tbuckley/cabot-search huggingface dataset:
Acetylsalicylic Acid Governs the Effect of Sorafenib in <i>RAS</i>-Mutant Cancers
Authors: Heinz Hammerlindl, Dinoop Ravindran Menon, Sabrina Hammerlindl, Abdullah Al Emran, Joachim Torrano, Katrin Sproesser, Divya Thakkar, Min Xiao, Victoria G. Atkinson, Brian Gabrielli, Nikolas K. Haass, Meenhard Herlyn, Clemens Krepler, Helmut Schaider
Journal: Clinical Cancer Research (2017)

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult-to-treat RAS-mutant cancer.Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivoResults: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (Celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyperactivation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, such as metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacologic inhibitors of RAF (LY3009120), MEK (trametinib), or AMPK (compound C). The combination was found to be specific for RAS/RAF-mutant cells and had no significant effect in RAS/RAF-wild-type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared with each single-agent treatment.Conclusions: Combination sorafenib and aspirin exerts cytotoxicity against RAS/RAF-mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers. Clin Cancer Res; 24(5); 1090-102. ©2017 AACR.
Cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase (DPD) deficiency in patients with colorectal cancer.
Authors: Gul Ahmed, Jo O' Keeffe, Denise O Mullane, Alison Bransfield, Andrew Kenny, Aiman Mohd Nor, Nurul Asykin Hashim, Roisin O Sullivan, Kate Murphy, Raimundas Galiauskas, Brian Richard Bird, Conleth G. Murphy
Journal: Journal of Clinical Oncology (2013)

3627 Background: DPD is an enzyme encoded by the DPYD gene involved in the metabolism of the chemotherapy drug 5-fluorouracil (5FU) and the oral 5FU prodrug capecitabine. Patients (pts) with DPYD mutations are at risk of severe toxicities from standard dose 5FU, although they may safely receive lower dose therapy with careful monitoring and dose escalation. Methods: In this retrospective study we identified all pts starting 5FU-based chemotherapy for colorectal cancer (CRC) at our institution between Jan 1 2010 and Dec 31 2012. During this time DPD testing was usually performed in a reactive manner, typically for pts experiencing severe toxicities. We reviewed the charts of pts who tested positive for DPYD mutations and assessed the financial implications of their hospitalizations with toxicity. These costs were compared to the costs which would have incurred if all pts starting such therapy had been proactively tested. Results: A total of 134 pts started first-line 5FU-based chemotherapy for CRC over the study period, 66 in the adjuvant setting and 68 for metastatic disease. 31 pts had DPYD mutation testing performed. 6 tests (19% of those tested, 4.5% of the total population) revealed heterozygote DPYD mutations. 5 pts had already experienced severe treatment-related toxicity resulting in cessation of therapy, while one was tested prospectively and received chemotherapy with dose reduction ab initio. The total cost related to hospitalization with toxicity for these 5 pts was €155,083. At €177 per test, the cost to prospectively test all pts starting first-line 5FU-based therapy over the time period would have been €23,718 representing a saving of €131,365 through avoiding these admissions alone. 4 pts who tested positive for DPYD mutations were receiving adjuvant therapy and none restarted therapy following severe toxicity early in their therapy. 2 pts subsequently relapsed with metastatic disease. Conclusions: Prospective testing for DPYD mutations in pts with CRC starting 5FU-based therapy for the first time represents a considerable cost-saving opportunity, in addition to potentially avoiding prolonged hospitalization and morbidity for a sizeable minority of pts.
Intravenous Immune Globulin for the Prevention of Bacterial Infections in Children with Symptomatic Human Immunodeficiency Virus Infection
Journal: New England Journal of Medicine (1991)

Serious recurrent bacterial infections are a major cause of morbidity and mortality in children infected with the human immunodeficiency virus (HIV). Because intravenous immune globulin has been shown to prevent bacterial infection in patients with primary immunodeficiency and in uncontrolled studies of HIV-infected children, we undertook a multicenter study of its safety and efficacy in children with symptomatic HIV infection.
Magnesium and Risk of Hip Fracture among Patients Undergoing Hemodialysis
Authors: Yusuke Sakaguchi, Takayuki Hamano, Atsushi Wada, Junichi Hoshino, Ikuto Masakane
Journal: Journal of the American Society of Nephrology (2017)

Magnesium is an essential mineral for bone metabolism. However, little is known about the relationship between magnesium and the risk of fractures. In this cohort study, we elucidated the association between serum magnesium level and the risk of incident hip fracture among patients undergoing hemodialysis. We identified 113,683 patients undergoing hemodialysis with no history of hip fracture from a nation-wide database of patients undergoing dialysis in Japan. During a 2-year follow-up, a total of 2305 (2%) new hip fractures occurred. The crude incidence rate was significantly higher among patients in the lower quartiles of serum magnesium levels (2.63%, 2.08%, 1.76%, and 1.49% in Q1–Q4, respectively; P &lt;0.001 for trend). The range of serum magnesium levels (in milligrams per deciliter) in each quartile was as follows: Q1, &lt;2.3; Q2, 2.4–2.6; Q3, 2.7–2.8, and Q4, &gt;2.9. After adjustment for demographic and clinical factors, patients in Q1 had a 1.23-fold higher risk for hip fracture than those in Q4 (95% confidence interval, 1.06 to 1.44; P &lt;0.01). Similarly, an inverse probability weighting analysis showed an increased risk of hip fracture among patients in the lower magnesium quartiles. We did not observe significant effect modifications in subgroup analyses. The population-attributable fraction of serum magnesium level for incident hip fractures was 13.7% (95% confidence interval, 3.7% to 22.7%), which was much higher than that of serum calcium, serum phosphate, and parathyroid hormone levels. Thus, mild hypermagnesemia is associated with a lower risk of hip fracture among patients undergoing hemodialysis.
Doxycycline and the treatment for bullous pemphigoid: what outcomes are most important to our patients?
Authors: A.R. Cardones, R.P. Hall
Journal: British Journal of Dermatology (2017)

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and its incidence is increasing.1 The treatment of BP can be uniquely challenging because it affects a much older population. In fact, many patients with BP are over 70 years of age, are more likely to be on multiple medications and have significant comorbidities such as neurological and cardiovascular disease, malignancies and diabetes.2 3 The morbidity and discomfort from BP not only comes from the extent of the blistering, but also from the severe debilitating pruritus, which often accompanies this disease. Oral corticosteroids can ameliorate symptoms, but can bring about a slew of adverse medical consequences and even increase mortality, especially with long‐term use. A treatment that can induce rapid relief of symptoms and long‐term remission, while avoiding or minimizing systemic corticosteroid side‐effects, remains the elusive ‘Holy Grail’ in BP therapy.4 The aggressive application of high‐potency topical corticosteroids (up to 40 gm per day of clobetasol propionate) can be effective in the management of BP and has been proposed as an alternative to systemic steroids.5 Applying a topical medication to a large body surface area several times a day can be difficult for these patients and in some instances can be prohibitively expensive. Topical corticosteroid therapy can still be associated with a relatively high frequency of serious adverse events (59%) and death (39%) at 1‐year follow‐up.6 Tetracyclines have anti‐inflammatory and possibly neuroprotective properties7 and have been proposed as an effective ‘steroid‐sparing’ agent for patients with BP.8 A secondary theoretical benefit of preventing secondary infections among patients with extensive bullae, or on high doses of corticosteroids, has made tetracyclines an attractive therapeutic option for decades.9 However, conclusive data supporting the efficacy of tetracyclines in the treatment of BP is lacking.
Vigilância da doença sistémica invasiva causada por Estreptococos do grupo A, em Itália 1994-1996
Authors: B Suligoi, C Von Hunolstein, G Orefici, F Scopetti, M Pataracchia, D Greco
Journal: Eurosurveillance (1998)

Em finais de Maio de 1994, na sequencia de relatorios sobre um surto de Estreptococus do grupo A beta-hemolitico (SGA) no Reino Unido (1), o Istituto Superiore di Sanita (ISS) criou um sistema de vigilância para doencas sistemicas invasivas por SGA. Este sistema de vigilância foi tambem a resposta a um pedido da Organizacao Mundial de Saude (OMS) em Maio de 1994 para a criacao, na Europa, de sistemas especificos de vigilância das infeccoes sistemicas por SGA (2). Eram objectivos deste sistema coligir dados sobre a ocorrencia destas infeccoes em Italia e identificar surtos.
Emergency Department Stroke Care
Authors: Neal Little, W. Richard Bukata
Journal: JAMA Neurology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
The decrease in global cancer mortality.
Authors: Paolo Boffetta, Eva Negri, Carlo La Vecchia
Journal: Journal of Clinical Oncology (2014)

1608 Background: A decrease in cancer mortality has been reported in the United States, Europe and other developed regions of the world during the last two decades. Whether similar trends apply to less-developed countries – and globally – is unclear. Methods: We aimed at describing the global patterns of cancer mortality by conducting a systematic analysis of the WHO mortality database for countries for which high- or intermediate-quality data on death certifications are available for a period of at least 10 years (typically 2003-2012). We included 60 countries in the analysis, and calculated age-specific and age-adjusted mortality rates. Results: A decrease in overall cancer mortality of approximately 1% per year was present in both developed and less-developed regions, and in both genders. For cancers of the esophagus, stomach, larynx and thyroid, the average decrease in global mortality rate was greater than 2% per year. Individual cancers which showed an increase in mortality rates on a global scale are limited to pancreas and brain (both genders), lung (women), melanoma and kidney (men) and endometrium. Conclusions: Reasons for the decrease in cancer mortality in less-developed countries may include decrease in cancer incidence, shift in the stage distribution, shift in the proportional contribution of individual cancers, and improved therapy. The increase in the number of cancer deaths, globally and in less-developed countries, is primarily driven by changes in the demographic structure of the population, but the risk of the individual of dying from cancer appears to decrease in all countries with reliable data. Cancers with increasing mortality rates should be given priority for research.
Data sharing statements for clinical trials: a requirement of the International Committee of Medical Journal Editors
Authors: Darren B Taichman, Peush Sahni, Anja Pinborg, Larry Peiperl, Christine Laine, Astrid James, Sung-Tae Hong, Abraham Haileamlak, Laragh Gollogly, Fiona Godlee, Frank A Frizelle, Fernando Florenzano, Jeffrey M Drazen, Howard Bauchner, Christopher Baethge, Joyce Backus
Journal: The Lancet (2017)
Narrowing the spectrum: the new frontier of precision antimicrobials
Authors: Alexandra E. Paharik, Henry L. Schreiber, Caitlin N. Spaulding, Karen W. Dodson, Scott J. Hultgren
Journal: Genome Medicine (2017)

Antibiotics have become the standard of care for bacterial infections. However, rising rates of antibiotic-resistant infections are outpacing the development of new antimicrobials. Broad-spectrum antibiotics also harm beneficial microbial communities inhabiting humans. To combat antibiotic resistance and protect these communities, new precision antimicrobials must be engineered to target specific pathogens.
Esophageal Mucosal Impedance Patterns Discriminate Patients With Eosinophilic Esophagitis From Patients With GERD
Authors: Yash Choksi, Pooja Lal, James C. Slaughter, Rohit Sharda, Jacob Parnell, Tina Higginbotham, Michael F. Vaezi
Journal: Clinical Gastroenterology and Hepatology (2017)
Abstract A21: Inhibition of Sonic Hedgehog Pathway by small molecule inhibitors: Targeting colon cancer stem cells
Authors: Aadilah Omar, Clement Penny, Paul Ruff
Journal: Cancer Research (2017)

Abstract The existence of Cancer Stem Cells (CSCs) has been proven extensively in recent years. CSCs have been positively identified in, and isolated from colon cancer. They have been found to be resilient to therapy and are highly metastatic and it has been suggested that this could be attributed to the presence of CSCs expressing cell surface CD133. An active Hedgehog-Gli pathway has been detected in human colon carcinoma cells as well as their stem cells. Sonic Hedgehog (Shh) inhibitors such as cyclopamine have been successful in the treatment of other cancer types. CSCs were isolated from HT29 and DLD1 cells using the CD133 surface protein and these cells were further characterized via their expression of key stem cell markers using fluorescence microscopy. These markers included c-Myc, KLF4 and alkaline phosphatase, all of which showed elevated expression levels in the CSC fraction. The growth pattern of CSCs in comparison to non-CSCs was analyzed using cell-impedance (xCELLigence) assays, with clear differences noted in their growth rates. Adhesion assays revealed that although CSCs have a lower proliferation rate, their adhesive potential proved to be greater, possibly due to them being highly metastatic. The effects of the Shh inhibitors cyclopamine and SANT-2 on cellular adhesion of colon CSCs were compared to the Shh pathway control molecule tomatidine, and a marked decrease in adhesion potential was noted. With regard to cell invasion, this was significantly decreased when CSCs were treated with the small molecule inhibitors. In cell migration/scratch assays a similar trend was seen, wherein cell migration was retarded by Hh pathway inhibition. Using confocal microscopy, the cell surface expression of Shh and CD133 was observed following treatment with cyclopamine and while found to significantly reduce Shh expression, CD133 expression remained unaffected. Considering these in vitro results small molecule inhibitors targeting the Shh pathway appear to be promising therapeutic tools for the treatment of metastatic colon CSCs. Citation Format: Aadilah Omar, Clement Penny, Paul Ruff. Inhibition of Sonic Hedgehog Pathway by small molecule inhibitors: Targeting colon cancer stem cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A21.
Association Between Low Plasma Level of Citrulline Before Allogeneic Hematopoietic Cell Transplantation and Severe Gastrointestinal Graft vs Host Disease
Authors: Thomas Hueso, Jordan Gauthier, Marie Joncquel Chevalier-Curt, Leonardo Magro, Valérie Coiteux, Rémy Dulery, Benjamin Carpentier, Julien Labreuche, Gandhi Damaj, Ibrahim Yakoub-Agha, David Seguy
Journal: Clinical Gastroenterology and Hepatology (2017)
European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α<sub>1</sub>-antitrypsin deficiency
Authors: Marc Miravitlles, Asger Dirksen, Ilaria Ferrarotti, Vladimir Koblizek, Peter Lange, Ravi Mahadeva, Noel G. McElvaney, David Parr, Eeva Piitulainen, Nicolas Roche, Jan Stolk, Gabriel Thabut, Alice Turner, Claus Vogelmeier, Robert A. Stockley
Journal: European Respiratory Journal (2017)

α 1 -antitrypsin deficiency (AATD) is the most common hereditary disorder in adults. It is associated with an increased risk of developing pulmonary emphysema and liver disease. The pulmonary emphysema in AATD is strongly linked to smoking, but even a proportion of never-smokers develop progressive lung disease. A large proportion of individuals affected remain undiagnosed and therefore without access to appropriate care and treatment. The most recent international statement on AATD was published by the American Thoracic Society and the European Respiratory Society in 2003. Since then there has been a continuous development of novel, more accurate and less expensive genetic diagnostic methods. Furthermore, new outcome parameters have been developed and validated for use in clinical trials and a new series of observational and randomised clinical trials have provided more evidence concerning the efficacy and safety of augmentation therapy, the only specific treatment available for the pulmonary disease associated with AATD. As AATD is a rare disease, it is crucial to organise national and international registries and collect information prospectively about the natural history of the disease. Management of AATD patients must be supervised by national or regional expert centres and inequalities in access to therapies across Europe should be addressed.
NIH support of mobile, imaging, pervasive sensing, social media and location tracking (MISST) research: laying the foundation to examine research ethics in the digital age
Authors: Sarah Dunseath, Nadir Weibel, Cinnamon S. Bloss, Camille Nebeker
Journal: npj Digital Medicine (2017)

Mobile Imaging, pervasive Sensing, Social media and location Tracking (MISST) tools used in research are raising new ethical challenges for scientists and the Institutional Review Boards (IRBs) charged with protecting human participants. Yet, little guidance exists to inform the ethical design and the IRB's regulatory review of MISST research. MISST tools/methods produce personal health data that is voluminous and granular and, which may not be subject to policies like the Health Information Portability and Accessibility Act (HIPAA). The NIH Research Portfolio Online Reporting Tools (RePORTER) database was used to identify the number, nature and scope of MISST-related studies supported by the NIH at three time points: 2005, 2010 and 2015. The goal was to: 1-examine the extent to which the NIH is supporting this research and, 2-identify how these tools are being used in research. The number of funded MISST research projects increased 384% from 2005 to 2015. Results revealed that while funding of MISST research is growing, it only represented about 1% of the total NIH budget in 2015. However, the number of institutes, agencies, and centers supporting MISST research increased by roughly 50%. Additionally, the scope of MISST research is diverse ranging from use of social media to track disease transmission to personalized interventions delivered through mobile health applications. Given that MISST research represents about 1% of the NIH budget and is on an increasing upward trajectory, support for research that can inform the ethical, legal and social issues associated with this research is critical.
Ecoendoscopia en tumores quísticos pancreáticos. Factores diagnósticos y pronósticos relacionados con la supervivencia
Authors: P Rodríguez López, A Velasco Guardado, A Álvarez Delgado, ÁF Marcos Martín, HM Marcos Prieto, A Jiménez Jurado, V Calabuig Mazzola, M García Prada, A González-Cotorruelo González, A Rodríguez Pérez
Journal: Endoscopy (2017)

Aunque se han publicado múltiples guías para el abordaje de lesiones quísticas pancreáticas, su potencial de malignización persiste como uno de los principales problemas en su manejo.
Mitral Valve Adaptation to Isolated Annular Dilation
Authors: Dae-Hee Kim, Ran Heo, Mark D. Handschumacher, Sahmin Lee, Yun-Sil Choi, Kyu-Ri Kim, Yewon Shin, Hong-Kyung Park, Joyce Bischoff, Elena Aikawa, Jong-Min Song, Duk-Hyun Kang, Robert A. Levine, Jae-Kwan Song
Journal: JACC. Cardiovascular imaging (2017)
Exosomal adrenomedullin derived from cancer-associated fibroblasts promotes lipolysis in adipose tissue
Authors: Fanyang Kong, Lei Li, Yiqi Du, Huiyun Zhu, Zhaoshen Li, Xiangyu Kong
Journal: Gut (2017)

We read with great interest the recent publication by Sagar et al , which reported activated lipolysis in adipose tissues induced by exosome-transmitted adrenomedullin (AM) from pancreatic cancer (PC) cells.1 Researchers detected AM expressed in PC-derived exosomes and observed elevated AM expression in both tissue and plasma specimens from patients with PC. Biofunctional analysis showed that both AM and PC-derived exosomes promoted lipolysis and this effect could be abolished by blocking the AM receptor, suggesting PC-induced lipolysis is dependent on exosomal AM. A further mechanistic experiment illustrated that the lipolysis induced by AM is mediated through mitogen-activated protein kinases p38 and ERK1/2. Taken together, the results published by Sagar et al reveal a novel molecular mechanism of adipose tissue loss, providing novel insight into early-onset paraneoplastic effects of PC.

Exosomal AM derived from cancer-associated fibroblasts (CAF) promotes lipolysis in adipose tissue. Intriguingly, we noticed that in addition to PC cells, stromal cells also stained positively for AM in …