tbuckley/cabot-search huggingface dataset:
Noncalcemic Actions of Vitamin D Receptor Ligands
Authors: Sunil Nagpal, Songqing Na, Radhakrishnan Rathnachalam
Journal: Endocrine Reviews (2005)

1α,25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the active metabolite of vitamin D3, is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)2D3 and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)2D3 are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)2D3 in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
Mental models and syllogisms
Authors: P. N. Johnson-Laird, Ruth M. J. Byrne
Journal: Behavioral and Brain Sciences (1996)

We resolve the two problems that Hardman raises. The first problem arises from a misunderstanding: the crucial distinction is between one-model and multiple-model problems. The second problem illuminates a deeper principle: conclusions depend on the procedures for interpreting models. We describe an algorithm that obviates the problem and empirical work that reveals a new view of syllogistic reasoning.
Milk Fat Globule Protein Epidermal Growth Factor-8
Authors: Zongming Fu, Mingyi Wang, Marjan Gucek, Jing Zhang, James Wu, Liqun Jiang, Robert E. Monticone, Benjamin Khazan, Richard Telljohann, Julie Mattison, Simon Sheng, Robert N. Cole, Gaia Spinetti, Gianfranco Pintus, Lijuan Liu, Frank D. Kolodgie, Renu Virmani, Harold Spurgeon, Donald K. Ingram, Allen D. Everett, Edward G. Lakatta, Jennifer E. Van Eyk
Journal: Circulation Research (2009)

Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMCs from old rats. Treatment of VSMCs with MFG-E8 increases MCP-1 expression and VSMCs invasion that are inhibited by the MCP-1 receptor blocker vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMCs invasion capacity. The data indicate that arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the angiotensin II/MCP-1/VSMC invasion signaling cascade. Thus, targeting of MFG-E8 within this signaling axis pathway is a potential novel therapy for the prevention and treatment of the age-associated vascular diseases such as atherosclerosis.
Latex allergy: characterization of major allergens and isotypic expression
Authors: H Chardin, C Mayer, Fx Desvaux, H Sénéchal, G Peltre, H Chardin
Journal: Allergy (1999)

Latex allergy is now known to be related to type I hypersensitivity. In latex products, several reports have identified at least 10 allergens. However, 56 polypeptides have been shown to react to IgE by two‐dimensional gel electrophoresis and immunoprints. All studies using immunoprints have analyzed a relatively small number of sera. The aim of the present study was to analyze the specificity and the isotypic expression of a wide sample of latex‐sensitive patients. Latex proteins were separated by SDS–PAGE in an 8–18% gel gradient, transferred onto a nitrocellulose sheet by Western blot, and revealed by serum from latex‐sensitive patients. The presence of IgE, IgA, IgG1, IgG2, IgG3, and IgG4 was analyzed for each of the 54 sera. The results showed Hev b 3 to be the most frequently recognized protein, followed by Hev b 1, Hev b 7, and molecules of 94 kDa and 6–8 kDa. The most common isotypic association was IgE‐IgG1, frequently with IgA. IgG4 was also present in a little less than half of the IgE‐positive sera. IgG3 was also expressed but frequently recognized nonallergenic molecules. IgG2 was present in only two cases. Thus, as several authors have proposed a protective role for IgG in the allergic reaction, it may be of interest to compare these results with the course of the disease.
Cigarette smoke extract suppresses the maturation and function of bone marrow derived dendritic cells
Authors: Masoumeh Givi, Frank Redegeld, Gert Folkerts, Esmaeil Mortaz
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. Cigarette smoke has been considered as a major risk factor in the pathogenesis of COPD. The potential role of DCs in the the respiratory tract of smoker9s and COPD patients is poorly understood. In aim of this study is to investigate the effects of cigarette smoke extract (CSE) on the maturation, development and function of mouse bone marrow. Bone marrow derived DCs were developed by culturing isolated cells by femurs of BALB/c mice in presence of GM-CSF (20 ng/ml) for 10 days. CSE was added to cells cultures for 10 days. The surface expression of maturation and co-stimulatory markers were CD11C-MHC11-CD83 and CD86, CD40 and CD80, respectively, as measured by FACS analysis. The functional capacity of DCs was measured by uptake of Dextran-FITC as maesured by FACS analysis. The production of TNF-a, IL-6 and IL-12 was measured by ELISA. After 10 days of incubation with CSE, the DCs maturation was significantly decreased (MHCII/CD11C compared to control, P≤0.05) and co-stimulatory receptors (CD11C/CD 86, CD11C/CD40 compared to control, P≤ 0.05). The cytokine production did not differ between the experimental groups. However, restimulation with CSE resulted is significant less cytokine production of DCs that had been exposed to CSE for 10 days compared to the non exposed cells. In addition, the uptake of FITC-Dextran was significantly decreased in DCs that had been exposed for 10 days to CSE. It cannot be excluded that the exacerbations in COPD patients might be due to a decreased maturation, development and function of DCs induced by cigarette smoke.
Improved functional recovery by ischaemic preconditioning is not mediated by adenosine in the globally ischaemic isolated rat heart
Authors: A. C Cave, C. S Collis, J. M Downey, D. J Hearse
Journal: Cardiovascular Research (1993)

Objective: A brief period of ischaemia (5 min) and reperfusion (5 min), prior to a longer period of ischaemia and reperfusion, has been shown to reduce the extent of injury (necrosis, arrhythmias, or postischaemic contractile malfunction) caused by a subsequent longer period of ischaemia and reperfusion. Adenosine has been identified as a factor in the protection afforded against regional tissue necrosis by such preconditioning. The aim of this study was to assess the role of adenosine in preconditioning induced protection of postischaemic function in the globally ischaemic isolated rat heart. Methods: The ability of global ischaemia to precondition against postischaemic contractile malfunction was first confirmed in the isolated ejecting rat heart preparation. Hearts (n=6 per group) were perfused aerobically (37°C, paced at 350 beats·min−1) for 20 min, at the end of which contractile function was measured. This was followed by 10 min of Langendorff perfusion (control group) or 5 min of global ischaemia plus 5 min of Langendorff reperfusion (preconditioned group). The hearts were then subjected to 20 min of global ischaemia (37°C) and 35 min of reperfusion (15 min Langendorff and 20 min ejecting); function was then reassessed. Results: Postischaemic recovery of aortic flow was 26(SEM 8)% in the control group v 57(4)% in the preconditioned group (p<0.05). To assess whether exogenous adenosine could mimic this protection, the experiments were repeated with the 5 min period of ischaemic preconditioning replaced by 5 min of aerobic Langendorff perfusion with adenosine-containing buffer (100, 50, or 10 μ-mol·litre−1). No protection of postischaemic function was observed in any of the adenosine treated groups. In further experiments, we assessed whether ischaemic preconditioning persisted in the presence of the A1/A2adenosine antagonist, 8 (p-sulphophenyl) theophylline (8-SPT). Since pacing was not used in these studies, the ability of ischaemia to precondition the myocardium was again confirmed; the protocol was then repeated with 8-SPT (10 μmol·litre−1) present in the perfusate throughout. Although 8-SPT depressed recovery in both control and preconditioned hearts it failed to abolish the protective effects of ischaemic preconditioning. Conclusions: There is no evidence from these results to support the involvement of adenosine to any major extent in preconditioning induced protection of postischaemic contractile function in the isolated rat heart. Cardiovascular Research 1993;27:663-668
Long-term follow-up high-resolution CT findings in non-specific interstitial pneumonia
Authors: M. Akira, Y. Inoue, T. Arai, T. Okuma, Y. Kawata
Journal: Thorax (2010)

<h3>Background</h3> The aims of this study were to retrospectively assess the change in findings on follow-up CT scans of patients with non-specific interstitial pneumonia (NSIP; median, 72 months; range, 3–216 months) and to clarify the correlation between the baseline CT findings and mortality. <h3>Methods</h3> The study included 50 patients with a histologic diagnosis of NSIP. Two observers evaluated the high-resolution CT (HRCT) findings independently and classified each case into one of the following three categories: (1) compatible with NSIP, (2) compatible with UIP or (3) suggestive of alternative diagnosis. The correlation between the HRCT findings and mortality was evaluated using the Kaplan–Meier method and the log-rank test, as well as Cox proportional hazards regression models. <h3>Results</h3> Ground-glass opacity and consolidation decreased, whereas coarseness of fibrosis and traction bronchiectasis increased on the follow-up HRCT scans, however, in 78% of cases the overall extent of parenchymal abnormalities had no change or decreased. Patients with HRCT diagnosed compatible with NSIP had a longer survival than those with HRCT findings more compatible UIP or an alternative diagnosis. On multivariate analysis, the coarseness of fibrosis alone was associated with prognosis (HR: 1.480; 95% CIs 1.100 to 1.990). <h3>Conclusions</h3> The HRCT patterns seen in patients with a histopathologic diagnosis of NSIP progress in a variable manner. Overall disease extent may decrease over time in some, while fibrosis may progress in others. The initial HRCT diagnosis may impact survival in this group of patients.
Importance of total serum IgE for improvement in airways hyperresponsiveness with inhaled corticosteroids in asthma and chronic obstructive pulmonary disease. The Dutch CNSLD Study Group.
Authors: H A Kerstjens, J P Schouten, P L Brand, D F Schoonbrood, P J Sterk, D S Postma
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Airways hyperresponsiveness is a hallmark of asthma, and many patients with COPD also demonstrate hyperresponsiveness. Inhaled corticosteroids improve hyperresponsiveness, but the extent of improvement may vary considerably between patients. This study was designed to determine which patient characteristics predict these differences in response. Patients with mild to moderately severe obstructive airways disease (asthma and COPD) were selected if PC20 < or = 8 mg/ml and FEV1 < 95% confidence interval of predicted normal. They were followed for 2.5 yr, during which one-third received inhaled corticosteroids. The independent influences of baseline FEV1/IVC, bronchodilator response, PC20, smoking habits, allergy, age, and sex on the improvement in airways hyperresponsiveness with inhaled corticosteroids were analyzed. Total serum IgE was taken as a parameter of allergy, next to specific IgE for house dust mite, skin tests, and blood eosinophils. Total serum IgE was found to be the most important and single independent predictor of change in PC20 with inhaled corticosteroids: patients with a higher IgE had a greater increase in PC20 when administered inhaled corticosteroids than those with lower IgE levels. Alternatively, patients with a higher IgE who did not receive corticosteroids had a decrease in PC20 compared with patients with a lower IgE. This effect was most prominent in asthma but was inconsistent in asthmatic bronchitis and COPD. The level of IgE cannot be used to predict the response to inhaled corticosteroids in individuals accurately. Total serum IgE is the single most important predictor of change in PC20 with and without inhaled corticosteroids.(ABSTRACT TRUNCATED AT 250 WORDS)
Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial
Authors: Alexander GG Turpie, Michael R Lassen, Bruce L Davidson, Kenneth A Bauer, Michael Gent, Louis M Kwong, Fred D Cushner, Paul A Lotke, Scott D Berkowitz, Tiemo J Bandel, Alice Benson, Frank Misselwitz, William D Fisher
Journal: The Lancet (2009)
First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors
Authors: Geoffrey I. Shapiro, Eunice Kwak, Bruce J. Dezube, Murray Yule, John Ayrton, John Lyons, Daruka Mahadevan
Journal: Clinical Cancer Research (2014)

AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.Standard 3+3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.Sixty-two patients were treated with doses ranging from 10 to 120 mg/m(2) twice weekly and 150 to 310 mg/m(2) once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m(2), which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m(2) as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.
The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy
Authors: Michael Goldstein, Michael B. Kastan
Journal: Annual Review of Medicine (2014)

Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.
Ca <sup>2+</sup> /Calmodulin-Dependent Kinase IIδ Causes Heart Failure by Accumulation of p53 in Dilated Cardiomyopathy
Authors: Haruhiro Toko, Hidehisa Takahashi, Yosuke Kayama, Toru Oka, Tohru Minamino, Sho Okada, Sachio Morimoto, Dong-Yun Zhan, Fumio Terasaki, Mark E. Anderson, Masashi Inoue, Atsushi Yao, Ryozo Nagai, Yasushi Kitaura, Toshiyuki Sasaguri, Issei Komuro
Journal: Circulation (2010)

Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown.We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function.CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.
Long-Term Treatment With <i> N <sup>ω</sup> </i> -Nitro- <scp>l</scp> -Arginine Methyl Ester Causes Arteriosclerotic Coronary Lesions in Endothelial Nitric Oxide Synthase-Deficient Mice
Authors: Osamu Suda, Masato Tsutsui, Tsuyoshi Morishita, Akihide Tanimoto, Masataka Horiuchi, Hiromi Tasaki, Paul L. Huang, Yasuyuki Sasaguri, Nobuyuki Yanagihara, Yasuhide Nakashima
Journal: Circulation (2002)

N(omega)-nitro-L-arginine methyl ester (l-NAME) is widely used to inhibit endothelial synthesis of NO in vivo. However, it is controversial whether the long-term vascular effects of l-NAME are mediated primarily by inhibition of endothelial NO synthesis. We addressed this point in mice that are deficient in the endothelial NO synthase gene (eNOS-KO mice).Wild-type and eNOS-KO mice received l-NAME in drinking water for 8 weeks. In wild-type mice, long-term treatment with l-NAME caused significant medial thickening and perivascular fibrosis in coronary microvessels but not in large coronary arteries. Importantly, in eNOS-KO mice, treatment with l-NAME also caused an extent of medial thickening and perivascular fibrosis in coronary microvessels that was comparable to that in wild-type mice and that was not prevented by supplementation of L-arginine. Vascular NO and cGMP levels were not significantly reduced by l-NAME treatment, and no expression of inducible or neuronal NO synthase was noted in microvessels of eNOS-KO mice, suggesting an involvement of NO-independent mechanisms. Treatment with l-NAME caused an upregulation of vascular ACE and an increase in cardiac lucigenin chemiluminescence that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or CS866 (angiotensin II type 1 receptor antagonist) along with the suppression of vascular lesion formation.These results provide the first direct evidence that the long-term vascular effects of l-NAME are not mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of local ACE and increased oxidative stress appear to be involved in the long-term vascular effects of l-NAME in vivo.