tbuckley/cabot-search huggingface dataset:
Prioritizing Surgical Care on National Health Agendas: A Qualitative Case Study of Papua New Guinea, Uganda, and Sierra Leone
Authors: Anna J. Dare, Katherine C. Lee, Josh Bleicher, Alex E. Elobu, Thaim B. Kamara, Osborne Liko, Samuel Luboga, Akule Danlop, Gabriel Kune, Lars Hagander, Andrew J. M. Leather, Gavin Yamey
Journal: PLoS Medicine (2016)

Background Little is known about the social and political factors that influence priority setting for different health services in low- and middle-income countries (LMICs), yet these factors are integral to understanding how national health agendas are established. We investigated factors that facilitate or prevent surgical care from being prioritized in LMICs. Methods and Findings We undertook country case studies in Papua New Guinea, Uganda, and Sierra Leone, using a qualitative process-tracing method. We conducted 74 semi-structured interviews with stakeholders involved in health agenda setting and surgical care in these countries. Interviews were triangulated with published academic literature, country reports, national health plans, and policies. Data were analyzed using a conceptual framework based on four components (actor power, ideas, political contexts, issue characteristics) to assess national factors influencing priority for surgery. Political priority for surgical care in the three countries varies. Priority was highest in Papua New Guinea, where surgical care is firmly embedded within national health plans and receives significant domestic and international resources, and much lower in Uganda and Sierra Leone. Factors influencing whether surgical care was prioritized were the degree of sustained and effective domestic advocacy by the local surgical community, the national political and economic environment in which health policy setting occurs, and the influence of international actors, particularly donors, on national agenda setting. The results from Papua New Guinea show that a strong surgical community can generate priority from the ground up, even where other factors are unfavorable. Conclusions National health agenda setting is a complex social and political process. To embed surgical care within national health policy, sustained advocacy efforts, effective framing of the problem and solutions, and country-specific data are required. Political, technical, and financial support from regional and international partners is also important.
Clinical Trials Cannot Substitute for Health System Strengthening Initiatives or Specifically Designed Health Policy and Systems Research
Authors: Kwaku Poku Asante, Caroline Jones, Sodiomon Bienvenu Sirima, Sassy Molyneux
Journal: The American Journal of Bioethics (2016)

Denburg and colleagues (2016) present an interesting hypothesis that the existence of clinical trials infrastructure may function as a quality improvement lever for all patients in an institution o...
West Nile virus lineage 2 isolated from Culex modestus mosquitoes in the Czech Republic, 2013: expansion of the European WNV endemic area to the North?
Authors: I Rudolf, T Bakonyi, O Šebesta, J Mendel, J Peško, L Betášová, H Blažejová, K Venclíková, P Straková, N Nowotny, Z Hubálek
Journal: Eurosurveillance (2014)

We report the detection and isolation of four almost identical strains of West Nile virus (WNV) lineage 2 from Culex modestus mosquitoes collected at three fish ponds in South Moravia, Czech Republic, during August 2013. Phylogenetic analysis demonstrated that the Czech WNV strains isolated are closely related to Austrian, Italian and Serbian strains reported in 2008, 2011 and 2012, respectively. Our findings show the current northernmost range of lineage 2 WNV in Europe.
Abstract P3-03-01: Intracranial PDX models of breast cancer metastasis
Authors: CH Nielsen, MK Nedergaard, MJ Wick, K Papadopoulos, AW Tolcher, A Kjaer
Journal: Cancer Research (2016)

Abstract Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases. Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs. Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET. Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time. Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs. Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-01.
Abstract P2-05-15: NOS2&amp;COX2 activation of TLR4 &amp; EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation
Authors: S Glynn, P Garrrido-Cuesta, D Wink, L Ridnour, S Ambs, M Keane, E Walsh, G Callagy
Journal: Cancer Research (2016)

Abstract Background We seek to further elucidate mechanisms by which inflammatory mediators promote estrogen receptor (ER)-negative breast cancer progression and poor survival. We previously reported association between inducible nitric oxide synthase (NOS2) and poor outcome in ER-negative tumours. In tumours aberrant NOS2 induction facilitates tissue remodelling and stimulates neovascularisation. Also involved in inflammation and wound healing is cyclooxygenase-2 (COX2). We demonstrated that COX2 is associated with Akt activation and poor outcome in ER-negative tumours. We hypothesise that co-expression COX2 with NOS2 in ER-negative tumours amplifies effects of NOS2 on poor outcome, via EGFR and TLR4 signalling loop activation, and polarization of the tumour immune-compartment to pro-tumorigenic M2 phenotype. Methodology We determined the association of NOS2 and COX2 co-expression on breast cancer specific survival in ER-negative and triple negative breast tumours (N=102), via immunohistochemistry and cox regression statistical analysis. To explore the mechanism of NOS2 induction of COX2 through transactivation of EGFR, NO donors in combination with EGFR inhibitors were used to determine if NO exposure results in amplified EGFR and PGE2 pro-survival and pro-metastatic signalling in triple negative breast cancer cell lines. Finally, we explored the ability of NO to modify the ability of triple negative breast cancer secretome to induce polarisation of macrophages to a pro-tumorigenic M2 phenotype. Results Co-expression of NOS2 and COX2 in triple negative breast cancer results in poor outcome, via activation of pro-survival signalling and modification of the immune compartment to a pro-tumorigenic M2 associated phenotype. NO induces activation of growth factor signalling pathways and secretion of M2 promoting cytokines that induce THP1 macrophage polarization to an M2 phenotype. Citation Format: Glynn S, Garrrido-Cuesta P, Wink D, Ridnour L, Ambs S, Keane M, Walsh E, Callagy G. NOS2&amp;COX2 activation of TLR4 &amp; EGFR signalling causes poor outcome in oestrogen receptor-negative breast cancer via pro-survival signals and immune polarisation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-15.
Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel
Authors: Raul D Santos, Samuel S Gidding, Robert A Hegele, Marina A Cuchel, Philip J Barter, Gerald F Watts, Seth J Baum, Alberico L Catapano, M John Chapman, Joep C Defesche, Emanuela Folco, Tomas Freiberger, Jacques Genest, G Kees Hovingh, Mariko Harada-Shiba, Steve E Humphries, Ann S Jackson, Pedro Mata, Patrick M Moriarty, Frederick J Raal, Khalid Al-Rasadi, Kausik K Ray, Zelijko Reiner, Eric J G Sijbrands, Shizuya Yamashita
Journal: The Lancet Diabetes & Endocrinology (2016)
Hypermethylation-Induced Inactivation of the<i>IRF6</i>Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus
Authors: John Charles Rotondo, Alessandro Borghi, Rita Selvatici, Eros Magri, Enzo Bianchini, Elena Montinari, Monica Corazza, Annarosa Virgili, Mauro Tognon, Fernanda Martini
Journal: JAMA Dermatology (2016)

The molecular mechanism leading to the development of vulvar squamous cell carcinoma (VSCC) from vulvar lichen sclerosus (VLS) is unknown.To assess the possible involvement of the IRF6 tumor-suppressor gene in the development of VSCC from VLS.In laboratories at the University of Ferrara, Ferrara, Italy, IRF6 gene expression and promoter methylation were investigated in paraffin-embedded VSCC and adjacent vulvar intraepithelial neoplasia (VIN) and VLS specimens, in cancer-free VLS (cfVLS) specimens, and in healthy skin specimens by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis and by sequencing of PCR-amplified bisulfite-treated DNA. Methylation-induced dysregulation was assessed by expression of p63, the IRF6-transactivator gene.IRF6 expression, correlation with promoter methylation and p63 expression, and association with development of VSCC from VLS.Specimens from 60 participating women (1 specimen from each) were analyzed for the study (mean [SD] age, 66.3 [12.1] years): 20 paraffin-embedded specimens of VSCC (patient age, 75.3 [8.3] years) with adjacent VLS lesions, in 5 of which VIN preneoplastic tissue was also present (patient age, 64.3 [15.3] years); 20 cfVLS specimens (patient age, 62.1 [11.4] years) obtained from diagnostic biopsies; and 20 normal skin specimens from noncancer surgical patients (patient age, 61.4 [9.1] years). IRF6 messenger RNA was found to be reduced 4.5-, 2.9-, 6.6-, and 2.2-fold in VLS, VIN, VSCC, and cfVLS specimens, respectively, compared with controls, although p63 was still expressed in all specimens. IRF6 promoter was hypermethylated in 9 (45%) of 20 VLS specimens, 1 (20%) of 5 VIN specimens, 16 (80%) of 20 VSCC specimens, 2 (10%) of 20 cfVLS specimens, and 0 normal skin specimens.IRF6 dysregulation may be involved in the development of VSCC from VLS. Methylation of the IRF6 promoter may be a marker of cancer risk in patients with VLS.
Amish study, V: Lithium-sodium countertransport and catechol O- methyltransferase in pedigrees of bipolar probands
Authors: J A Egeland, J R Kidd, A Frazer, K K Kidd, V I Neuhauser
Journal: American Journal of Psychiatry (1984)

The authors studied 87 individuals from four large Amish pedigrees to determine the relationship between susceptibility to affective disorders and variation in the measures of two biochemical variables, catechol O-methyltransferase (COMT) and lithium countertransport. Assays were done in duplicate and blind to diagnostic or pedigree status. Data were analyzed separately within families as well as by pooling ill and well subjects across pedigrees. Various statistical analyses yielded no significant differences in lithium measures or COMT activity levels between members diagnosed as having a form of affective disorder and the normal members.
Von Willebrand factor regulates complement on endothelial cells
Authors: Damien G. Noone, Magdalena Riedl, Fred G. Pluthero, Mackenzie L. Bowman, M. Kathryn Liszewski, Lily Lu, Yi Quan, Steve Balgobin, Reinhard Schneppenheim, Sonja Schneppenheim, Ulrich Budde, Paula James, John P. Atkinson, Nades Palaniyar, Walter H.A. Kahr, Christoph Licht
Journal: Kidney International (2016)
Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy
Authors: M DIAZ
Journal: Cardiovascular Research (2004)

Objective: Recent work has identified reductions in the systolic Ca2+ transient in cardiac disease states. The aim of the present study was to identify the mechanisms responsible for perturbations of intracellular calcium homeostasis in isolated cardiac myocytes and determine if such changes can quantitatively explain the reduced systolic Ca2+ transient. Methods: Left ventricular hypertrophy (LVH) was induced by aortic coarctation in adult ferrets. Changes in intracellular Ca2+ regulation, sarcolemmal Ca2+ fluxes and SR function were measured in single left ventricular cardiac myocytes. Results: Cardiac hypertrophy was associated with a 29% increase in action potential duration (APD90); a 48% reduction in the amplitude of and 19% slowing in the rate of decay of the systolic Ca2+ transient; a 20% decrease in SR Ca2+ content and a 36% increase in inward Na+–Ca2+ exchange current for a given change in [Ca2+]i (all P<0.05). Peak L-type Ca2+ current density, integrated Ca2+ influx and SERCA2a protein levels remained unchanged in hypertrophy. By determining the relationship between SR Ca2+ content and systolic Ca2+, the reduction in SR Ca2+ content quantitatively explained the smaller systolic Ca2+ transient. The reduced SR Ca2+ content also accounted for a smaller fractional release of Ca2+ from the SR and lower gain of excitation contraction coupling in cardiac hypertrophy. The increased sarcolemmal-mediated Ca2+ efflux was sufficient to explain the reduction in SR Ca2+ content. Conclusions: The findings indicate that the primary mechanism underlying the smaller systolic Ca2+ transient amplitude in cardiac hypertrophy is decreased SR Ca2+ content occurring as a consequence of reduced SR Ca2+-ATPase-mediated Ca2+ uptake and increased sarcolemmal-mediated Ca2+ efflux from the cell. The increased Na+–Ca2+ exchange-mediated current for a given change in intracellular Ca2+ concentration provides a mechanism for the development of arrhythmias in the face of a reduced SR Ca2+ load in cardiac hypertrophy.
Scrub Typhus
Authors: Chang-Seop Lee, Jeong-Hwan Hwang
Journal: New England Journal of Medicine (2015)

A 65-year-old woman was admitted with fever and rash. On physical examination, an erosion 1.5 cm by 1.5 cm with a torn bulla was observed in the right axilla, and a generalized, nonpruritic, maculopapular rash was found over the whole body.
The Writer
Authors: Robert O'Leary
Journal: New England Journal of Medicine (1973)

His was a quiet eloquence. Informed with erudition, wisdom and humor, his writing never sounded the strident note. He felt deeply about many issues; he never hesitated to express his convictions, but always in terms acceptable to supporter and adversary alike.In his early years as a practicing pediatrician he found time not only for scientific studies but also for essays on a broad range of topics. Thus, side by side with his articles on the thymus, on splenic-artery aneurysm with rupture and on varicella after exposure to herpes zoster, one comes across homilies, wise and readable and often witty, . . .
Men having sex with men and HIV/AIDS prevention in Switzerland: 1987-2000
Authors: F Dubois-Arber, F Moreau-Gruet
Journal: Eurosurveillance (2002)

Although the latest survey on prevention behaviours of men having sex with men (MSMs) in Switzerland shows a decreasing number of HIV cases since 1992, a decrease in the protection level has also been observed. This could lead to a higher rate of HIV notifications in 2001 compared to 2000.
Major Changes in Systemic Therapy for Advanced Melanoma
Authors: John A Thompson
Journal: Journal of the National Comprehensive Cancer Network (2016)

Over the past 5 years, a host of new agents have radically changed the therapeutic landscape in advanced melanoma; gone are the days when the only active agents were interferon and dacarbazine. Nearly 25 years ago, few patients with stage IV melanoma reached 2-year survival; today, these survival curves have risen substantially. At the NCCN 21st Annual Conference, John A. Thompson, MD, discussed updates with longer duration of patient follow-up for immune checkpoint therapies. He also reviewed some of the newer approvals in advanced melanoma, including the combination of ipilimumab and nivolumab, high-dose ipilimumab, the oncolytic virus therapy talimogene laherparepvec, and the molecularly targeted combination of the BRAF and MEK inhibitors vemurafenib and cobimetinib.
Inhibiting thrombosis without causing bleeding: can EP3 blockers fulfil the dream?
Authors: R. De Caterina
Journal: Cardiovascular Research (2014)

This editorial refers to ‘Blocking the EP3 receptor for PGE2 with DG-041 decreases thrombosis without impairing haemostatic competence’ by P. Tilly et al. , pp. 482–491, this issue. 

Pharmacologists designing and clinicians dealing with antithrombotic drugs have always faced the problem that preventing thrombosis—by inhibiting one or more of the haemostatic pathways—always entails increased risk of bleeding. This paradigm has been over and over confirmed with the newer antithrombotic drugs, either inhibiting platelet function—such as prasugrel, ticagrelor, or cangrelor1—or inhibiting coagulation—the new direct oral anticoagulants, such as thrombin or activated Factor X inhibitors.2 No matter which new drug has been tested compared with older drugs or placebo, here the issue at stake is never increased potency or better safety in isolation, but always a better benefit–risk balance. Contrary to, for example, drugs lowering low-density lipoprotein (LDL) cholesterol, antithrombotic treatments have always been a perilous navigation between the Scylla of thrombosis and the Charybdis of bleeding. This latter itself also conjures with thrombosis because of the ominous consequences of bleeding, itself often precipitating thrombosis for a variety of reasons.3 Therefore, always protection from thrombosis has come to the expenses of increased bleeding—no free lunch.

Tilly et al. 4 are now going to re-ignite the hypes and the hopes for such a class of magic compounds. Here inhibiting in vivo the receptor EP3 for prostaglandin (PG) E2 with the blocking agent DG-041 reduced murine thrombosis triggered by local delivery of arachidonic acid (AA) or ferric chloride on healthy arteries. Such a treatment also reduced thrombosis triggered by scratching murine atherosclerotic plaques. Blocking EP3 did not alter murine tail, liver, or cerebral haemostasis. Furthermore, blocking EP3 reduced murine pulmonary embolism and intensified platelet inhibition by clopidogrel, leaving tail bleeding times unchanged. In healthy humans, DG-041 reduced platelet aggregation, but …
Deanol in the treatment of tardive dyskinesia
Authors: D E Casey, D Denny
Journal: American Journal of Psychiatry (1975)

A patient who developed severe tardive dyskinesia after the termination of long-term phenothiazine therapy was successfully treated with deanol, a possible precursor of acetylcholine. Physiological measurements were obtained to quantify the clinical course. The authors discuss the practical and heuristic implications of these observations and suggest further consideration of therapy directed toward enhancement of cholinergic activity in the central nervous system.
A Maternal Influence on the Growth Rate of a Transplantable Tumor in Hybrid Mice&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: Morris K. Barrett, Walter C. Morgan
Journal: JNCI Journal of the National Cancer Institute (1949)

Journal Article A Maternal Influence on the Growth Rate of a Transplantable Tumor in Hybrid Mice Get access Morris K. Barrett, Morris K. Barrett National Cancer Institute, National Institutes of Health, Public Health Service, Bethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar Walter C. Morgan Walter C. Morgan National Cancer Institute, National Institutes of Health, Public Health Service, Bethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 10, Issue 1, August 1949, Pages 81–88, https://doi.org/10.1093/jnci/10.1.81 Published: 01 August 1949 Article history Received: 27 January 1949 Published: 01 August 1949