tbuckley/cabot-search huggingface dataset:
Opposing Risks of Gastric Cardia and Noncardia Gastric Adenocarcinomas Associated With Helicobacter pylori Seropositivity
Authors: Farin Kamangar, Sanford M. Dawsey, Martin J. Blaser, Guillermo I. Perez-Perez, Pirjo Pietinen, Craig J. Newschaffer, Christian C. Abnet, Demetrius Albanes, Jarmo Virtamo, Philip R. Taylor
Journal: JNCI Journal of the National Cancer Institute (2006)

Colonization with Helicobacter pylori is a risk factor for gastric adenocarcinoma, but the magnitude of this association and its relationship to anatomic location of the cancer, duration of follow-up, age at diagnosis, histologic subtype, and H. pylori strain differences are less clear. We conducted a prospective nested case-control study of H. pylori serology to address these questions.Case and control subjects were selected from the 29,133 50- to 69-year-old males recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. At baseline, detailed demographic data and a serum sample were collected. From 1985 to 1999, 243 incident cases of gastric adenocarcinoma were diagnosed in cohort members. Serum samples from 234 case subjects (173 with noncardia gastric cancers and 61 with gastric cardia cancers) and 234 age-matched control subjects were assayed for antibodies against H. pylori whole-cell and CagA antigens. We fit conditional logistic regression models to estimate the unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association of H. pylori seropositivity, defined as seropositivity to either whole-cell or CagA antigens, with noncardia gastric and gastric cardia cancers. All statistical tests were two-sided.H. pylori seropositivity was strongly associated with the risk of noncardia gastric cancer (adjusted OR = 7.9, 95% CI = 3.0 to 20.9) but was inversely associated with the risk of gastric cardia cancer (adjusted OR = 0.31, 95% CI = 0.11 to 0.89). H. pylori seropositivity rates did not vary statistically significantly by length of follow-up, age at diagnosis, or histologic subtype. A calculation of rates showed that the absolute risks of noncardia gastric and cardia gastric adenocarcinomas in the H. pylori-positive participants of this cohort would be 63 and 12 per 100,000 person-years, respectively, whereas corresponding rates in H. pylori-negative participants would be 8 and 37 per 100,000 person-years, respectively.H. pylori is a strong risk factor for noncardia gastric cancer but is inversely associated with the risk of gastric cardia cancer. These findings bolster the hypothesis that decreasing H. pylori prevalence during the past century may have contributed to lower rates of noncardia cancer and higher rates of cardia cancer in Western countries.
Hyperglycaemia-induced cardiomyocyte death is mediated via MCP-1 production and induction of a novel zinc-finger protein MCPIP
Authors: Craig W. Younce, Kangkai Wang, Pappachan E. Kolattukudy
Journal: Cardiovascular Research (2010)

AimsCardiomyocyte apoptosis contributes to the development of diabetic cardiomyopathy. How the elevated glucose levels associated with diabetes cause cell death is unknown. Here we report that high glucose-induced cardiomyocyte death is mediated via monocyte chemotactic protein-1 (MCP-1) production and induction of a novel zinc-finger protein.
Whistleblower in Bristol case says funding was put before patients
Authors: C. Dyer
Journal: BMJ (1999)

Stephen Bolsin, the anaesthetist who blew the whistle about serious problems with paediatric heart surgery at the Bristol Royal Infirmary, claimed this week that patients were sacrificed to keep government funding He believed that the infirmary's wish to keep its designation as a specialist heart facility was a main reason for the failure to act over his concerns about poor outcomes, he told the public inquiry looking into children's heart surgery at Bristol.

Dr Bolsin, who flew to Britain from …
Early-onset hypogammaglobulinemia: A survey of 44 patients
Authors: Anne C. Brignier, Nizar Mahlaoui, Christian Reimann, Capucine Picard, Sven Kracker, Nathalie de Vergnes, Frederic Rieux-Laucat, Pierre Frange, Felipe Suarez, Bénédicte Neven, Agathe Masseau, Nathalie Aladjidi, Jean Donadieu, Anne Corby, Boris Bienvenu, Pascale Cony-Makhoul, Alain Fischer, Marina Cavazzana, Anne Durandy
Journal: Journal of Allergy and Clinical Immunology (2015)
Inferring the Rate and Time-Scale of Dengue Virus Evolution
Authors: S. Susanna Twiddy, Edward C. Holmes, Andrew Rambaut
Journal: Molecular Biology and Evolution (2003)

Dengue is often referred to as an emerging disease because of the rapid increases in incidence and prevalence that have been observed in recent decades. To understand the rate at which genetic diversification occurs in dengue virus and to infer the time-scale of its evolution, we employed a maximum likelihood method that uses information about times of virus sampling to estimate the rate of molecular evolution in a large number of viral envelope (E) gene sequences and to place bounds around the dates of appearance of all serotypes and specific genotypes. Our analysis reveals that dengue virus generally evolves according to a molecular clock, although some serotype-specific and genotype-specific rate differences were observed, and that its origin is more recent than previously suggested, with the virus appearing approximately 1000 years ago. Furthermore, we estimate that the zoonotic transfer of dengue from sylvatic (monkey) to sustained human transmission occurred between 125 and 320 years ago, that the current global genetic diversity in the four serotypes of dengue virus only appeared during the past century, and that the recent rise in genetic diversity can be loosely correlated both to human activities such as population growth, urbanization, and mass transport and to the emergence of dengue hemorrhagic fever as a major disease problem.
Association between human parvovirus B19 infection and arthritis.
Authors: P Cassinotti, S Bas, G Siegl, T L Vischer
Journal: Annals of the Rheumatic Diseases (1995)

To gain information concerning the association between parvovirus B19 infection and arthritis.Blood or synovial fluid, or both, from a total of 77 adult patients with various arthropathies (rheumatoid arthritis 13; mechanical arthropathies 11; crystal induced arthritis 13; idiopathic mono/oligoarthritis 25; suspicion of viral arthritis 15) were tested for the presence of the viral genome and anti-B19 antibodies. B19 DNA in blood and synovial fluid was investigated by nested polymerase chain reaction, and anti-B19 IgM and IgG antibodies were detected in blood by enzyme immunoassay.A recent parvovirus infection was documented by the presence of anti-B19 IgM antibodies in the blood of 13 patients. B19 DNA, together with anti-B19 IgM and IgG antibodies, were detected in the blood of seven patients who had an acute transient arthritis, putatively of viral origin. Viral DNA was detected in a synovial fluid sample and in the blood of one patient with monoarthritis who had an anti-B19 IgG response only.The prevalence of anti-B19 IgG antibody in these patients with various forms of arthritis (63%) was within the same range as that in the general population (blood donors). However, for the patients with clinical suspicion of viral arthritis, the increased seroprevalence of anti-B19 IgM and the presence of the B19 genome point to an association between human parvovirus infections and acute forms of arthritis.
Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets
Authors: Michael W. Tusche, Lesley A. Ward, Frances Vu, Doug McCarthy, Miguel Quintela-Fandino, Jurgen Ruland, Jennifer L. Gommerman, Tak W. Mak
Journal: The Journal of Experimental Medicine (2009)

B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor κB (NF-κB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-κB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-κB2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1−/− marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1−/− MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell–intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.
IL-22 Ameliorates Renal Ischemia-Reperfusion Injury by Targeting Proximal Tubule Epithelium
Authors: Ming-Jiang Xu, Dechun Feng, Hua Wang, Youfei Guan, Xiaoqiang Yan, Bin Gao
Journal: Journal of the American Society of Nephrology (2014)

IL-22 is an epithelial cell survival cytokine that is currently under development for the treatment of acute liver damage. Here, we used a mouse model of renal ischemia/reperfusion (I/R) injury to investigate whether IL-22 has therapeutic potential for the treatment of AKI. The action of IL-22 is mediated by binding to IL-22R1 and leads to STAT3 activation. Under physiologic conditions, renal expression of IL-22R1 was detected only in the brush border of the renal proximal tubular epithelial cells (RPTECs). Renal I/R elevated serum IL-22 levels slightly but did not induce STAT3 phosphorylation in RPTECs. IL-22-deficient mice had slightly increased I/R-induced injury compared with wild-type mice. In contrast, treatment with IL-22 or overexpression of IL-22 by either gene targeting (IL-22 transgenic mice) or administration of adenovirus expressing IL-22 increased STAT3 phosphorylation in RPTECs, ameliorated I/R-induced renal inflammation and tubular cell injury, and preserved renal functions. Overexpression of IL-22 increased the phosphorylation of STAT3 and Akt, upregulated antiapoptotic genes (e.g., Bcl-2), and downregulated proapoptotic genes (e.g., Bad) in the kidneys of mice subjected to I/R. Notably, phosphorylation of Akt increased and expression of Bad decreased in proximal tubular cells under these conditions. Furthermore, compared with wild-type mice, IL-22 transgenic mice had increased survival rates, whereas IL-22-deficient mice had reduced survival rates after I/R injury. In summary, renal expression of IL-22R1 is restricted to RPTECs, and treatment with IL-22 protects against renal I/R injury by activating STAT3 and AKT, suggesting that IL-22 has therapeutic potential for the treatment of AKI.
New Monoclonal Antibodies to Mesothelin Useful for Immunohistochemistry, Fluorescence-Activated Cell Sorting, Western Blotting, and ELISA
Authors: Masanori Onda, Mark Willingham, Satoshi Nagata, Tapan K. Bera, Richard Beers, Mitchell Ho, Raffit Hassan, Robert J. Kreitman, Ira Pastan
Journal: Clinical Cancer Research (2005)

Mesothelin is a cell surface protein that is highly expressed in some malignant tumors, and is a promising target for immunotherapy. Recent data suggests that mesothelin is an adhesive protein and may have a role in the metastases of ovarian cancer. Although a few monoclonal antibodies (MAb) to mesothelin have been produced, they have limitations for the study of expression of native mesothelin because of their low affinity or reactivity only with denatured mesothelin protein. We have produced novel MAbs to mesothelin to help study mesothelin function and to develop improved diagnosis and immunotherapy of mesothelin-expressing tumors.Mesothelin-deficient mice were immunized with plasmid cDNA encoding mesothelin, and boosted with a mesothelin-rabbit IgG Fc fusion protein prior to cell fusion. Hybridomas were screened by an ELISA using plates coated with mesothelin-Fc protein.Seventeen hybridomas producing anti-mesothelin antibodies were established and shown to react with two epitopes on mesothelin. One group reacts with the same epitope as the low affinity antibody K1 that was originally used to identify mesothelin. The other is a new group that reacts with a new epitope. One antibody from each group was chosen for further study and shown to react strongly on ELISA, on immunohistochemistry, and by fluorescence-activated cell sorting on living cells.Our two newly established MAbs, MN and MB, have different and useful properties compared with current antibodies used for the detection of mesothelin by immunohistochemistry, fluorescence-activated cell sorting, ELISA, and Western blotting.
Surrogate Endpoints: Wishful Thinking or Reality?
Authors: Stuart G. Baker
Journal: JNCI Journal of the National Cancer Institute (2006)

More than 100 years ago, the noted French mathematician Henri Poincare quoted the following remark about the assumption of a normal distribution: “ Everybody fi rmly believes in it because the mathematicians imagine it is a fact of observation, and observers that it is a theory of mathematics ” ( 1 ) . A similar generalization could be made about methods to validate surrogate endpoints: Biostatisticians believe that the methods they propose are useful because clinicians adopt them, and clinicians believe that the methods proposed by biostatisticians are useful because they have the “ imprimatur ” of mathematical statistics. Given this state of affairs, a critical examination of methods to validate surrogate endpoints is needed. However, before delving further it is necessary to precisely state the role of surrogate endpoints. The purpose of a surrogate endpoint is to draw conclusions about the effect of intervention on true endpoint without having to observe the true endpoint. If this purpose could be achieved, clinical research would be greatly accelerated. Unfortunately it is a tall order, and many proposed surrogate endpoints have subsequently been shown to have led to incorrect conclusions about the effect of intervention on the true endpoints ( 2 ) . Therefore, before a surrogate endpoint can be used with confi dence, it must be validated. Part of the controversy with the use of surrogate endpoints is that there is no agreed-upon defi nition of a validated surrogate endpoint. Essentially, validation of a surrogate endpoint consists of whatever the investigators think will make them and others feel confi dent about the use of the surrogate endpoint in a future trial. Validation measures must ensure that this confi dence is grounded more in reality than wishful thinking.
Abstract 5531: Combination drug delivery using PBM nanoparticle to improve prostate cancer therapy
Authors: Rajesh Singh, Shailesh Singh, Guru P. Sonpavde, James W. Lillard
Journal: Cancer Research (2015)

Abstract Docetaxel is the standard first-line chemotherapy for advanced prostate cancer (PCa). The key challenges in this treatment option are dose-limiting toxicities, acquired resistance, and lack of tumor cell specificity. Adjuvants and docetaxel encapsulation have been proposed to mitigate many of these hindrances. The proposed study evaluated a novel method for targeted delivery of resveratrol alone or in combination with docetaxel at desired rates. We described a proprietary planetary ball milling approach (PBM) that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with novel folate-conjugated poly (ϵ-caprolactone) / poly (ethylene glycol) co-polymer, which allows binding to high affinity folate receptors present on PCa cells. The resulting PBM nanoparticles were shown to be rapidly internalized and induce significant cancer cell apoptosis at lower doses, than compared to unformulated resveratrol and/or docetaxel. Importantly, negative controls showed that PBM nanoparticles without resveratrol or docetaxel had no toxic effects on PCa cells. Furthermore, our data also suggests that resveratrol potently synergizes with docetaxel to inhibit proliferation and induce 60% cell death in PCa cell lines at concentrations lower than the IC50. Since docetaxel is associated with various debilitating toxicities, a synergistic combination of resveratrol-docetaxel with targeted delivery to tumor cells could provide a more potent therapeutic effect at lower drug concentrations and improve therapeutic index. Citation Format: Rajesh Singh, Shailesh Singh, Guru P. Sonpavde, James W. Lillard. Combination drug delivery using PBM nanoparticle to improve prostate cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5531. doi:10.1158/1538-7445.AM2015-5531
Reduced baroreceptor sensitivity in borderline hypertension.
Authors: A Takeshita, S Tanaka, A Kuroiwa, M Nakamura
Journal: Circulation (1975)

The sensitivity of the baroreceptor reflex in nine patients with borderline hypertension (mean age 19.1 plus or minus 0.2 years) was compared to that in six normal subjects of comparable age (mean 18.8 plus or minus 0.3 years) and that in 14 patients with established hypertension (mean age 48.3 plus or minus 3.1 years). The sensitivity of the baroreceptor reflex was assessed by determining the slope of the regression line relating the rise of systolic pressure to the prolongation of the R-R Interval during the transient rise of arterial pressure induced by an intravenous injection of phenylephrine. The average baroreceptor slope in nine patients with borderline hypertension was 9.1 plus or minus 0.8 msec/mm Hg, which was significantly less than that in six normal subjects (16.0 plus or minus 2.0; P smaller than 0.01), but was greater than that in 14 patients with established hypertension (4.9 plus or minus 0.7; P smaller than 0.01). The significant negative correlation was found as the baroreceptor slope was related to the mean arterial pressure in patients with borderline hypertension and normal subjects, all of whom were 20 years old or less. Attenuation of the baroreceptor sensitivity may influence the maintenance of raised arterial pressure in borderline hypertension.
Omega-3 Fatty Acid Treatment of Women With Borderline Personality Disorder: A Double-Blind, Placebo-Controlled Pilot Study
Authors: Mary C. Zanarini, Frances R. Frankenburg
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: The purpose of this study was to compare the efficacy of ethyl-eicosapentaenoic acid (E-EPA) and placebo in the treatment of female subjects with borderline personality disorder. METHOD: The authors conducted an 8-week, placebo-controlled, double-blind study of E-EPA in 30 female subjects meeting Revised Diagnostic Interview for Borderlines and DSM-IV criteria for borderline personality disorder. RESULTS: Twenty subjects were randomly assigned to 1 g of E-EPA; 10 subjects were given placebo. Ninety percent of those in both groups completed all 8 weeks of the trial. Analyses that used random-effects regression modeling and controlled for baseline severity showed E-EPA to be superior to placebo in diminishing aggression as well as the severity of depressive symptoms. CONCLUSIONS: The results of this study suggest that E-EPA may be a safe and effective form of monotherapy for women with moderately severe borderline personality disorder.
Therapeutic Targets: Progress of Their Exploration and Investigation of Their Characteristics
Authors: C. J. Zheng, L. Y. Han, C. W. Yap, Z. L. Ji, Z. W. Cao, Y. Z. Chen
Journal: Pharmacological Reviews (2006)

Modern drug discovery is primarily based on the search and subsequent testing of drug candidates acting on a preselected therapeutic target. Progress in genomics, protein structure, proteomics, and disease mechanisms has led to a growing interest in and effort for finding new targets and more effective exploration of existing targets. The number of reported targets of marketed and investigational drugs has significantly increased in the past 8 years. There are 1535 targets collected in the therapeutic target database compared with ∼500 targets reported in a 1996 review. Knowledge of these targets is helpful for molecular dissection of the mechanism of action of drugs and for predicting features that guide new drug design and the search for new targets. This article summarizes the progress of target exploration and investigates the characteristics of the currently explored targets to analyze their sequence, structure, family representation, pathway association, tissue distribution, and genome location features for finding clues useful for searching for new targets. Possible "rules" to guide the search for druggable proteins and the feasibility of using a statistical learning method for predicting druggable proteins directly from their sequences are discussed.
Asthma and comorbid medical illness
Authors: M. Cazzola, L. Calzetta, G. Bettoncelli, L. Novelli, C. Cricelli, P. Rogliani
Journal: European Respiratory Journal (2010)

Asthma is associated with several comorbidities but the magnitude of the association has not been clearly defined. We aimed to examine the relationship between asthma and comorbidities using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (Società Italiana Medici Generici, Florence, Italy). We conducted a population-based retrospective study using information obtained from the HSD. The software system used codes of all the diagnostic records using the 9th revision of the International Classification of Diseases. Asthma appeared to be weakly associated with cardiovascular and hypertensive diseases. Intriguingly, the odds ratio of acute or old myocardial infarction was 0.84 (95% CI 0.77–0.91). Asthma was also weakly associated with depression, diabetes mellitus, dyslipidaemia, osteoporosis and rhinosinusitis. In contrast, it was strongly associated with gastro-oesophageal reflux disease (GORD) and, particularly, allergic rhinitis. Age did not influence the association of asthma with comorbidities whereas sex had a different impact according to the specific comorbidity. Our results indicate that asthma is weakly associated with several comorbidities, whereas its association with allergic rhinitis or GORD is stronger.
The Nature of Small-Airway Obstruction in Chronic Obstructive Pulmonary Disease
Authors: James C. Hogg, Fanny Chu, Soraya Utokaparch, Ryan Woods, W. Mark Elliott, Liliana Buzatu, Ruben M. Cherniack, Robert M. Rogers, Frank C. Sciurba, Harvey O. Coxson, Peter D. Paré
Journal: New England Journal of Medicine (2004)

Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD.The small airways were assessed in surgically resected lung tissue from 159 patients--39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD).The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed.Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways.