tbuckley/cabot-search huggingface dataset:
Development of an Autoimmune Syndrome Affecting the Skin and Internal Organs in P‐Selectin Glycoprotein Ligand 1 Leukocyte Receptor–Deficient Mice
Authors: A. Pérez‐Frías, R. González‐Tajuelo, N. Núñez‐Andrade, R. Tejedor, M. J. García‐Blanco, E. Vicente‐Rabaneda, S. Castañeda, C. Gamallo, J. Silván, A. Esteban‐Villafruela, L. Cubero‐Rueda, C. García‐García, C. Muñoz‐Calleja, A. García‐Diez, A. Urzainqui
Journal: Arthritis & Rheumatology (2014)

To define and characterize the progression of the spontaneous autoimmune disease that develops in mice in the absence of the leukocyte adhesion receptor P-selectin glycoprotein ligand 1 (PSGL-1).Skin-resident immune cells from PSGL-1-deficient mice and C57BL/6 control mice of different ages were isolated and analyzed by flow cytometry. Biochemical parameters were analyzed in mouse serum and urine, and the presence of serum autoantibodies was investigated. Skin and internal organs were extracted, and their structure was analyzed histologically.Skin-resident innate and adaptive immune cells from PSGL-1(-/-) mice had a proinflammatory phenotype with an imbalanced T effector cell:Treg cell ratio. Sera from PSGL-1(-/-) mice had circulating autoantibodies commonly detected in connective tissue-related human autoimmune diseases. Biochemical and histologic analysis of skin and internal organs revealed skin fibrosis and structural and functional abnormalities in the lungs and kidneys. Furthermore, PSGL-1(-/-) mice exhibited vascular alterations, showing loss of dermal vessels, small vessel medial layer remodeling in the lungs and kidneys, and ischemic processes in the kidney that promote renal infarcts.Our study demonstrates that immune system overactivation due to PSGL-1 deficiency triggers an autoimmune syndrome with characteristics similar to systemic sclerosis, including skin fibrosis, vascular alterations, and systemic organ involvement. These results suggest that PSGL-1 expression contributes to the maintenance of the homeostasis of the immune system and could act as a barrier for autoimmunity in mice.
Abstract 3696: Inhibition of OATP1B1 by tyrosine kinase inhibitors: <i>in vitro</i>-<i>in vivo</i> correlations
Authors: Shuiying Hu, Peter D. Bruijn, Ron H.j. Mathijssen, Sharyn D. Baker, Alex Sparreboom
Journal: Cancer Research (2014)

Abstract Background: Several tyrosine kinase inhibitors (TKIs) evaluated in combination regimens with docetaxel, including axitinib, pazopanib, and sorafenib, can increase the systemic exposure to taxane in cancer patients by an unknown mechanism. We previously reported that differential expression of organic anion transporting polypeptides of the OATP1B-family in the human liver regulate the initial, rate-limiting step in the elimination of docetaxel, in advance of metabolism. In the current study, we tested the hypothesis that these interactions are mediated by the hepatic uptake transporter OATP1B1 using in vitro and in vivo models. Materials and Methods: The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent OATP1B2, determined by assessing the effect of TKIs on the intracellular accumulation of estradiol-17β-D-glucuronide, or docetaxel. Contribution of this process to an interaction with docetaxel in vivo was determined by pharmacokinetic studies using mice that are knock-out for OATP1B2 or knock-in for OATP1B1. Results: Axitinib, nilotinib, pazopanib, and sorafenib were identified as potent inhibitors of OATP1B1 (&amp;gt;90% inhibition) when using estradiol-17β-D-glucuronide as a prototypical model substrate. As a representative of this class of TKIs, sorafenib was further evaluated and found to also potently inhibit OATP1B1-mediated transport of docetaxel with a half-inhibitory maximum concentration (IC50) of 6.96 nM, and almost completely inhibited the function of OATP1B1 and OATP1B2 at a concentration readily achievable in humans and mice. While OATP1B2-deficiency was associated with significantly increased exposure to docetaxel, as measured by peak plasma concentration (Cmax, P&amp;lt;0.05) and area under the curve (AUC, P&amp;lt;0.001), co-administration of a single or multiple oral dose of sorafenib did not result in statistically significantly altered exposure to docetaxel in either wildtype or OATP1B2 (-/-) mice. Conclusion: These findings support a direct contribution of OATP1B1 in previously recorded pharmacokinetic interactions between TKIs and docetaxel, which can be predicted from a simple in vitro experiment. Our failure to reproduce this interaction in mice suggests that caution is warranted when attempting to extrapolate in vivo findings to a clinical scenario. Citation Format: Shuiying Hu, Peter De Bruijn, Ron H.j. Mathijssen, Sharyn D. Baker, Alex Sparreboom. Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3696. doi:10.1158/1538-7445.AM2014-3696
Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study
Authors: Peter Hillmen, John G. Gribben, George A. Follows, Donald Milligan, Hazem A. Sayala, Paul Moreton, David G. Oscier, Claire E. Dearden, Daniel B. Kennedy, Andrew R. Pettitt, Amit Nathwani, Dena Cohen, Andy Rawstron, Christopher F.E. Pocock
Journal: Blood (2010)
Gene signature of cancer stem cells is manifested within an intrinsic subgroup of breast cancers with mesenchymal properties
Authors: Melissa Landis, Chad Creighton, Michael Lewis, Xiaoxian Li, Helen Wong, Anna Tsimelzon, Jason Herschko, Cheng Fan, Xiaping He, C. Kent Osborne, Anne Pavlick, J. Michael Dixon, Susan Hilsenbeck, Charles Perou, Jeffrey Rosen, Jenny Chang
Journal: Clinical Cancer Research (2008)

PL05-01    Background.  Breast cancer stem cells characterized by CD44 + /CD24 -/low  may be resistant to therapy and responsible for relapse. Mmammospheres (MSs) can be propogated as an  in vitro  surrogate assay for increased self-renewal. We set out to define a “signature” expression pattern associated with CD44 + /CD24 -/low , mammosphere-forming cells.   Methods.  Breast cancer biopsies (n=19) were digested, stained with CD24, CD44, and lineage antibodies, and analyzed by flow cytometry. A portion of the unsorted cells were plated under serum-free conditions to form MSs (n=16). Gene expression, using the Affymetrix U133 GeneChip platform, of cancer cells bearing CD44 + /CD24 -/low  vs.  other sorted cells, and between cancer MS  vs.  the primary invasive cancers were analyzed. Gene expression from two trials (neoadjuvant letrozole N=18, and docetaxel, N=12) were used as validation studies.   Results.  In the flow-sorted CD44 + /CD24 -/low  vs.  other cells, 1,424 named genes were elevated ( p  1.5, FDR=0.20). The comparison between MSs  vs.  primary cancers yielded 1,890 elevated genes (FDR=0.25). Between the two sets, 380 genes were in common, a highly significant overlap ( p =1E-5, one-sided Fisher’s exact). This overlap was ~40% greater than what would be expected (n=110) if the two sets had no biological relevance. Differential pathways included genes in PI3K/AKT signaling (PI3K3R3, ErbB3, FGFR2, PRLR), and the Notch pathway - a known regulator of normal and malignant stem/progenitor cells (Jagged-2, MAML2, Deltex, HES1). This signature was found exclusively activated in tumors of the recently identified “claudin-low” subtype, characterized by overexpression of many mesenchymal genes. Both signatures were validated in two independent data sets comparing the expression profiles of paired breast cancer core biopsies before vs. after letrozole or docetaxel chemotherapy.   Conclusion.  The mesenchymal association provides a possible explanation for the intrinsic resistance of breast cancer stem cells to therapy.
Abstract 13659: Development of a TransAtlantic Cardiovascular risk Calculator for Rheumatoid Arthritis (ATACC-RA)
Authors: Anne Grete Semb
Journal: Circulation (2014)

Introduction: Patients with rheumatoid arthritis (RA) have an increased risk of cardiovascular disease (CVD), which is not accurately predicted by risk calculators designed for the general population. Hypothesis: To develop a RA specific CVD risk calculator. Methods: The study population included RA patient cohorts from 8 centres in 7 countries. In all cases, data had been collected prospectively on CV outcomes (MI, revascularization, angina, stroke, TIA, PAD and CV death). At baseline RA characteristics (duration, seropositivity, disease activity (DAS28) and CRP/ESR) were collected in addition to traditional CV risk factors. Cox models stratified by centre were used to develop a CVD risk calculator considering traditional CV risk factors and RA characteristics. Model performance was assessed using measures of discrimination and calibration. Results: In total 3176 RA patients who did not have prior CVD were included (mean age: 55 [SD: 14] years, 73% female). During a mean follow-up of 7.8 years (24733 person years), 314 had a CVD event. The multivariable risk score modelling revealed 2 models including either seropositivity or DAS28 along with age, sex, current smoking, presence of hypertension, and ratio of total cholesterol to high-density lipoprotein (table). Both 10-fold cross validation and multiple imputation analyses confirmed these findings with little change to the estimated coefficients. Both models demonstrated good discrimination (c-statistic: 0.76 and 0.74) and calibration (observed/predicted ratio: 1.00; 95% confidence interval: 0.89, 1.12). The ATACC-RA (mean: 11.5%, SD 14.1%) showed significantly improved discrimination compared to either Framingham (c-statistic: 0.71, p&lt;0.001) or SCORE (c-statistic: 0.72, p&lt;0.001) risk algorithms. Conclusions: Development of an RA-specific CVD risk calculator is feasible by pooling resources from many centres. Further development including external validation is underway.
Abstract P013: Prevalence and Prognostic Impact of Kidney Dysfunction among Patients with Acute Decompensated Heart Failure in Community: The ARIC Community Surveillance
Authors: Kunihiro Matsushita, Noorie Hyun, Sunil K Agarwal, Laura R Loehr, Hanyu Ni, Patricia P Chang, Lisa M Wruck, Josef Coresh, Wayne D Rosamond
Journal: Circulation (2014)

Introduction: Several studies reported that kidney dysfunction is prevalent and is associated with poor prognosis in patients with acute decompensated heart failure (ADHF). However, most of these reports were from clinical trials or a single hospital, limiting their generalizability to clinical practice in the community. Methods: We tackled these questions using data from community-based surveillance for ADHF conducted as a part of the ARIC Study from 2005 to 2009 for residents aged ≥55 years in 4 US communities (Jackson, Mississippi; Washington County, Maryland; Minneapolis, Minnesota; and Forsyth County, North Carolina). All analyses were weighted to account for the stratified sampling design. The association of kidney function with mortality (in-hospital, 28-day, and 1-year) was assessed using logistic regression. The CKD-EPI equation with worst serum creatinine during hospitalization was used to calculate estimated glomerular filtration rate (eGFR), and persons from nonblack and nonwhite racial groups or with missing key variables were excluded. Results: Among 10,450 sampled hospitalizations, 3,651 ADHF events adjudicated as definite or probable were included in this analysis, corresponding to weighted 17,378 events after applying sample weights (average length of stay, 8.3 days). The prevalence of reduced eGFR (defined as &lt;60 ml/min/1.73m 2 ) was 83.4% overall, and 37.7% of ADHF cases had eGFR &lt;30. Lower eGFR, particularly eGFR &lt;30, was significantly associated with higher mortality during hospitalization or 1 year of follow-up independently of potential confounders (Table). The association was largely consistent across demographic and clinical subgroups. Conclusion: Severely reduced eGFR (&lt;30 ml/min/1.73m 2 ) was observed in ~38% of ADHF cases during hospitalization and was a strong predictor of poor prognosis during hospitalization or after discharge in community. These findings suggest that ADHF patients with kidney dysfunction warrant special attention in the management for ADHF.
226. Developing a CNS-Specific Inflammatory Model To Investigate Gene Therapy/Inflammation Interactions in the Context of Neurodegeneration
Authors: Michelle C. Janelsins, Michael A. Mastrangelo, Howard J. Federoff, William J. Bowers
Journal: Molecular Therapy (2004)

Top of pageAbstract
Gene therapy represents a promising modality that may have clinical merit for preventing and/or treating a variety of neurodegenerative diseases, such as Alzheimer's disease (AD), Multiple Sclerosis (MS), and Parkinson's disease (PD). These disorders have been shown to include an inflammatory component that could significantly influence the efficacy and safety profiles of gene-based therapies. Direct gene transfer into an inflamed brain may lead to reduced therapeutic gene expression, or even worse, exacerbation of inflammation. To better assess these therapies, it is essential that they be tested in a more appropriate context. We have devised a mouse model in which inflammation can be triggered in the brain in a temporal and spatial manner. This mouse, designated NSE-IFNγ/lacZ XAT, harbors a transcription unit that contains the neuron-specific enolase (NSE) promoter, a loxP site-flanked strong transcriptional/translational stop cassette, the cDNA encoding the IFNγ gene, an internal ribosomal entry sequence (IRES), the β-galactosidase reporter gene (lacZ) and a 3' untranslated regulatory region. An inflammatory process can be induced focally upon somatic delivery of cre recombinase or widely via crossing to a cre recombinase-expressing transgenic mouse. We have confirmed cre-mediated expression of IFNγ (ELISA) and β-galactosidase (Galacto-Lite Assay and X-gal staining) in vitro. Additionally, we have successfully created founder mice and have been able to transmit the transgene in the F1 generation. We are currently assessing the functionality of the construct in vivo. Ongoing studies in our laboratory include use of this mouse to assess the effects of inflammation on direct herpes simplex virus amplicon gene transfer in the brain and to understand how inflammation influences the safety and efficacy of peripheral gene-based vaccination for AD. Although our investigative group is primarily interested in understanding AD-related inflammatory cascades, this model can be applied to numerous CNS and peripheral diseases.
Abstract P082: Estimating Equation for Computed Tomography Derived Visceral Fat: The Multi-Ethnic Study of Atherosclerosis
Authors: Morgana L Mongraw-Chaffin, Mark Woodward, Matthew A Allison, Sherita H Golden, Richard Kronmal, Pamela Ouyang, Moyses Szklo, Cheryl A Anderson
Journal: Circulation (2014)

Background: The only way to determine visceral fat separately from subcutaneous fat is through magnetic resonance imaging (MRI) or computed tomography (CT) scans. The use of MRI or CT scans is unacceptable for screening in the general population. Given this, estimating equations for visceral fat that use commonly collected clinical variables have potential utility. Methods: Data are from 1842 participants, aged 45 to 84, from the Multi-Ethnic Study of Atherosclerosis with visceral fat assessed by CT scan at study visit 2 or 3, and anthropometry measured at matched visits. We excluded 19 participants with reported thiazolidinedione use, 11 with waist circumference greater than 140cm, and 5 with BMI greater than 45kg/m 2 . Visceral fat area, measured in cm 2 , was calculated as the average area from two CT scan slices at the L4/L5 vertebrae. Visceral fat was naturally log transformed to account for non-normality. Anthropometric indices included: height(cm), weight(kg), BMI(kg/m 2 ), waist circumference(cm), hip circumference(cm), waist to hip ratio, and waist to height ratio. Other variables included sex, Black, Asian, and Hispanic race/ethnicities, and age. Data were separated into training and testing datasets containing 2/3 and 1/3 of the data, respectively. Multivariable linear models were used to generate coefficients for the estimating equations and included non-linear and interaction terms. The PRESS statistic, R 2 , and RMSE were used to determine goodness of fit and likelihood ratio tests were used for variable and model selection. Results: Models including multiple measures of anthropometry performed better than models including only waist circumference or BMI. Models including non-linear terms for anthropometry and interaction by sex and race performed better than simple linear models. After analysis, the final estimating equation was: Ln Visceral Fat = -8.64 + 0.006*age - 8.42*sex - 8.53*black - 0.099*weight + 0.41*bmi + 0.022*waist + 0.029*hip + 8.58*waist/hip - 0.00396*bmi 2 +0.00015*waist 2 - 0.0003*hip 2 - 4.89*(waist/hip) 2 - 0.014*weight*sex - 0.066*waist*sex + 0.076*hip*sex + 8.57*(waist/hip)*sex - 0.097*waist*black + 0.088*hip*black + 10.31*(waist/hip)*black. The R 2 in the testing dataset for this model was 0.62. The estimates of visceral fat from the final equation provided estimates within 10% of measured values for nearly 90% of the observations. Conclusion: Our final model, that predicts visceral fat from CT scans, is highly parsimonious involving only seven variables that can be easily collected in the clinical setting. This practical equation might help improve the estimation of visceral fat in order to determine who is at greatest risk for CVD and who might benefit most from weight loss interventions.
Iron Stores as a Risk Factor for Diabetes in Women—Reply
Authors: Rui Jiang, JoAnn E. Manson, Frank B. Hu
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Effects of aclidinium on airway remodelling in guinea pigs chronically exposed to cigarette smoke
Authors: David Domínguez-Fandos, Raquel Puig-Pey, Elisabet Ferrer, Cristina Carreño, Mònica Aparici, Jorge Beleta, Neus Prats, Montserrat Miralpeix, Amadeu Gavaldà, Victor I. Peinado, Joan Albert Barberà
Journal: European Respiratory Journal (2011)

Introduction:  Exposure to cigarette smoke (CS) causes airway remodelling and airflow obstruction; it is a main risk factor in chronic obstructive pulmonary disease.   Aims:  To investigate whether aclidinium bromide, a novel muscarinic antagonist, reduces airway remodelling in guinea pigs chronically exposed to CS.   Methods:  Male guinea pigs (n=46) were divided into 2 groups: control (n=22) and exposed to CS (n=24; 6 cigarettes/day, 5 days/week for 24 weeks). Animals received nebulised vehicle, aclidinium 10μg/mL or aclidinium 30μg/mL 60 min before CS exposure. The thickness of the adventitia, muscularis and mucosal layers of the airway wall was measured by planimetry in immunostained sections. Emphysema and goblet cell metaplasia were evaluated using sections stained with haematoxylin-eosin and alcian blue, respectively. The internal luminal perimeter of each airway served as a reference to normalise and stratify the assessments.   Results:  Aclidinium prevented thickening of the small airway muscularis layer in animals exposed to CS. Thickness after CS exposure was: aclidinium 10μg/mL 18μm and aclidinium 30μg/mL 21μm vs vehicle 32μm (p   Conclusions:  Aclidinium 10μg/mL and 30μg/mL reduce airway remodelling in guinea pigs by reducing the muscularisation of small airways seen after chronic CS exposure.  This study was supported by Almirall S.A., Barcelona, Spain, and Consorcios Estrategicos Nacionales en Investigaciόn Tecnica (CENIT).
Magnesium Sulfate for Preterm Neuroprotection
Authors: Cande V Ananth, Anthony M Vintzileos
Journal: JAMA (2004)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal