tbuckley/cabot-search huggingface dataset:
Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease
Authors: Sanjay Rajagopalan, Emile R. Mohler, Robert J. Lederman, Farrell O. Mendelsohn, Jorge F. Saucedo, Corey K. Goldman, John Blebea, Jennifer Macko, Paul D. Kessler, Henrik S. Rasmussen, Brian H. Annex
Journal: Circulation (2003)

Background— “Therapeutic angiogenesis” seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor (VEGF) gene transfer for the treatment of peripheral artery disease (PAD). Methods and Results— This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4×10 9 PU) AdVEGF121, high-dose (4×10 10 PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (ΔPWT) at 12 weeks, did not differ between the placebo (1.8±3.2 minutes), low-dose (1.6±1.9 minutes), and high-dose (1.5±3.1 minutes) groups. Secondary measures, including ΔPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema. Conclusions— A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF 121 as a treatment strategy in patients with unilateral PAD.
Overexpressed eIF4E Is Functionally Active in Surgical Margins of Head and Neck Cancer Patients via Activation of the Akt/Mammalian Target of Rapamycin Pathway
Authors: Cherie-Ann O. Nathan, Nazanin Amirghahari, Fleurette Abreo, Xiaohua Rong, Gloria Caldito, M. Lamar Jones, Huijuan Zhou, Melanie Smith, Donnellan Kimberly, Jonathan Glass
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway Experimental Design: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. Results: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P &amp;lt; 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P &amp;lt; 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (β, γ, and δ) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated α isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P &amp;lt; 0.05). Conclusions: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.
Akt/Protein Kinase B and Endothelial Nitric Oxide Synthase Mediate Muscular Neovascularization Induced by Tissue Kallikrein Gene Transfer
Authors: Costanza Emanueli, Maria B. Salis, Sophie Van Linthout, Marco Meloni, Elisa Desortes, Jean-Sebastien Silvestre, Michel Clergue, Carlos D. Figueroa, Sergio Gadau, Gianluigi Condorelli, Paolo Madeddu
Journal: Circulation (2004)

Angiogenesis gene therapy with human tissue kallikrein (hTK) has shown promise for ischemic disease. The present study was undertaken to (1) assess an optimal gene transfer modality, (2) clarify hTK angiogenic pathways, and (3) discount possible side effects.The hTK gene was transferred to murine adductors by increasing doses of an adenovirus (Ad.hTK). Heterologous protein production was evaluated by ELISA and immunohistochemistry. Structural and functional characteristics of hTK-induced neovascularization were assessed. Muscular endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF)-A mRNA and protein content were evaluated by real-time polymerase chain reaction and Western blotting. The ability of hTK to phosphorylate-activate Akt/protein kinase B (Akt-B) and VEGF receptor 2 (VEGF-R2) was also determined. Implication of the aforementioned mechanisms in Ad.hTK-induced neovascularization was challenged by blocking Akt-B with a dominant-negative Akt construct; NOS with N(G)-nitro-L-arginine methyl ester; and VEGF-A with neutralizing antibody, VEGF-R2 antagonist, or Ad carrying soluble VEGF-R1 gene. We found that 10(7) PFU Ad.hTK led to peak increases in capillary and arteriole density. Newly developed arterioles persisted for up to 8 weeks. Ad.hTK did not change microvascular permeability. Ad.hTK upregulated eNOS mRNA and protein and activated Akt-B through Ser-473 phosphorylation. Inhibitory studies documented that these biochemical events were instrumental to Ad.hTK-induced neovascularization. In contrast, Ad.hTK neither affected VEGF-A and VEGF-R2 levels nor increased VEGF-R2 phosphorylation. Consistently, Ad.hTK-induced neovascularization was not disturbed by any of the different approaches used to block VEGF-A.Our findings provide new information on the pathway involved in hTK-induced neoangiogenesis and represent an advancement toward clinical applications with Ad.hTK.
Lowering patients' cholesterol
Authors: R. H Jay
Journal: BMJ (1995)

in better paediatric care, education, or social environment, which are more likely than in vitro fertilisation to maximise utility.When resources for health care are scarce we need to consider the opportunity costs of any investment.While infertility can cause psychological distress, a better use of resources may be to offer counselling to allow couples to accept their condition, or to attempt to alter the expectations of relatives and friends.
Protein Expression Profiling and Molecular Classification of Gastric Cancer by the Tissue Array Method
Authors: Hye Seung Lee, Sung-Bum Cho, Hee Eun Lee, Min A Kim, Ji Hun Kim, Do Joong Park, Ju Han Kim, Han-Kwang Yang, Byung Lan Lee, Woo Ho Kim
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Gastric cancer is heterogeneous clinically and histologically, and prognosis prediction by tumor grade or type is difficult. Although previous studies have suggested that frozen tissue–based molecular classifications effectively predict prognosis, prognostic classification on formalin-fixed tissue is needed, especially in early gastric cancer. Experimental Design: We immunostained 659 consecutive gastric cancers using 56 tumor-associated antibodies and the tissue array method. Hierarchical cluster analyses were done before and after feature selection. To optimize classifier number and prediction accuracy for prognosis, a supervised analysis using a support vector machine algorithm was used. Results: Of 56 gene products, 27 survival-associated proteins were selected (feature selection), and hierarchical clustering identified two clusters: cluster 1 and cluster 2. Cluster 1 cancers were more likely to have intestinal type, earlier stage, and better prognosis than cluster 2 (P &amp;lt; 0.05). In 187 early gastric cancers (pT1), cluster 2 was associated with the presence of metastatic lymph nodes (P = 0.026). Kaplan-Meier survival curves stratified by pathologic tumor-lymph node metastasis revealed that cluster 2 was associated with poor prognosis in stage I or II cancer (P &amp;lt; 0.05). Support vector machines and genetic algorithms selected nine classifiers from the whole data set, another nine classifiers for stage I and II, and eight classifiers for stage III and IV. The prediction accuracies for patient outcome were 73.1%, 88.1%, and 76%, respectively. Conclusions: Protein expression profiling using the tissue array method provided a useful means for the molecular classification of gastric cancer into survival-predictive subgroups. The molecular classification predicted lymph node metastasis and prognosis in early stage gastric cancer.
Color realism and color science
Authors: Alex Byrne, David R. Hilbert
Journal: Behavioral and Brain Sciences (2003)

Abstract The target article is an attempt to make some progress on the problem of color realism. Are objects colored? And what is the nature of the color properties? We defend the view that physical objects (for instance, tomatoes, radishes, and rubies) are colored, and that colors are physical properties, specifically, types of reflectance. This is probably a minority opinion, at least among color scientists. Textbooks frequently claim that physical objects are not colored, and that the colors are “subjective” or “in the mind.” The article has two other purposes: First, to introduce an interdisciplinary audience to some distinctively philosophical tools that are useful in tackling the problem of color realism and, second, to clarify the various positions and central arguments in the debate. The first part explains the problem of color realism and makes some useful distinctions. These distinctions are then used to expose various confusions that often prevent people from seeing that the issues are genuine and difficult, and that the problem of color realism ought to be of interest to anyone working in the field of color science. The second part explains the various leading answers to the problem of color realism, and (briefly) argues that all views other than our own have serious difficulties or are unmotivated. The third part explains and motivates our own view, that colors are types of reflectances and defends it against objections made in the recent literature that are often taken as fatal.
Smooth Muscle–Specific Expression of the Smooth Muscle Myosin Heavy Chain Gene in Transgenic Mice Requires 5′-Flanking and First Intronic DNA Sequence
Authors: Cort S. Madsen, Christopher P. Regan, Jill E. Hungerford, Sheryl L. White, Ichiro Manabe, Gary K. Owens
Journal: Circulation Research (1998)

Abstract —The smooth muscle myosin heavy chain (SM-MHC) gene encodes a major contractile protein whose expression exclusively marks the smooth muscle cell (SMC) lineage. To better understand smooth muscle differentiation at the transcriptional level, we have initiated studies to identify those DNA sequences critical for expression of the SM-MHC gene. Here we report the identification of an SM-MHC promoter-intronic DNA fragment that directs smooth muscle–specific expression in transgenic mice. Transgenic mice harboring an SM-MHC- lac Z reporter construct containing ≈16 kb of the SM-MHC genomic region from −4.2 to +11.6 kb (within the first intron) expressed the lac Z transgene in all smooth muscle tissue types. The inclusion of the intronic sequence was required for transgene expression, since 4.2 kb of the 5′-flanking region alone was not sufficient for expression. In the adult mouse, transgene expression was observed in both arterial and venous smooth muscle, in airway smooth muscle of the trachea and bronchi, and in the smooth muscle layers of all abdominal organs, including the stomach, intestine, ureters, and bladder. During development, transgene expression was first detected in airway SMCs at embryonic day 12.5 and in vascular and visceral SMC tissues by embryonic day 14.5. Of interest, expression of the SM-MHC transgene was markedly reduced or absent in some SMC tissues, including the pulmonary circulation. Moreover, the transgene exhibited a heterogeneous pattern between individual SMCs within a given tissue, suggesting the possibility of the existence of different SM-MHC gene regulatory programs between SMC subpopulations and/or of episodic rather than continuous expression of the SM-MHC gene. To our knowledge, results of these studies are the first to identify a promoter region that confers complete SMC specificity in vivo, thus providing a system with which to define SMC-specific transcriptional regulatory mechanisms and to design vectors for SMC-specific gene targeting.
A retrospective study of the impact of the doctors’ strike in England on 21 June 2012
Authors: Milagros Ruiz, Alex Bottle, Paul Aylin
Journal: Journal of the Royal Society of Medicine (2013)

Objective To examine the effect of the 24-h doctors’ strike on 21 June 2012 on hospital activity in English NHS hospitals. Design Retrospective descriptive study of inpatient, outpatient and Accident and Emergency (A&amp;E) activity in NHS hospitals over the strike period. Setting All English NHS hospitals. Participants Patients admitted to hospital, patients with outpatient appointments and A&amp;E attendances over a three-week period (from 11 to 29 June 2012), excluding weekends and spanning the strike day. Main outcome measures Numbers and percentage change of inpatient admissions (elective and emergency), day surgery cases, outpatient appointments cancellations, A&amp;E attendances and in-hospital deaths on the day of the strike compared with patient activity on the Thursday before and the Thursday after the strike week. Results There were a total of 795,267 admissions, 5,602,971 outpatient appointments, 356,645 outpatient cancellations (by NHS provider), 4,470,208 outpatients seen by medical staff, 986,322 A&amp;E attendances and 13,857 in-hospital deaths over the three-week period. Compared with the non-strike period, on the day of the strike, emergency admissions fell by 2.4% while the elective admissions decreased by 12.8%. There was a 7.8% drop in the number of outpatients seen by medical staff on the day of the strike and a 45.5% increase in the number of cancelled appointments by NHS hospitals, while A&amp;E attendances dropped by 4.7%. The impact of the strike across regional Health Authorities in England was varied. The North West Health Authority was affected the most while the least affected Health Authorities were the South West, East of England and South Central. Conclusions The 24-h doctors’ strike in England on 21 June 2012 significantly affected the provision of healthcare by NHS hospitals. We observed regional variations on NHS service levels on the day of the strike.
Burkitt Lymphoma in the Mouse
Authors: Alexander L. Kovalchuk, Chen-Feng Qi, Ted A. Torrey, Lekidelu Taddesse-Heath, Lionel Feigenbaum, Sung Sup Park, Armin Gerbitz, Gustav Klobeck, Konstanze Hoertnagel, Axel Polack, Georg W. Bornkamm, Siegfried Janz, Herbert C. Morse
Journal: The Journal of Experimental Medicine (2000)

Chromosomal translocations juxtaposing the MYC protooncogene with regulatory sequences of immunoglobulin (Ig) H chain or kappa (Igκ) or lambda (Igλ) L chain genes and effecting deregulated expression of MYC are the hallmarks of human Burkitt lymphoma (BL). Here we report that lymphomas with striking similarities to BL develop in mice bearing a mutated human MYC gene controlled by a reconstructed Igλ locus encompassing all the elements required for establishment of locus control in vitro. Diffusely infiltrating lymphomas with a typical starry sky appearance occurred in multiple founders and an established line, indicating independence from positional effects. Monoclonal IgM+CD5−CD23− tumors developed from an initially polyclonal population of B cells. These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL.
Debate: challenges in sports cardiology; US versus European approaches
Authors: Bruce Hamilton, Benjamin D Levine, Paul D Thompson, Gregory P Whyte, Mathew G Wilson
Journal: British Journal of Sports Medicine (2012)

For practitioners working with elite athletes, the field of sports cardiology provides clinical, academic, administrative and fiscal challenges. These challenges are exemplified and reinforced by the lack of consistency and consensus both in the literature and academic presentations. Through the presentation of a series of clinical questions, this debate attempts to ‘cut to the chase’ on cardiovascular issues relevant to the clinician dealing with elite athletes. In so doing, we hope to crystallize some of the most important elements of the complex cardiological management of elite athletes, in a concise, readable format. Frequently over the last 10 years, many of the controversies in this field have been (rightly or wrongly) presented in a Europe versus USA paradigm. We have chosen to test whether there really are polarised views across the Atlantic, by deliberately pitting specialists from the USA against those from the UK. Professors Levine and Thompson are both internationally recognised sports cardiologists, with immense academic and clinical credibility, and who will represent the ‘US approach’. Professor Whyte and Doctor Wilson are cardiac physiologists with a wealth of experience in the testing, evaluation and screening of elite athletes, and who have equally impressive academic credibility and for the purposes of this debate, they will be representing the ‘European approach’. To initiate this process, each team was required to provide a concise answer (circa 200–300 words) to a series of five clinical conundrums. Subsequently, each team had the opportunity to provide a rebuttal to the opposing team's answers, and the following reflects the consolidation of those answers.

A popular debate in the literature and the conference podium is the clinical utility of the ECG in the preparticipation screening of athletes. If one assumes that the overall cost:benefit of cardiac screening for athletes remains to be determined, is it now established that the …
Free fatty acid metabolism of the human heart at rest
Authors: Albert S. Most, Norman Brachfeld, Richard Gorlin, John Wahren
Journal: Journal of Clinical Investigation (1969)

Myocardial substrate metabolism was studied in 13 subjects at the time of diagnostic cardiac catheterization by means of palmitic acid-(14)C infusion with arterial and coronary sinus sampling. Two subjects were considered free of cardiac pathology and all, with one exception, demonstrated lactate extraction across the portion of heart under study. Data for this single lactate-producing subject were treated separately.The fractional extraction of (14)C-labeled free fatty acids (FFA) (44.4+/-9.5%) was nearly twice that of unlabeled FFA (23.2+/-7.8%) and raised the possibility of release of FFA into the coronary sinus. FFA uptake, based on either the arterial minus coronary sinus concentration difference or the FFA-(14)C fractional extraction, was directly proportional to the arterial FFA concentration. Gas-liquid chromatography failed to demonstrate selective handling of any individual FFA by the heart. Fractional oxidation of FFA was 53.5+/-12.7%, accounting for 53.2+/-14.4% of the heart's oxygen consumption while nonlipid substrates accounted for an additional 30.0+/-17.3%. Determinations of both labeled and unlabeled triglycerides suggested utilization of this substrate by the fasting human heart. Direct measurement of FFA fractional oxidation as well as FFA uptake, exclusive of possible simultaneous FFA release, would appear necessary in studies concerned with human myocardial FFA metabolism.
BCL-2 FAMILY: Regulators of Cell Death
Authors: Debra T. Chao, Stanley J. Korsmeyer
Journal: Annual Review of Immunology (1998)

▪ Abstract An expanding family of BCL-2 related proteins share homology, clustered within four conserved regions, namely BCL-2 homology (BH1-4) domains, which control the ability of these proteins to dimerize and function as regulators of apoptosis. Moreover, BCL-X L , BCL-2, and BAX can form ion-conductive pores in artificial membranes. The BCL-2 family, comprised of both pro-apoptotic and anti-apoptotic members, acts as a checkpoint upstream of CASPASES and mitochondrial dysfunction. BID and BAD possess the minimal death domain BH3, and the phosphorylation of BAD connects proximal survival signals to the BCL-2 family. BCL-2 and BCL-X L display a reciprocal pattern of expression during lymphocyte development. Gain- and loss-of-function models revealed stage-specific roles for BCL-2 and BCL-X L . BCL-2 can rescue maturation at several points of lymphocyte development. The BCL-2 family also reveals evidence for a cell-autonomous coordination between the opposing pathways of proliferation and cell death.
Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?
Authors: L. R. Guerin, J. R. Prins, S. A. Robertson
Journal: Human Reproduction Update (2009)

BACKGROUNDAdaptation of the maternal immune response to accommodate the semi-allogeneic fetus is necessary for pregnancy success, and disturbances in maternal tolerance are implicated in infertility and reproductive pathologies. T regulatory (Treg) cells are a recently discovered subset of T-lymphocytes with potent suppressive activity and pivotal roles in curtailing destructive immune responses and preventing autoimmune disease.
Local adenoviral-mediated inducible nitric oxide synthase gene transfer inhibits neointimal formation in the porcine coronary stented model
Authors: Kai Wang, Paul D Kessler, Zhongmin Zhou, Marc S Penn, Farhad Forudi, Xiaorong Zhou, Khaldoun Tarakji, Melina Kibbe, Imre Kovesdi, Douglas E Brough, Eric J Topol, A.Michael Lincoff
Journal: Molecular Therapy (2003)

In this study the effect of local adenoviral-mediated delivery of inducible nitric oxide synthase on restenosis was evaluated in a porcine coronary stented model. Local gene transfer of recombinant adenoviral vectors that encode human inducible nitric oxide synthase (AdiNOS) was tested. Control vector (AdNull) lacked a recombinant transgene. Endoluminal delivery of 1.0 x 10(11) adenoviral particles was accomplished in 45 s using the Infiltrator catheter (Interventional Technologies, San Diego, CA). Coronary stents were deployed, oversized by a ratio of 1.2:1, in the treated segments immediately after gene transfer. Fourteen animals were sacrificed at day 28 to evaluate the effects of iNOS gene transfer on morphometric indices, and 4 animals were sacrificed at day 4 for detection of human iNOS expression by RT-PCR. iNOS mRNA was detected in six of eight iNOS-transferred arteries, whereas no expression of human iNOS was detected in the nontarget arteries. Morphometric analysis showed that iNOS transfer significantly reduced neointimal formation (3.41 +/- 1.12 mm(2) vs 2.14 +/- 0.68 mm(2), P < 0.05). We concluded that efficient intramural adenovirus-mediated iNOS transfer can be achieved by using Infiltrator catheters. iNOS gene transfer significantly reduces neointimal hyperplasia following stent injury.