tbuckley/cabot-search huggingface dataset:
Impact of ethnicity upon cardiovascular adaptation in competitive athletes: relevance to preparticipation screening
Authors: Michael Papadakis, Mathew G Wilson, Saqib Ghani, Gaelle Kervio, Francois Carre, Sanjay Sharma
Journal: British Journal of Sports Medicine (2012)

Regular participation in intensive physical exercise is associated with several structural and electrophysiological cardiac adaptations that enhance diastolic filling and facilitate a sustained increase in the cardiac output that is fundamental to athletic excellence. Such cardiac adaptations are collectively referred to as the 'Athlete's Heart' and are frequently reflected on the 12-lead ECG and imaging studies. Thorough knowledge relating to exercise-associated cardiovascular adaptation is imperative for the purposes of differentiating physiological adaptation from cardiac pathology, since an erroneous diagnosis of cardiac disease has potentially serious consequences for the athlete's physical, psychological, social and financial well-being. The majority of studies investigating the cardiovascular adaptation to exercise are based on cohorts of Caucasian athletes. However, there is mounting evidence that ethnicity is an important determinant of the objective manifestations of cardiovascular adaptation to exercise. The most pronounced paradigm of ethnically distinct cardiovascular adaptation to exercise stems from athletes of African/Afro-Caribbean descent, who exhibit a significantly higher prevalence of repolarisation anomalies and left ventricular hypertrophy, compared to Caucasian athletes; the differentiation between athlete's heart and hypertrophic cardiomyopathy is particularly challenging in this ethnic group. The extrapolation of ECG and echocardiographic criteria used to diagnose potentially serious cardiac disorders in Caucasian athletes to the African/Afro-Caribbean athlete population would result in an unacceptable number of unnecessary investigations and increased risk of false disqualification from competitive sport. Accurate interpretation of the athlete's ECG and echocardiogram is crucial, particularly when one considers the continuous expansion of preparticipation screening programmes. This review attempts to highlight ethnically determined differences in cardiovascular adaptation to exercise and provides a practical guide for the interpretation of baseline investigations in athletes of diverse ethnic backgrounds.
Targeting the Tumor Microenvironment: From Understanding Pathways to Effective Clinical Trials
Authors: Hua Fang, Yves A. DeClerck
Journal: Cancer Research (2013)

Abstract It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell–stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents. Cancer Res; 73(16); 4965–77. ©2013 AACR.
Von Hippel-Lindau–Coupled and Transcription-Coupled Nucleotide Excision Repair–Dependent Degradation of RNA Polymerase II in Response to Trabectedin
Authors: Gregory J. Aune, Kazutaka Takagi, Olivier Sordet, Josée Guirouilh-Barbat, Smitha Antony, Vilhelm A. Bohr, Yves Pommier
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Ecteinascidin 743 (Et743; trabectedin, Yondelis) has recently been approved in Europe for the treatment of soft tissue sarcomas and is undergoing clinical trials for other solid tumors. Et743 selectively targets cells proficient for TC-NER, which sets it apart from other DNA alkylating agents. In the present study, we examined the effects of Et743 on RNA Pol II. Experimental Design and Results: We report that Et743 induces the rapid and massive degradation of transcribing Pol II in various cancer cell lines and normal fibroblasts. Pol II degradation was abrogated by the proteasome inhibitor MG132 and was dependent on TC-NER. Cockayne syndrome (CS) cells and xeroderma pigmentosum (XP) cells (XPD, XPA, XPG, and XPF) were defective in Pol II degradation, whereas XPC cells whose defect is limited to global genome NER in nontranscribing regions were proficient for Pol II degradation. Complementation of the CSB and XPD cells restored Pol II degradation. We also show that cells defective for the VHL complex were defective in Pol II degradation and that complementation of those cells restores Pol II degradation. Moreover, VHL deficiency rendered cells resistant to Et743-induced cell death, a similar effect to that of TC-NER deficiency. Conclusion: These results suggest that both TC-NER–induced and VHL-mediated Pol II degradation play a role in cell killing by Et743.
Wet dressing therapy in conjunction with topical corticosteroids is effective for rapid control of severe pediatric atopic dermatitis: Experience with 218 patients over 30 years at Mayo Clinic
Authors: Tushar S. Dabade, Dawn M.R. Davis, David A. Wetter, Jennifer L. Hand, Marian T. McEvoy, Mark R. Pittelkow, Rokea A. el-Azhary, Mark D.P. Davis
Journal: Journal of the American Academy of Dermatology (2011)
Endoscopic examination of the gastric remnant 31-39 years after subtotal gastrectomy for peptic ulcer.
Authors: I R Pickford, J L Craven, R Hall, G Thomas, W D Stone
Journal: Gut (1984)

In York between 1941 and 1949, 632 patients underwent Polya partial gastrectomy for peptic ulcer. Of 307 patients who were followed up in the York Gastric Clinic from 1971 to 1980, nine died of gastric cancer, three times the expected number. If gastrectomy was performed for gastric ulcer the risk of later development of carcinoma (7%) was significantly greater than that following operation for duodenal ulcer (1.6%) (p less than 0.001). No cancers were diagnosed in the 54 patients endoscoped. Atrophic gastritis was found in 98% of patients and intestinal metaplasia in 44%. Dysplasia was present in 35% but in no case was it severe. Although we have found that there is an increased risk of cancer developing in the gastric remnant we do not consider routine endoscopic follow up of all postgastrectomy patients to be a practical proposition.
Renal Insufficiency and Subsequent Death Resulting from Cardiovascular Disease in the United States
Authors: Paul Muntner, Jiang He, Lee Hamm, Catherine Loria, Paul K. Whelton
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Several epidemiologic studies reported that persons with renal insufficiency might have increased cardiovascular disease-related mortality rates in select populations. The association between renal insufficiency and increased cardiovascular disease-related and all-cause mortality rates during 16 yr of follow-up monitoring was examined among participants who were 30 to 74 yr of age at the baseline examinations in 1976 to 1980, with urinary protein dipstick measurements ( n = 8786) or serum creatinine levels of ≤3.0 mg/dl ( n = 6354), from the Second National Health and Nutrition Examination Survey Mortality Study. GFR were estimated by adjusting serum creatinine levels for age, race, and gender, using the Modification of Diet in Renal Disease formula. Cardiovascular disease-related mortality rates were 6.2, 17.9, and 37.2 deaths/1000 person-yr among subjects with urinary protein levels of &lt;30, 30 to 299, and ≥300 mg/dl and were 4.1, 8.6, and 20.5 deaths/1000 person-yr among participants with estimated GFR of ≥90, 70 to 89, and &lt;70 ml/min, respectively. After adjustment for potential confounders, the relative hazards (and 95% confidence intervals) for cardiovascular disease-related death were 1.57 (0.99 to 2.48) and 1.77 (0.97 to 3.21) among subjects with urinary protein levels of 30 to 299 and ≥300 mg/dl, respectively, compared with &lt;30 mg/dl ( P trend = 0.02). The corresponding relative hazards for all-cause-related death were 1.64 (1.23 to 2.18) and 2.00 (1.13 to 3.55; P trend &lt; 0.001). Compared with subjects with estimated GFR of ≥90 ml/min, those with estimated GFR of &lt;70 ml/min exhibited higher relative risks of death from cardiovascular disease and all causes [1.68 (1.33 to 2.13) and 1.51 (1.19 to 1.91), respectively]. This study indicates that, in a representative sample of the United States general population, renal insufficiency is independently associated with increased cardiovascular disease-related and all-cause mortality rates.
Attenuated <i>Salmonella</i> Targets Prodrug Activating Enzyme Carboxypeptidase G2 to Mouse Melanoma and Human Breast and Colon Carcinomas for Effective Suicide Gene Therapy
Authors: Frank Friedlos, Panos Lehouritis, Lesley Ogilvie, Douglas Hedley, Lawrence Davies, David Bermudes, Ivan King, Jan Martin, Richard Marais, Caroline J. Springer
Journal: Clinical Cancer Research (2008)

Abstract Purpose: We engineered the oncolytic Salmonella typhimurium–derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs. Experimental Design: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with postmortem analysis of bacterial and CPG2 concentration in the tumors. Results: CPG2 is expressed within the bacterial periplasm. It activates prodrugs and induces cytotoxicity in human tumor cells but not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 × 107/g to 2 × 108/g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to 6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of prodrugs further reduces significantly the growth of the xenografts. Conclusions: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce the growth of tumors. However, in the presence of prodrugs activated by CPG2, this oncolytic effect is greatly increased. We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment of a range of cancers.
Laser and brachytherapy in the palliation of adenocarcinoma of the oesophagus and cardia.
Authors: G M Spencer, S M Thorpe, I R Sargeant, G M Blackman, J Solano, J S Tobias, S G Bown
Journal: Gut (1996)

BACKGROUND: Palliation of malignant dysphagia is possible by a variety of methods although all have significant drawbacks. Laser therapy is an effective and safe treatment but has to be repeated at four to five weekly intervals to maintain palliation. A means of augmenting the benefits while reducing the need for repeat treatments would be highly beneficial to these patients. AIMS: To prospectively explore the safety and efficacy of intraluminal radiotherapy (brachytherapy) when used to augment laser recanalisation for malignant dysphagia. PATIENTS: Nineteen patients with dysphagia due to advanced adenocarcinoma of the oesophagus or cardia were recruited. METHODS: All patients received laser recanalisation until able to swallow a soft diet or better, before the application of a single dose of brachytherapy (10 Gy at 1 cm from the source). Patients were followed up and treated promptly by further endoscopic means in the event of their dysphagia worsening. RESULTS: Six patients (32%) required no further treatment until death at a median of 10 weeks (range 1-20 weeks). Further therapy was required at a median of 11 weeks (range 4-37 weeks) after brachytherapy for those 13 patients with recurrent dysphagia. Subsequent symptom control required endoscopic intervention at an average of once every nine weeks. There was no mortality associated with laser or brachytherapy. Median survival from initial treatment and including the one survivor was 36 weeks (range 5-132 weeks). CONCLUSIONS: Laser plus brachytherapy offers a safe and effective means of palliating malignant dysphagia due to adenocarcinoma, with a longer dysphagia free interval than historical controls treated with laser alone.
Treatment of medulloblastoma with a modified measles virus
Authors: A. W. Studebaker, C. R. Kreofsky, C. R. Pierson, S. J. Russell, E. Galanis, C. Raffel
Journal: Neuro-Oncology (2010)

Although treatment of medulloblastoma has improved, at least 30% of patients with this tumor die of progressive disease. Unfortunately, many of the children who survive suffer long-term treatment-related morbidity. Previous studies have demonstrated the efficacy of using oncolytic viruses to eradicate brain tumors. The objective of this study was to test the efficacy of measles virus in treating medulloblastoma. To determine whether medulloblastoma cells are susceptible, 5 different human medulloblastoma cell lines were analyzed for the expression of the measles virus receptor CD46. Fluorescence-activated cell-sorting analysis confirmed expression of CD46 on all cell lines tested, with UW288-1 having the most prominent expression and D283med displaying the lowest expression. CD46 expression was also demonstrated, using immunohistochemistry, in 13 of 13 medulloblastoma tissue specimens. All 5 medulloblastoma cell lines were examined for their susceptibility to measles virus killing in vitro. A measles virus containing the green fluorescent protein (GFP) gene as a marker for infection (MV-GFP) was used. All cell lines exhibited significant killing when infected with MV-GFP, all formed syncytia with infection, all showed fluorescence, and all allowed viral replicaton after infection. In an intracerebral murine xenograft model, a statistically significant increase in survival was seen in animals treated with the active measles virus compared with those treated with inactivated virus. These data demonstrate that medulloblastoma is susceptible to measles virus killing and that the virus may have a role in treating this tumor in the clinical setting.
Domiciliary Nebulized Pentamidine for Secondary Prophylaxis against Pneumocystis Carinii Pneumonia
Authors: S T Green, D Nathwani, P R Christie, D J Goldberg, D H Kennedy, W Campbell Love
Journal: Journal of the Royal Society of Medicine (1990)

The viability of a programme for delivering aerosolized pentamidine within the patient's home setting for the secondary prophylaxis of Pneumocystis carinii pneumonia (PCP) has been explored with seven homosexual AIDS patients, the major objectives being the assessment of the safety and acceptability of the treatment and the discovery of the most suitable care setting (home, ward, outpatient clinic) for the administration of therapy. It is concluded that a domiciliary prophylaxis programme is a viable alternative.
Potent<i>In vitro</i>and<i>In vivo</i>Activity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia
Authors: Holly M. Horton, Matthew J. Bernett, Erik Pong, Matthias Peipp, Sher Karki, Seung Y. Chu, John O. Richards, Igor Vostiar, Patrick F. Joyce, Roland Repp, John R. Desjarlais, Eugene A. Zhukovsky
Journal: Cancer Research (2008)

Abstract CD19 is a pan B-cell surface receptor expressed from pro–B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non–Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fcγ receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibody-dependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fcγ receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19+ hematologic malignancies. [Cancer Res 2008;68(19):8049–57]
S9 Acute Inflammatory Presentation Associates With Survival In Interstitial Lung Disease And Extracorporeal Membrane Oxygenation-requiring Severe Respiratory Failure: A Single Centre Case Series
Authors: L. Starsmore, B. Lams, S. Agarwal, A. Nair, R. Preston, N. Barrett, G. Glover, N. Ioannou, C. Langrish, D. Wyncoll, C. Meadows
Journal: Thorax (2014)

<h3>Introduction</h3> Patients with interstitial lung disease (ILD) and severe respiratory failure (SRF) requiring mechanical ventilation are widely perceived to have poor outcomes. A therapeutic strategy incorporating extracorporeal membrane oxygenation (ECMO) improves all cause SRF survival. There exist no data on the use of ECMO in severe ILD. ECMO may offer lung rest, reduce the inflammatory burden associated with mechanical ventilation and allow time for effective immunosuppression. We hypothesised that the use of ECMO and early immunosuppression increases survival in patients with ILD in whom mechanical ventilation was failing. <h3>Methods</h3> Retrospective interrogation of a single centre ECMO database for patients with ILD between 2011 and 2014. Variables collected included diagnosis; immunosuppression regimen; duration of symptoms prior to ECMO initiation; serum biochemistry; clinical severity score (SOFA) and survival to ECMO decannulation, ICU discharge and at 6 months. ECMO centre admission computed tomography (CT) thorax scans were independently analysed for pattern and degree of abnormality by two radiologists. Variables were compared between responders (those who survived without lung transplant) and non responders (composite group of those who died and one patient who survived with lung transplantation). Two-tailed t-tests were used for all comparisons. <h3>Results</h3> 12 patients with an ILD diagnosis who received ECMO were identified. ECMO and ICU survival was 58.3%. The group of responders had a shorter duration of symptoms prior to ECMO (p = 0.04), a higher CRP (p = 0.046), a higher SOFA score (p = 0.01) and a lower preponderance of diffuse alveolar damage (DAD) on CT (p = 0.19) although there was no difference in overall extent of CT abnormality. (Table 1). <h3>Conclusions</h3> The use of ECMO and early immunosuppression led to a 58.3% survival in a group of ILD associated SRF who would otherwise have been highly likely to die. The responders were characterised by a more acute and more inflammatory presentation. We suggest that ECMO and immunosuppression should be considered in patients with ILD and SRF who are failing mechanical ventilation.
What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis?
Authors: J-P Pelletier, C Cooper, C Peterfy, J-Y Reginster, M-L Brandi, O Bruyère, R Chapurlat, F Cicuttini, P G Conaghan, M Doherty, H Genant, G Giacovelli, M C Hochberg, D J Hunter, J A Kanis, M Kloppenburg, J-D Laredo, T McAlindon, M Nevitt, J-P Raynauld, R Rizzoli, C Zilkens, F W Roemer, J Martel-Pelletier, A Guermazi
Journal: Annals of the Rheumatic Diseases (2013)

Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.
Olanzapine Versus Placebo in the Treatment of Acute Mania
Authors: Mauricio Tohen, Todd M. Sanger, Susan L. McElroy, Gary D. Tollefson, K.N. Roy Chengappa, David G. Daniel, Frederick Petty, Franca Centorrino, Richard Wang, Starr L. Grundy, Michael G. Greaney, Thomas G. Jacobs, Stacy R. David, Verna Toma, None The Olanzapine HGEH Study Group
Journal: American Journal of Psychiatry (1999)

The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania.The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score.The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group.The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.