tbuckley/cabot-search huggingface dataset:
Clusterin-Mediated Apoptosis Is Regulated by Adenomatous Polyposis Coli and Is p21 Dependent but p53 Independent
Authors: Tingan Chen, Joel Turner, Susan McCarthy, Maurizio Scaltriti, Saverio Bettuzzi, Timothy J. Yeatman
Journal: Cancer Research (2004)

Clusterin is a widely expressed glycoprotein that has been paradoxically observed to have both pro- and antiapoptotic functions. Recent reports suggest this apparent dichotomy of function may be related to two different isoforms, one secreted and cytoplasmic, the other nuclear. To clarify the functional role of clusterin in regulating apoptosis, we examined its expression in human colon cancer tissues and in human colon cancer cell lines. We additionally explored its expression and activity using models of adenomatous polyposis coli (APC)- and chemotherapy-induced apoptosis. Clusterin RNA and protein levels were decreased in colon cancer tissues largely devoid of wild-type APC when compared with matched normal tissue controls, suggesting a means for invasive cancers to avoid apoptosis. Conversely, induction of apoptosis by expression of wild-type APC or by treatment with chemotherapy led to increased clusterin RNA and protein levels localizing to apoptotic nuclei. We found that transient transfection of clusterin to colon cancer cell lines directly enhanced basal and chemotherapy-induced apoptosis. Clusterin-induced apoptosis was inhibited by antisense clusterin and was found to be highly dependent on p21 but not p53 expression, yet a deficit in p21 can be subverted by clusterin transfection. Collectively, these data support the hypothesis that nuclear clusterin function is proapoptotic when induced by APC or chemotherapy in the context of p21 expression. Absent of p21, clusterin in not induced, and apoptosis is significantly inhibited. These data support a potential therapeutic role for clusterin in enhancing chemotherapy-induced apoptosis and in promoting apoptosis in cells deficient in p21.
Five-Year Surveillance of Aminoglycoside Usage in a University Hospital
Authors: ROBERT F. BETTS
Journal: Annals of Internal Medicine (1984)

Because an increased incidence of nosocomial bacteremia due to gentamicin-resistant organisms occurred in our hospital, amikacin was substituted for gentamicin as the primary empiric aminoglycoside. Prospective surveillance of aminoglycoside use and of bacterial resistance to aminoglycosides was done before and after the substitution. We compared the baseline period when gentamicin was the primary aminoglycoside with the subsequent period when amikacin accounted for 81% of aminoglycoside used. During the two periods the patient population did not differ with regard to indications for aminoglycoside therapy. Among the gram-negative organisms isolated, rates of amikacin resistance during the baseline (1.1%) and usage (1.05%) periods were not significantly different (p > 0.6). Resistance to gentamicin and tobramycin during the period of amikacin use showed a statistically significant decrease (p > 0.001) due to decreased resistance to gentamicin of Providencia, Serratia, indole-positive Proteus, and decreased resistance to tobramycin of Pseudomonas aeruginosa. Unrestricted use of amikacin does not necessarily lead to increase in amikacin resistance but may lead to a decrease in resistance to gentamicin and tobramycin among gram-negative organisms.
Paraquat: model for oxidant-initiated toxicity.
Authors: J S Bus, J E Gibson
Journal: Environmental Health Perspectives (1984)

Paraquat, a quaternary ammonium bipyridyl herbicide, produces degenerative lesions in the lung after systemic administration to man and animals. The pulmonary toxicity of paraquat resembles in several ways the toxicity of several other lung toxins, including oxygen, nitrofurantoin and bleomycin. Although a definitive mechanism of toxicity of paraquat has not been delineated, a cyclic single electron reduction/oxidation of the parent molecule is a critical mechanistic event. The redox cycling of paraquat has two potentially important consequences relevant to the development of toxicity: generation of "activated oxygen" (e.g., superoxide anion, hydrogen peroxide, hydroxyl radical) which is highly reactive to cellular macromolecules; and/or oxidation of reducing equivalents (e.g., NADPH, reduced glutathione) necessary for normal cell function. Paraquat-induced pulmonary toxicity, therefore, is a potentially useful model for evaluation of oxidant mechanisms of toxicity. Furthermore, characterization of the consequences of intracellular redox cycling of xenobiotics will no doubt provide basic information regarding the role of this phenomena in the development of chemical toxicity.
Abstract 2667: Inhibition of CYP3A4 expression by camptothecin via blocking activation of pregnane X receptor
Authors: Yakun Chen, Yong Tang, Gregory Thomas Robbins, Daotai Nie
Journal: Cancer Research (2010)

Abstract Individual variation in drug metabolism is a major cause of unpredictable side effects during cancer therapy. Drug metabolism is controlled by a class of orphan nuclear receptors (NRs), which regulate the expression of cytochrome 3A4 (CYP3A4), an enzyme metabolizing more than 60% of clinically used drugs. In our study, it was found that xenobiotic-mediated induction of CYP3A4 gene expression in primary human hepatocytes was inhibited by camptothecin (CPT) but not by its analogue, irinotecan (CPT-11). CPT exerted its effect by inhibiting the activation of NR, human pregnenolone X receptor (hPXR). In contrast, irinotecan was found to be an hPXR agonist in the same tests. CPT disrupted the interaction of hPXR with steroid receptor coactivator-1 (SRC-1) but had no effects on the formation of the hPXR and retinoid X receptor α (RXRα) heterodimer. Nor had it effects on the interactions between the regulatory complex and DNA responsive elements. CPT treatment resulted in delayed metabolism of nifedipine induced by rifampicin in human hepatocytes, suggesting a potential drug-drug interaction (DDI) between CPT and CYP3A4 metabolized drugs. The study found a novel potent hPXR antagonist and indicated the potential of a new class of compounds to control drug efficacies in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2667.
The Crush of Cars
Authors: Lee N. Hames
Journal: JAMA (1973)

The contribution of the motor vehicle to the growing lack of space in our urban areas hardly needs to be documented. The space required for its movement, parking, upkeep, and eventual disposal is enormous. Enormous, also, is the price we pay in injury, death, and environmental damage for the undeniable convenience, pleasure, and profit it provides. Only recently have we become really aware that the crush of cars in our cities is more than just a traffic-slowing nuisance. It has reached the point where people are expressing vociferous objections to the building of new roads and expressways, where cities are prohibiting cars from certain downtown streets and turning the space into attractive shopping malls for pedestrians, and where cities such as Chicago are threatening to raze existing downtown parking facilities to discourage cars from coming into the most congested areas. If use of cars is prohibited or discouraged, an alternative
?3?1-integrin as a critical mediator of the hepatic differentiation response to the extracellular matrix
Authors: José M. Lora, Kathleen E. Rowader, Lorena Soares, Filippo Giancotti, Kenneth S. Zaret
Journal: Hepatology (1998)

The extracellular matrix (ECM) promotes the differentiation of many cell types, and ECM remodeling in the liver has been implicated in embryonic development, tissue injury, and oncogenesis. Integrins are heterodimeric ECM receptors that play critical roles in transducing the composition of the ECM in the cell environment. We previously showed that mouse H2.35 cells, a conditionally transformed, liver-derived cell line, assume a more differentiated hepatocyte morphology and enhanced liver-specific gene expression when the cells are cultured on gelatinous ECM substrata. Here we show that H2. 35 cells express relatively high levels of alpha3beta1-integrins, similar to that previously shown for immature hepatocytes, transformed hepatocytes, and biliary cells. However, the cell morphological responses that depend on alpha3beta1-integrin have not been defined. We found that transfecting H2.35 cells with antisense RNA construct directed to alpha3-subunit messenger RNA perturbs the initial cell attachment to laminin and collagen, and strongly inhibits cell morphological, proliferative, and gene expression responses to a collagen gel substratum. In situ hybridization to mouse embryo tissues demonstrates the presence of alpha3-subunit messenger RNAs in newly formed hepatocytes. We suggest that alpha3beta1-integrins are important for immature and transformed hepatocytes to respond morphologically to the extracellular matrix.
The Cracking of the Mold
Authors: Fredric L. Coe
Journal: Annals of Internal Medicine (1998)

Ad Libitum15 February 1998The Cracking of the MoldFredric L. Coe, MDFredric L. Coe, MDThe University of Chicago; Chicago, IL 60637Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-128-4-199802150-00016 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail your high and soldierly ... Author, Article, and Disclosure InformationAffiliations: The University of Chicago; Chicago, IL 60637Corresponding Author: Fredric L. Coe, MD, Department of Medicine, Program in Nephrology, The University of Chicago, 5841 South Maryland Avenue, Box 28, Chicago, IL 60637. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 February 1998Volume 128, Issue 4Page: 317-318KeywordsAdolescentsAgingBloodBoneHearingPharynx ePublished: 15 August 2000 Issue Published: 15 February 1998 Copyright & PermissionsCopyright © 1998 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Acquired perforating dermatosis in a British dialysis population
Authors: C.A. MORTON, I.S. HENDERSON, M.C. JONES, J.G. LOWE
Journal: British Journal of Dermatology (1996)

A perforating disorder of the skin developing in association with chronic renal failure and often also diabetes, acquired perforating dermatosis (APD), affects up to 10% of patients receiving maintenance haemodialysis in North America. The prevalence of this condition in British dialysis patients has not yet been ascertained. We have undertaken a skin survey of our dialysis population (n = 80) to determine the prevalence and clinical presentation of APD, with subsequent assessment of disease management and outcome. Of 72 patients who participated in the survey, eight were found to have APD, seven of whom were also diabetic. Skin lesions had developed pre-dialysis in two patients, on commencement of dialysis in one, and after 1-3 years on dialysis in the remaining five. Patients typically presented with pruritic dome-shaped papules with central crusts arising on the trunk and extensor limb surfaces. Histological examination of biopsy specimens revealed two types of lesion, typified by either narrow or broad ulcer craters, each showing perforation of both collagen and elastic fibres. Topical/intradermal steroid or topical retinoid were effective therapies in certain of our patients. Clinical clearance was achieved after 3-12 months of treatment in five patients with improvement in the remaining two patients who received treatment. Of the four patients who were alive at 2-year review, three remained clear, while one patient continued to develop new lesions. We report an 11% prevalence of APD in our dialysis population, suggesting the disorder to be as prevalent in patients with chronic renal failure in Britain as in North America. An association of the disorder with long-standing diabetes was confirmed.
Evaluation of the Effect of Bilateral Internal-Mammary-Artery Ligation on Cardiac Output and Coronary Blood Flow
Authors: George G. Rowe, George M. Maxwell, Cesar A. Castillo, C. W. Crumpton, Richard J. Botham, William P. Young
Journal: New England Journal of Medicine (1959)

THE therapy of angina pectoris has been a very difficult medical and surgical problem, and consequently new therapeutic approaches in this disease are avidly accepted by the lay public as well as the medical profession. Recently, there has been considerable interest in the procedure of bilateral internal-mammary-artery ligation for angina pectoris, and reports have ranged from those of enthusiasm1 2 3 4 to those of discouragement.5 The present study was undertaken to obtain objective evaluation of the procedure in human subjects with angina pectoris.Material and MethodsThe study was done on 5 subjects with severe angina pectoris that had failed to respond . . .
Evidence based management
Authors: Sean O'Kelly
Journal: Journal of the Royal Society of Medicine (2008)

Although waiting to witness flamingos in flight is a great improvement on pigs, I believe Hadridge and Pow (JRSM 2008;101:7–11)1 understate some of the issues to be addressed before the NHS flock can take to the air. Their exhortation to have more confidence and curiosity, become more connected and show more compassion would seem worthy enough, but their strategy for inducing the cultural change required to ‘sort out’ the health system stops short of describing meaningful action below the layer of high level organizational leaders. This may be an unfortunate emphasis, as previous calls for studies to increase our improvement effectiveness have highlighted issues associated with the inverted power structure of healthcare organizations and the need to explore and understand this dynamic.2

In contrast to Hadridge and Pow, though sharing similar objectives, Keroack and colleagues3 describe how they developed and used a composite index of quality and safety, based on patient-level data and the six attributes of an ideal health system articulated by the US Institute of Medicine: safe, effective, timely, efficient, equitable and patient-centred.4 Keroack et al. looked in depth at 79 US Academic Medical Centres and identified a distinctive set of behaviours and organizational practices which were uniquely associated with the top-performing hospitals. Although themes identified by this group have clear echoes with Hadridge and Pow's ‘four Cs’, the work of Keroack et al. might help further NHS organizational quality improvement in at least two important ways. First, by describing an approach that produces robust evidence supporting the value of specific operational practices it helps address the increasingly heard call for evidence-based management. Second, by encouraging the pursuit of improved healthcare through interventions at levels deeper than senior leadership, it brings a focus to the interface between those in service-line clinical leadership positions and front-line workers. Having experienced healthcare improvement efforts from the perspective of a Medical Director, Clinical Director and front-line clinician, I suspect that effective engagement at this interface may be a crucial factor if NHS improvement is to spread its wings.
Labelling index in the mucosal lesions of lichen planus
Authors: D. M. WALKER, A. E. DOLBY
Journal: British Journal of Dermatology (1974)

The labelling indices of the epithelium of the lesions of oral lichen planus (LP) have been estimated, using in vitro labelling with tritiated thymidine. The relationship between this epithelial labeling index and the underlying inflammatory cell density was also examined. The total labelling activity in the LP lesion was comparable with that of normal mucosa but was redistributed as follows. The labelling index of the basal epithelial layer was increased above that of normal controls and the labeling in the suprabasal layer was decreased. Thus 50% of mitoses occur basally in involved atrophic LP epithelium. The implications of this redistribution of mitotic activity are discussed. The labelling index of epithelium was reduced where the inflammatory cell density was exceptionally high, but no simple inverse relationship between labelling index and inflammatory cell density was apparent. This supports the concept that the primary event in lichen planus seems to occur in the basal epithehal layer followed by an inflammatory cell response in the underlying connective tissue. Subsequent secondary damage to the epithelium, including inhibition of mitosis, may be produced by this inflammatory infiltrate only if it is very dense.
Genesis of high frequency notching of QRS complexes in an in vivo cardiac model.
Authors: C R Vanderark, E W Reynolds
Journal: Circulation (1975)

High frequency notching of the QRS complex is associated with transmural infarction, cardiomyopathies, and ventricular hypertrophy from any cause. The mechanism producing notching is unknown; but the presence of a discrete anatomic lesion is not an essential feature. The hypothesis that notching was produced by activation across, rather than along, myocardial fibers was investigated by stimulation at 12 points around a clock electrode attached to the epicardium while mapping isoschronous lines in the area activated. All fibers at the subendocardial layer beneath the clock electrode were ligated by a pursestring suture. Propagation direction, as measured by isoschronous maps, produced more notched QRS compleses when the path was across, rather than paralled with, the myocardial fibers. Using grouped data and a 5 times 6 table, notches versus the angle formed between fiber direction and orientation of the direction of travel were shown to be related (P less than 0.001). The hypothesis that cross-fiber activation enhances notching was confirmed. retrograde activation did not increase notching nor did ligation of subendocardial fibers.
Left ventricular regional wall stress in dilated cardiomyopathy.
Authors: W Hayashida, T Kumada, R Nohara, H Tanio, M Kambayashi, N Ishikawa, Y Nakamura, Y Himura, C Kawai
Journal: Circulation (1990)

Left ventriculography with simultaneous pressure micromanometry was performed in 11 normal control subjects and 17 patients with dilated cardiomyopathy (DCM). Left ventricular silhouettes in the right anterior oblique projection were divided into eight areas, and regional wall stress was computed by Janz's method in each area excluding the two most basal areas. Wall stress was higher in DCM patients than in control subjects (p less than 0.01). The percent area changes from end diastole to end systole in each area were lower in DCM patients than in control subjects (mean for six areas, 22 +/- 14% versus 54 +/- 9%, respectively, p less than 0.01), but the coefficient of variation for the percent area changes in the six areas of the left ventricle in DCM patients was greater than that in control subjects (32 +/- 17% versus 15 +/- 4%, respectively, p less than 0.01), indicating regional differences in hypokinesis. There was a significant negative correlation between end-systolic regional wall stress and percent area change (r = -0.60 to -0.86, p less than 0.05) in each area. Thus, excessive regional afterload may play an important role in causing regional hypokinesis in DCM.
THE ANTIRACHITIC INFLUENCE OF EGG YOLK
Authors: HORTON CASPARIS
Journal: JAMA (1923)

It is a recognized fact that active rickets is relatively uncommon after the second year. This has been attributed by many to the more liberal diet that children receive at this period of life. Exactly what particular foodstuff is responsible for the antirachitic effect has not been determined. Still<sup>1</sup>says, "Next to milk I know of no food which is of more value in the prevention of rickets and in the cure of it than yolk of egg." The same author, however, says further, "There seems to be no specific virtue in cod liver oil; any other oil will do equally well." Doubtless other people have used egg for the same purpose. No objective evidence of the value of any one of the ordinary foodstuffs in curing rickets in children has ever been presented. Mellanby<sup>2</sup>was the first to show that a dog made rachitic by diet can
Impact of Pay for Performance on Ethnic Disparities in Intermediate Outcomes for Diabetes: A Longitudinal Study
Authors: Christopher Millett, Gopalakrishnan Netuveli, Sonia Saxena, Azeem Majeed
Journal: Diabetes Care (2008)

The purpose of this study was to examine the impact of a major pay for performance incentive on trends in the quality of diabetes care in white, black, and South Asian ethnic groups in an urban setting in the U.K.We developed longitudinal models examining the quality of diabetes care in a cohort of ethnically diverse patients in Southwest London using electronic family practice records. Outcome measures were mean blood pressure and A1C values between 2000 and 2005.The introduction of pay for performance was associated with reductions in mean systolic and diastolic blood pressure, which were significantly greater than those predicted by the underlying trend in the white (-5.8 and -4.2 mmHg), black (-2.5 and -2.4 mmHg), and South Asian (-5.5 and -3.3 mmHg) groups. Reductions in A1C levels were significantly greater than those predicted by the underlying trend in the white group (-0.5%) but not in the black (-0.3%) or South Asian (-0.4%) groups. Ethnic group disparities in annual measurement of blood pressure and A1C were abolished before the introduction of pay for performance.The introduction of a pay for performance incentive in U.K. primary care was associated with improvements in the intermediate outcomes of diabetes care for all ethnic groups. However, the magnitude of improvement appeared to differ between ethnic groups, thus potentially widening existing disparities in care. Policy makers should consider the potential impacts of pay for performance incentives on health disparities when designing and evaluating such programs.
Requirements for the construction of antibody heterodimers for the direction of lysis of tumors by human T cells.
Authors: C F Scott, W A Blättler, J M Lambert, R S Kalish, C Morimoto, S F Schlossman
Journal: Journal of Clinical Investigation (1988)

We constructed a series of MAb heterodimers consisting of the J5 (anti-common acute lymphoblastic leukemia antigen [CALLA]) antibody and antibodies to a variety of structures present on the surface of activated human T cells, including CD3 antigen (T cell receptor-associated glycoproteins), CD2 antigen (T11/E-rosette receptor), CD25 antigen (IL-2 receptor), and the transferrin receptor. We tested the ability of these heterodimers to direct a CD2 + CD3 + CD8 + CD4 - CD25 + transferrin receptor + MHC-restricted human cytolytic T lymphocyte (CTL) clone to lyse a CALLA + human tumor in vitro. Only heterodimers containing an anti-CD3 antibody or activating antibodies to CD2 could direct the clone to lyse these human tumor targets, even when the clone was additionally activated with anti-CD3 or anti-CD2 antibodies. Our findings may have implications in the design of strategies for the use of such reagents in the treatment of human neoplasia.
991 FINAL RESULTS OF THE IDEAL (INDIVIDUALIZED DOSING EFFICACY VERSUS FLAT DOSING TO ASSESS OPTIMAL PEGYLATED INTERFERON THERAPY) PHASE IIIB STUDY
Authors: M. Sulkowski, E. Lawitz, M.L. Shiffman, A.J. Muir, G. Galler, J. McCone, L. Nyberg, W.M. Lee, R. Ghalib, E. Schiff, J. Galati, B. Bacon, M. Davis, P. Mukhopadhyay, S. Noviello, L. Pedicone, J. Albrecht, J. McHutchison
Journal: Journal of Hepatology (2008)