tbuckley/cabot-search huggingface dataset:
Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members
Authors: Jennifer M. MacArthur, Joseph R. Bishop, Kristin I. Stanford, Lianchun Wang, André Bensadoun, Joseph L. Witztum, Jeffrey D. Esko
Journal: Journal of Clinical Investigation (2007)

We examined the role of hepatic heparan sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that heparan sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte heparan sulfate. These findings show that under normal physiological conditions, hepatic heparan sulfate proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.
Contribution of Intimal Smooth Muscle Cells to Cholesterol Accumulation and Macrophage-Like Cells in Human Atherosclerosis
Authors: Sima Allahverdian, Ali Cyrus Chehroudi, Bruce M. McManus, Thomas Abraham, Gordon A. Francis
Journal: Circulation (2014)

Background— Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte-derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined. Methods and Results— Human coronary artery sections from hearts explanted at the time of transplantation were processed to clearly delineate intracellular and extracellular lipids and allow costaining for cell-specific markers. Costaining for oil red O and the SMC-specific marker SM α-actin of foam cell–rich lesions revealed that 50±7% (average±standard error of the mean, n=14 subjects) of total foam cells were SMC derived. ABCA1 expression by intimal SMCs was significantly reduced between early and advanced atherosclerotic lesions, with no loss in ABCA1 expression by myeloid lineage cells. Costaining with the macrophage marker CD68 and SM α-actin revealed that 40±6% (n=15) of CD68-positive cells originated as SMCs in advanced human coronary atherosclerosis. Conclusions— These findings suggest SMCs contain a much larger burden of the excess cholesterol in human coronary atherosclerosis than previously known, in part, because of their relative inability to release excess cholesterol via ABCA1 in comparison with myeloid lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC derived.
A real opportunity to improve neurology services in England
Authors: David E Bateman
Journal: BMJ (2015)

Morrish describes very well the shortcomings of adult neurology services in England.1 Despite several recent reports suggesting solutions to these problems,2 3 4 improvements have been difficult to achieve. The recent National Audit Office review commented that further work is needed to achieve better services and outcomes for people with neurological conditions.5

However, recent changes in commissioning and the …
Hexa-arginine enhanced uptake and residualization of selective high affinity ligands by Raji lymphoma cells
Authors: Rod Balhorn, Saphon Hok, Sally DeNardo, Arutselvan Natarajan, Gary Mirick, Michele Corzett, Gerald DeNardo
Journal: Molecular Cancer (2009)

A variety of arginine-rich peptide sequences similar to those found in viral proteins have been conjugated to other molecules to facilitate their transport into the cytoplasm and nucleus of targeted cells. The selective high affinity ligand (SHAL) (DvLPBaPPP)2LLDo, which was developed to bind only to cells expressing HLA-DR10, has been conjugated to one of these peptide transduction domains, hexa-arginine, to assess the impact of the peptide on SHAL uptake and internalization by Raji cells, a B-cell lymphoma. An analog of the SHAL (DvLPBaPPP)2LLDo containing a hexa-arginine peptide was created by adding six D-arginine residues sequentially to a lysine inserted in the SHAL's linker. SHAL binding, internalization and residualization by Raji cells expressing HLA-DR10 were examined using whole cell binding assays and confocal microscopy. Raji cells were observed to bind two fold more 111In-labeled hexa-arginine SHAL analog than Raji cells treated with the parent SHAL. Three fold more hexa-arginine SHAL remained associated with the Raji cells after washing, suggesting that the peptide also enhanced residualization of the 111In transported into cells. Confocal microscopy showed both SHALs localized in the cytoplasm of Raji cells, whereas a fraction of the hexa-arginine SHAL localized in the nucleus. The incorporation of a hexa-D-arginine peptide into the linker of the SHAL (DvLPBaPPP)2LLDo enhanced both the uptake and residualization of the SHAL analog by Raji cells. In contrast to the abundant cell surface binding observed with Lym-1 antibody, the majority of (DvLPBaPPP)2LArg6AcLLDo and the parent SHAL were internalized. Some of the internalized hexa-arginine SHAL analog was also associated with the nucleus. These results demonstrate that several important SHAL properties, including uptake, internalization, retention and possibly intracellular distribution, can be enhanced or modified by conjugating the SHALs to a short polypeptide.
Should CA-125 Response Criteria Be Preferred to Response Evaluation Criteria in Solid Tumors (RECIST) for Prognostication During Second-Line Chemotherapy of Ovarian Carcinoma?
Authors: Bo Gronlund, Claus Høgdall, Jørgen Hilden, Svend A. Engelholm, Estrid V.S. Høgdall, Heine H. Hansen
Journal: Journal of Clinical Oncology (2004)

The aim of the study was to compare the prognostic value of a response by the Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA) -125 response criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) on survival in patients with ovarian carcinoma receiving second-line chemotherapy.From a single-institution registry of 527 consecutive patients with primary ovarian carcinoma, 131 records satisfied the inclusion criteria: ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IC to IV, first-line chemotherapy with paclitaxel and a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method.In patients with measurable disease by RECIST and with assessable disease by the CA-125 criteria (n = 68), the CA-125 criteria were 2.6 times better than the RECIST at disclosing survival. In a multivariate Cox analysis with inclusion of nine potential prognostic parameters, CA-125 response (responders v nonresponders; hazard ratio, 0.21; P < .001) and number of relapse sites (solitary v multiple; hazard ratio, 0.47; P = .020) were identified as contributory prognostic factors for survival, whereas the parameters of RECIST (responders v nonresponders), as well as the remaining variables, had nonsignificant prognostic impact.The GCIG CA-125 response criteria are a better prognostic tool than RECIST in second-line treatment with topotecan or paclitaxel plus carboplatin in patients with ovarian carcinoma.
<i>NBS1</i> Knockdown by Small Interfering RNA Increases Ionizing Radiation Mutagenesis and Telomere Association in Human Cells
Authors: Ying Zhang, Chang U.K. Lim, Eli S. Williams, Junqing Zhou, Qinming Zhang, Michael H. Fox, Susan M. Bailey, Howard L. Liber
Journal: Cancer Research (2005)

Abstract Hypomorphic mutations which lead to decreased function of the NBS1 gene are responsible for Nijmegen breakage syndrome, a rare autosomal recessive hereditary disorder that imparts an increased predisposition to development of malignancy. The NBS1 protein is a component of the MRE11/RAD50/NBS1 complex that plays a critical role in cellular responses to DNA damage and the maintenance of chromosomal integrity. Using small interfering RNA transfection, we have knocked down NBS1 protein levels and analyzed relevant phenotypes in two closely related human lymphoblastoid cell lines with different p53 status, namely wild-type TK6 and mutated WTK1. Both TK6 and WTK1 cells showed an increased level of ionizing radiation–induced mutation at the TK and HPRT loci, impaired phosphorylation of H2AX (γ-H2AX), and impaired activation of the cell cycle checkpoint regulating kinase, Chk2. In TK6 cells, ionizing radiation–induced accumulation of p53/p21 and apoptosis were reduced. There was a differential response to ionizing radiation–induced cell killing between TK6 and WTK1 cells after NBS1 knockdown; TK6 cells were more resistant to killing, whereas WTK1 cells were more sensitive. NBS1 deficiency also resulted in a significant increase in telomere association that was independent of radiation exposure and p53 status. Our results provide the first experimental evidence that NBS1 deficiency in human cells leads to hypermutability and telomere associations, phenotypes that may contribute to the cancer predisposition seen among patients with this disease.
Obesity and comorbidity are independently associated with a failure to achieve remission in patients with established rheumatoid arthritis
Authors: Nicolas Ellerby, Derek L Mattey, Jonathan Packham, Peter Dawes, Samantha L Hider
Journal: Annals of the Rheumatic Diseases (2014)

We read with interest the recent paper by Sandberg et al 1 highlighting the negative impact of obesity on disease remission in a cohort of patients with early rheumatoid arthritis (RA).

We have investigated the impact of both obesity and comorbidity on disease remission in an established RA cohort. Data were collected prospectively between 2003 and 2011 from the Haywood Hospital, North Staffordshire, UK. Patients fulfilled the 1987 American College of Rheumatology criteria for RA,2 had been followed up for 3 years and were taking conventional (non-biologic disease-modifying antirheumatic drugs (DMARDs)) at baseline. Participants underwent an annual standardised research assessment, separate to their routine clinical care, including demographics, body mass index (BMI) and disease …
Regression models in periodontal epidemiology: purpose, approach and interpretation
Authors: Monik Jimenez, Thomas Dietrich
Journal: Periodontology 2000 (2011)

Abstract Statistical models, including those using regression analyses, are ubiquitous in periodontal research. However, many investigators may not have a thorough understanding of the concepts underlying the complex statistical models used in much of the current literature. This review aims to demystify biostatical regression models and familiarize the reader with the regression models most commonly encountered in the periodontal literature. Complex models can be intuitively understood in terms of stratified analyses. Therefore, we discuss the use of stratified analyses and emphasize their natural connection to regression models using examples from the periodontal research literature. We critically review various types of regression models, as well as the fundamental assumptions unique to each. An introduction to the fundamentals of model building describes the basics of variable selection procedures and variable management, including discussions regarding the assumptions inherent in common practices. Lastly, modeling approaches to assess confounding and effect modification are discussed by use of examples from the periodontal epidemiological literature.
Use of Preoperative Plasma Endoglin for Prediction of Lymph Node Metastasis in Patients with Clinically Localized Prostate Cancer
Authors: Jose A. Karam, Robert S. Svatek, Pierre I. Karakiewicz, Andrea Gallina, Claus G. Roehrborn, Kevin M. Slawin, Shahrokh F. Shariat
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Current predictive tools and imaging modalities are not accurate enough to preoperatively diagnose lymph node metastases in patients with prostate cancer. The aim of the study was to evaluate whether preoperative plasma endoglin improves the prediction of lymph node metastases in patients with clinically localized prostate cancer. Experimental Design: Endoglin levels were measured using a commercially available ELISA assay in banked plasma from 425 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at two university hospitals between July 1994 and November 1997. Logistic regression analyses were undertaken to evaluate whether endoglin improves the accuracy of a standard preoperative model for prediction of lymph node metastasis and to build a predictive nomogram. Results: Preoperative plasma endoglin levels were higher in patients with higher preoperative total serum prostate-specific antigen (PSA; Spearman correlation coefficient 0.296, P &amp;lt; 0.001), positive surgical margins (P = 0.03), higher pathologic Gleason sum (P = 0.04), and lymph node metastasis (P &amp;lt; 0.001). In a preoperative multivariable logistic regression analysis that included PSA and clinical stage, only preoperative endoglin (odds ratio, 1.17; 95% confidence interval, 1.09-1.26; P &amp;lt; 0.001) and biopsy Gleason sum (odds ratio, 18.57; 95% confidence interval, 1.08-318.36; P = 0.04) were associated with metastasis to lymph nodes. The addition of endoglin to a standard preoperative model (including PSA, clinical stage, and biopsy Gleason sum) significantly improved its accuracy for prediction of lymph node metastasis from 89.4% to 97.8% (P &amp;lt; 0.001). Conclusions: Preoperative plasma endoglin improves the accuracy for prediction of pelvic lymph node metastasis in patients treated with radical prostatectomy for clinically localized prostate cancer by a statistically and clinically significant margin.
Suppression of Rheumatoid Arthritis B Cells by XmAb5871, an Anti‐CD19 Antibody That Coengages B Cell Antigen Receptor Complex and Fcγ Receptor IIb Inhibitory Receptor
Authors: Seung Y. Chu, Karen Yeter, Roshan Kotha, Erik Pong, Yvonne Miranda, Sheryl Phung, Hsing Chen, Sung‐Hyung Lee, Irene Leung, Christine Bonzon, John R. Desjarlais, William Stohl, David E. Szymkowski
Journal: Arthritis & Rheumatology (2013)

Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages FcγRIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to FcγRIIb, we correlated RF titers with the potency of XmAb5871.We analyzed the expression of CD19, FcγRIIb, and CD86 on naive and memory B cells from 50 patients with RA and 66 healthy donors, quantified XmAb5871-induced promotion of FcγRIIb phosphorylation and suppression of calcium flux in activated B cells, measured CD86 inhibition in whole blood, and correlated RF and anti-citrullinated protein antibody (ACPA) levels with drug potency. We engrafted RA peripheral blood mononuclear cells (PBMCs) into SCID mice, treated them with XmAb5871, and quantified human total IgG, total IgM, and anti-tetanus IgG antibody levels in vivo.B cells from all donors expressed CD19 and FcγRIIb, and the expression of FcγRIIb was higher on naive, but not memory, B cells from donors with RA compared with healthy donors. BCR-mediated calcium flux was suppressed by XmAb5871 and was associated with FcγRIIb phosphorylation. XmAb5871 inhibited CD86 induction, and the levels of RF and ACPAs did not affect efficacy. XmAb5871 suppressed B cell activation regardless of disease severity. In SCID mice engrafted with PBMCs from a patient with RA, XmAb5871 suppressed humoral responses.Coengagement of the BCR complex and FcγRIIb by XmAb5871 inhibits B cell activation and function. The similar potency in patients with RA and healthy donors and the absence of autoantibody interference suggest that XmAb5871 may represent a new therapeutic strategy to suppress autoreactive B cells in RA.
Screening for Glaucoma: U.S. Preventive Services Task Force Recommendation Statement
Authors: Virginia A Moyer
Journal: Annals of Internal Medicine (2013)

Update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for glaucoma.The USPSTF reviewed evidence on the benefits and harms of screening for glaucoma and of medical and surgical treatment of early glaucoma. Beneficial outcomes of interest included improved vision-related quality of life and reduced progression of early asymptomatic glaucoma to vision-related impairment. The USPSTF also considered evidence on the accuracy of glaucoma screening tests.This recommendation applies to adults who do not have vision symptoms and are seen in a primary care setting.The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary open-angle glaucoma in adults. (I statement)
Postischemic myocardial "stunning". Identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog.
Authors: J F Triana, X Y Li, U Jamaluddin, J I Thornby, R Bolli
Journal: Circulation Research (1991)

Recent studies suggest that oxygen-derived free radicals contribute to the pathogenesis of postischemic myocardial dysfunction (myocardial "stunning"). This concept, however, is predicated exclusively on results obtained in open-chest preparations, which are subject to the confounding influence of many unphysiological conditions. The lack of supporting evidence in more physiological animal models represents a major persisting limitation of the oxy-radical hypothesis of myocardial stunning. The goal of this study was to address two fundamental (and related) questions: 1) Does the open-chest animal model alter the phenomenon of myocardial stunning? 2) If so, how valid are the concepts, derived from such a model, regarding the pathogenetic role of oxy-radicals? In part 1 of the study, myocardial stunning after a 15-minute coronary occlusion was compared in 30 pentobarbital-anesthetized open-chest dogs and in 19 conscious dogs. For any given level of collateral flow during occlusion, the recovery of systolic wall thickening after reperfusion was markedly less in open-chest animals. In an additional group of five open-chest dogs, a close inverse relation was noted between body temperature and postischemic wall thickening, indicating that the recovery of the stunned myocardium in acute experiments may vary markedly depending on how temperature is controlled. Because of these major differences between open-chest and conscious dogs, the oxy-radical hypothesis needs to be tested in the latter model. Thus, in part 2 of the study, conscious unsedated dogs undergoing a 15-minute coronary occlusion were randomized to an intravenous infusion of either saline (19 coronary occlusions) or superoxide dismutase (SOD) plus catalase (CAT) (21 coronary occlusions). Despite the fact that the plasma levels of SOD and CAT declined rapidly after reperfusion, postischemic wall thickening was significantly greater in treated compared with control dogs throughout the first 6 hours of reflow. Thus, a brief (60-minute) infusion of SOD and CAT produced a sustained improvement of recovery of contractility. The magnitude of this beneficial effect was a function of the severity of ischemia: the lower the collateral perfusion, the greater the improvement effected by the enzymes. The accelerated recovery produced by SOD and CAT was not followed by any deterioration of contractility, suggesting that postischemic dysfunction is not a teleologically "protective" phenomenon. In conclusion, the severity of myocardial stunning is greatly exaggerated by the unphysiological conditions present in the barbiturate-anesthetized open-chest dog.(ABSTRACT TRUNCATED AT 400 WORDS)
Direct Imaging of Exercise-Induced Myocardial Ischemia With Fluorine-18–Labeled Deoxyglucose and Tc-99m-Sestamibi in Coronary Artery Disease
Authors: Zuo-Xiang He, Rong-Fang Shi, Yong-Jian Wu, Yue-Qin Tian, Xiu-Jie Liu, Shi-Wen Wang, Rui Shen, Xue-Wen Qin, Run-Lin Gao, Jagat Narula, Diwakar Jain
Journal: Circulation (2003)

Scintigraphic myocardial perfusion imaging is the most widely used noninvasive modality for the detection of coronary artery disease (CAD). A technique for direct imaging of exercise-induced myocardial ischemia is highly desirable and preferable over perfusion imaging but is presently unavailable. We evaluated the feasibility and diagnostic accuracy of direct imaging of exercise-induced myocardial ischemia with fluorine-18-2-deoxyglucose (18FDG).Twenty-six patients with known or suspected CAD and no prior myocardial infarction underwent simultaneous myocardial perfusion and ischemia imaging after the intravenous injection of Tc-99m-sestamibi (99mTc-sestamibi) and 18FDG at peak exercise. Rest perfusion imaging was carried out separately. All patients underwent coronary angiography. Exercise 18FDG myocardial images were compared with exercise-rest 99mTc-sestamibi images and coronary angiography. Of 22 patients with > or =50% narrowing of > or =1 coronary arteries, 18 had perfusion abnormalities (sensitivity 82%) whereas 20 had abnormal myocardial 18FDG uptake (sensitivity 91%, P=NS). Perfusion abnormalities were seen in myocardial segments corresponding to 25 vascular territories of a total of 51 vessels with > or =50% luminal narrowing in 22 patients (sensitivity 49%), whereas increased 18FDG uptake was seen in 34 vascular territories (sensitivity 67%, P=0.008). 18FDG images were of high quality and easy to interpret but required simultaneous perfusion images for localizing abnormal myocardial 18FDG uptake.Exercise-induced myocardial ischemia can be imaged directly with 18FDG. Combined exercise 18FDG-99mTc-sestamibi imaging provides a better assessment of exercise-induced myocardial ischemia compared with exercise-rest perfusion imaging. Direct ischemia imaging eliminates some of the limitations of presently used myocardial perfusion imaging. Large-scale clinical studies are warranted.