Cohen, Anthony S. Fauci, Harold Varmus, Gary J. Nabel
Journal: Science Translational Medicine (2011)

Participants at the February 2011 meeting at the U.S. National Institutes of Health on Epstein-Barr virus (EBV) vaccine research recommend that future clinical trials have two goals: prevention of infectious mononucleosis and EBV-associated cancers, facilitated by identification of disease-predictive surrogate markers.
Symptom association analysis in ambulatory gastro-oesophageal reflux monitoring
Authors: A J Bredenoord
Journal: Gut (2005)

During the past three decades, prolonged monitoring of oesophageal pH has become increasingly popular among physicians.Most of the studies carried out with this technique focused on oesophageal acid exposure, defined as percentage of time with pH below 4.However, in most cases acid exposure variables are not very useful in the evaluation of patients with symptoms and signs of gastro-oesophageal reflux disease (GORD).An often neglected aspect of 24 hour pH recording is assessment of the temporal relation between reflux and symptoms.Various methods to quantify this relationship were developed.Here, we review these methods and the contribution of symptom association analysis to the evaluation of patients with symptoms suggestive of GORD.www.gutjnl.
Reduced life span of anergic self-reactive B cells in a double-transgenic model.
Authors: D A Fulcher, A Basten
Journal: The Journal of Experimental Medicine (1994)

The life span of anergic self-reactive B cells was determined by 5-bromo-2'-deoxyuridine (BrdU) loading of tolerant double-transgenic (Dbl-Tg) mice produced by mating hen egg lysozyme (HEL)-transgenic mice with the corresponding immunoglobulin-transgenic (Ig-Tg) mice, the B cells of which express anti-HEL IgM and IgD. B cells from Dbl-Tg mice, despite being exposed to soluble antigen throughout their development, are not deleted, but persist in an anergic state. As a prelude to studying the life span of these anergic B cells, BrdU was administered to nontransgenic mice; B cells from the bone marrow, spleen, and lymph nodes displayed distinct kinetic profiles based on reciprocal expression of the B220 isoform of CD45 and heat-stable antigen (HSA). Thus, immature B220lo/HSAhi B cells incorporated BrdU rapidly suggesting recent generation from dividing precursors, whereas uptake by B cells expressing the mature B220hi/HSAlo phenotype was significantly slower, consistent with a longer life span. Such gating allowed analysis to be directed at the stable mature B cell population in transgenic mice. Comparison of BrdU uptake in Ig- and Dbl-Tg mice indicated that B cells from Dbl-Tg mice were renewed at a much higher rate (50% renewal times of 0.64 vs. 3.4 wk for total B cells, and 1.2 vs. 5.0 wk for mature B200hi/HSAlo cells from Dbl- and Ig-transgenic mice, respectively). This difference was even more marked when analysis in Dbl-Tg mice was restricted to HEL-binding cells, which had a 50% renewal time of 3-4 d compared with 4-5 wk for non-HEL-binding B cells. While the proportion of B cells in cell cycle, and the rate of entry of newly generated B cells into the spleen of Ig- and Dbl-Tg mice, were similar, B cell numbers were reduced in Dbl-Tg mice. It was therefore concluded that anergic B cells have a markedly decreased life span in the periphery. According to studies in radiation chimeras produced by reconstituting HEL-transgenic recipients expressing different serum levels of antigen with Ig-Tg bone marrow, the reduced life span of anergic B cells was associated with the anergic state per se, the serum concentration of HEL being important only in attaining the critical threshold necessary for tolerance induction. B cells rendered tolerant by exposure to soluble self-antigen therefore survive for a relatively short period in an anergic state once they have reached peripheral lymphoid tissue and fail to enter the long-lived compartment.(ABSTRACT TRUNCATED AT 400 WORDS)
Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice
Authors: Kristoffer W Brudvik, Jan E Paulsen, Einar M Aandahl, Borghild Roald, Kjetil Taskén
Journal: Molecular Cancer (2011)

Abstract Background The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E 2 (PGE 2 ) - PI-3 kinase pathways. Recent reports show that PGE 2 -induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE 2 on β-catenin homeostasis. Findings Treatment of Apc Min/+ mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE 2 -induced β-catenin phosphorylation and c-Myc upregulation. Conclusion Based on our findings we suggest that PGE 2 act through PKA to promote β-catenin nuclear translocation and tumor development in Apc Min/+ mice in vivo , indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.
Study on complex formation between recombinant human thrombomodulin fragment and thrombin using surface plasmon resonance
Authors: Akio Kishida, Mihoko Nakashima, Nobuyuki Sakamoto, Takeshi Serizawa, Ikuro Maruyama, Mitsuru Akashi
Journal: American Journal of Hematology (2000)

Human thrombomodulin (hTM) is a newly described endothelial cell associated protein that functions as a potent natural anticoagulant by converting thrombin from a procoagulant protease to an anticoagulant. The affinity constant of recombinant human soluble TM (rhs-TM) and a peptide containing active site of hTM fragment (f-hTM) with thrombin were determined using the surface plasmon resonance. The interaction of f-hTM with thrombin could be analyzed by a simple model, whereas the association and the dissociation steps of rhs-TM with thrombin consisted of at least two kinds of interaction phases. The dissociation constant for complex (KD) of f-hTM and thrombin was determined to be 205 nM, which was more than twice as high as that of rhs-TM (6.7 and 75 nM). The lower affinity of f-hTM was not due to the slow association rate but to the rapid dissociation rate. It comes clear that f-hTM interacts with thrombin rapidly. Am. J. Hematol. 63:136–140, 2000. © 2000 Wiley-Liss, Inc.
Qualitative changes with age of proteoglycans of human lumbar discs.
Authors: P Adams, H Muir
Journal: Annals of the Rheumatic Diseases (1976)

A detailed study of the biochemistry of each of the lower lumbar intervertebral discs from 3 spines aged 8, 16, and 44 years has shown progressive changes down the spine in a number of biochemical parameters. These were most apparent in the 44-year-old spine. The chemical composition of proteoglycans of the nucleus pulposus and of its constituent proteoglycans differed from those of the corresponding annulus fibrosus of all three spines. The interaction of proteoglycans with collagen, as assessed by extractability, changed markedly with advancing age, while the molecular size of the proteoglycans from both regions decreased and their keratan sulphate content increased. These changes would be expected to affect the mechanical properties of the disc.
American Diabetes Association diabetes diagnostic criteria, advancing age, and cardiovascular disease risk profiles: results from the Third National Health and Nutrition Examination Survey.
Authors: H E Resnick, M I Harris, D B Brock, T B Harris
Journal: Diabetes Care (2000)

To evaluate age-specific effects on diabetes prevalence estimates resulting from the American Diabetes Association (ADA) recommendation against use of the oral glucose tolerance test (OGTT), we contrasted the prevalence of two mutually exclusive groups: undiagnosed diabetes according to ADA criteria (no report of diabetes and fasting glucose [FG] > or =126 mg/dl) and isolated postchallenge hyperglycemia (IPH) (FG <126 mg/dl and OGTT > or =200 mg/dl), a group designated to have diabetes by World Health Organization (WHO) criteria but not ADA criteria.The weighted age-specific ratios of undiagnosed diabetes:IPH were calculated for 2,844 subjects aged 40-74 years without reported diabetes who had both FG and OGTT. A ratio > 1.0 indicated that the proportion of undiagnosed diabetes was greater than that of IPH. Mean levels of HbA1c and cardiovascular disease (CVD) risk factors were contrasted among people with undiagnosed diabetes and IPH and those without either abnormality ("nondiabetic").Both undiagnosed diabetes and IPH increased with age, but age-specific undiagnosed diabetes:IPH ratios decreased from 5.49 in the 40-44 age-group to 0.77 in the 70-74 age-group. Regression analysis showed a significant (P = 0.006) negative association between age and these ratios. Mean HbA1c was 7.1% in the undiagnosed diabetes group and differed significantly from that of the IPH and nondiabetic groups (5.6 and 5.3%, respectively). Individuals with undiagnosed diabetes had less favorable triglycerides, BMI, and HDL cholesterol compared with people with IPH.Compared with WHO criteria, the ADA criteria underestimate glucose abnormalities more with increasing age. However, compared to those with undiagnosed diabetes, individuals with IPH had a mean HbA1c level that is considered in the nondiabetic range, and this group had significantly more favorable levels of several key CVD risk factors. These findings suggest that the ADA criteria, although underestimating the abnormalities of postchallenge hyperglycemia that occur frequently with increasing age, appear to be effective at identifying a group of individuals with both unfavorable CVD risk factor profiles and evidence of long-term exposure to hyperglycemia.