tbuckley/cabot-search huggingface dataset:
Giant unions unite to stop government white paper's NHS reforms
Authors: A. O'Dowd
Journal: BMJ (2010)

Ten of the United Kingdom’s largest trade unions have launched a joint campaign to stop what they describe as the coalition government’s “controversial” health white paper Equity and Excellence: Liberating the NHS. 

Unions representing around four million workers, including Unison, Unite, and the GMB, have come together with grassroots health campaigners and patients’ groups in a coordinated move against the new reforms, which were unveiled in July.

Organised by the NHS Support Federation, an independent pressure group that aims to protect and promote the NHS, the campaign warned in its launch statement that the NHS was under threat. The campaign aims to mobilise NHS staff and patients against the white paper to exert pressure on MPs …
Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E–deficient mice
Authors: Patrizia Nigro, Kimio Satoh, Michael R. O'Dell, Nwe Nwe Soe, Zhaoqiang Cui, Amy Mohan, Jun-ichi Abe, Jeffrey D. Alexis, Janet D. Sparks, Bradford C. Berk
Journal: The Journal of Experimental Medicine (2010)

Cyclophilin A (CyPA; encoded by Ppia) is a ubiquitously expressed protein secreted in response to inflammatory stimuli. CyPA stimulates vascular smooth muscle cell migration and proliferation, endothelial cell adhesion molecule expression, and inflammatory cell chemotaxis. Given these activities, we hypothesized that CyPA would promote atherosclerosis. Apolipoprotein E–deficient (Apoe−/−) mice fed a high-cholesterol diet for 16 wk developed more severe atherosclerosis compared with Apoe−/−Ppia−/− mice. Moreover, CyPA deficiency was associated with decreased low-density lipoprotein uptake, VCAM-1 (vascular cell adhesion molecule 1) expression, apoptosis, and increased eNOS (endothelial nitric oxide synthase) expression. To understand the vascular role of CyPA in atherosclerosis development, bone marrow (BM) cell transplantation was performed. Atherosclerosis was greater in Apoe−/− mice compared with Apoe−/−Ppia−/− mice after reconstitution with CyPA+/+ BM cells, indicating that vascular-derived CyPA plays a crucial role in the progression of atherosclerosis. These data define a role for CyPA in atherosclerosis and suggest CyPA as a target for cardiovascular therapies.
Physical Activity after Diagnosis and Risk of Prostate Cancer Progression: Data from the Cancer of the Prostate Strategic Urologic Research Endeavor
Authors: Erin L. Richman, Stacey A. Kenfield, Meir J. Stampfer, Alan Paciorek, Peter R. Carroll, June M. Chan
Journal: Cancer Research (2011)

Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, nonvigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person-years. Walking accounted for nearly half of all activity. Men who walked briskly for 3 h/wk or more had a 57% lower rate of progression than men who walked at an easy pace for less than 3 h/wk (HR = 0.43; 95% CI: 0.21-0.91; P = 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace = 0.52; 95% CI: 0.29-0.91; P(trend) = 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 h/wk vs. none = 0.63; 95% CI: 0.32-1.23; P(trend) = 0.17). Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity, respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer.
Proteomic Analysis of Ubiquitin Ligase KEAP1 Reveals Associated Proteins That Inhibit NRF2 Ubiquitination
Authors: Bridgid E. Hast, Dennis Goldfarb, Kathleen M. Mulvaney, Michael A. Hast, Priscila F. Siesser, Feng Yan, D. Neil Hayes, Michael B. Major
Journal: Cancer Research (2013)

Abstract Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes. However, many tumors display high NRF2 activity in the absence of mutation, supporting the hypothesis that alternative mechanisms of pathway activation exist. Previously, we and others discovered that via a competitive binding mechanism, the proteins WTX (AMER1), PALB2, and SQSTM1 bind KEAP1 to activate NRF2. Proteomic analysis of the KEAP1 protein interaction network revealed a significant enrichment of associated proteins containing an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Like WTX, PALB2, and SQSTM1, we found that the dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an “ETGE” motif to displace NRF2, thus inhibiting NRF2 ubiquitination and driving NRF2-dependent transcription. Comparing the spectrum of KEAP1-interacting proteins with the genomic profile of 178 squamous cell lung carcinomas characterized by The Cancer Genome Atlas revealed amplification and mRNA overexpression of the DPP3 gene in tumors with high NRF2 activity but lacking NRF2 stabilizing mutations. We further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition and that DPP3 overexpression in the presence of these mutants further promotes NRF2 activation. Collectively, our findings further support the competition model of NRF2 activation and suggest that “ETGE”-containing proteins such as DPP3 contribute to NRF2 activity in cancer. Cancer Res; 73(7); 2199–210. ©2013 AACR.
Gossypol: A Potential Antifertility Agent for Males
Authors: S Qian, Z Wang
Journal: The Annual Review of Pharmacology and Toxicology (1984)

The discussion provides a general review of gossypol as a potential male contraceptive, focusing on the pharmacological features not discussed in previous review articles. Attention is directed to the chemistry of gossypol, the antifertility effect of gossypol, its metabolism and toxicity, the genetic and endocrine effects of gossypol; clinical trails of gossypol; hypokalemic paralysis; and the site and mechanism of action. Gossypol is a yellowish phenolic compound ocurring naturally in certain species of cotton plants of the family Malvaciae, mostly in the seeds and root bark. The Hubei Provincial group documented the antispermatogenic effects of crude cottonseed oil in rats and monkeys, and since then a number of workers have investigated the active principle(s) in cottonseed and cotton root bark. The work on gossypol as an antifertility agent, initiated by Liu (1957) and pursued actively, has stimulated nationwide attention. After publication of a review article by the National Coordinating Group, it attracted universal interest. 3 forms of gossypol -- gossypol, gossypol acetic acid, and gossypol formic acid -- have been used in laboratory investigations and clinical trials. They are very much the same in their biological activities and are discussed as a whole under the generic name gossypol. Unless psecified otherwise, the term refers to the racemate administered orally. There are pronounced differences among animal species in their sensitivity to the antifertility action of gossypol. Gossypol is absorbed through the intestine as well as through the epithelial lining of the stomach. In an attempt to mitigate the gastric side effects of gossypol, 1 group of clinicians adopted enteric-coated tablets for the clinical trial. They found that both the antifertiltiy effect and the systemic side effects of these tablets were much less than those of ordinary tablets. Gossypol is an effective antispermatogenic agent for certain susceptible animals and humans and represents the only approach which has a reasonable chance to reach the stage of large scale clinical testing before the end of this decade. Much work must be done, particularly in regard to its toxicology, before it (or 1 of its analogues) can be developed into a practical male antifertility drug. The following points suggest the main directions for future research in the scope of pharmacology and toxicology: hypokalemia -- exploration of the contributing factor(s), means to prevent its occurrence, mechanism(s) of development, production of animal model; irreversibility; general toxicological assessment; and studies on the mechanism of action, which also may be helpful in the development of gossypol analogue(s) exhibiting satisfactory antifertility and minimal toxic effects.
Recommendations for the Use of Mechanical Circulatory Support: Device Strategies and Patient Selection
Authors: Jennifer L. Peura, Monica Colvin-Adams, Gary S. Francis, Kathleen L. Grady, Timothy M. Hoffman, Mariell Jessup, Ranjit John, Michael S. Kiernan, Judith E. Mitchell, John B. O'Connell, Francis D. Pagani, Michael Petty, Pasala Ravichandran, Joseph G. Rogers, Marc J. Semigran, J. Matthew Toole
Journal: Circulation (2012)

T he era of mechanical circulatory support (MCS) began in 1953 with the development of cardiopulmonary bypass to facilitate open heart surgery. 1 In 1964, the National Heart Institute (now the National Heart, Lung, and Blood Institute) funded the Artificial Heart Program and became actively involved in MCS development.This led to requests for Proposals issued in 1977 and 1980, which laid the foundation for the development of implantable MCS for long-term use, including devices capable of hospital discharge, in the 1990s.Although heart transplantation is now commonplace at many hospitals, the inadequate supply of donor hearts and patient contraindications to transplantation continue to severely restrict its application.As the demand for long-term replacement of diseased hearts increases, there is a clear need for innovative, safe, and durable MCS to treat the growing population of patients with advanced heart failure (HF).Many exciting changes in the field of MCS have occurred in the past few years, including the development of smaller portable pumps and the concept of destination therapy (DT), or permanent pump placement as an alternative to heart transplantation.Currently, there are no published guidelines for the use of MCS.Thus, it is our intent that this statement will provide the contemporary cardiologist and other HF providers with an understanding of general considerations when determining the appropriateness of MCS. Definition of Advanced HFThere is little hope that complete consensus will ever be reached on the definition of advanced HF, but most physicians caring for such patients on a regular basis readily identify the characteristics of these patients.Advanced HF patients are those with clinically significant circulatory compromise who require special care, including consideration for heart transplantation, continuous intravenous inotropic therapy, MCS, or hospice. 2,3Typically, such patients have symptoms at rest or with minimal exertion and cannot perform many activities of daily living. 3Commonly used objective measures of functional limitations include a peak Vo ˙2 Յ14The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
Modulation of Irinotecan Metabolism by Ketoconazole
Authors: Diederik F.S. Kehrer, Ron H.J. Mathijssen, Jaap Verweij, Peter de Bruijn, Alex Sparreboom
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m 2 intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m 2 ) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography. RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P = .002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P = .004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P = .90) and formation of SN-38G (P = .93). CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.
STUDIES ON THE OXIDATION-REDUCTION OF HEMOGLOBIN AND METHEMOGLOBIN
Authors: James M. Neill
Journal: The Journal of Experimental Medicine (1925)

The oxidation-reduction systems of anaerobic bacteria manifest their action upon the blood pigments by marked deoxygenation of oxyhemoglobin, prompt reduction of methemoglobin to hemoglobin, and to a less marked degree oxidation of hemoglobin to methemoglobin. The action of sterile plant tissue upon oxyhemoglobin, hemoglobin, and methemoglobin has been studied. The oxidations and reductions of the blood pigments which are induced by sterile plant tissue are similar to the reactions which are brought about by pneumococci and by anaerobic bacteria.
Minister backs EU plan for alert system on doctors whose fitness to practise is questioned
Authors: A. O'Dowd
Journal: BMJ (2011)

The UK government is backing European Union proposals for a cross country alert system to deal with doctors whose fitness to practise is questioned.

Alerts were vital for patient safety, said the public health minister, Anne Milton, who was appearing before the House of Lords’ EU social policies and consumer protection subcommittee on 14 July, as part of the committee’s inquiry into the European directive that regulates the movement of healthcare professionals across the EU.

The European Commission is reviewing the directive on the mutual recognition of professional qualifications, so that all member states recognise each other’s healthcare qualifications and simplify movement of clinicians across countries. The commission has produced a green paper on …
Abstract DDT02-01: In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric cancer
Authors: Charlotte Kopitz, Anette Sommer, Stefanie Hammer, Axel Harrenga, Beatrix Stelte-Ludwig, Frank Dittmer, Frank Reetz, Ekkehard May, Ruprecht Zierz, Sabine Wittemer-Rump, Christoph Schatz, H. T. Huynh, Karl Ziegelbauer, Bertolt Kreft
Journal: Cancer Research (2014)

Abstract Gastric cancer is the second most common cause of cancer-related mortality worldwide, thus new treatment options are urgently needed. In a subset of gastric cancers, over-expression of fibroblast growth factor receptor 2 (FGFR2), a receptor tyrosine kinase, has been described and may represent a potential therapeutic target for the treatment of FGFR2-positive gastric cancer patients. To this end, we have generated a fully human anti-FGFR2 antibody (BAY 1179470) using the BioInvent Phage Display library. BAY 1179470 binds to a unique FGFR2-specific epitope that is present in all FGFR2 isoforms. Upon binding to FGFR2, BAY 1179470 induces receptor dimerization, internalization and degradation, resulting in significant tumor growth inhibition in vivo in cell line-based and patient-derived gastric cancer models overexpressing FGFR2. Additive anti-tumor efficacy in vivo was achieved by combining BAY 1179470 with either cisplatin or paclitaxel. BAY 1179470 is fully cross-reactive with FGFR2 orthologues of mouse, rat, pig, cynomolgus monkey and rhesus macaque. No significant safety findings have been seen in animal studies. Thus, BAY 1179470 represents a novel anti-FGFR2 antibody with high anti-tumor activity in gastric cancer models and an excellent preclinical safety profile. BAY 1179470 is currently being tested in a first-in-man study in all-comers (NCT01881217) in Japan. Citation Format: Charlotte Kopitz, Anette Sommer, Stefanie Hammer, Axel Harrenga, Beatrix Stelte-Ludwig, Frank Dittmer, Frank Reetz, Ekkehard May, Ruprecht Zierz, Sabine Wittemer-Rump, Christoph Schatz, H. T. Huynh, Karl Ziegelbauer, Bertolt Kreft. In vitro and in vivo characterization of a novel anti-fibroblast growth factor receptor (FGFR) 2 antibody (BAY 1179470) for the treatment of gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2014-DDT02-01
Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls
Authors: I.-M. Gilboe
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> To examine bone mineral density (BMD) frequency of osteoporosis and reduced bone mass in systemic lupus erythematosus (SLE), and compare the data of the SLE patients with matched rheumatoid arthritis (RA) patients and healthy controls. Secondly, to study possible correlations between BMD, demographic and disease variables in the SLE patients. <h3>METHODS</h3> Measures of BMD assessed by dual energy <i>x</i> ray absorptiometry were obtained from 75 SLE patients aged ⩽ 70 years, 75 RA patients matched for age, sex and disease duration, and from 75 healthy controls matched for age, sex and geographical area. Disease activity and accumulated organ damage were assessed in the SLE patients. <h3>RESULTS</h3> The SLE patients had significantly lower BMD values at lumbar spine L2-L4 and hip, and higher frequency of osteoporosis at all sites of measurement compared with matched healthy controls. The matched SLE and RA patients had similar BMD, prevalence of osteoporosis and reduced bone mass. In the SLE patients BMD was more strongly correlated with accumulated organ damage than with markers of disease activity or duration. In multivariate analyses BMD was at all sites predicted by age and body mass, at lumbar spine also by the current corticosteroid dose. <h3>CONCLUSION</h3> The study showed reduced BMD in patients with SLE compared with matched healthy controls. Premenopausal women taking corticosteroids were especially affected. Furthermore, the BMD of matched SLE and RA patients was reduced to a similar extent.
Glucose Measurement: Confounding Issues in Setting Targets for Inpatient Management
Authors: Kathleen M. Dungan
Journal: Diabetes Care (2007)

We thank Mahoney and Ellison (1) for their interest in the study of glucose measurement in the hospital (2). We agree that not all devices using the same enzyme display the same degree of interference (3). Furthermore, the introduction of a third electrode does not always compensate for the interference (3). It …
Aerosolized rhDNase in cystic fibrosis: effect on leucocyte proteases in sputum
Authors: T Rochat, FD Pastore, SE Schlegel-Haueter, I Filthuth, R Auckenthaler, D Belli, S Suter
Journal: European Respiratory Journal (1996)

In cystic fibrosis (CF), large amounts of free leucocyte proteases are present in bronchial secretions, contributing to progressive lung damage. Recombinant, human deoxyribonuclease (rhDNase) is a new therapeutic agent that decreases sputum viscosity. However, deoxyribonuclease has been shown, in vitro, to release cationic enzymes from complexes with deoxyribonucleic acid (DNA). The present study was conducted to assess this effect in vivo. Free human leucocyte elastase (HLE), human leucocyte cathepsin G (HCG), total chemotactic activity, and interleukin-8 (IL-8) were determined in sputum from eight patients before, during and after rhDNase treatment. After 15 days of treatment, HLE activity increased by 81+/-44% (NS), and HCG by 189+/-70% (p&lt;0.05). One week after stopping a 4-6 months treatment, HLE activity decreased by 35+/-18% (p&lt;0.05), and HCG by 43+/-11% (p&lt;0.05). Sputum bacterial density, chemotactic activity, and IL-8 concentration did not change. Thus, treatment with rhDNase can indeed increase the activity of HLE and HCG in the bronchial secretions of CF patients, and this effect is still detectable after several months of treatment. If this can be shown to be clinically relevant, combination therapy of recombinant human deoxyribonuclease with protease inhibitors should be considered as an approach to the problem.
Partner Diagnostics and the “Choosing Wisely” Campaign
Authors: Jodie E. Battley, Dearbhaile Collins, Seamus O'Reilly
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: The recent article by Schnipper et al 1 is a welcome contribution to the important discussion regarding optimum stewardship of precious health care resources. Their fifth recommendation regarding targeted therapy use only when the patient’s tumor has been tested with a validated test is prescient but would be enhanced, we believe, by highlighting the importance of quality assurance in testing. Past experience with the detection of biomarkers has been far from perfect. Erroneous estrogen receptor (ER) immunohistochemical assessment in breast cancer has come to the fore on a number of occasions; an estimated 40% of 2,000 retested specimens in the United States in 2006 has been incorrectly identified as ER negative. 2 Additional data from the United Kingdom National External Quality Assessment Scheme for Immunocytochemistry reveals significant interlaboratory discrepancies. 3 Points of weakness include the specimen preparation process, antigen retrieval, and antibody staining along with postanalytic failures. ER is not alone in this regard. Central testing for human epidermal growth factor receptor 2 (HER2) status in patients with breast cancer enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation trial demonstrated that up to 6% of patients who were enrolled were not subsequently confirmed as being HER2 positive. 4 A similar story exists for other biomarkers. 5-7 Although guidelines such as those developed for HER2 testing in breast cancer 8 have reduced false-positive results, it is reasonable to assume that similar issues pertain to other targeted therapy–associated biomarkers, leading to costly inappropriate therapy for patients. Previous experience with targeted agents carries important lessons for more recently developed agents, which are increasingly used. The oncology community needs to place greater emphasis on an awareness