tbuckley/cabot-search huggingface dataset:
Re: Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer
Authors: A. Olsen, R. Egeberg, A. Tjonneland
Journal: JNCI Journal of the National Cancer Institute (2009)

plemented by another study recently published in the Journal ( 5 ), showing rather strong increased risks of prostate cancer, especially the more advanced stages, among men with high serum levels of vitamin D. We argue the need for caution before recommending that the population take high doses of vitamin D supplements. We agree that many interesting studies indicate promising effects of vitamin D regarding public health, but the past has shown us (with the history of -carotene and lung cancer as the scariest lesson) that observational studies on micronutrient blood levels cannot always be extrapolated to positive effects of high-dose supplementation. Furthermore, it is rather interesting that both high physical activity and low body mass index seem to be strongly associated with high vitamin D blood levels ( 1 , 5 ). Could confounding by these two important health measures be an important part of the explanation for the preventive effects observed in some studies regarding vitamin D?
Evolution of the Fot1 Transposons in the Genus Fusarium: Discontinuous Distribution and Epigenetic Inactivation
Authors: Marie-Josée Daboussi, Jean-Michel Davière, Stéphane Graziani, Thierry Langin
Journal: Molecular Biology and Evolution (2002)

To understand the evolution of Fot1, a member of the pogo family widely dispersed in ascomycetes, we have performed a phylogenetic survey across the genus Fusarium divided into six sections. The taxonomic distribution of Fot1 is not homogeneous but patchy; it is prevalent in the Fusarium oxysporum complex, absent in closely related sections, and found in five species from the most distant section Martiella. Multiple copies of Fot1 were sequenced from each strain in which the element occurs. In three species, the Fot1 nucleotide sequence is 98% identical to that from F. oxysporum (Fox), whereas nucleotide divergence for host genes is markedly higher: 11% for partial nuclear 28S rDNA and up to 30% for the gene encoding nitrate reductase (nia). In two species, sequence divergence of Fot1-related elements relative to Fox ranged from 7% to 23% (16% average). Most of the sequence differences (82%) were C-to-T and G-to-A transitions. These mutations are distributed throughout the Fot1 sequences, although they tend to be concentrated in the middle portion of the elements. Analysis of the local sequence context of transitions revealed a hierarchy of site preferences. These characteristics are typical of the repeat-induced point mutation process, first discovered in Neurospora crassa. The spotty distribution of Fot1 elements among species together with the high degree of similarity between Fot1 sequences present in distant species strongly suggests a case of horizontal transfer.
Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines
Authors: P J Koshy
Journal: Annals of the Rheumatic Diseases (2002)

To investigate whether interleukin 17 (IL17), derived specifically from T cells, can promote type II collagen release from cartilage. The ability of IL17 to synergise with other proinflammatory mediators to induce collagen release from cartilage, and what effect anti-inflammatory agents had on this process, was also assessed.IL17 alone, or in combination with IL1, IL6, oncostatin M (OSM), or tumour necrosis factor alpha (TNFalpha), was added to bovine nasal cartilage explant cultures. Proteoglycan and collagen release were determined. Collagenolytic activity was determined by bioassay. Chondroprotective effects of IL4, IL13, transforming growth factor beta1 (TGFbeta1) and insulin-like growth factor-1 (IGF1) were assessed by inclusion in the explant cultures.IL17 alone stimulated a dose dependent release of proteoglycan and type II collagen from bovine nasal cartilage explants. Suboptimal doses of IL17 synergised potently with TNFalpha, IL1, OSM, and IL6 to promote collagen degradation. This collagen release was completely inhibited by tissue inhibitor of metalloproteinase-1 and BB-94 (a synthetic metalloproteinase inhibitor), and was significantly reduced by IL4, IL13, TGFbeta1, and IGF1. In IL17 treated chondrocytes, mRNA expression for matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 was detected. Moreover, a synergistic induction of these MMPs was seen when IL17 was combined with other proinflammatory cytokines.IL17 can, alone and synergistically in combination with other proinflammatory cytokines, promote chondrocyte mediated MMP dependent type II collagen release from cartilage. Because levels of all these proinflammatory cytokines are raised in rheumatoid synovial fluids, this study suggests that IL17 may act as a potent upstream mediator of cartilage collagen breakdown in inflammatory joint diseases.
T2 MSCTRAIL as a Novel Cellular Therapy For Malignant Mesothelioma
Authors: EK Sage, K McNulty, K Kolluri, A Giangreco, SM Janes
Journal: Thorax (2012)

<h3>Background</h3> Malignant pleural mesothelioma (MPM) is an aggressive fatal cancer with no effective treatments. Mesenchymal stem cells (MSCs) migrate and incorporate into tumour stroma making them good vehicles for the delivery ofanti-cancer therapies. TNF-relatedapoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells without affecting healthy tissues. This study aimed to test whether MSCs modified to express TRAIL (MSCTRAIL) could be a successful cell therapy for MPM. <h3>Methods</h3> Human MSCs were transduced with a lentiviral vector containing TRAIL IRES-GFP under the control of a tetracycline dependent promoter. Successful transduction was measured using flow cytometry and TRAIL expression was confirmed by immuno-blotting and ELISA. The biological activity of MSCTRAIL was determined using co-culture experiments. DiI stained MPM cells were plated in a 1:1 ratio with MSCTRAIL cells. TRAIL production was activated and cells were treated for 48 hours. Both cells and supernatant were collected and stained with Annexin V and DAPI to detect apoptosis and death respectively on flow cytometry. To test the effect of MSCTRAIL in vivo a bioluminescent tumour model was established. Plasmid containing fireflyluciferase and YFP was expanded and the correct sequences confirmed by restriction digest. Lentivirus was produced, viral titres were determined using flow cytometry and MPM cells were transduced (MPMLuc). A pure population was generated using hygromycin selection. 80,000 MPMLuc cells were injected into the pleural cavity of NOD/SCID mice and their growth was assessed using an IVIS Lumina system to detect bioluminescence. 1 million MSCTRAIL cells were delivered via tail vein injections on days 5, 9, 12, 15 and 18 post tumour inoculation and bioluminescence was measured twice weekly. <h3>Results</h3> MSCs were successfully transduced with TRAIL with 96% efficiency and TRAIL production was confirmed by ELISA. Seven human MPM cell lines were tested with 6/7 (86%) being sensitive to MSCTRAIL. In vivo delivery of MSCTRAIL resulted in a significant reduction in MPM tumour growth. <h3>Conclusions</h3> Delivery of TRAIL via MSCs causes a significant reduction in MPM tumour growth and is a potential novel cellular therapy for this currently incurable disease.
Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway and is increased after pancreatic duct obstruction.
Authors: T Hirano, A Saluja, P Ramarao, M M Lerch, M Saluja, M L Steer
Journal: Journal of Clinical Investigation (1991)

Lysosomal hydrolases such as cathepsin B are apically secreted from rabbit pancreatic acinar cells via a regulated as opposed to a constitutive pathway. Intravenous infusion of the cholecystokinin analogue caerulein results in highly correlated apical secretion of digestive and lysosomal enzymes, suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter that compartment as a result of missorting. After 7 h of duct obstruction is relieved, caerulein-stimulated apical secretion of cathepsin B and amylase is increased, but the ratio of cathepsin B to amylase secretion is not different than that following caerulein stimulation of animals never obstructed. These findings indicate that duct obstruction causes an increased amount of both lysosomal and digestive enzymes to accumulate within the secretagogue releasable compartment but that duct obstruction does not increase the degree of lysosomal enzyme missorting into that compartment. Pancreatic duct obstruction causes lysosomal hydrolases to become colocalized with digestive enzymes in organelles that, in size and distribution, resemble zymogen granules but that are not subject to secretion in response to secretagogue stimulation. These organelles may be of importance in the development of pancreatitis.
Coalescent-Based Estimation of Population Parameters When the Number of Demes Changes Over Time
Authors: G. Ewing
Journal: Molecular Biology and Evolution (2006)

We expand a coalescent-based method that uses serially sampled genetic data from a subdivided population to incorporate changes to the number of demes and patterns of colonization. Often, when estimating population parameters or other parameters of interest from genetic data, the demographic structure and parameters are not constant over evolutionary time. In this paper, we develop a Bayesian Markov chain Monte Carlo method that allows for step changes in mutation, migration, and population sizes, as well as changing numbers of demes, where the times of these changes are also estimated. We show that in parameter ranges of interest, reliable estimates can often be obtained, including the historical times of parameter changes. However, posterior densities of migration rates can be quite diffuse and estimators somewhat biased, as reported by other authors.
Association Between Myocardial Infarction and Fractures
Authors: Yariv Gerber, L. Joseph Melton, Susan A. Weston, Véronique L. Roger
Journal: Circulation (2011)

Data on the association between myocardial infarction (MI) and fractures are scarce. Recent changes in the epidemiology of MI justify exploring this relationship. We evaluated whether MI constitutes a risk factor for osteoporotic fracture and examined secular trends in this association.Consecutive Olmsted County, Minnesota, residents with incident MI diagnosed in 1979 to 2006 and community control subjects individually matched (1:1) to cases on age, sex, and year of onset (n=6642) were followed up through 2009. Outcome measures were time to osteoporotic fracture, overall and by anatomic site, and death. Fracture incidence rates were stable in controls but increased markedly over time among MI cases. Accordingly, although an overall excess of fracture risk after MI was observed (adjusted hazard ratio, 1.32; 95% confidence interval, 1.12 to 1.56), substantial temporal variations were noted (1979 to 1989: hazard ratio, 0.81; 95% confidence interval, 0.58 to 1.12; 1990 to 1999: hazard ratio, 1.47; 95% confidence interval, 1.10 to 1.96; 2000 to 2006: hazard ratio, 1.73; 95% confidence interval, 1.32 to 2.27; P for trend <0.001). Trends were similar regardless of age, sex or fracture site. Conversely, the overall hazard ratio for death in MI cases versus controls did not change materially despite a continuous decline in 30-day case fatality rate (12.5% in 1979 to 1989; 6.7% in 2000 to 2006). Observed changes in the baseline prevalence of cardiovascular risk factors, MI characteristics, and comorbidities did not fully account for the trends in fracture risk.Over the past decades, the association between MI and osteoporotic fractures increased steadily. The trend is consistent with the displacement of post-MI outcomes toward noncardiovascular events, highlighting the need for comprehensive prevention strategies to accommodate the changing epidemiology of MI.
Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children
Authors: Melanie White-Koning, Elodie Civade, Birgit Geoerger, Fabienne Thomas, Marie-Cécile Le Deley, Isabelle Hennebelle, Jean-Pierre Delord, Etienne Chatelut, Gilles Vassal
Journal: Clinical Cancer Research (2011)

The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients.Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults.A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h(-1)·kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h(-1)·kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC.The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities.
THE INFLUENCE OF HIP JOINT CONTROL ON KNEE JOINT VALGUS MOMENT IN YOUNG FEMALE ELITE ATHLETES
Authors: J Bencke, HB Lauridsen, K Thorborg, P Hölmich, LL Andersen, P Aagaard, MK Zebis
Journal: British Journal of Sports Medicine (2014)

Background Biomechanical investigations of sports-specific movements may yield information on which measures could be most efficient for prevention of Anterior Cruciate Ligament (ACL) injuries. High knee valgus moments have been related to increased risk of ACL injury, but further knowledge is needed on how hip strength and hip joint control may influence valgus moments during sidecutting. Objective To investigate the relation between isolated hip muscle strength, hip kinematics and knee valgus moments. Design Cross-sectional. Setting Biomechanical laboratory. Youth elite level. Participants 97 female handball and football players aged 15–19 yrs selected for the youth national teams were recruited. Assessment of risk factors Maximal isometric hip strength was measured during hip abduction, hip extension and hip external rotation [N/kg BM]) by a handheld dynamometer. A standardized sidecutting was performed by each player and hip joint kinematics were measured at initial contact (IC) along with identification of the peak knee joint valgus moment in the contact phase. Main outcome measurements Regression analysis was used to determine which of the measured parameters would affect knee valgus moment, and as such represent potential risk factors that should be targeted in future prophylactic training regimes. Results No relation between maximal isometric hip muscle strength and knee valgus moment was found. Regression analysis showed weak but significant effect of hip internal rotation at IC and hip abduction at IC on knee valgus moment (r 2 =.33, P&lt;.001, β-coefficients=0.49 and 0.35 for hip internal rotation and hip abduction, respectively). Conclusions The study shows that isometric hip muscle strength did not relate to peak knee valgus moment in young female elite handball and football players. However, increased hip internal rotation and increased hip abduction appeared to negatively influence the magnitude of knee valgus moment during sidecutting, and thus potentially increase the risk of ACL-injury.
Effects of immunoscintigraphy with monoclonal antibodies in assays of hormones and tumour markers.
Authors: J. A. Janssen, P. J. Blankestijn, R. Docter, B. G. Blijenberg, T. A. Splinter, H. van Toor, M. A. Schalekamp, S. W. Lamberts, E. P. Krenning
Journal: BMJ (1989)

assumed the chairmanship; they were repeated recently when a minister warned that if the system failed "it could not be imagined that nothing would be put in its place."This was when the various expressions of concern
Mechanism of adenosine inhibition of catecholamine-induced responses in heart.
Authors: J G Dobson
Journal: Circulation Research (1983)

The properties of adenosine inhibition of catecholamine-induced responses were investigated, using an isolated rat heart preparation. Perfusion of hearts with 0.1 microM isoproterenol increased myocardial cAMP content 2.8-fold, activation of cAMP-dependent protein kinase 4.4-fold, phosphorylase a formation 3.4-fold, left ventricular pressure 1.8-fold, rate of ventricular pressure development 2.1-fold, and rate of ventricular relaxation 2.2-fold within 1 minute. When perfused with the isoproterenol, 10 microM adenosine reduced the catecholamine-produced increase in cAMP, cAMP-dependent protein kinase, and phosphorylase by 30-40%, and the elevation in left ventricular pressure and rate of ventricular pressure development by 40-70% within 40 seconds. More than 2 minutes were required for the nucleoside to significantly reduce the isoproterenol-elicited increase in the rate of ventricular relaxation. Perfusion of adenosine alone at concentrations from 0.1 to 10 microM were without effect on the above parameters. Theophylline at 50 microM had no effect alone on the above parameters but blocked the inhibitory actions of adenosine on the isoproterenol-induced responses. In the presence of 15 mM Mg++ adenosine reduced by approximately 56% the 2-fold increase in myocardial membrane adenylate cyclase activity produced by 1 microM isoproterenol without affecting basal or fluoride-stimulated activity. Adenosine also reduced the isoproterenol-induced increase in enzyme activity assayed at 1-2 mM Mg++, a level that more closely approximates the intracellular activity of the ion. The results suggest that physiological concentrations of adenosine attenuate the catecholamine-induced increase in cAMP content, cAMP-dependent protein kinase activation, phosphorylase a formation, and contractile parameters in the working heart, via reducing the beta-adrenergic activation of adenylate cyclase.
Optical Metabolic Imaging Identifies Glycolytic Levels, Subtypes, and Early-Treatment Response in Breast Cancer
Authors: Alex J. Walsh, Rebecca S. Cook, H. Charles Manning, Donna J. Hicks, Alec Lafontant, Carlos L. Arteaga, Melissa C. Skala
Journal: Cancer Research (2013)

Abnormal cellular metabolism is a hallmark of cancer, yet there is an absence of quantitative methods to dynamically image this powerful cellular function. Optical metabolic imaging (OMI) is a noninvasive, high-resolution, quantitative tool for monitoring cellular metabolism. OMI probes the fluorescence intensities and lifetimes of the autofluorescent metabolic coenzymes reduced NADH and flavin adenine dinucleotide. We confirm that OMI correlates with cellular glycolytic levels across a panel of human breast cell lines using standard assays of cellular rates of glucose uptake and lactate secretion (P < 0.05, r = 0.89). In addition, OMI resolves differences in the basal metabolic activity of untransformed from malignant breast cells (P < 0.05) and between breast cancer subtypes (P < 0.05), defined by estrogen receptor and/or HER2 expression or absence. In vivo OMI is sensitive to metabolic changes induced by inhibition of HER2 with the antibody trastuzumab (herceptin) in HER2-overexpressing human breast cancer xenografts in mice. This response was confirmed with tumor growth curves and stains for Ki67 and cleaved caspase-3. OMI resolved trastuzumab-induced changes in cellular metabolism in vivo as early as 48 hours posttreatment (P < 0.05), whereas fluorodeoxyglucose-positron emission tomography did not resolve any changes with trastuzumab up to 12 days posttreatment (P > 0.05). In addition, OMI resolved cellular subpopulations of differing response in vivo that are critical for investigating drug resistance mechanisms. Importantly, OMI endpoints remained unchanged with trastuzumab treatment in trastuzumab-resistant xenografts (P > 0.05). OMI has significant implications for rapid cellular-level assessment of metabolic response to molecular expression and drug action, which would greatly accelerate drug development studies.
HOW MUCH CAN THE NHS AFFORD TO SPEND TO SAVE A LIFE OR AVOID A SEVERE DISABILITY?
Authors: Nicholas Wald, Peter Oppenheimer, K.D Bagshawe, Mahesh Patel, Ian Leck, J.Elizabeth Macgregor, N.E Day, A.B Miller, D.M Parkin, AlanM Smith, Richard Peto, DavidS Grimes, J.G.B Russell, S Stewart-Brown, M Freeman
Journal: The Lancet (1985)
Spontaneous Echocardiographic Wall Motion Abnormalities in Variant Angina
Authors: Luigi Politi, Daniel Enrique Monopoli, Fabio Alfredo Sgura, Rosario Rossi, Francesca Bursi, Maria Grazia Modena
Journal: Circulation (2008)

V ariant angina, defined as spontaneous angina pectoris associated with transient ST-segment elevation, is usually caused by episodic coronary spasm.At present, coronary artery spasm is a reversible coronary stenosis that limits coronary blood flow under resting conditions.
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Authors: William Pao, Theresa Y Wang, Gregory J Riely, Vincent A Miller, Qiulu Pan, Marc Ladanyi, Maureen F Zakowski, Robert T Heelan, Mark G Kris, Harold E Varmus
Journal: PLoS Medicine (2005)

Somatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.We sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug.Our results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.
Teicoplanin induced drug hypersensitivity syndrome
Authors: C M Perrett, S R McBride
Journal: BMJ (2004)

screening to detect breast cancer, 2 such that the increase in false positive recall is not offset by improved cancer detection.Our finding that the effect of hormone replacement therapy takes several years to wear off does not support suggestions that the high rates of false positive recall in current users could be largely reversed if women ceased use of hormones weeks or months before mammography.We thank the many women who completed questionnaires for this study.We are grateful to the staff at the collaborating breast screening units and at the Million Women Study coordinating centre for their valuable contribution to the study and to Adrian Goodill for producing the figure.