tbuckley/cabot-search huggingface dataset:
Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer
Authors: Nicolò Rigamonti, Giusy Capuano, Alessia Ricupito, Elena Jachetti, Matteo Grioni, Luca Generoso, Massimo Freschi, Matteo Bellone
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b+Gr1+ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-l-arginine methyl ester (l-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity. Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, l-NAME or sildenafil, and evaluated for CD11b+ cells accumulation in the blood, several organs, and the tumor mass and for disease progression. Results: CD11b+Gr1high, CD11b+Gr1int, and CD11b+Gr1− cells differently accumulated in different organs and especially in the tumor of the two mouse models. l-NAME and sildenafil impaired the immunosuppressive function of CD11b+ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice. Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. Clin Cancer Res; 17(5); 1012–23. ©2011 AACR.
Association of Serum Antibodies to Heat-Shock Protein 65 With Coronary Calcification Levels
Authors: Jianhui Zhu, Richard J. Katz, Arshed A. Quyyumi, Daniel A. Canos, David Rott, Gyorgy Csako, Alexandra Zalles-Ganley, Jibike Ogunmakinwa, Alan G. Wasserman, Stephen E. Epstein
Journal: Circulation (2003)

Previous studies demonstrated an association between antibodies to mycobacterial heat-shock protein 65 (mHSP65) and carotid artery thickening. We examined whether mHSP65 antibodies are associated with levels of coronary calcification that appear to reflect preclinical coronary artery disease (CAD).Serum specimens from 201 healthy asymptomatic subjects (52% male; mean age, 56.6 years) undergoing electron-beam computed tomographic imaging were used to measure levels of mHSP65 and human HSP60 antibodies and antibodies to several infectious pathogens. We found that 84% of the study subjects had anti-mHSP65 IgG antibodies. Mean titers of mHSP65 antibodies were higher (1:394 versus 1:267, P=0.012) in individuals with than in those without elevated levels of coronary calcium (calcium score > or =150). Increasing titers of mHSP65 antibodies were significantly associated, in a dose-response manner, with elevated levels of coronary calcification. Individuals with the highest titers of mHSP65 antibodies (> or =1:800) had an adjusted odds ratio (OR) of 14.3 for having elevated coronary calcium (P=0.004). Association of mHSP65 antibodies with elevated coronary calcification levels was independent of CAD risk factors after multivariate adjustment (P=0.037). Interestingly, mHSP65 antibody titers were correlated with Helicobacter pylori infection (P=0.004), which maintained significance after adjustment for CAD risk factors and seropositivities to other pathogens (adjusted OR, 3.1; 95% CI, 1.4 to 6.6). No association was found between antibodies to human HSP60 and levels of coronary calcification.Antibodies to mHSP65 are associated with elevated levels of coronary calcification and correlated with H pylori infection, suggesting that pathogen-triggered autoimmunity plays a role in early atherosclerosis.
Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development
Authors: Yi-An Ko, Davoud Mohtat, Masako Suzuki, Ae Seo Deok Park, Maria Concepcion Izquierdo, Sang Youb Han, Hyun Mi Kang, Han Si, Thomas Hostetter, James M Pullman, Melissa Fazzari, Amit Verma, Deyou Zheng, John M Greally, Katalin Susztak
Journal: Genome biology (2013)

One in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. Epigenetic information represents a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences.We identify differentially methylated regions and validate these in a large replication dataset. The differentially methylated regions are rarely observed on promoters, but mostly overlap with putative enhancer regions, and they are enriched in consensus binding sequences for important renal transcription factors. This indicates their importance in gene expression regulation. A core set of genes that are known to be related to kidney fibrosis, including genes encoding collagens, show cytosine methylation changes correlating with downstream transcript levels.Our report raises the possibility that epigenetic dysregulation plays a role in chronic kidney disease development via influencing core pro-fibrotic pathways and can aid the development of novel biomarkers and future therapeutics.
Comparison of Clinical Presentations and Outcomes Between Patients With <i>TGFBR2</i> and <i>FBN1</i> Mutations in Marfan Syndrome and Related Disorders
Authors: David Attias, Chantal Stheneur, Carine Roy, Gwenaëlle Collod-Béroud, Delphine Detaint, Laurence Faivre, Marie-Ange Delrue, Laurence Cohen, Christine Francannet, Christophe Béroud, Mireille Claustres, Franck Iserin, Philippe Khau Van Kien, Didier Lacombe, Martine Le Merrer, Stanislas Lyonnet, Sylvie Odent, Henri Plauchu, Marlène Rio, Annick Rossi, Daniel Sidi, Philippe Gabriel Steg, Philippe Ravaud, Catherine Boileau, Guillaume Jondeau
Journal: Circulation (2009)

TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear.Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age- and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35+/-16 versus 39+/-13 years, respectively) and aortic dissection (14% versus 10% and 38+/-12 versus 39+/-9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all P<0.05). Aortic dilatation, dissection, or sudden death was the index event leading to genetic diagnosis in 65% of families with TGFBR2 mutations, versus 32% with FBN1 mutations (P=0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; P=1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome.Clinical outcomes appear similar between treated patients with TGFBR2 mutations and individuals with FBN1 mutations. Prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 gene mutation.
Hematopoietic stem cell markers are expressed by ductal plate and bile duct cells in developing human liver
Authors: Karin Blakolmer, Kasimirsz Jaskiewicz, Harold A. Dunsford, Simon C. Robson
Journal: Hepatology (1995)

The identification of ductal plate cells as likely progenitors for bile duct epithelium and hepatocytes and their possible reappearance as oval cells in the regenerating liver have generated much interest in their pluripotential capacities. We have examined the distribution of three hematopoietic stem cell markers, c-kit, CD34, and CD33 in addition to laminin, the standard cytokeratin markers CAM 5.2, CK 18, and CK 7 and the oval cell marker OV-6 in fetal liver during various stages of development. Hematopoietic stem cell markers were expressed in ductal plate cells in a pattern similar to the early cytokeratin markers CAM 5.2 and CK 18. Cells stained strongly for these early cytokeratin markers until 22 weeks. Thereafter, the expression of these markers decreased while positivity for CK 7 increased. Bile duct cells showed a distribution of hematopoietic and cytokeratin markers resembling that of ductal plate cells. Both ductal plate cells and bile duct cells expressed OV-6 strongly throughout development. This study showed similarity between hepatic and bile duct precursors and bone marrow stem cells. The comparable distribution of markers in bile duct epithelium and ductal plate cells may imply fewer transitional stages between ductal plate cells and bile duct epithelium than between the putative stem cells and hepatocytes.
THE EFFECTS OF X-RAYS AND BETA RAYS (TRITIUM) ON THE GROWTH OF RICKETTSIA MOOSERI AND RICKETTSIA AKARI IN EMBRYONATE EGGS
Authors: Donald Greiff, E. L. Powers, Walter E. Kisieleski, Henry Pinkerton
Journal: The Journal of Experimental Medicine (1960)

The growth of Rickettsia mooseri was accelerated and quantitatively increased in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg during the growth period. The eggs of a group containing 22.5 mc./egg showed only a slight increase in the rate of growth of organisms; the infections in the eggs of a group given 11.2 mc./egg did not differ significantly from those of the control group. On the other hand, growth of R. akari was inhibited in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg, and partially inhibited in groups containing 22.5 and 11.2 mc./egg. The patterns of growth of R. mooseri and of R. akari exposed to tritium oxide for 6 hours prior to inoculation into embryonate eggs did not differ significantly from that of the control group. Single and divided doses of x-rays to the host resulted in partial inhibition of the growth of R. akari.
Morphology of Tumor Cell Nuclei Is Significantly Related with Survival Time of Patients with Glioblastomas
Authors: Reinhold Nafe, Kea Franz, Wolfgang Schlote, Berthold Schneider
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To investigate whether histomorphology of tumor cell nuclei has a significant and independent relation to survival time of patients with glioblastomas. Experimental Design: Seventy-two tumors from 72 patients were investigated by means of digital image analysis. Proliferating and nonproliferating nuclei were separately measured and parameters of nuclear size, shape, texture, and spatial relationships (topometric parameters) were detected. Survival analysis was done regarding morphometric data together with the patients' age, the amount of resection (total or subtotal), and the classification of the tumor as a “primary” (de novo) or “secondary” glioblastoma. Results: The overall relation of all morphometric data to the time of survival was highly significant (Cox analysis, P &amp;lt; 0.0001). Apart from the extent of surgical resection, parameters of nuclear shape and topometric variables, such as the distance between two nuclei lying nearest to each other, showed an independent and significant relation to survival time. The patients' age had also a significant but comparably slight relation to survival time. Conclusions: The morphology of tumor cell nuclei, as represented by morphometric data, shows a significant relation to survival time of patients with glioblastomas. This relation is statistically independent from the amount of surgical resection, from the patients' age and from the classification of the glioblastoma as being primary or secondary. The results support the view that histomorphometry of tumor cell nuclei is a valuable prognostic marker for patients with glioblastomas. We believe that such a marker ought to be incorporated into the formation of individual therapeutic decisions.
PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection
Authors: Yong-Feng Xu, Yong Yi, Shuang-Jian Qiu, Qiang Gao, Yi-Wei Li, Chen-Xin Dai, Ming-Yan Cai, Min-Jie Ju, Jian Zhou, Bo-Heng Zhang, Jia Fan
Journal: Journal of Hepatology (2010)
A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma
Authors: Gregory L. Beatty, Drew A. Torigian, E. Gabriela Chiorean, Babak Saboury, Alex Brothers, Abass Alavi, Andrea B. Troxel, Weijing Sun, Ursina R. Teitelbaum, Robert H. Vonderheide, Peter J. O'Dwyer
Journal: Clinical Cancer Research (2013)

This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle.CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007).CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.
Antibodies against MICA Antigens and Kidney-Transplant Rejection
Authors: Yizhou Zou, Peter Stastny, Caner Süsal, Bernd Döhler, Gerhard Opelz
Journal: New England Journal of Medicine (2007)

Good HLA-A, HLA-B, and HLA-DR matches do not guarantee rejection-free renal transplantation. Some kidney transplants fail despite such matches, suggesting that other antigens might be targets for rejection. Major-histocompatibility-complex (MHC) class I-related chain A (MICA) antigens are polymorphic and can elicit antibody production. We sought to determine whether an immune response to MICA antigens might play a role in the failure of kidney allografts.Pretransplantation serum samples from 1910 recipients of kidney transplants from deceased donors were tested for anti-MICA antibodies with an assay in which single MICA antigens were attached to polystyrene microspheres.Antibodies against MICA alleles were detected in 217 of the 1910 patients (11.4%). The presence of MICA antibodies was associated with renal-allograft rejection. The mean (+/-SE) 1-year graft-survival rate was 88.3+/-2.2% among recipients with anti-MICA antibodies as compared with 93.0+/-0.6% among recipients without anti-MICA antibodies (P=0.01). Among recipients of first kidney transplants, the survival rate was even lower among MICA antibody-positive patients (87.8+/-2.4%) than among MICA antibody-negative recipients (93.5+/-0.6%, P=0.005). In addition, the association of MICA sensitization with reduced graft survival was more evident in kidney-transplant recipients with good HLA matching: among 326 recipients who received well-matched kidneys (0 or 1 HLA-A plus HLA-B plus HLA-DR mismatch), sensitization against MICA was associated with poorer allograft survival (83.2+/-5.8% among those with anti-MICA antibodies vs. 95.1+/-1.3% among those without such antibodies, P=0.002).Presensitization of kidney-transplant recipients against MICA antigens is associated with an increased frequency of graft loss and might contribute to allograft loss among recipients who are well matched for HLA.
The Pathogenesis of Systemic Sclerosis
Authors: Tamiko R. Katsumoto, Michael L. Whitfield, M. Kari Connolly
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Systemic sclerosis (SSc), also known as scleroderma, is a rare connective tissue disease characterized by vascular and immune dysfunction, leading to fibrosis that can damage multiple organs. Its pathogenesis is complex and poorly understood. Two major clinical subtypes are the limited and diffuse forms. Research into SSc has been hampered by its rarity, its clinical heterogeneity, and the lack of mouse models that accurately recapitulate the disease. Clinical and basic studies have yielded some mechanistic clues regarding pathogenesis. Recent insights gained through the use of microarrays have revealed distinctive subsets of SSc within and beyond the limited and diffuse subsets. In this review, we discuss potential mechanisms underlying the vascular, autoimmune, and fibrotic points of dysregulation. Proper categorization of SSc patients for research studies by use of microarrays or other biomarkers is critical, as disease heterogeneity may explain some of the inconsistencies of prior studies.
Nosocomial bacterial pneumonia in human immunodeficiency virus infected subjects: incidence, risk factors and outcome
Authors: M. Tumbarello, E. Tacconelli, K. de Gaetano Donati, S. Bertagnolio, M. Cataldo, T. Pirronti, F. Ardito, R. Cauda
Journal: European Respiratory Journal (2001)

The presented study examined the incidence, risk factors and outcome of nosocomial bacterial pneumonia (NBP) in human immunodeficiency virus (HIV)-infected subjects. Forty-two cases of NBP were ascertained by a 5-yr prospective surveillance and were matched to 84 controls. NBP incidence was 10.8 per 10,000 hospital patient-days. In particular, the incidence of NBP was 13.9 per 10,000 patient-days in the period 1994–1996 and 5.6 per 10,000 patient-days in the period 1997–1998 (p=0.01). By using regression analysis, predictors for developing NBP were an increasing value of Acute Physiology and Chronic Health Evaluation (APACHE) III score (p&lt;0.01) and the presence of acquired immune deficiency syndrome (AIDS)-related central nervous system (CNS) diseases (p=0.01). The additional hospital stay attributable to NBP was 15 days. The attributable mortality rate was estimated to be 29%. Nosocomial bacterial pneumonia is more common in patients with advanced human immunodeficiency virus infection, high Acute Physiology and Chronic Health Evaluation III score and central nervous system diseases. Although the incidence of nosocomial bacterial pneumonia, as well of other opportunistic infections, decreased considerably in the era of highly active antiretroviral therapy, it still represents an important cause of mortality.
SOME IMMUNOCHEMICAL PROPERTIES OF PENICILLENIC ACID
Authors: Alain L. de Weck, Herman N. Eisen
Journal: The Journal of Experimental Medicine (1960)

Under mild conditions, benzylpenicillin in aqueous solution rearranges to benzylpenicillenic acid, which reacts, under suitable conditions, to form stable disulfides and mercaptides. Through reaction with native proteins or especially with proteins that are enriched in SH groups ("thiolated"), penicillenic acid forms, ma mixed disulfide linkages, stable highly substituted conjugates. These conjugates are potent antigens, inducing the formation of substantial amounts of antibodies specific for the penicillenic acid structure. The implications of these findings for penicillin hypersensitivity in man are discussed.
Pulmonary function, inflammation, exercise capacity and quality of life in cystic fibrosis
Authors: J. Bradley, O. McAlister, S. Elborn
Journal: European Respiratory Journal (2001)

The aim of the study was to determine the extent to which treatment induced changes in exercise capacity and quality of life (QoL) are related to spirometric measures of lung function and other measures of disease impairment. Twenty patients admitted to hospital with an exacerbation of pulmonary disease were recruited. Measures of disease impairment, disability and QoL were obtained at the beginning and end of an intravenous course of antibiotic therapy. Intravenous antibiotic treatment resulted in a significant improvement in all measures of disease impairment, disability and handicap. The only significant predictor of treatment induced change in exercise capacity was C-reactive protein (CRP) and this explained 28% of the variance in change in exercise capacity. In the case of QoL, two predictors (change in exercise capacity and sputum output) contributed significantly to the change in QoL and collectively explained 54% of the variance in QoL. Lung function provides a limited index of treatment outcome. Exercise capacity and quality of life assessment have the potential to make a significant contribution to the decision making process regarding treatment choices in cystic fibrosis and should be measured directly if a comprehensive evaluation of the effect of treatment is required.
Hypersomnia following uvulopalatopharyngoplasty for snoring
Authors: R.P. Smith, J-L. Pépin, J.R. Catterall, P.A. Lévy
Journal: European Respiratory Journal (1999)

This report describes three cases who underwent uvulopalatopharyngoplasty for severe snoring and who subsequently developed progressive excessive daytime sleepiness. All three cases were shown to have sleep fragmentation as a result of non-apnoeic episodic upper airway narrowing. These cases raise the possibility that increased upper airway resistance during sleep may be exacerbated or even caused by uvulopalatopharyngoplasty. Ideally, sleep-disordered breathing should be carefully excluded before this surgery is offered as treatment for severe snoring.