tbuckley/cabot-search huggingface dataset:
p53 Improves Aerobic Exercise Capacity and Augments Skeletal Muscle Mitochondrial DNA Content
Authors: Joon-Young Park, Ping-yuan Wang, Takumi Matsumoto, Ho Joong Sung, Wenzhe Ma, Jeong W. Choi, Stasia A. Anderson, Scot C. Leary, Robert S. Balaban, Ju-Gyeong Kang, Paul M. Hwang
Journal: Circulation Research (2009)

Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health.The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity.Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis. As p53 did not affect baseline cardiac function or inotropic reserve, we focused on the involvement of skeletal muscle and now report a wider role for p53 in modulating skeletal muscle mitochondrial function. p53 interacts with Mitochondrial Transcription Factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance, and regulates mtDNA content. The increased mtDNA in p53(+/+) compared to p53(-/-) mice was more marked in aerobic versus glycolytic skeletal muscle groups with no significant changes in cardiac tissue. These in vivo observations were further supported by in vitro studies showing overexpression of p53 in mouse myoblasts increases both TFAM and mtDNA levels whereas depletion of TFAM by shRNA decreases mtDNA content.Our current findings indicate that p53 promotes aerobic metabolism and exercise capacity by using different mitochondrial genes and mechanisms in a tissue-specific manner.
The Architecture of the Heart in Systole and Diastole
Authors: JOHN ROSS, EDMUND H. SONNENBLICK, JAMES W. COVELL, GERARD A. KAISER, DAVID SPIRO
Journal: Circulation Research (1967)

Techniques for rapid fixation of the canine left ventricle in systole or diastole that have permitted analysis of ventricular geometry under known hemodynamic conditions are described. Six ventricles were arrested at and diastole, 7 at end ejection, and 7 in diastole following acute ventricular overdistension. The architecture of the ventricles was analyzed from measurements of the fixed ventricles and silicone-rubber casts of the ventricular cavities. In ventricles of matched weights, the average reduction, from end diastole to end ejection, of the apex to mitral valve distance was 4.6%, while that from apex to aortic valve was less than 1%. The minor internal equator was reduced by 26%, the midwall radius by 16%, and the outer radius by 8.5%. The ratio of the average end-diastolic volume minus end-systolic volume to the end-diastolic volume (analogous to stroke volume/end-diastolic volume) averaged 59%. The average wall thickness was 28% greater in systolic than in diastolic ventricles. The papillary muscle volume averaged 5.0%e of ventricular volume at end diastole and 14.7% at end systole. The area of the mitral valve orifice averaged 28% less at end systole than at end diastole; this area was 39% more in the hearts subjected to over-transfusion than in those with normal filling pressures. These data provide a framework for construction of a geometric model suitable for use in analyses of the mechanics of left ventricular contraction. Moreover, the methods described offer the possibility of correlating ventricular geometry and ultrastructure with cardiac function in normal and in abnormal hearts.
Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies
Authors: Torsten Haferlach, Claudia Schoch, Helmut Löffler, Winfried Gassmann, Wolfgang Kern, Susanne Schnittger, Christa Fonatsch, Wolf-Dieter Ludwig, Christian Wuchter, Brigitte Schlegelberger, Peter Staib, Albrecht Reichle, Uschi Kubica, Hartmut Eimermacher, Leopold Balleisen, Andreas Grüneisen, Detlef Haase, Carlo Aul, Jochen Karow, Eva Lengfelder, Bernhard Wörmann, Achim Heinecke, Maria Cristina Sauerland, Thomas Büchner, Wolfgang Hiddemann
Journal: Journal of Clinical Oncology (2003)

On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification.We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study.Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P <.001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P <.001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics.Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.
The Tyrosine Kinase Inhibitor Imatinib Mesylate Enhances the Efficacy of Photodynamic Therapy by Inhibiting ABCG2
Authors: Weiguo Liu, Maria R. Baer, Mary Jo Bowman, Paula Pera, Xiang Zheng, Janet Morgan, Ravindra A. Pandey, Allan R. Oseroff
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The ATP-binding cassette protein ABCG2 (breast cancer resistance protein) effluxes some of the photosensitizers used in photodynamic therapy (PDT) and, thus, may confer resistance to this treatment modality. Tyrosine kinase inhibitors (TKI) can block the function of ABCG2. Therefore, we tested the effects of the TKI imatinib mesylate (Gleevec) on photosensitizer accumulation and in vitro and in vivo PDT efficacy. Experimental Design: Energy-dependent photosensitizer efflux and imatinib mesylate's effects on intracellular accumulation of clinically used second- and first-generation photosensitizers were studied by flow cytometry in murine and human cells with and without ABCG2 expression. Effects of ABCG2 inhibition on PDT were examined in vitro using cell viability assays and in vivo measuring photosensitizer accumulation and time to regrowth in a RIF-1 tumor model. Results: Energy-dependent efflux of 2-(1-hexyloxethyl)-2-devinyl pyropheophorbide-a (HPPH, Photochlor), endogenous protoporphyrin IX (PpIX) synthesized from 5-aminolevulenic acid, and the benzoporphyrin derivative monoacid ring A (BPD-MA, Verteporfin) was shown in ABCG2+ cell lines, but the first-generation multimeric photosensitizer porfimer sodium (Photofrin) and a novel derivative of HPPH conjugated to galactose were minimally transported. Imatinib mesylate increased accumulation of HPPH, PpIX, and BPD-MA from 1.3- to 6-fold in ABCG2+ cells, but not in ABCG2− cells, and enhanced PDT efficacy both in vitro and in vivo. Conclusions: Second-generation clinical photosensitizers are transported out of cells by ABCG2, and this effect can be abrogated by coadministration of imatinib mesylate. By increasing intracellular photosensitizer levels in ABCG2+ tumors, imatinib mesylate or other ABCG2 transport inhibitors may enhance efficacy and selectivity of clinical PDT.
Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study Commentary: Role of other genes and environment should not be overlooked in monogenic disease
Authors: E. J G Sijbrands
Journal: BMJ (2001)

To estimate all cause mortality from untreated familial hypercholesterolaemia free from selection for coronary artery disease.Family tree mortality study.Large pedigree in Netherlands traced back to a single pair of ancestors in the 19th century.All members of pedigree aged over 20 years with 0.5 probability of carrying a mutation for familial hypercholesterolaemia.All cause mortality.A total of 70 deaths took place among 250 people analysed for 6950 person years. Mortality was not increased in carriers of the mutation during the 19th and early 20th century; it rose after 1915, reached its maximum between 1935 and 1964 (standardised mortality ratio 1.78, 95% confidence interval 1.13 to 2.76; P=0.003), and fell thereafter. Mortality differed significantly between two branches of the pedigree (relative risk 3.26, 95% confidence interval 1.74 to 6.11; P=0.001).Risk of death varies significantly among patients with familial hypercholesterolaemia. This large variability over time and between branches of the pedigree points to a strong interaction with environmental factors. Future research is required to identify patients with familial hypercholesterolaemia who are at extreme risk and need early and vigorous preventive measures.
An Official American Thoracic Society Statement: Position Statement on ATS Activities for the Promotion of Respiratory and Sleep/Wake Health and the Care of the Critically Ill in the United States
Authors: Lee K. Brown, Derek C. Angus, Matthew G. Marin, John R. Balmes, Alan F. Barker, Gary Ewart, Ann C. Halbower, Peter O. Lutz, Richard A. Mularski, Ian T. Nathanson, Mark H. Sanders, George L. Stewart, Dona J. Upson
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

The 1997 American Thoracic Society (ATS) statement "A Framework for Health Care Policy in the United States" outlined core principles for the Society's activities in the public health arena. In the succeeding 10 years, profound changes have taken place in the United States health care environment. In addition, the 2005 publication of the Society's Vision highlighted some differences between the original Statement and our current priorities. Therefore, the Health Policy Committee embarked on a re-analysis and re-statement of the Society's attitudes and strategies with respect to health and public policy. This Statement reflects the findings of the Committee.To outline the key aspects of an internal ATS strategy for the promotion of respiratory and sleep/wake health and the care of the critically ill in the United States.Committee discussion and consensus-building occurred both before and after individual members performed literature searches and drafted sections of the document. Comments were solicited on the draft document from ATS committee and assembly chairs and the Executive Committee, resulting in substantive revisions of the final document.Specific strategies are suggested for the ATS in the arenas of research, training and education, patient care, and advocacy so as to enhance the delivery of health care in the fields of respiratory medicine, sleep medicine, and critical care.The American Thoracic Society's Mission, Core Principles, and Vision provide clear guidance for the formulation of specific strategies that will serve to promote improved respiratory health and care of the critically ill in the United States.
Evidence for discrete stages of human natural killer cell differentiation in vivo
Authors: Aharon G. Freud, Akihiko Yokohama, Brian Becknell, Melissa T. Lee, Hsiaoyin C. Mao, Amy K. Ferketich, Michael A. Caligiuri
Journal: The Journal of Experimental Medicine (2006)

Human natural killer (NK) cells originate from CD34(+) hematopoietic progenitor cells, but the discrete stages of NK cell differentiation in vivo have not been elucidated. We identify and functionally characterize, from human lymph nodes and tonsils, four NK cell developmental intermediates spanning the continuum of differentiation from a CD34(+) NK cell progenitor to a functionally mature NK cell. Analyses of each intermediate stage for CD34, CD117, and CD94 cell surface expression, lineage differentiation potentials, capacity for cytokine production and natural cytotoxicity, and ETS-1, GATA-3, and T-BET expression provide evidence for a new model of human NK cell differentiation in secondary lymphoid tissues.
Small-bowel neoplasms in patients undergoing video capsule endoscopy: a multicenter European study
Authors: E. Rondonotti, M. Pennazio, E. Toth, P. Menchen, M. Riccioni, G. De Palma, F. Scotto, D. De Looze, T. Pachofsky, I. Tacheci, T. Havelund, G. Couto, A. Trifan, A. Kofokotsios, R. Cannizzaro, E. Perez-Quadrado, R. de Franchis
Journal: Endoscopy (2008)

Small-bowel tumors account for 1% - 3% of all gastrointestinal neoplasms. Recent studies with video capsule endoscopy (VCE) suggest that the frequency of these tumors may be substantially higher than previously reported. The aim of the study was to evaluate the frequency, clinical presentation, diagnostic/therapeutic work-up, and endoscopic appearance of small-bowel tumors in a large population of patients undergoing VCE.Identification by a questionnaire of patients with VCE findings suggesting small-bowel tumors and histological confirmation of the neoplasm seen in 29 centers of 10 European Countries.Of 5129 patients undergoing VCE, 124 (2.4%) had small-bowel tumors (112 primary, 12 metastatic). Among these patients, indications for VCE were: obscure gastrointestinal bleeding (108 patients), abdominal pain (9), search for primary neoplasm (6), diarrhea with malabsorption (1). The main primary small-bowel tumor type was gastrointestinal stromal tumor (GIST) (32%) followed by adenocarcinoma (20%) and carcinoid (15%); 66% of secondary small-bowel tumors were melanomas. Of the tumors, 80.6% were identified solely on the basis of VCE findings. 55 patients underwent VCE as the third procedure after negative bidirectional endoscopy. The lesions were single in 89.5% of cases, and multiple in 10.5%. Retention of the capsule occurred in 9.8% of patients with small-bowel tumors. After VCE, 54/124 patients underwent 57 other examinations before treatment; in these patients enteroscopy, when performed, showed a high diagnostic yield. Treatment was surgery in 95% of cases.Our data suggest that VCE detects small-bowel tumors in a small proportion of patients undergoing this examination, but the early use of this tool can shorten the diagnostic work-up and influence the subsequent management of these patients.
Analysis of T cell hybridomas. IV. Characterization of inducible suppressor cell hybridomas.
Authors: M Minami, K Okuda, S Furusawa, M E Dorf
Journal: The Journal of Experimental Medicine (1983)

The Ts3 subset of suppressor cells is generated after antigen priming, but, in order to express suppressor activity these cells require an additional activation step involving triggering with specific suppressor factors (TsF2). This report characterizes two cloned hybridoma cell lines (pTs3 hybridomas) that represent this stage of Ts3 cell differentiation. These hybridoma cells could be specifically activated with TsF2 to release another antigen-specific suppressor factor (TsF3) within 6 h. The inducible feature of these cells permitted analysis of the signals necessary for Ts3 activation. Antigen was not required for activation. Only TsF2 factors derived from antiidiotypic second-order suppressor cells could activate pTs3 hybridoma cells. There were stringent genetic restrictions on the ability of Ts2 to activate pTs3 cells. Triggering of pTs3 required corecognition of two determinants on the TsF2 molecular complex, i.e., the I-J and Igh-related idiotypic determinants. Thus, although pTs3 cells could absorb TsF2 from an I-J-mismatched source, these pTs3 were not activated by the allogeneic TsF2. For activation to occur, the H-2 (I-J) and Igh complexes of the TsF2 donor had to match those of the strain from which the pTs3 cells were derived. Mixing two distinct TsF2, one derived from an H-2-matched source and the other from an Igh-matched source, failed to activate pTs3 cells. Once activated, the pTs3 cells released a suppressive material that was indistinguishable from the TsF3 factors previously characterized in this system. Finally, the activation of the pTs3 cells apparently does not induce the de novo synthesis of TsF3 since the suppressive activity could be extracted from nonactivated pTs3 cells. Thus, the inducible pTs3 hybridomas represent a mature stage in the differentiation cycle of Ts3 cells and provide a means for studying the nature of the specific signals required for Ts3 activation.
Aquaporin Expression in Normal Human Kidney and in Renal Disease
Authors: Jennifer J. Bedford, John P. Leader, Robert J. Walker
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Aquaporins (AQPs), membrane-inserted water channel proteins, play a highly important role in the reabsorption of water from the renal tubular fluid. Experimentally, both in rats and mice, failure to insert functional AQP molecules into renal tubular membranes leads to nephrogenic diabetes insipidus. In humans, most forms of renal disease lead to a reduction in the water handling capacity of the kidney. AQP distribution in various forms of human renal disease has not been documented. Immunohistochemical studies of biopsy samples from a wide range of renal diseases revealed a substantial and striking upregulation of AQP-1 in the glomeruli of most diseased kidneys. AQP-1 expression remained prominent in proximal tubules in all lesions. In contrast, there was judged qualitatively to be a reduction in the amounts of AQP-2 and AQP-3 expression, especially in lesions with substantial interstitial fibrosis and nephron loss, as compared with a healthy region of normal kidneys. The results were quantitatively confirmed by real-time reverse transcriptase–PCR. This is the first documentation of altered AQP expression in human renal disease. The significance of the increased AQP-1 expression requires further studies. E-mail: rob.walker@stonebow.otago.ac.nz
Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer
Authors: Anne-Marie C Dingemans, Vivian van den Boogaart, Bettine A Vosse, Robert-Jan van Suylen, Arjan W Griffioen, Victor L Thijssen
Journal: Molecular Cancer (2010)

Selection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer.A retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8.The expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same.Integrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.
Use of the Web for Medical Information by a Gastroenterology Clinic Population
Authors: J. Barry O'Connor
Journal: JAMA (2000)

Surveys have shown that 60 million persons in the United States searched for health information online in 1998. However, lack of sampling from a clinic population limits the generalizability of these surveys to clinical practice.To determine gastroenterology patients' access to and use of the Web as a medical information resource, to identify for what information patients search, and to determine how often physicians recommend that patients search the Web.Cross-sectional survey of 1006 gastroenterology outpatients in Durham, NC, and Rockford, Ill, conducted in August 1999.Patient characteristics and education level, access to the Web, use of the Web as a medical information resource, search methods, and plans for future Web use.A total of 924 patients (92%) completed the questionnaire. Median age was 53 years, 41% were men, and the median education level was having completed some college. Fifty percent (462/924) reported having access to the Web. Of the 462 with access, 235 (51%) had searched the Web for medical information within the previous 12 months. Therefore, 25.5% of all patients surveyed had searched the Web for medical information within the previous year. Sixty percent of patients intended to use the Web as a medical information resource in the future. Only 35 (4%) of 825 had ever been referred to the Web by a physician.In this clinic setting, more than one quarter of gastroenterology outpatients reported having obtained medical information from the Web within the previous year. More than two thirds of patients stated they would use the Web as a medical information resource in the future. JAMA. 2000;284:1962-1964.