tbuckley/cabot-search huggingface dataset:
Use of CT colonography in the English Bowel Cancer Screening Programme
Authors: Andrew A Plumb, Steve Halligan, Claire Nickerson, Paul Bassett, Andrew F Goddard, Stuart A Taylor, Julietta Patnick, David Burling
Journal: Gut (2013)

<h3>Objective</h3> To examine use of CT colonography (CTC) in the English Bowel Cancer Screening Programme (BCSP) and investigate detection rates. <h3>Design</h3> Retrospective analysis of routinely coded BCSP data. Guaiac faecal occult blood test (gFOBt)-positive screenees undergoing CTC from June 2006 to July 2012 as their first-line colonic investigation were included. Abnormalities found at CTC, subsequent polyp, adenoma and cancer detection and positive predictive value (PPV) were calculated. Detection rates were compared with those observed in gFOBt-positive screenees investigated by colonoscopy. Multilevel logistic regression was used to examine factors associated with variable detection. <h3>Results</h3> 2731 screenees underwent CTC. Colorectal cancer (CRC) or polyps were suspected in 1027 individuals (37.6%; 95% CI 33.8% to 41.4%); 911 of these underwent confirmatory testing. 124 screenees had CRC (4.5%) and 533 had polyps (19.5%), 468 adenomatous (17.1%). Overall detection was 24.1% (95% CI 21.5% to 26.6%) for CRC or polyps and 21.7% (95% CI 19.2% to 24.1%) for CRC or adenoma. Advanced neoplasia was detected in 504 screenees (18.5%; 95% CI 16.1% to 20.8%). PPV for CRC or polyp was 72.1% (95% CI 66.6% to 77.6%). By comparison, 9.0% of 72 817 screenees undergoing colonoscopy had cancer and 50.6% had polyps; advanced neoplasia was detected in 32.7%. CTC detection rates and PPV were higher at centres with experienced radiologists (&gt;1000 examinations) and at high-volume centres (&gt;175 cases/radiologist/annum). Centres using three-dimensional interpretation detected more neoplasia. <h3>Conclusions</h3> In the BCSP, detection rates after positive gFOBt are lower for CTC than colonoscopy, although populations undergoing the two tests are different. Centres with more experienced radiologists have higher detection and accuracy. Rigorous quality assurance of BCSP radiology is needed.
Molecular Pathways: Niches in Metastatic Dormancy
Authors: Kenji Yumoto, Matthew R. Eber, Janice E. Berry, Russell S. Taichman, Yusuke Shiozawa
Journal: Clinical Cancer Research (2014)

Despite the best available treatments for primary tumors, cancer can return, even after a long disease-free interval. During this period, cancer cells are believed to lie dormant in either primary sites, metastatic sites, or independent sites like bone marrow, effectively escaping adjuvant cytotoxic treatments. To date, little is known about how these cells transition to dormancy, or how they are reactivated if cancer recurs. Recent studies have revealed the effects of tumor microenvironment or niche on the regulation of tumor dormancy via the signaling pathways of growth arrest-specific 6, bone morphogenetic protein 7, and TGFβ1, and that the balance between activation of p38 MAPK and ERK MAPK plays a pivotal role in tumor dormancy. In this review, we discuss tumor dormancy from the perspective of the niche and consider potential therapeutic targets. Greater understanding of the mechanisms involved will help guide innovation in the care of patients with advanced cancer.
Effects of 12 months of exercise training on salivary secretory IgA levels in elderly subjects
Authors: T Akimoto, Y Kumai, T Akama, E Hayashi, H Murakami, R Soma, S Kuno, I Kono
Journal: British Journal of Sports Medicine (2003)

The immune system declines in efficiency with advancing age, making the elderly less resistant to pathogenic microorganisms. Upper respiratory tract infection (URTI) is a common illness. Recent studies have shown that suppression of secretory immunoglobulin A (SIgA) is associated with increased incidence of URTI.To assess the effect of exercise on salivary SIgA in elderly subjects.Forty five elderly subjects (18 men, 27 women; mean (SD) age 64.9 (8.4) years) performed both 60 minute resistance and 60 minute moderate endurance training a week for 12 months. Saliva samples were obtained before training, and at four and 12 months during the training period. Salivary SIgA concentrations were measured by enzyme linked immunosorbent assay, and the SIgA secretion rate was calculated.SIgA concentrations before training, and at four and 12 months during training were 24.7 (14.4), 27.2 (14.2), and 33.8 (18.5) micro g/ml respectively. SIgA secretion rates were 29.5 (26.0), 33.8 (27.2) and 46.5 (35.1) micro g/min respectively. The results indicate that both the concentration and secretion rate of SIgA significantly (p<0.01) increased during 12 months of exercise in these elderly subjects.Regular moderate exercise seems to enhance mucosal immune function in elderly subjects.
Efficacy of Weekly Docetaxel and Bevacizumab in Mesenchymal Chondrosarcoma: A New Theranostic Method Combining Xenografted Biopsies with a Mathematical Model
Authors: Boris Gorelik, Irit Ziv, Revital Shohat, Michael Wick, W. David Hankins, David Sidransky, Zvia Agur
Journal: Cancer Research (2008)

Abstract The paucity of clinical treatment data on rare tumors, such as mesenchymal chondrosarcoma (MCS), emphasizes the need in theranostic tools for these diseases. We put forward and validated a new theranostic method, combining tumor xenografts and mathematical models, and used it to suggest an improved treatment schedule for a particular MCS patient. Growth curves and gene expression analysis of xenografts, derived from a patient's lung metastasis, served for creating a mathematical model of MCS progression and adapting it to the xenograft setting. The pharmacokinetics and pharmacodynamics of six drugs were modeled, with model variables being adjusted by patient-specific chemosensitivity tests. The xenografted animals were treated by various monotherapy and combination schedules, and the MCS xenograft model was computer simulated under the same treatment scenario. The mathematical model for xenograft growth was then up-scaled to retrieve the MCS patient's tumor progression under different treatment schedules. An average accuracy of 87.1% was obtained when comparing model predictions with the observed tumor growth inhibition in the xenografted animals. Simulation results suggested that a regimen containing bevacizumab applied i.v. in combination with once-weekly docetaxel would be more efficacious in the MCS patient than all other simulated schedules. Weekly docetaxel in the patient resulted in stable metastatic disease and relief of pancytopenia due to tumor infiltration. We suggest that the advantage of weekly docetaxel on the triweekly regimen is directly related to the angiogenesis rate of the tumor. Further validation of this conclusion, and the theranostic method we provide, may facilitate personalization of solid cancer pharmacotherapy. [Cancer Res 2008;68(21):9033–40]
Acute Cardiovascular Effects of Fetal Surgery in the Human
Authors: Jack Rychik, Zhiyun Tian, Meryl S. Cohen, Stanford G. Ewing, David Cohen, Lori J. Howell, R. Douglas Wilson, Mark P. Johnson, Holly L. Hedrick, Alan W. Flake, Timothy M. Crombleholme, N. Scott Adzick
Journal: Circulation (2004)

Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system.Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery.Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.
Visiting through the night.
Authors: C Salisbury
Journal: BMJ (1993)

To describe the time distribution of visits at night and to evaluate trends in night visits from 1982 to 1992.Analysis of a sample of one in 12 claim forms for night visits submitted over one year beginning 1 July 1991, and estimation of the number of night visits in previous years from data on payment. Further information was obtained from performance indicators from the Department of Health.General practices responsible to Berkshire family health services authority.Times of night visits, proportion performed by deputies, and trend in number of night visits after adjusting for the increased hours during which visits are claimed.The change in the hours for which payment may be claimed accounted for 33.8% (536/1584) of all night visits in the sample. After visits during these extra two hours were excluded, claims increased by 38.7% from 1989 to 1992 and more than doubled in the past 10 years. Use of deputies both in Berkshire and in England and Wales dropped by more than half since 1989. General practitioners in Berkshire claimed 31.5 night visits per 1000 population in 1992.The increase in the number of night visits is only partly due to the change in hours during which visits may be claimed. It is also due to a long term and possibly accelerating rise in demand. This is despite a major reduction in the proportion of calls performed by deputising services, the use of which had been said to be the main factor increasing the numbers of night visits.
[625] NOVEL MODE OF VIRAL DECLINE DURING TELAPREVIR (VX-950) AND PEG-IFN COMBINATION TREATMENT PREDICTED BY A NEW COMBINED INTRACELLULAR AND CELLULAR HEPATITIS C VIRAL DYNAMICS MODEL
Authors: A.U. Neumann, L. Rozenberg, H.W. Reesink, S. Zeuzem, H.M. Chu
Journal: Journal of Hepatology (2007)
Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction
Authors: Emeline Perrier, Benoît-Gilles Kerfant, Nathalie Lalevee, Patrice Bideaux, Michel F. Rossier, Sylvain Richard, Ana María Gómez, Jean-Pierre Benitah
Journal: Circulation (2004)

Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development.Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca2+ current (I(Ca)) and a decrease in K+ transient outward current (I(to)) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca2+ channel alpha1C subunit (Ca(v)1.2) increased, and that of the K+ channel K(v)4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I(Ca) density, Ca(v)1.2, and K(v)4.2 mRNA levels regained control levels, but I(to) density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy.Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.
Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation
Authors: Alena M. Gallegos, Michael J. Bevan
Journal: The Journal of Experimental Medicine (2004)

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.
Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo
Authors: Masaru Ishii, Junichi Kikuta, Yutaka Shimazu, Martin Meier-Schellersheim, Ronald N. Germain
Journal: The Journal of Experimental Medicine (2010)

Sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, controls the dynamic migration of osteoclast (OC) precursors (OPs) between the blood and bone, in part via the S1P receptor 1 (S1PR1) which directs positive chemotaxis toward S1P. We show that OPs also express S1PR2, an S1P receptor which mediates negative chemotaxis (or chemorepulsion). OP-positive chemotaxis is prominent in gradients with low maximal concentrations of S1P, whereas such behavior is minimal in fields with high maximal S1P concentrations. This reverse-directional behavior is caused by S1PR2-mediated chemorepulsion acting to override S1PR1 upgradient motion. S1PR2-deficient mice exhibit moderate osteopetrosis as a result of a decrease in osteoclastic bone resorption, suggesting that S1PR2 contributes to OP localization on the bones mediated by chemorepulsion away from the blood where S1P levels are high. Inhibition of S1PR2 function by the antagonist JTE013 changed the migratory behavior of monocytoid cells, including OPs, and relieved osteoporosis in a mouse model by limiting OP localization and reducing the number of mature OCs attached to the bone surface. Thus, reciprocal regulation of S1P-dependent chemotaxis controls bone remodeling by finely regulating OP localization. This regulatory axis may be promising as a therapeutic target in diseases affecting OC-dependent bone remodeling.
Molecular basis of substrate and inhibitory specificity of tyrosinase: phenolic compounds
Authors: S. PASSI, M. NAZZARO-PORRO
Journal: British Journal of Dermatology (1981)

In order to investigate the molecular basis of substrates, and the inhibitory specificity of tyrosinase, a large series of phenolic compounds have been analysed by using a High Performance Liquid Chromatographic-Scanning Spectrophotometric system. Depending on their chemical structure, phenolic compounds may act as substrates or as competitive inhibitors of tyrosinase. The ability to act as substrates requires the presence in the molecule of electron donor groups, while competitive inhibition on the contrary requires the presence of powerful electron acceptor groups. Certain phenolic compounds used as therapeutic agents or as food preservatives are chemically capable of acting as alternative substrates or competitive inhibitors of tyrosinase in vitro; their effect on melanocytes in vivo therefore merits investigation.
Thioredoxin-2 Inhibits Mitochondria-Located ASK1-Mediated Apoptosis in a JNK-Independent Manner
Authors: Rong Zhang, Rafia Al-Lamki, Lanfang Bai, Jeffrey W. Streb, Joseph M. Miano, John Bradley, Wang Min
Journal: Circulation Research (2004)

Apoptosis signal-regulating kinase 1 (ASK1) mediates cytokines and oxidative stress (ROS)-induced apoptosis in a mitochondria-dependent pathway. However, the underlying mechanism has not been defined. In this study, we show that ASK1 is localized in both cytoplasm and mitochondria of endothelial cells (ECs) where it binds to cytosolic (Trx1) and mitochondrial thioredoxin (Trx2), respectively. Cys-250 and Cys-30 in the N-terminal domain of ASK1 are critical for binding of Trx1 and Trx2, respectively. Mutation of ASK1 at C250 enhanced ASK1-induced JNK activation and apoptosis, whereas mutation of ASK1 at C30 specifically increased ASK1-induced apoptosis without effects on JNK activation. We further show that a JNK-specific inhibitor SP600125 completely blocks TNF induced JNK activation, Bid cleavage, and Bax mitochondrial translocation, but only partially inhibits cytochrome c release and EC death, suggesting that TNF induces both JNK-dependent and JNK-independent apoptotic pathways in EC. Mitochondria-specific expression of a constitutively active ASK1 strongly induces EC apoptosis without JNK activation, Bid cleavage, and Bax mitochondrial translocation. These data suggest that mitochondrial ASK1 mediates a JNK-independent apoptotic pathway induced by TNF. To determine the role of Trx2 in regulation of mitochondrial ASK1 activity, we show that overexpression of Trx2 inhibits ASK1-induced apoptosis without effects on ASK1-induced JNK activation. Moreover, specific knockdown of Trx2 in EC increases TNF/ASK1-induced cytochrome c release and cell death without increase in JNK activation, Bid cleavage, and Bax translocation. Our data suggest that ASK1 in cytoplasm and mitochondria mediate distinct apoptotic pathways induced by TNF, and Trx1 and Trx2 cooperatively inhibit ASK1 activities.
Strand-specific RNA sequencing reveals extensive regulated long antisense transcripts that are conserved across yeast species
Authors: Moran Yassour, Jenna Pfiffner, Joshua Z Levin, Xian Adiconis, Andreas Gnirke, Chad Nusbaum, Dawn-Anne Thompson, Nir Friedman, Aviv Regev
Journal: Genome biology (2010)

Abstract Background Recent studies in budding yeast have shown that antisense transcription occurs at many loci. However, the functional role of antisense transcripts has been demonstrated only in a few cases and it has been suggested that most antisense transcripts may result from promiscuous bi-directional transcription in a dense genome. Results Here, we use strand-specific RNA sequencing to study anti-sense transcription in Saccharomyces cerevisiae . We detect 1,103 putative antisense transcripts expressed in mid-log phase growth, ranging from 39 short transcripts covering only the 3' UTR of sense genes to 145 long transcripts covering the entire sense open reading frame. Many of these antisense transcripts overlap sense genes that are repressed in mid-log phase and are important in stationary phase, stress response, or meiosis. We validate the differential regulation of 67 antisense transcripts and their sense targets in relevant conditions, including nutrient limitation and environmental stresses. Moreover, we show that several antisense transcripts and, in some cases, their differential expression have been conserved across five species of yeast spanning 150 million years of evolution. Divergence in the regulation of antisense transcripts to two respiratory genes coincides with the evolution of respiro-fermentation. Conclusions Our work provides support for a global and conserved role for antisense transcription in yeast gene regulation.
High Qualitative and Quantitative Conservation of Alternative Splicing in Caenorhabditis elegans and Caenorhabditis briggsae
Authors: Jakob Lewin Rukov, Manuel Irimia, Søren Mørk, Viktor Karlovich Lund, Jeppe Vinther, Peter Arctander
Journal: Molecular Biology and Evolution (2007)

Alternative splicing (AS) is an important contributor to proteome diversity and is regarded as an explanatory factor for the relatively low number of human genes compared with less complex animals. To assess the evolutionary conservation of AS and its developmental regulation, we have investigated the qualitative and quantitative expression of 21 orthologous alternative splice events through the development of 2 nematode species separated by 85–110 Myr of evolutionary time. We demonstrate that most of these alternative splice events present in Caenorhabditis elegans are conserved in Caenorhabditis briggsae. Moreover, we find that relative isoform expression levels vary significantly during development for 78% of the AS events and that this quantitative variation is highly conserved between the 2 species. Our results suggest that AS is generally tightly regulated through development and that the regulatory mechanisms controlling AS are to a large extent conserved during the evolution of Caenorhabditis. This strong conservation indicates that both major and minor splice forms have important functional roles and that the relative quantities in which they are expressed are crucial. Our results therefore suggest that the quantitative regulation of isoform expression levels is an intrinsic part of most AS events. Moreover, our results indicate that AS contributes little to transcript variation in Caenorhabditis genes and that gene duplication may be the major evolutionary mechanism for the origin of novel transcripts in these 2 species.
MISMATCHED FAMILY DONORS FOR BONE-MARROW TRANSPLANTATION AS TREATMENT FOR ACUTE LEUKAEMIA
Authors: R.L. Powles, H.E.M. Kay, H.M. Clink, A. Barrett, M.H. Depledge, J. Sloane, H. Lumley, S.D. Lawler, G.R. Morgenstern, T.J. Mcelwain, P.J. Dady, B. Jameson, J.G. Watson, M. Leigh, D. Hedley, J. Filshie, B. Robinson
Journal: The Lancet (1983)