tbuckley/cabot-search huggingface dataset:
Kinetics of neurodegeneration based on a risk-related biomarker in animal model of glaucoma
Authors: Takuya Hayashi, Masamitsu Shimazawa, Hiroshi Watabe, Takayuki Ose, Yuta Inokuchi, Yasushi Ito, Hajime Yamanaka, Shin-ichi Urayama, Yasuyoshi Watanabe, Hideaki Hara, Hirotaka Onoe
Journal: Molecular Neurodegeneration (2013)

Neurodegenerative diseases including Parkinson's and Alzheimer's diseases progress slowly and steadily over years or decades. They show significant between-subject variation in progress and clinical symptoms, which makes it difficult to predict the course of long-term disease progression with or without treatments. Recent technical advances in biomarkers have facilitated earlier, preclinical diagnoses of neurodegeneration by measuring or imaging molecules linked to pathogenesis. However, there is no established "biomarker model" by which one can quantitatively predict the progress of neurodegeneration. Here, we show predictability of a model with risk-based kinetics of neurodegeneration, whereby neurodegeneration proceeds as probabilistic events depending on the risk. We used five experimental glaucomatous animals, known for causality between the increased intraocular pressure (IOP) and neurodegeneration of visual pathways, and repeatedly measured IOP as well as white matter integrity by diffusion tensor imaging (DTI) as a biomarker of axonal degeneration. The IOP in the glaucomatous eye was significantly increased than in normal and was varied across time and animals; thus we tested whether this measurement is useful to predict kinetics of the integrity. Among four kinds of models of neurodegeneration, constant-rate, constant-risk, variable-risk and heterogeneity models, goodness of fit of the model and F-test for model selection showed that the time course of optic nerve integrity was best explained by the variable-risk model, wherein neurodegeneration kinetics is expressed in an exponential function across cumulative risk based on measured IOP. The heterogeneity model with stretched exponential decay function also fit well to the data, but without statistical superiority to the variable-risk model. The variable-risk model also predicted the number of viable axons in the optic nerve, as assessed by immunohistochemistry, which was also confirmed to be correlated with the pre-mortem integrity of the optic nerve. In addition, the variable-risk model identified the disintegrity in the higher-order visual pathways, known to underlie the transsynaptic degeneration in this disease. These findings indicate that the variable-risk model, using a risk-related biomarker, could predict the spatiotemporal progression of neurodegeneration. This model, virtually equivalent to survival analysis, may allow us to estimate possible effect of neuroprotection in delaying progress of neurodegeneration.
Human alveolar macrophages present antigen ineffectively due to defective expression of B7 costimulatory cell surface molecules.
Authors: C J Chelen, Y Fang, G J Freeman, H Secrist, J D Marshall, P T Hwang, L R Frankel, R H DeKruyff, D T Umetsu
Journal: Journal of Clinical Investigation (1995)

Alveolar macrophages, resident phagocytic cells in the lung that derive from peripheral blood monocytes, are paradoxically ineffective in presenting antigen to T cells. We found that antigen presentation by alveolar macrophages could be restored by the addition of anti-CD28 mAb to cultures of T cells and macrophages, indicating that costimulation by alveolar macrophages via the CD28 pathway was defective. In addition, we found that alveolar macrophages activated with IFN-gamma failed to express B7-1 or B7-2 antigens, which normally ligate CD28 on T cells and provide a costimulatory signal required for the activation of T cells. These observations are the first to demonstrate the inability of a "professional" antigen-presenting cell type to effectively express the costimulatory molecules B7-1 and B7-2. Inasmuch as immune reactions within the lung are inevitably associated with inflammatory injury to pulmonary tissue, these observations suggest that reduced expression of B7-1 and B7-2 by alveolar macrophages may be advantageous, as a critical mechanism involved in the induction of peripheral tolerance to the abundance of antigens to which mucosal tissues are continuously exposed.
Proliferating alveolar macrophages in BAL and lung function changes in interstitial lung disease
Authors: A Pforte, C Gerth, A Voss, B Beer, K Haussinger, U Jutting, G Burger, HW Ziegler-Heitbrock
Journal: European Respiratory Journal (1993)

In interstitial lung disease, the number of alveolar macrophages (AMs) can be increased. This may be caused by recruitment of precursor cells from peripheral blood and/or local proliferation in the lung. We therefore analysed proliferation, by studying both the expression of the nuclear proliferation antigen, Ki67, and the deoxyribonucleic acid (DNA) content, using the Feulgen reaction followed by cytometry. The patients had interstitial lung disease, i.e. sarcoidosis (n = 20), extrinsic allergic alveolitis (n = 20), idiopathic lung fibrosis or lung involvement in collagen-vascular disease (n = 19). In all patient groups there was a significant increase in proliferating AMs compared to healthy controls (4.2 versus 1.4% Feulgen, 2.1 versus 0.5% Ki67), with a significant correlation between these two parameters. A positive correlation was also found in bronchoalveolar lavage (BAL) between numbers of lymphocytes and proliferating cells in sarcoidosis and in fibrosis. In fibrosis, numbers of eosinophils and proliferating cells were also positively correlated. Our main finding was, however, a positive correlation between numbers of proliferating cells (Feulgen) and lung function parameters, especially vital capacity and oxygen tension (PO2) at rest, in patients with sarcoidosis and lung fibrosis. By contrast, in extrinsic allergic alveolitis, no correlation could be observed between proliferating cells and cell population or lung function. Our results suggest that local proliferation of macrophages is an important element in interstitial lung disease.
Association between VEGF Splice Isoforms and Progression-Free Survival in Metastatic Colorectal Cancer Patients Treated with Bevacizumab
Authors: David O. Bates, Paul J. Catalano, Kirsty E. Symonds, Alex H.R. Varey, Pramila Ramani, Peter J. O'Dwyer, Bruce J. Giantonio, Neal J. Meropol, Al Bowen Benson, Steven J. Harper
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF165b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF165b levels treated with bevacizumab. Experimental Design: Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF165b and VEGFtotal by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF165b:VEGFtotal for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio. Results: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF165b:VEGFtotal ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P &amp;lt; 0.02), but no effect of bevacizumab on PFS in patients with VEGF165b:VEGFtotal ratio &amp;gt;median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF165b group, but this did not reach statistical significance. There was no difference in the high VEGF165b:VEGFtotal group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3months). Conclusion: Low VEGF165b:VEGFtotal ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. Clin Cancer Res; 18(22); 6384–91. ©2012 AACR.
Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin
Authors: Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory
Journal: Journal of Clinical Investigation (2008)

Apoptosis is a noninflammatory, programmed form of cell death. One mechanism underlying the non-phlogistic nature of the apoptosis program is the swift phagocytosis of the dying cells. How apoptotic cells attract mononuclear phagocytes and not granulocytes, the professional phagocytes that accumulate at sites of inflammation, has not been determined. Here, we show that apoptotic human cell lines of diverse lineages synthesize and secrete lactoferrin, a pleiotropic glycoprotein with known antiinflammatory properties. We further demonstrated that lactoferrin selectively inhibited migration of granulocytes but not mononuclear phagocytes, both in vitro and in vivo. Finally, we were able to attribute this antiinflammatory function of lactoferrin to its effects on granulocyte signaling pathways that regulate cell adhesion and motility. Together, our results identify lactoferrin as an antiinflammatory component of the apoptosis milieu and define what we believe to be a novel antiinflammatory property of lactoferrin: the ability to function as a negative regulator of granulocyte migration.
Identification of Decatenation G2 Checkpoint Impairment Independently of DNA Damage G2 Checkpoint in Human Lung Cancer Cell Lines
Authors: Taku Nakagawa, Yoji Hayashita, Ken Maeno, Akira Masuda, Nobuyoshi Sugito, Hirotaka Osada, Kiyoshi Yanagisawa, Hiromichi Ebi, Kaoru Shimokata, Takashi Takahashi
Journal: Cancer Research (2004)

Abstract It has been suggested that attenuation of the decatenation G2 checkpoint function, which ensures sufficient chromatid decatenation by topoisomerase II before entering into mitosis, may contribute to the acquisition of genetic instability in cancer cells. To date, however, very little information is available on this type of checkpoint defect in human cancers. In this study, we report for the first time that a proportion of human lung cancer cell lines did not properly arrest before entering mitosis in the presence of a catalytic, circular cramp-forming topoisomerase II inhibitor ICRF-193, whereas the decatenation G2 checkpoint impairment was present independently of the impaired DNA damage G2 checkpoint. In addition, the presence of decatenation G2 checkpoint dysfunction was found to be associated with diminished activation of ataxia-telangiectasia mutated in response to ICRF-193, suggesting the potential involvement of an upstream pathway sensing incompletely catenated chromatids. Interestingly, hypersensitivity to ICRF-193 was observed in cell lines with decatenation G2 checkpoint impairment and negligible activation of ataxia-telangiectasia mutated. These findings suggest the possible involvement of decatenation G2 checkpoint impairment in the development of human lung cancers, as well as the potential clinical implication of selective killing of lung cancer cells with such defects by this type of topoisomerase II inhibitor.
Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events
Authors: Adam E. Mullick, Katrin Soldau, William B. Kiosses, Thomas A. Bell, Peter S. Tobias, Linda K. Curtiss
Journal: The Journal of Experimental Medicine (2008)

Toll-like receptors (TLRs) are pattern recognition receptors of innate immunity. TLRs initiate inflammatory pathways that may exacerbate chronic inflammatory diseases like atherosclerosis. En face laser scanning confocal microscopy (LSCM) of isolated aortic segments revealed the distribution of intimal TLR2 expression and the atheroprotective outcomes resulting from a TLR2 deficiency. TLR2 expression was restricted to endothelial cells in regions of disturbed blood flow, such as the lesser curvature region, in atherosclerosis-prone, low-density lipoprotein receptor–deficient (LDLr−/−) mice. Diet-induced hyperlipidemia in LDLr−/− mice increased this regional endothelial TLR2 expression. Bone marrow (BM) reconstitution of LDLr−/− and LDLr−/−TLR2−/− mice created chimeric mice with green fluorescent protein (GFP) expression in BM-derived cells (BMGFP+). Lesser curvature BMGFP+ leukocyte accumulation, lipid accumulation, foam cell generation and endothelial cell injury were all increased by hyperlipidemia, whereas hyperlipidemic double mutant BMGFP+LDLr−/−TLR2−/− mice had reduced BMGFP+ leukocyte accumulation, lipid accumulation, foam cells, and endothelial cell injury. This is the first report of in vivo site-specific expression of endothelial cell TLR2. Expression of this receptor on endothelial cells contributed to early atherosclerotic processes in lesion-prone areas of the mouse aorta.
&lt;emph type="ital"&gt;Ginkgo biloba&lt;/emph&gt; for Prevention of Dementia&lt;subtitle&gt;A Randomized Controlled Trial&lt;/subtitle&gt;
Authors: Steven T. DeKosky
Journal: JAMA (2008)

<h3>Context</h3>Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G biloba on dementia incidence are lacking.<h3>Objective</h3>To determine effectiveness of G biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).<h3>Design, Setting, and Participants</h3>Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia.<h3>Intervention</h3>Twice-daily dose of 120-mg extract of G biloba (n = 1545) or placebo (n = 1524).<h3>Main Outcome Measures</h3>Incident dementia and AD determined by expert panel consensus.<h3>Results</h3>Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39).<h3>Conclusions</h3>In this study, G biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00010803
Clouds of Oxygen: Adolescents With Cancer Tell Their Story in Music
Authors: Andrea Ferrari, Laura Veneroni, Carlo Alfredo Clerici, Michela Casanova, Stefano Chiaravalli, Chiara Magni, Roberto Luksch, Monica Terenziani, Filippo Spreafico, Daniela Polastri, Cristina Meazza, Serena Catania, Elisabetta Schiavello, Veronica Biassoni, Marta Podda, Luca Bergamaschi, Nadia Puma, Carla Moscheo, Giacomo Gotti, Maura Massimino
Journal: Journal of Clinical Oncology (2014)

Andrea Ferrari, Michela Casanova, Stefano Chiaravalli, Chiara Magni, Roberto Luksch, Monica Terenziani, Filippo Spreafico, Daniela Polastri, Cristina Meazza, Serena Catania, Elisabetta Schiavello, Veronica Biassoni, Marta Podda, Luca Bergamaschi, Nadia Puma, Carla Moscheo, Giacomo Gotti, Maura Massimino, Fondazione IRCCS Istituto Nazionale Tumori; Laura Veneroni, Carlo Alfredo Clerici, University of Milan, Milan, Italy.
Ethics of placebo controlled studies of inhaled steroids for COPD
Authors: D L Hahn
Journal: Thorax (2004)

The meta-analysis by Sutherland et al 1 of the effect of inhaled corticosteroids on the progression of airflow limitation in patients with chronic obstructive pulmonary disease (COPD) found a small improvement in forced expiratory volume in 1 second (FEV1) of −7.7 ml/year (95% CI −14.2 to −1.3) which is similar to the results of the meta-analysis performed by Highland et al 2 (−5 ml/year (95% CI −11.2 to 1.2)) using a very similar data set. The meta-analyses employed slightly different study selection criteria and analytical techniques, and questioned the clinical significance of such small differences in FEV1. The selected primary studies suffered from potential drop-out bias and significant selection bias, in that almost all of the studies subjected to these meta-analyses excluded patients with a bronchodilator response.2 Studies of asthma and COPD as separate entities are limited because asthma and COPD (observed in cross section) represent a continuum,3 and the small number of available prospective observations indicates that asthma and COPD are sometimes different clinical manifestations of the same underlying aetiology evolving over time.4 Given all the uncertainties, questions and limitations, Highland et al 2 concluded (correctly in my opinion) that “additional studies are needed …
Detection of human papillomavirus and response to topical 5% imiquimod in a case of stucco keratosis
Authors: E. Stockfleth, J. Röwert, R. Arndt, E. Christophers, T. Meyer
Journal: British Journal of Dermatology (2000)

Stucco keratosis is a skin disorder with papular warty lesions that usually appear on the lower limbs in elderly people. The aetiology, pathogenesis and treatment is still a matter of debate. We report a 75-year-old non-immunosuppressed man with extensive lesions all over his body, which had not responded to curettage or electrodesiccation. To determine the possible role of human papillomavirus (HPV) in stucco keratosis, we used nested polymerase chain reaction (PCR) to identify HPV DNA in the lesions. To include a broad range of both cutaneous and mucosal HPV types, PCR was performed with two sets of degenerate primers. Using this approach we detected HPV types 9, 16, 23b, DL322 and a variant of HPV type 37 in multiple stucco keratoses. Imiquimod (5% cream), a new compound that modifies the immune response by stimulating production of cytokines, applied overnight, three times a week for 5 weeks, resulted in resolution of all treated lesions.
Peptic ulceration in Crohn's disease (regional enteritis)
Authors: J. F. Fielding, W. T. Cooke
Journal: Gut (1970)

The incidence of peptic ulceration in a personal series of 300 patients with Crohn9s disease was 8%. Resection of 60 or more centimetres of the small intestine was associated with significantly increased acid output, both basally and following pentagastrin stimulation. Only five (4%) of the 124 patients who received steroid steroid therapy developed peptic ulceration. It is suggested that resection of the distal small bowel may be a factor in the probable increase of peptic ulceration in Crohn9s disease.
Selective activation of TACI by syndecan-2
Authors: Daniela Bischof, Sherine F. Elsawa, George Mantchev, Juhan Yoon, Grace E. Michels, Allan Nilson, Shari L. Sutor, Jeffrey L. Platt, Stephen M. Ansell, Gotz von Bulow, Richard J. Bram
Journal: Blood (2005)
Sports medicine handbook.: Eds R Hackney, A Wallace. (Pp 512; pound75.00.) BMA House, Tavistock Square, London WC1H 9JR: BMJ Books, 1999. ISBN 0-7279-1031-0.
Authors: Desmond Thompson
Journal: British Journal of Sports Medicine (2000)

Having recently taken up the post as medical officer to a 2nd division football club, I was pleased to have a chance to read and review this book, hoping it would plug the not inconsiderable gaps in my knowledge. It covers almost the whole spectrum of sports medicine, from training, stretching, and drugs, through the management of injuries in …
Adjuvant Cisplatin Plus Methotrexate Versus Methotrexate, Vinblastine, Epirubicin, and Cisplatin in Locally Advanced Bladder Cancer: Results of a Randomized, Multicenter, Phase III Trial (AUO-AB 05/95)
Authors: Jan Lehmann, Margitta Retz, Christina Wiemers, Joachim Beck, Joachim Thüroff, Christoph Weining, Peter Albers, Detlef Frohneberg, Tanja Becker, Peter-Jörg Funke, Peter Walz, Sigrun Langbein, Frank Reiher, Matthias Schiller, Kurt Miller, Stephan Roth, Tilman Kälble, Donald Sternberg, Stefan Wellek, Michael Stöckle
Journal: Journal of Clinical Oncology (2005)

Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy.A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm(2) on day 1 and methotrexate 40 mg/qm(2) on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm(2) on days 1, 15, and 22, vinblastine 3 mg/qm(2) on days 2, 15, and 22, epirubicin 45 mg/qm(2) on day 2, and cisplatin 70 mg/qm(2) on day 2 of a 28-day cycle (M-VEC).The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (alpha = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates +/- SE) for CM versus M-VEC were 46.3% +/- 4.6% v 48.8% +/- 4.5%, 52.0% +/- 4.6% v 52.3% +/- 4.8%, and 46.1% +/- 4.3% v 45.1% +/- 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001).CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.