tbuckley/cabot-search huggingface dataset:
Down-Regulation of Regulatory Subunit Type 1A of Protein Kinase A Leads to Endocrine and Other Tumors
Authors: Kurt J. Griffin, Lawrence S. Kirschner, Ludmila Matyakhina, Sotirios Stergiopoulos, Audrey Robinson-White, Sara Lenherr, Frank D. Weinberg, Edward Claflin, Elise Meoli, Yoon S. Cho-Chung, Constantine A. Stratakis
Journal: Cancer Research (2004)

Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.
Modulation of Blood Flow, Hypoxia, and Vascular Function in Orthotopic Prostate Tumors During Exercise
Authors: Danielle J. McCullough, John N. Stabley, Dietmar W. Siemann, Bradley J. Behnke
Journal: JNCI Journal of the National Cancer Institute (2014)

Previous studies have hypothesized that tumor blood flow may be elevated or reduced during exercise, which could impact the tumor microenvironment. However, to date technical limitations have precluded the measurement of tumor blood flow during exercise. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that during exercise tumors would experience 1) diminished vascular resistance, 2) augmented blood flow, 3) increased numbers of perfused vessels, and 4) decreased tissue hypoxia and, furthermore, that the increased perfusion would be associated with diminished vasoconstriction in prostate tumor arterioles. Dunning R-3327 MatLyLu tumor cells were injected into the ventral prostate of male Copenhagen rats aged 4 to 6 months randomly assigned to tumor-bearing (n = 42) or vehicle control (n = 14) groups. Prostate tumor blood flow, vascular resistance, patent vessel number, and hypoxia were measured in vivo in conscious rats at rest and during treadmill exercise, and vasoconstrictor responsiveness of resistance arterioles was investigated in vitro. During exercise there was a statistically significant increase in tumor blood flow (approximately 200%) and number of patent vessels (rest mean ± standard deviation [SD] = 12.7±1.3; exercise mean ± SD = 14.3±0.6 vessels/field; Student t test two-sided P = .02) and decreased hypoxia compared with measurements made at rest. In tumor arterioles, the maximal constriction elicited by norepinephrine was blunted by approximately 95% vs control prostate vessels. During exercise there is enhanced tumor perfusion and diminished tumor hypoxia due, in part, to a diminished vasoconstriction. The clinical relevance of these findings are that exercise may enhance the delivery of tumor-targeting drugs as well as attenuate the hypoxic microenvironment within a tumor and lead to a less aggressive phenotype.
Breast Cancer Cell Lines Contain Functional Cancer Stem Cells with Metastatic Capacity and a Distinct Molecular Signature
Authors: Emmanuelle Charafe-Jauffret, Christophe Ginestier, Flora Iovino, Julien Wicinski, Nathalie Cervera, Pascal Finetti, Min-Hee Hur, Mark E. Diebel, Florence Monville, Julie Dutcher, Marty Brown, Patrice Viens, Luc Xerri, François Bertucci, Giorgio Stassi, Gabriela Dontu, Daniel Birnbaum, Max S. Wicha
Journal: Cancer Research (2009)

Tumors may be initiated and maintained by a cellular subcomponent that displays stem cell properties. We have used the expression of aldehyde dehydrogenase as assessed by the ALDEFLUOR assay to isolate and characterize cancer stem cell (CSC) populations in 33 cell lines derived from normal and malignant mammary tissue. Twenty-three of the 33 cell lines contained an ALDEFLUOR-positive population that displayed stem cell properties in vitro and in NOD/SCID xenografts. Gene expression profiling identified a 413-gene CSC profile that included genes known to play a role in stem cell function, as well as genes such as CXCR1/IL-8RA not previously known to play such a role. Recombinant interleukin-8 (IL-8) increased mammosphere formation and the ALDEFLUOR-positive population in breast cancer cell lines. Finally, we show that ALDEFLUOR-positive cells are responsible for mediating metastasis. These studies confirm the hierarchical organization of immortalized cell lines, establish techniques that can facilitate the characterization of regulatory pathways of CSCs, and identify potential stem cell markers and therapeutic targets.
New Promise for Autologous Marrow Transplants in Leukemia
Authors: Richard J. O'Reilly
Journal: New England Journal of Medicine (1986)

In the past five years, the chances of successfully using autologous marrow transplants in cancers that may involve the marrow itself have been dramatically improved with the development of strategies for eradicating contaminating malignant cells from the autologous marrow inoculum. At several centers, attention has been focused on the use of monoclonal antibodies for the elimination of such malignant cells. Efficient killing of leukemic cells that contaminate marrow has been achieved when the marrow has been incubated in vitro with monoclonal antibodies and complement, or with monoclonal antibodies that have been chemically coupled to toxins such as ricin-A. In addition, . . .
Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation
Authors: Markus Munder, Moisés Mallo, Klaus Eichmann, Manuel Modolell
Journal: The Journal of Experimental Medicine (1998)

Interferon (IFN)-gamma, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow- derived macrophages (BMMPhi) secrete large amounts of IFN-gamma upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-gamma mRNA transcripts, the combined stimulation of BMMPhi with both cytokines leads to the efficient production of IFN-gamma protein. The macrophage-derived IFN-gamma is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-gamma but also a potent IFN-gamma-producing cell.
PTU-004 The use of a “Moodle” Virtual Learning Environment (VLE) in Gastroenterology Training
Authors: D Rogers, T Delahooke
Journal: Gut (2013)

<h3>Introduction</h3> The East Midlands Healthcare Workforce Deanery launched a VLE pilot in 2009 and subsequently rolled out the “Moodle” based platform to all Postgraduate schools. Some schools have used the VLE as an information repository only, but The School of Gastroenterology South was keen to exploit the full potential by developing interactive activities and evaluating their acceptability to trainees. <h3>Methods</h3> In addition to using our “Moodle” page as a repository for training information, rotation and teaching event details and Journal club records we have also developed Endoscopy and Gastro-radiology atlases. Forums for Case, Endoscopy and Radiology Presentations have also been developed, and these are “Question and Answer” forums in which trainees post a short introduction and others reply with their thoughts. Other trainee’s postings become visible once an individual has posted themselves, thus removing the chance that all replies will mirror that of the first reply. As the discussion progresses the case is updated by the original poster to mirror how the case developed in real life. To augment the learning during regional teaching, quizzes are placed on the VLE following each session and immediate feedback is given. Teaching evaluation is also obtained through the VLE which simplifies the analysis of this feedback. We have surveyed how the trainee’s use the VLE and which areas they find most useful via a questionnaire in order to guide further development. <h3>Results</h3> Pleasingly all trainees were aware of the existence of a VLE for Gastroenterology and have accessed it at some stage. The case discussion forums are used most and found useful by all trainees. All those who have used the Endoscopy and Radiology libraries find them useful, and all trainees report finding the Journal Club records and the single point of access for training information, e-learning resources and rotation details useful. The quizzes following teaching sessions were seen as less helpful, but two thirds still found them to be useful. The medical apps area is not used by any trainees and this may relate more to the ready access to medical apps available on smart phones. <h3>Conclusion</h3> The interactive use of the VLE has been accepted by most trainees and has led to evidence based discussion around cases and consolidation of learning together with providing a repository for the storage of information and resources. The “moodle” platform requires only simple IT skills and material can be developed by anybody with basic word processor skills. Further development is planned that will include blueprinting of the curriculum to the rotation and learning material available, together with further interactive case discussions. <h3>Disclosure of Interest</h3> None Declared
Risk of Fracture After Radical Cystectomy and Urinary Diversion for Bladder Cancer
Authors: Amit Gupta, Coral L. Atoria, Behfar Ehdaie, Shahrokh F. Shariat, Farhang Rabbani, Harry W. Herr, Bernard H. Bochner, Elena B. Elkin
Journal: Journal of Clinical Oncology (2014)

Purpose Radical cystectomy and urinary diversion may cause chronic metabolic acidosis, leading to long-term bone loss in patients with bladder cancer. However, the risk of fractures after radical cystectomy has not been defined. We assessed whether radical cystectomy and intestinal urinary diversion are associated with increased risk of fracture. Patients and Methods Population-based study using SEER-Medicare–linked data from 2000 through 2007 for patients with stage 0-III bladder cancer. We evaluated the association between radical cystectomy and risk of fracture at any site, controlling for patient and disease characteristics. Results The cohort included 50,520 patients, of whom 4,878 had cystectomy and urinary diversion. The incidence of fracture in the cystectomy group was 6.55 fractures per 100 person-years, compared with 6.39 fractures per 100 person-years in those without cystectomy. Cystectomy was associated with a 21% greater risk of fracture (adjusted hazard ratio, 1.21; 95% CI, 1.10 to 1.32) compared with no cystectomy, controlling for patient and disease characteristics. There was no evidence of an interaction between radical cystectomy and age, sex, comorbidity score, or cancer stage. Conclusion Patients with bladder cancer who have radical cystectomy and urinary diversion are at increased risk of fracture.
Human red cell aquaporin CHIP. I. Molecular characterization of ABH and Colton blood group antigens.
Authors: B L Smith, G M Preston, F A Spring, D J Anstee, P Agre
Journal: Journal of Clinical Investigation (1994)

Blood group antigens are structural variants in surface carbohydrate or amino acid polymorphisms on extracellular domains of membrane proteins. The red cell water channel-forming integral protein (Aquaporin CHIP) is a homotetramer with only one N-glycosylated subunit, however no CHIP-associated blood group antigens have yet been identified. Immunoblotting, monosaccharide composition analysis, and selective glycosidase digestions revealed that the CHIP-associated oligosaccharide contains ABH determinants and resembles a band 3-type glycan that cannot be cleaved from intact membranes by Peptide:N-glycosidase F. The molecular structure of the Colton antigens was previously unknown, but CHIP was selectively immunoprecipitated with anti-Coa or anti-Co(b). The DNA sequence from Colton-typed individuals predicted that residue 45 is alanine in the Co(a+b-) phenotype and valine in the Co(a-b+) phenotype. The nucleotide polymorphism corresponds to a PflMI endonuclease digestion site in the DNA from Co(a-b+) individuals. These studies have defined antigens within two blood group systems on CHIP: (a) an ABH-bearing polylactosaminoglycan attached to a poorly accessible site in the native membrane; and (b) the Colton antigen polymorphism which may permit the identification of rare individuals with defective water channel expression.
Soft tissue sarcomas of the trunk wall (STS-TW): a study of 343 patients from the French Sarcoma Group (FSG) database
Authors: S. Salas, B. Bui, E. Stoeckle, P. Terrier, D. Ranchere-Vince, F. Collin, A. Leroux, L. Guillou, J.J. Michels, M. Trassard, I. Valo, Y.-M. Robin, B. Marques, V. Brouste, J.-M. Coindre
Journal: Annals of Oncology (2009)
PWE-142 Does The Pre-Bone Mineral Density Frax Score Predict Fracture Risk in Patients with Cirrhosis?
Authors: T Barrie, S Yeung, S Fathima, Q M Anstee, S Masson, S Mcpherson
Journal: Gut (2013)

<h3>Introduction</h3> Cirrhosis is an independent risk factor for osteoporosis, with risk of morbidity through fragility fractures. BSG guidelines recommend that all patients with cirrhosis should be offered DEXA scans to measure bone mineral density (BMD), and receive appropriate treatment. The FRAX score is a widely used internet-based algorithm that predicts fracture risk, which can be calculated with or without BMD data. The aim of this study was to determine if the FRAX score without BMD is effective in predicting fracture risk in patients with cirrhosis to potentially reduce the need for BMD testing. <h3>Methods</h3> Between Nov 11 and Jan 12 consecutive patients with cirrhosis who were reviewed in 3 sub-specialist liver clinics (ALD, NASH and HCV) at the Freeman Hospital were included. Clinical and demographic patient information was collected retrospectively. FRAX scores were calculated with and without BMD data. <h3>Results</h3> 146 patients (46 NASH, 50 ALD and 50 HCV) were studied (mean age 59±12, 68% male, mean BMI 30±6). 91 patients had BMD assessed (9 [10%] were osteoporotic and 43 [47%] were osteopenic at the spine and/or hip). 10 (6.8%) had a previous osteoporotic fracture. The pre-BMD FRAX score categorised fracture risk as high in no patients, intermediate in 26 (18%) and low in 120 (82%). Overall, 11 (18%) were categorised as high risk with the post-BMD FRAX. 9 patients (10%) moved from a low risk with pre-BMD FRAX to a high risk with post BMD FRAX. In addition 2 (3%) moved from intermediate to high with post-BMD FRAX. Only 5 of 9 (55%) of patients with osteoporosis on BMD were classified as high risk with post BMD FRAX score. There were no significant differences in fracture risk or BMD between patients with ALD, NASH or HCV. <h3>Conclusion</h3> The pre-BMD FRAX score underestimates fracture risk in patients with cirrhosis. Therefore, assessment of BMD should continue to form part of the assessment of fracture risk in patients with cirrhosis. As the post-BMD FRAX score includes other risk factors for fracture in addition to bone density it might be the most appropriate to determine which patients require treatment to prevent fractures. <h3>Disclosure of Interest</h3> None Declared.
The Combination of <i>p53</i> Mutation and <i>neu/erb</i>B-2 Amplification Is Associated With Poor Survival in Node-Negative Breast Cancer
Authors: Shelley B. Bull, Hilmi Ozcelik, Dushanthi Pinnaduwage, Martin E. Blackstein, Donald A.J. Sutherland, Kathleen I. Pritchard, Anjela T. Tzontcheva, Saul Sidlofsky, Wedad M. Hanna, Ali H. Qizilbash, Mary E. Tweeddale, Sheldon Fine, David R. McCready, Irene L. Andrulis
Journal: Journal of Clinical Oncology (2003)

Purpose Increases in neu/erbB-2 have been implicated in breast cancer prognosis, but do not predict all recurrences. On the basis of evidence that p53 mutation is involved in the development of human neoplasia, we examined the prognostic value of p53 alterations in combination with neu/erbB-2 amplification. Patients and Methods A consecutive series of women were observed for recurrence and death (median follow-up of 85 months) and tumors from 543 individuals were analyzed for p53 mutation status and neu/erbB-2 amplification. Exons 4 through 10 of the p53 gene were analyzed by single-stranded conformational polymorphism and mutations were confirmed by DNA sequencing. The association of p53 mutation status and neu/erbB-2 amplification with risk of recurrence and death was examined in survival analyses with traditional and histologic markers as prognostic factors. Results p53 mutations occurred in 24.5% of the axillary node-negative breast carcinomas. Mutations were more frequent in carcinomas with neu/erbB-2 amplification: 38.9% compared with only 20.9% in those without neu/erbB-2 amplification. We found elevated risks of disease recurrence and overall mortality in patients with both p53 mutation and neu/erbB-2 amplification in their tumor compared with patients with neither or only one of the alterations. This increase persisted with adjustment for other prognostic factors (relative risk, 2.32; P = .002 for recurrence; relative risk, 2.22; P = .004 for death). Conclusion Evaluation of tumors for p53 mutations may be beneficial to identify women at higher risk of disease recurrence and death when the tumor has neu/erbB-2 amplification, but in the absence of neu/erbB-2 amplification, the presence of p53 mutation may not provide additional independent prognostic information.
Survival in pulmonary hypertension in Spain: insights from the Spanish registry
Authors: Pilar Escribano-Subias, Isabel Blanco, Manuel López-Meseguer, Carmen Jimenez Lopez-Guarch, Antonio Roman, Pilar Morales, María Jesús Castillo-Palma, Javier Segovia, Miguel A. Gómez-Sanchez, Joan Albert Barberà
Journal: European Respiratory Journal (2012)

A pulmonary hypertension (PH) registry (Spanish Registry of Pulmonary Arterial Hypertension) was undertaken to analyse prevalence, incidence and survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain, and to assess the applicability of recent survival prediction equations. Voluntary reporting of previously diagnosed and incident PAH or CTEPH cases (July 2007-June 2008) was performed. Demographic, functional and haemodynamic variables were evaluated. 866 patients with PAH and 162 with CTEPH were included. PAH associated with toxic oil syndrome and pulmonary veno-occlusive disease were reported for the first time in a PAH registry. Estimated prevalences were as follows: PAH, 16 and CTEPH, 3.2 cases per million adult inhabitants (MAI). Estimated incidences were as follows: PAH, 3.7 and CTEPH, 0.9 cases per MAI per yr. 1-, 3- and 5-yr survival was 87%, 75% and 65%, respectively, with no differences between PAH and CTEPH. Male sex, right atrial pressure and cardiac index were independent predictors of death. Matching between observed survival and that predicted by different equations was closer when the characteristics of the cohorts were similar. Epidemiology and survival of PAH patients in the Spanish registry are similar to recent registries. Characteristics of the population from which survival prediction equations are derived influence their applicability to a different cohort. CTEPH is much less prevalent than PAH, although has a similar survival rate.
Comment on “Community-Wide Isoniazid Preventive Therapy Drives Drug-Resistant Tuberculosis: A Model-Based Analysis”
Authors: Kingsley N. Ukwaja
Journal: Science Translational Medicine (2013)

Mills et al. recently used mathematical modeling to show that community-wide isoniazid preventative therapy may lead to a long-term increase in resistance at the population level. Although community-wide isoniazid preventive therapy may be useful in preventing tuberculosis (TB) in low-TB/HIV settings, isoniazid resistance is especially of concern in high TB/HIV populations.
Tacrolimus vs. clobetasol propionate in the treatment of facial cutaneous lupus erythematosus: a randomized, double-blind, bilateral comparison study
Authors: T-Y. Tzung, Y-S. Liu, H-W. Chang
Journal: British Journal of Dermatology (2006)

Journal Article Tacrolimus vs. clobetasol propionate in the treatment of facial cutaneous lupus erythematosus: a randomized, double‐blind, bilateral comparison study Get access T‐Y. Tzung, T‐Y. Tzung Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, TaiwanSchool of Medicine, National Yang‐Ming University, Taipei, Taiwan Search for other works by this author on: Oxford Academic Google Scholar Y‐S. Liu, Y‐S. Liu Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar H‐W. Chang H‐W. Chang Department of Biological Sciences, National Sun‐Yat‐Sen University, Kaohsiung, Taiwan E‐mail: tytzung@isca.vghks.gov.tw Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 1, 1 January 2007, Pages 191–192, https://doi.org/10.1111/j.1365-2133.2006.07595.x Published: 01 January 2007
Ways of seeing: Biomedical perspectives on the social world
Authors: C. Humphrey
Journal: Journal of the Royal Society of Medicine (2006)

In the UK health arena it has become axiomatic that, despite medicine's great achievements in the past, a biomedical perspective is no longer adequate on its own. Multidisciplinarity is increasingly regarded as a prerequisite for effective health-care education, practice, policy and research, and a plethora of initiatives exists in all these areas: common learning programmes for health professionals; flexible roles in patient-centred teams; patient participation in NHS decision-making and an increasing emphasis on interdisciplinary research.