tbuckley/cabot-search huggingface dataset:
High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats
Authors: Tiziana Bachetti, Evasio Pasini, Enrico Clini, George Cremona, Roberto Ferrari
Journal: Circulation (1999)

Background —Platelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo. Methods and Results —Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, P &lt;0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with N G -nitro- l -arginine methyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (+26.9±4.8 versus +48.3±9.1 mm Hg, P &lt;0.05), and further infusion of the biological ecNOS substrate l -arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (−1% versus 28% vasodilatation, P &lt;0.001). Conclusions —High-dose heparin can significantly affect vascular reactivity in vivo by downregulation of ecNOS protein expression.
Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA
Authors: T J M Smeets
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVES</h3> Examination of synovial tissue (ST) obtained at surgery because of end stage destructive rheumatoid arthritis (RA) showed that macrophages and fibroblasts are the major cell types at the cartilage-pannus junction (CPJ). This study aimed at defining the cell infiltrate and mediators of joint destruction in ST selected at arthroscopy from the CPJ in patients with RA who did not require joint surgery. <h3>METHODS</h3> Paired synovial biopsy specimens were obtained at arthroscopy from ST adjacent to the CPJ and the suprapatellar pouch from the knee joints of 17 patients with RA. Immunohistological analysis was performed using monoclonal antibodies to detect T cells, B cells, plasma cells, macrophages, fibroblast-like synoviocytes, mast cells, and granzyme B+ cytotoxic cells as well as the expression of metalloproteinase (MMP)-1, MMP-3, and MMP-13. The sections were evaluated by computer assisted image analysis and semiquantitative analysis. <h3>RESULTS</h3> The cell infiltrate comprised mainly T cells, macrophages, and plasma cells. The ST was also infiltrated by the other cell types, but at lower numbers. Expression of MMPs was abundant, especially MMP-3. The features of ST at the CPJ were generally similar to those at the suprapatellar pouch. <h3>CONCLUSIONS</h3> The synovium at the CPJ in patients with RA who did not require joint surgery exhibits, in general, the same type of cell infiltrate and expression of MMPs and granzymes as ST from the suprapatellar pouch. The pathological changes that have been described at the CPJ in patients with RA with end stage, destructive disease may well reflect the transition to a process in which macrophages, fibroblast-like synoviocytes, and other cell types become increasingly important.
The role of endothelin in mediating virus‐induced changes in endothelinB receptor density in mouse airways
Authors: P.J. Henry, M.J. Carr, R.G. Goldie, A.Y. Jeng
Journal: European Respiratory Journal (1999)

Emerging evidence supports a mediator role for endothelin (ET)-1 in airway diseases including asthma. Respiratory tract viral infections, are associated with increased levels of ET and altered ET receptor density and function in murine airways. To determine whether these virus-induced effects are causally linked, perhaps involving ET-1-induced ET(B) receptor downregulation, the current study investigated the influence of in vivo administration of CGS 26303, an ET-converting enzyme inhibitor, on virus-induced changes in ET-content and ET(B) receptor density. CGS 26303 (5 mg x kg(-1) x day(-1)) or placebo was administered to mice via osmotic minipumps implanted subcutaneously. Two days after implantation, mice were inoculated with influenza A/PR-8/34 virus or sham-infected, and all measurements were performed on tissue obtained on the fourth day post-inoculation. Viral infection was associated with elevated levels of immunoreactive ET and decreased densities of ET(B) receptors in murine airways. Both of these effects were attenuated in virus-infected mice that had received CGS 26303. Virus-induced increases in wet lung weight were also inhibited by CGS 26303. Importantly, administration of CGS 26303 had no effect on the titres of infectious virus in the lungs and similarly, viral infection had no effect on the plasma levels of free CGS 26303. In summary, CGS 26303 inhibited the virus-induced changes in both immunoreactive endothelin content and endothelinB receptor density. These findings are consistent with the postulate that the elevated epithelial expression of endothelin-1 during respiratory tract viral infection is a contributing factor in the downregulation of endothelinB receptors in airway smooth muscle. Whether inhibitors of endothelin synthesis attenuate virus-induced exacerbations of asthma or airways hyperresponsiveness remains to be established.
Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis
Authors: Marco Dal Molin, Ming Zhang, Roeland F. de Wilde, Niki A. Ottenhof, Neda Rezaee, Christopher L. Wolfgang, Amanda Blackford, Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Ralph H. Hruban, Anirban Maitra, Laura D. Wood
Journal: Clinical Cancer Research (2015)

The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTS). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival.We sequenced the exomes of eight PDACs from patients who survived ≥10 years. On the basis of the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs.KRAS mutations were identified in 33 of 35 cancers (94%) from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in four of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared with available data from PDACs unselected for survival. Comparison of clinicopathologic features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade, or nodal disease did not preclude long-term survival.Our results suggest that in most patients, somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.
First-Trimester or Second-Trimester Screening, or Both, for Down's Syndrome
Authors: Fergal D. Malone, Jacob A. Canick, Robert H. Ball, David A. Nyberg, Christine H. Comstock, Radek Bukowski, Richard L. Berkowitz, Susan J. Gross, Lorraine Dugoff, Sabrina D. Craigo, Ilan E. Timor-Tritsch, Stephen R. Carr, Honor M. Wolfe, Kimberly Dukes, Diana W. Bianchi, Alicja R. Rudnicka, Allan K. Hackshaw, Geralyn Lambert-Messerlian, Nicholas J. Wald, Mary E. D'Alton
Journal: New England Journal of Medicine (2005)

It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters.
Risk factors for local recurrences after limb-salvage surgery for high-grade osteosarcoma of the extremities
Authors: P. Picci, L. Sangiorgi, L. Bahamonde, P. Aluigi, J. Bibiloni, M. Zavatta, M. Mercuri, A. Briccoli, M. Campanacci
Journal: Annals of Oncology (1997)
A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study
Authors: J.G. Aerts, H. Codrington, N.A.G. Lankheet, S. Burgers, B. Biesma, A.-M.C. Dingemans, A.D. Vincent, O. Dalesio, H.J.M. Groen, E.F. Smit
Journal: Annals of Oncology (2013)
The Effects of Amiodarone on the Thyroid*
Authors: Enio Martino, Luigi Bartalena, Fausto Bogazzi, Lewis E. Braverman
Journal: Endocrine Reviews (2001)

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.
Psychic trauma in children: observations following the Chowchilla school-bus kidnapping
Authors: Lenore C. Terr
Journal: American Journal of Psychiatry (1981)

Twenty-three children involved in a school-bus kidnapping were studied from 5 to 13 months following the event. Each child suffered posttraumatic emotional sequelae. The author found that the children suffered from initial misperceptions, early fears of further trauma, hallucinations, and "omen" formation. Later they experienced posttraumatic symptoms consisting of posttraumatic play, reenactment, personality change, repeated dreams (including predictive dreams and those in which they died), fears of being kidnapped again, and "fear of the mundane." Differences between child and adult response to psychic trauma are discussed.
Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β
Authors: Jonathan A. Kirk, Ronald J. Holewinski, Viola Kooij, Giulio Agnetti, Richard S. Tunin, Namthip Witayavanitkul, Pieter P. de Tombe, Wei Dong Gao, Jennifer Van Eyk, David A. Kass
Journal: Journal of Clinical Investigation (2013)

Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HF(dys)) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HF(dys); however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HF(dys) cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). We found that GSK-3β was deactivated in HF(dys) and reactivated by CRT. Mass spectrometry of myofilament proteins from HF(dys) animals incubated with GSK-3β confirmed GSK-3β–dependent phosphorylation at many of the same sites observed with CRT. GSK-3β restored calcium sensitivity in HF(dys), but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HF(dys) through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function
Expression of P2X7 Receptor Increases<i>In Vivo</i>Tumor Growth
Authors: Elena Adinolfi, Lizzia Raffaghello, Anna Lisa Giuliani, Luigi Cavazzini, Marina Capece, Paola Chiozzi, Giovanna Bianchi, Guido Kroemer, Vito Pistoia, Francesco Di Virgilio
Journal: Cancer Research (2012)

The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo.
The International Olympic Committee (IOC) Consensus Statement on periodic health evaluation of elite athletes March 2009
Authors: Arne Ljungqvist, Peter Jenoure, Lars Engebretsen, Juan Manuel Alonso, Roald Bahr, Anthony Clough, Guido De Bondt, Jiri Dvorak, Robert Maloley, Gordon Matheson, Willem Meeuwisse, Erik Meijboom, Margo Mountjoy, Antonio Pelliccia, Martin Schwellnus, Dominique Sprumont, Patrick Schamasch, Jean-Benoìt Gauthier, Christophe Dubi, Howard Stupp, Christian Thill
Journal: British Journal of Sports Medicine (2009)

The Olympic Games is the largest sport event in the world. In Beijing, 10 500 athletes competed, selected from a large group of elite athletes in 204 countries. Sports participation on the elite level, aside from winning medals, fame and other rewards, is also important from a health perspective. There is no longer any doubt that regular physical activity reduces the risk of premature mortality in general, and of coronary heart disease, hypertension, colon cancer, obesity and diabetes mellitus in particular. The question is whether the health benefits of sports participation outweigh the risk of injury and long-term disability, especially in high-level athletes. Sarna et al 1 have studied the incidence of chronic disease and life expectancy of former male world-class athletes from Finland in endurance sports, power sports and team sports. The overall life expectancy was longer in the high-level athlete compared with a reference group (75.6 vs 69.9 years). The same group also showed that the rate of hospitalisation later in life was lower for endurance sports and power sports compared with the reference group.2 This resulted from a lower rate of hospital care for heart disease, respiratory disease and cancer. However, the athletes were more likely to have been hospitalised for musculoskeletal disorders. Thus, the evidence suggests that although there is a general health benefit from sports participation, injuries represent a significant side effect.

One priority of the International Olympic Committee (IOC) is to protect the health of the athlete. During recent years, prevention of injuries and illnesses has been high on the IOC agenda. During the Athens Games, an injury surveillance system was applied for all team sports.3 During the Beijing Games, the IOC ran, for the first time, an injury surveillance system covering all the athletes, showing a 10% incidence of injuries.4 In …
Independent Validation of a Model Using Cell Line Chemosensitivity to Predict Response to Therapy
Authors: Wenting Wang, Keith A. Baggerly, Steen Knudsen, Jon Askaa, Wiktor Mazin, Kevin R. Coombes
Journal: JNCI Journal of the National Cancer Institute (2013)

Methods using cell line microarray and drug sensitivity data to predict patients' chemotherapy response are appealing, but groups may be reluctant to release details to preserve intellectual property. Here we describe a case study to validate predictions while treating the methods as a "black box." Medical Prognosis Institute (MPI) constructed cell-line-derived sensitivity scores (SSs) and combined scores (CSs) that incorporate clinical variables. MD Anderson researchers evaluated their predictions. We searched the Gene Expression Omnibus (GEO) to identify validation datasets, and we performed statistical evaluation of the agreement between prediction and clinical observation. We identified 3 suitable datasets: GSE16446 (n = 120; binary outcome), GSE17920 (n = 130; binary outcome), and GSE10255 (n = 161; continuous and time-to-event outcomes). The SS was statistically significantly associated with primary treatment responses for all studies (GSE16446: P = .02; GSE17920: P = .02; GSE10255: P = .02). Dichotomized SSs performed no better than chance for GSE16446 and GSE17920, and categorized SSs did not predict disease-free survival (GSE10255). SSs sometimes improved on predictions using clinical variables (GSE16446: P = .05; GSE17920: P = .31; GSE10255: P = .045), but gains were limited (95% confidence intervals for GSE16446 and GSE17920 include 0). The CS did not predict treatment response for GSE16446 (P = .55), but it did for GSE17920 (P < .001). Coefficients of clinical variables provided by MPI for CSs agree with estimates for GSE17920 better than estimates for GSE16446. Model predictions were better than chance in all three datasets. However, these scores added little to existing clinical predictors; statistically significant contributions were likely to be too small to change clinical practice. These findings suggest that discovering better predictors will require both cell line data and a clinical training dataset of patient samples.
The omega/lambda 5 surrogate immunoglobulin light chain is expressed on the surface of transitional B lymphocytes in murine bone marrow.
Authors: B J Cherayil, S Pillai
Journal: The Journal of Experimental Medicine (1991)

The membrane immunoglobulin heavy chain (micron) plays a feedback role during the pre-B stage of B lymphocyte differentiation. In pre-B cell lines, micron associates with two surrogate light chain proteins. The omega chain is disulfide linked to mu and was predicted to be the product of the lambda 5 gene. The iota chain is noncovalently associated with micron. We demonstrate that the omega protein is indeed the product of the lambda 5 gene and that mu, omega, and iota are coassociated in the same complex. Antibodies against the omega/lambda 5 protein demonstrate the existence of a subpopulation of "transitional" bone marrow B cells that express micron and omega on the cell surface. The majority of these cells also express surface kappa light chains, indicating that in B lymphoid ontogeny the lambda 5 gene is inactivated after the onset of kappa light chain expression.
Willie Sutton and the Future of Acute Respiratory Distress Syndrome Research
Authors: Nathan Brummel, Rameela Chandrasekhar, E. Wesley Ely
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

In this issue of the Journal, Sonnappa and colleagues (pp.79-86) compared spirometric measurements among children of Indian heritage who are living in different locations as an illustration of potential environmental effects among populations with similar genetic background (1).Strengths of the study include the consistency of equipment, training, and quality control for the
Multidrug-resistant Cancer Cells Facilitate E1-independent Adenoviral Replication
Authors: Per S. Holm, Hermann Lage, Stephan Bergmann, Karsten Jürchott, Gabriel Glockzin, Alexandra Bernshausen, Klaus Mantwill, Axel Ladhoff, Anke Wichert, Joe S. Mymryk, Thomas Ritter, Manfred Dietel, Bernd Gänsbacher, Hans-Dieter Royer
Journal: Cancer Research (2004)

Abstract Resistance to chemotherapy is responsible for a failure of current treatment regimens in cancer patients. We have reported previously that the Y-box protein YB-1 regulates expression of the P-glycoprotein gene mdr1, which plays a major role in the development of a multidrug resistant-tumor phenotype. YB-1 predicts drug resistance and patient outcome in breast cancer. Thus, YB-1 is a promising target for new therapeutic approaches to defeat multidrug resistance. In drug-resistant cancer cells and in adenovirus-infected cells YB-1 is found in the nucleus. Nuclear accumulation of YB-1 in adenovirus-infected cells is a function of the E1 region, and we have shown that YB-1 facilitates adenovirus replication. Here we report that E1A-deleted or mutant adenovirus vectors, such as Ad312 and Ad520, replicate efficiently in multidrug-resistant (MDR) cancer cells and induce an adenovirus cytopathic effect resulting in host cell lysis. Thus, replication-defective adenoviruses are a previously unrecognized vector system for a selective elimination of MDR cancer cells. Our work forms the basis for the development of novel oncolytic adenovirus vectors for the treatment of MDR malignant diseases in the clinical setting.