tbuckley/cabot-search huggingface dataset:
Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis: Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation
Authors: K. Tran-Lundmark, P.-K. Tran, G. Paulsson-Berne, V. Friden, R. Soininen, K. Tryggvason, T. N. Wight, M. G. Kinsella, J. Boren, U. Hedin
Journal: Circulation Research (2008)

Heparan sulfate (HS) has been proposed to be antiatherogenic through inhibition of lipoprotein retention, inflammation, and smooth muscle cell proliferation. Perlecan is the predominant HS proteoglycan in the artery wall. Here, we investigated the role of perlecan HS chains using apoE null (ApoE0) mice that were cross-bred with mice expressing HS-deficient perlecan (Hspg2(Delta3/Delta3)). Morphometry of cross-sections from aortic roots and en face preparations of whole aortas revealed a significant decrease in lesion formation in ApoE0/Hspg2(Delta3/Delta3) mice at both 15 and 33 weeks. In vitro, binding of labeled mouse triglyceride-rich lipoproteins and human LDL to total extracellular matrix, as well as to purified proteoglycans, prepared from ApoE0/Hspg2(Delta3/Delta3) smooth muscle cells was reduced. In vivo, at 20 minutes influx of human (125)I-LDL or mouse triglyceride-rich lipoproteins into the aortic wall was increased in ApoE0/Hspg2(Delta3/Delta3) mice compared to ApoE0 mice. However, at 72 hours accumulation of (125)I-LDL was similar in ApoE0/Hspg2(Delta3/Delta3) and ApoE0 mice. Immunohistochemistry of lesions from ApoE0/Hspg2(Delta3/Delta3) mice showed decreased staining for apoB and increased smooth muscle alpha-actin content, whereas accumulation of CD68-positive inflammatory cells was unchanged. We conclude that the perlecan HS chains are proatherogenic in mice, possibly through increased lipoprotein retention, altered vascular permeability, or other mechanisms. The ability of HS to inhibit smooth muscle cell growth may also influence development as well as instability of lesions.
Attenuation of myocardial reperfusion injury in pigs by Mirococept, a membrane-targeted complement inhibitor derived from human CR1
Authors: Y BANZ, O HESS, S ROBSON, E CSIZMADIA, D METTLER, P MEIER, A HAEBERLI, S SHAW, R SMITH, R RIEBEN
Journal: Cardiovascular Research (2007)

Membrane-targeted application of complement inhibitors may ameliorate ischemia/reperfusion (I/R) injury by directly targeting damaged cells. We investigated whether Mirococept, a membrane-targeted, myristoylated peptidyl construct derived from complement receptor 1 (CR1) could attenuate I/R injury following acute myocardial infarction in pigs.In a closed-chest pig model of acute myocardial infarction, Mirococept, the non-tailed derivative APT154, or vehicle was administered intracoronarily into the area at risk 5 min pre-reperfusion. Infarct size, cardiac function and inflammatory status were evaluated.Mirococept targeted damaged vasculature and myocardium, significantly decreasing infarct size compared to vehicle, whereas APT154 had no effect. Cardioprotection correlated with reduced serum troponin I and was paralleled by attenuated local myocardial complement deposition and tissue factor expression. Myocardial apoptosis (TUNEL-positivity) was also reduced with the use of Mirococept. Local modulation of the pro-inflammatory and pro-coagulant phenotype translated to improved left ventricular end-diastolic pressure, ejection fraction and regional wall motion post-reperfusion.Local modification of a pro-inflammatory and pro-coagulant environment after regional I/R injury by site-specific application of a membrane-targeted complement regulatory protein may offer novel possibilities and insights into potential treatment strategies of reperfusion-induced injury.
The Opportunities and Challenges of Developing Imaging Biomarkers to Study Lung Function and Disease
Authors: Daniel P. Schuster
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Recent advances in imaging offer exciting opportunities to develop and validate lung-specific biomarkers as valuable adjuncts to diagnosis, tests of treatment efficacy, and/or treatment monitoring. State-of-the-art structural, functional, and molecular imaging methods allow the lungs to be visualized noninvasively in vivo at submillimeter and subsecond spatial and temporal scales. However, the development and validation of imaging biomarkers present some special challenges, including the following: equipment evaluation, procedure standardization, data regarding reproducibility and replication, interrater variability, the production and measurement of reference standards, sensitivity to interventions or disease progression, intersubject variance, choice of image reconstruction and segmentation algorithms, automated versus observer-dependent image analysis, data acquisition during conditions of standardized lung volume, whether a reliable association can be demonstrated between the imaging biomarker and a clinical endpoint, and whether its use will have a favorable cost-effective impact on drug development or disease management. Establishing such performance characteristics, especially for single investigators at single institutions, can be daunting if not impossible for costly biomarkers such as imaging. Therefore, to take full advantage of the opportunities presented by state-of-the-art imaging methods, new approaches to analytic and clinical validation must be developed in collaboration with industry, foundation, and federal funding agencies.
Increased vascular endothelial growth factor in acute eosinophilic pneumonia
Authors: Y. Nishigaki, S. Fujiuchi, Y. Yamazaki, H. Matsumoto, A. Takeda, Y. Fujita, K. Okamoto, T. Fujikane, T. Shimizu, K. Kikuchi
Journal: European Respiratory Journal (2003)

Acute eosinophilic pneumonia (AEP) is associated with the presence of diffuse pulmonary infiltrates on the chest radiograph and an increased number of eosinophils and an elevation of interleukin (IL)‐5 levels in bronchoalveolar lavage (BAL) fluid. Vascular endothelial growth factor (VEGF) is a constitutively expressed protein encoded by messenger ribonucleic acid in human eosinophils and is released following stimulation with IL‐5. However, the roles of IL‐5 and VEGF in the pathogenesis or activity of this disease have not been clarified. The authors investigated the cells and the levels of these two factors in BAL fluid in five AEP patients and five normal controls before and after corticosteroid treatment. The absolute number of eosinophils·mL −1 , IL‐5 and VEGF levels in patients before treatment were higher than in controls (53.8 versus 0.3×10 4 ·mL −1 , 490.1 versus 5.2 pg·mL −1 and 643.0 versus 133.9 pg·mL −1 , respectively). IL‐5 and VEGF rapidly decreased to the control level in parallel with clinical improvement. The relationship between eosinophilia and IL‐5 and VEGF levels was strongly significant. Elevated interleukin‐5 in the lung may initiate the recruitment of eosinophils and enhance the release of mediators, such as vascular endothelial growth factor from eosinophils, which, in turn, increases the permeability of blood vessels.
Characterization of the dynamics of hepatitis B virus resistance to adefovir by ultra-deep pyrosequencing
Authors: Christophe Rodriguez, Stéphane Chevaliez, Paul Bensadoun, Jean-Michel Pawlotsky
Journal: Hepatology (2013)

Hepatitis B virus (HBV) resistance to nucleoside/nucleotide analogs is frequent. Ultra-deep pyrosequencing (UDPS) is a powerful new tool that can detect minor viral variants and characterize complex quasispecies mixtures. We used UDPS to analyze the dynamics of adefovir-resistant HBV variants in patients with chronic HBV infection in whom adefovir resistance occurred during treatment. Amino acid substitutions known to confer resistance to adefovir were detected at baseline in most patients. The dynamics of adefovir-resistant variants were complex and differed among patients as a result of evolving differences in variant fitness. UDPS analysis revealed successive waves of selection of HBV populations with single and multiple amino acid substitutions. Adefovir-resistant variants were partially inhibited by lamivudine, but remained fit in its presence. Conclusion: Substitutions conferring HBV resistance to nucleoside/nucleotide analogs exist before treatment, and that the dynamics of adefovir-resistant populations are much more complex and heterogeneous than previously thought and involve thus far unknown amino acid substitutions. The UDPS-based approach described here is likely to have important implications for the assessment of antiviral drug resistance in research and clinical practice. (Hepatology 2013;53:890–901)
Annual Report to the Nation on the Status of Cancer, 1975-2000, Featuring the Uses of Surveillance Data for Cancer Prevention and Control
Authors: Hannah K Weir, Michael J Thun, Benjamin F Hankey, Lynn A G Ries, Holly L Howe, Phyllis A Wingo, Ahmedin Jemal, Elizabeth Ward, Robert N Anderson, Brenda K Edwards
Journal: JNCI Journal of the National Cancer Institute (2003)

The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to update cancer rates and trends in the United States. This report updates statistics on lung, female breast, prostate, and colorectal cancers and highlights the uses of selected surveillance data to assist development of state-based cancer control plans.Age-adjusted incidence rates from 1996 through 2000 are from state and metropolitan area cancer registries that met NAACCR criteria for highest quality. Death rates are based on underlying cause-of-death data. Long-term trends and rates for major racial and ethnic populations are based on NCI and CDC data. Incidence trends from 1975 through 2000 were adjusted for reporting delays. State-specific screening and risk factor survey data are from the CDC and other federal and private organizations.Cancer incidence rates for all cancer sites combined increased from the mid-1970s through 1992 and then decreased from 1992 through 1995. Observed incidence rates for all cancers combined were essentially stable from 1995 through 2000, whereas the delay-adjusted trend showed an increase that had borderline statistical significance (P =.05). Increases in the incidence rates of breast cancer in women and prostate cancer in men offset a long-term decrease in lung cancer in men. Death rates for all cancer sites combined decreased beginning in 1994 and stabilized from 1998 through 2000, resulting in part from recent revisions in cause-of-death codes. Death rates among men continued to decline throughout the 1990s, whereas trends in death rates among women were essentially unchanged from 1998 through 2000. Analysis of state data for the leading cancers revealed mixed progress in achieving national objectives for improving cancer screening, risk factor reduction, and decreases in mortality.Overall cancer incidence and death rates began to stabilize in the mid- to late 1990s. The recent increase in the delay-adjusted trend will require monitoring with additional years of data. Further reduction in the burden of cancer is possible but will require the continuation of strong federal, state, local, and private partnerships to increase dissemination of evidence-based cancer control programs to all segments of the population.
Different mechanisms of cyclin D1 overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analysis of mRNA levels
Authors: Katja Specht, Eugenia Haralambieva, Karin Bink, Marcus Kremer, Sonja Mandl-Weber, Ina Koch, Raju Tomer, Heinz Hofler, Ed Schuuring, Philip M. Kluin, Falko Fend, Leticia Quintanilla-Martinez
Journal: Blood (2004)
Role of amifostine as a cytoprotectant in children ≥ 3 years with average risk (AR) medulloblastoma (MB) treated with craniospinal irradiation (CSI) and 4 courses of cisplatin (CDDP)-based high dose chemotherapy
Authors: M. Fouladi, M. Chintagumpala, D. Ashley, S. Kellie, A. Broniscer, T. E. Merchant, L. E. Kun, C. Stewart, D. Wallace, A. Gajjar
Journal: Journal of Clinical Oncology (2006)

9063 Background: Therapy for MB (CSI and CDDP-based chemotherapy) results in hearing loss before completion of therapy in 30%-50% of patients, who consequently require a reduced cisplatin dose. Cytoprotection against cisplatin-induced ototoxicity may be provided by amifostine, a thiol prodrug that protects many normal tissues against therapy-induced damage without diminishing antitumor effects. Method: This study was designed to detect a 20% decrease (80% power) in CDDP induced ototoxicity (defined as needing hearing aids) in AR MB patients with the use of amifostine (n=62) compared to historical controls (n=35) one year from diagnosis. An interim analysis was conducted after accrual of 32 pts on the experimental arm. A total of 67 AR MB patients received CSI (23.4 Gy) followed by 3-dimensional conformal boost to the tumor bed (total 55.8 Gy) and 4 cycles of high-dose cyclophsophamide (4,000 mg/m 2 per cycle), cisplatin (75 mg/m 2 per cycle), and vincristine (two 1.5 mg/m 2 doses per cycle). When used, amifostine (600 mg/m 2 per cycle) was given before and 3 hours into the cisplatin infusion. Results: The median age of the 40 male, 27 female patients was 8.7 (range, 3.2–20.2) yrs. The 2 groups had similar median ages (amifostine, 9.1; control, 7.8 years) and gender (male: amifostine, 66%; control, 54%). One year after the start of treatment, the objective criteria for needing a hearing aid in at least 1 ear were met by 13 (37%) of control-group patients and 6 (18.8%) of those who received amifostine. Conclusion: The interim analysis has demonstrated that the need for hearing aids in AR MB children treated with the above-described regimen is halved by using amifostine during CDDP administration. No significant financial relationships to disclose.
Ultrasound analysis of the effect of airways obstruction on diaphragm relaxation pattern
Authors: Alessandro Zanforlin, Andrea Smargiassi, Riccardo Inchingolo, Alessandro di Marco Berardino, Emilio Ramazzina
Journal: European Respiratory Journal (2013)

Diaphragm motion can be analysed with ultrasound using M-mode in anterior subcostal approach (Testa, A et al. Ultrasound Med Biol 2011;37:44-52). The diaphragm line during a forced expiration shows an initial drop off followed by a plateau in maximum expiration. Maximum expiratory diaphragmatic excursion (EDEMax) and forced expiratory diaphragmatic excursion in the first second (FEDE1) can be measured and considered as phisiopathological analogues of vital capacity (VC) and FEV1.  As the ratio FEV1/VC% is used as a marker of obstruction, the aim of our study was to assess if the ratio FEDE1/EDEMax% (M-mode Index of Obstruction [MIO]) is different between normal subjects and patients with obstructive spirometric pattern (Miller, MR. Eur Respir J. 2005;26:319-38).  4 operators in 2 centers examined with ultrasound the diaphragmatic motion of outpatients with known spirometric pattern using M-mode during a maximal forced expiration in semi supine position. FEDE1 and EDEMax were recorded and MIO calculated.  124 patients were examined, 61 normal and 63 obstructed. MIO values: in normal group 72.84 to 100, mean 87.08±6.64, median 87.21; in obstructed group 33.33 to 91.30, mean 67.09±12.49, median 70.48. MIO values of the two groups showed a minimum overlap and a significant difference (p  Ultrasound analysis of diaphragmatic motion could potentially identify an obstructive pattern, being a potential add-on screening technique for detecting airways obstruction.
Pragmatic randomized controlled trial of a structured allergy intervention for adults with asthma and rhinitis in general practice
Authors: H. Smith, D. Horney, S. Goubet, C. Jones, A. Raza, P. White, A. Frew
Journal: Allergy (2014)

Background It is widely believed that in patients with allergic rhinitis and asthma, avoidance of specific triggers can help improve symptom control and reduce need for medication. Whilst most patients with asthma or rhinitis are sensitized to airborne allergens, primary care diagnostic and management decisions are often made without either obtaining a detailed history of the patient's allergic triggers or performing skin prick tests. Thus, management decisions are empirical and allergen avoidance advice is either not given or, if given, not tailored to the patient's sensitivities. Method To ascertain whether allergy assessment and tailored advice in general practice for patients with asthma and rhinitis enhance well-being, we conducted a pragmatic, open, randomized controlled trial of allergy intervention (structured allergy history and skin prick testing and appropriate advice on allergy avoidance) versus usual care in adult patients with a working diagnosis of asthma and/or rhino-conjunctivitis. Outcomes were assessed after 12 months by an observer who was blinded to allocation. The main outcome measures were asthma and rhinitis symptoms, disease-specific health-related quality of life, generic quality of life and lung function. Results There were no significant differences in baseline demographics or disease characteristics between patients assigned to immediate or delayed skin prick testing. No significant differences were observed between groups for any measures of symptoms, quality of life or lung function at 12 months (all P > 0.05). Conclusion Amongst adults with known asthma and/or rhinitis in primary care, taking a structured allergy history with skin prick tests and giving tailored advice on allergy avoidance made no difference to their symptoms, quality of life or lung function as measured twelve months later.
Association between asthma and serum adiponectin concentration in women
Authors: A Sood, X Cui, C Qualls, W S Beckett, M D Gross, M W Steffes, L J Smith, D R Jacobs
Journal: Thorax (2008)

<h3>Background:</h3> The association of murine asthma with adiposity may be mediated by adiponectin, an anti-inflammatory adipokine with reduced serum concentrations in obese subjects. A study was undertaken to examine whether the serum adiponectin concentration is associated with human asthma and whether it explains the association between adiposity and asthma, particularly in women and in premenopausal women. <h3>Methods:</h3> A cross-sectional analysis was performed of 2890 eligible subjects at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and its YALTA ancillary study who had either current asthma or never asthma at that evaluation. Obesity was defined as body mass index (BMI) ⩾30 kg/m<sup>2</sup>. Multivariable logistic regression analysis was performed with current asthma status as the dependent variable. <h3>Results:</h3> Women, but not men, with current asthma had a lower mean unadjusted serum adiponectin concentration than those with never asthma (p&lt;0.001; p for sex interaction &lt;0.001). Similarly, current asthma was related to obesity only in women (OR 3.31, 95% CI 2.00 to 5.46, p for sex interaction = 0.004); this association was little affected by adjusting for serum adiponectin. The prevalence of current asthma in premenopausal women was reduced in the highest compared with the lowest tertile of serum adiponectin concentration (OR 0.46, 95% CI 0.26 to 0.84, p = 0.03), after adjusting for BMI. However, the interaction between serum adiponectin concentration and BMI category on current asthma status was not significant in premenopausal women or women overall. <h3>Conclusions:</h3> A high serum adiponectin concentration may protect against current asthma in premenopausal women but does not explain the association between asthma and adiposity.
Variants of CTGF are associated with hepatic fibrosis in Chinese, Sudanese, and Brazilians infected with Schistosomes
Authors: Alain Dessein, Christophe Chevillard, Violaine Arnaud, Xunya Hou, Anas Ahmed Hamdoun, Helia Dessein, Hongbin He, Suzan A. Abdelmaboud, Xinsong Luo, Jun Li, Arthur Varoquaux, Adil Mergani, Mohammed Abdelwahed, Jie Zhou, Ahmed Monis, Maira G.R. Pitta, Nagla Gasmelseed, Sandrine Cabantous, Yaqing Zhao, Aluizio Prata, Carlos Brandt, Nasr Eldin Elwali, Laurent Argiro, Yuesheng Li
Journal: The Journal of Experimental Medicine (2009)

Abnormal fibrosis occurs during chronic hepatic inflammations and is the principal cause of death in hepatitis C virus and schistosome infections. Hepatic fibrosis (HF) may develop either slowly or rapidly in schistosome-infected subjects. This depends, in part, on a major genetic control exerted by genes of chromosome 6q23. A gene (connective tissue growth factor [CTGF]) is located in that region that encodes a strongly fibrogenic molecule. We show that the single nucleotide polymorphism (SNP) rs9402373 that lies close to CTGF is associated with severe HF (P = 2 × 10−6; odds ratio [OR] = 2.01; confidence interval of OR [CI] = 1.51–2.7) in two Chinese samples, in Sudanese, and in Brazilians infected with either Schistosoma japonicum or S. mansoni. Furthermore, SNP rs12526196, also located close to CTGF, is independently associated with severe fibrosis (P = 6 × 10−4; OR = 1.94; CI = 1.32–2.82) in the Chinese and Sudanese subjects. Both variants affect nuclear factor binding and may alter gene transcription or transcript stability. The identified variants may be valuable markers for the prediction of disease progression, and identify a critical step in the development of HF that could be a target for chemotherapy.
Expression of the Receptor Tyrosine Kinase EphA2 Is Increased in Smokers and Predicts Poor Survival in Non–Small Cell Lung Cancer
Authors: Jennifer M. Brannan, Wenli Dong, Ludmila Prudkin, Carmen Behrens, Reuben Lotan, B. Nebiyou Bekele, Ignacio Wistuba, Faye M. Johnson
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Up-regulation of the receptor tyrosine kinase EphA2 has been shown in several epithelial cancers. Epidermal growth factor receptor (EGFR) and K-Ras have been reported to regulate EphA2 in several in vitro models, but this regulation has never been examined in tumors from patients. Because of the established importance of EGFR and K-Ras mutations in non–small cell lung cancer (NSCLC), we investigated the relationship between these mutations and EphA2 in this cancer type. The significance of EphA2 expression was further examined by testing for correlation with other clinical parameters. Experimental Design: EphA2 expression was analyzed by immunohistochemistry in tissue microarray format using surgically resected NSCLC specimens (n = 279). EGFR and K-Ras mutation status was determined for most specimens. The correlation between EphA2 expression and EGFR or K-Ras mutation status was examined, along with several clinicopathologic variables of the tumors. The effects of increasing EGFR and K-Ras activity on EphA2 expression and activity were examined in two cell lines. Results: EphA2 expression was detected in &amp;gt;90% of tumor samples. Expression of EphA2 was positively correlated with activated EGFR but not with EGFR mutations. EphA2 expression was increased in patients harboring K-Ras mutations. EphA2 expression was positively correlated with a history of smoking, and high EphA2 scores predicted poorer progression-free and overall survivals. Conclusions: EphA2 expression in NSCLC is associated with K-Ras mutations, EGFR activation, smoking history, and poor prognosis. EphA2 expression is up-regulated in the context of EGFR or K-Ras activation. The potential of EphA2 as a therapeutic target for NSCLC should be further investigated.