tbuckley/cabot-search huggingface dataset:
28Development and characterisation of a human ex-vivo model of aneurysm
Authors: R Bianco, K Di Gregoli, M Caputo, M Zakkar, S J George, J L Johnson
Journal: Cardiovascular Research (2018)

Introduction: microRNA miR487b has been shown to play an important role in cardiovascular pathology, despite having relatively few putative targets.Adenosine-to-inosine (A-to-I) editing of microRNAs by ADARs can cause a shift in target-site selection.Purpose: To investigate whether miR487b is subject to A-to-I editing during ischemia and how this affects the pool of target genes of miR487b.Methods: and Results: cDNA was prepared from muscle tissue of C57BL/6 mice subjected to hind limb ischemia.Using Sanger sequencing and sequence specific endonuclease digestion, we identified and confirmed A-to-I editing in the seed sequence of miR487b.Subsequent quantification revealed post-ischemic regulation of miR487b editing.In the ischemic gastrocnemius, primary-miR487b editing increased from 6.760.4% before to 11.761.6%(P¼0.02)one day after ischemia.Edited primary-miR487b is processed into a mature microRNA, miR487b-ED, which is also upregulated following ischemia.Primary human vascular cells were used to show that miR487b editing is conserved in human miR487b and that its precursor associates with both ADAR1 and -2.With specific in vitro siRNA knockdowns, we found that both ADAR1 and -2 can edit miR487b.The 3'UTR of IRS1 contains a binding site for both miR487b and miR487b-ED, whereas BMP1 contains six separate binding sites for miR487b-ED.Luciferase reporter gene assays using both endogenous and mutated IRS1 and BMP1 binding sites demonstrated that editing of miR487b's seed sequence does result in a complete shift in target site selection.In an identical context, binding of miR487b-ED induced stronger luciferase silencing than miR487b binding.Furthermore, a subset of putative target genes were validated to confirm specific regulation by either miR487b or miR487b-ED in gain-of-function experiments using primary human vascular cells.In contrast to wildtype miR487b's target pool, miR487b-ED's novel targetome is enriched for angiogenesis-associated pathways.Indeed, microRNA overexpression experiments showed that miR487b-ED causes a 2-fold increase in neovascularization compared to miR487b in an ex vivo aortic ring sprouting assay and also increases wound healing in scratch assays on both human vascular endothelial cells and fibroblasts.Finally, whole exome microarray was performed to measure average targetome expression after hind limb ischemia.We found that only miR487b-ED's targetome is actively repressed during active neovascularization after ischemia.Conclusions: MiR487b is edited in its seed-sequence in both mice and humans.Editing of miR487b is upregulated after ischemia and causes a shift in target gene selection, resulting in a novel, pro-angiogenic microRNA, miR487b-ED, with a unique targetome.Our results demonstrate that microRNA-editing plays an active role in neovascularization.
TCTAP A-128 Raised Level of Cardiac Troponin I (50 Folds Upper Limit of Normal) Is a Sensitive and Specific Marker for Extent of Coronary Artery Disease in First Attack of Non-ST Segment Elevation Myocardial Infarction in Bangladeshi Population.
Authors: Mahmood Hasan Khan
Journal: Journal of the American College of Cardiology (2018)
Re: Tobias Nordström, Andrew Vickers, Melissa Assel, Hans Lilja, Henrik Grönberg, Martin Eklund. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol 2015;68:139–46
Authors: Andrew Vickers, Tobias Nordström, Melissa Assel, Hans Lilja, Henrik Grönberg, Martin Eklund
Journal: European Urology (2018)
Leukotriene receptors as potential therapeutic targets
Authors: Takehiko Yokomizo, Motonao Nakamura, Takao Shimizu
Journal: Journal of Clinical Investigation (2018)

Leukotrienes, a class of arachidonic acid–derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.
Alan Gerald Amias
Authors: Alasdair Fraser
Journal: BMJ (2018)

Born and brought up in the East End of London, Alan Gerald Amias was sent away at the age of 11 as an evacuee, like many other war time children, to escape the bombing. He ended up in Bedford, his education disrupted and resulting distress always remembered. Nevertheless, on returning to London after two years, he achieved an early entry to medical school and after qualifying held house officer appointments at University College Hospital. After national service, when he was posted to an army hospital in Germany, he continued his specialist training. This followed the well trodden path, in those days, of obtaining junior posts in several specialised hospitals for postgraduate training and finally becoming a …
Oncogenic Mutants of <i>MEK1</i>: A Trilogy Unfolds
Authors: Joel D. Maust, Christopher E. Whitehead, Judith S. Sebolt-Leopold
Journal: Cancer Discovery (2018)

Abstract Summary: It has generally been assumed that MEK mutants function similarly to one another and respond in the same manner to targeted drugs. Gao and colleagues challenge this assumption and report that MEK1 mutants fall into three unique phenotypic classes with respect to RAF dependency. A new class of MEK1 mutants is shown here to be RAF-independent, resistant to allosteric MEK inhibitors, and yet sensitive to treatment with a new ATP-competitive MEK inhibitor. Cancer Discov; 8(5); 534–6. ©2018 AACR. See related article by Gao et al., p. 648.
HCV clearance and pro-thrombotic shift in advanced liver disease
Authors: E. Biliotti, D. Palazzo, R. Cangemi, R. Carnevale, R. Esvan, P. Maida, C. Nocella, P. Perinelli, M. Santori, M. Spaziante, L. Sulekova, F. Tamburini, F. Violi, G. Taliani
Journal: Journal of Hepatology (2018)
Modeling the Present and Future Incidence of Pediatric Hand, Foot, and Mouth Disease Associated with Ambient Temperature in Mainland China
Authors: Qi Zhao, Shanshan Li, Wei Cao, De-Li Liu, Quan Qian, Hongyan Ren, Fan Ding, Gail Williams, Rachel Huxley, Wenyi Zhang, Yuming Guo
Journal: Environmental Health Perspectives (2018)

Background: There is limited evidence about the association between ambient temperature and the incidence of pediatric hand, foot, and mouth disease (HFMD) nationwide in China. Objectives: We examined the childhood temperature-HFMD associations across mainland China, and we projected the change in HFMD cases due to projected temperature change by the 2090s. Methods: Data on daily HFMD (children 0–14 y old) counts and weather were collected from 362 sites during 2009–2014. Daily temperature by the 2090s was downscaled under the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Temperature-HFMD associations were quantified using a two-stage Poisson regression with a distributed lag nonlinear model. The impact of changes in temperature on the incidence of HFMD was estimated by combining the fitted temperature-HFMD associations with projected temperatures under each scenario, assuming a constant population structure. Sensitivity analyses were performed to assess the influence of primary model assumptions. Results: During 2009–2014, >11 million HFMD cases were reported. In most regions, the temperature-HFMD association had an inverted U shape with a peak at approximately 20°C, but the association leveled off or continued to increase in the Inner Mongolia and Northeast regions. When estimates were pooled across all regions and the population size was held constant, the projected incidence of HFMD increased by 3.2% [95% empirical confidence interval (eCI): −13.5%, 20.0%] and 5.3% (95% eCI: −33.3%, 44.0%) by the 2090s under the RCP 4.5 and 8.5 scenarios, respectively. However, regional projections suggest that HFMD may decrease with climate change in temperate areas of central and eastern China. Conclusion: Our estimates suggest that the association between temperature and HFMD varies across China and that the future impact of climate change on HFMD incidence will vary as well. Other factors, including changes in the size of the population at risk (children 0–14 y old) will also influence future HFMD trends. https://doi.org/10.1289/EHP3062
Evaluating the Association between Artificial Light-at-Night Exposure and Breast and Prostate Cancer Risk in Spain (MCC-Spain Study)
Authors: Ariadna Garcia-Saenz, Alejandro Sánchez de Miguel, Ana Espinosa, Antonia Valentin, Núria Aragonés, Javier Llorca, Pilar Amiano, Vicente Martín Sánchez, Marcela Guevara, Rocío Capelo, Adonina Tardón, Rosana Peiró-Perez, José Juan Jiménez-Moleón, Aina Roca-Barceló, Beatriz Pérez-Gómez, Trinidad Dierssen-Sotos, Tania Fernández-Villa, Conchi Moreno-Iribas, Victor Moreno, Javier García-Pérez, Gemma Castaño-Vinyals, Marina Pollán, Martin Aubé, Manolis Kogevinas
Journal: Environmental Health Perspectives (2018)

Background: Night shift work, exposure to light at night (ALAN) and circadian disruption may increase the risk of hormone-dependent cancers. Objectives: We evaluated the association of exposure to ALAN during sleeping time with breast and prostate cancer in a population based multicase–control study (MCC-Spain), among subjects who had never worked at night. We evaluated chronotype, a characteristic that may relate to adaptation to light at night. Methods: We enrolled 1,219 breast cancer cases, 1,385 female controls, 623 prostate cancer cases, and 879 male controls from 11 Spanish regions in 2008–2013. Indoor ALAN information was obtained through questionnaires. Outdoor ALAN was analyzed using images from the International Space Station (ISS) available for Barcelona and Madrid for 2012–2013, including data of remotely sensed upward light intensity and blue light spectrum information for each geocoded longest residence of each MCC-Spain subject. Results: Among Barcelona and Madrid participants with information on both indoor and outdoor ALAN, exposure to outdoor ALAN in the blue light spectrum was associated with breast cancer [adjusted odds ratio (OR) for highest vs. lowest tertile, OR=1.47; 95% CI: 1.00, 2.17] and prostate cancer (OR=2.05; 95% CI: 1.38, 3.03). In contrast, those exposed to the highest versus lowest intensity of outdoor ALAN were more likely to be controls than cases, particularly for prostate cancer. Compared with those who reported sleeping in total darkness, men who slept in “quite illuminated” bedrooms had a higher risk of prostate cancer (OR=2.79; 95% CI: 1.55, 5.04), whereas women had a slightly lower risk of breast cancer (OR=0.77; 95% CI: 0.39, 1.51). Conclusion: Both prostate and breast cancer were associated with high estimated exposure to outdoor ALAN in the blue-enriched light spectrum. https://doi.org/10.1289/EHP1837
High efficacy of resistance guided retreatment of Genotype 3 in real life
Authors: A.B.P. Jimenez, A. Sánchez, F.T. Pérez, M. Jiménez, J. Salmerón, J.M.R. Zabal, J.C.A. Arboledas, M. Casado, D. Merino, A.D.L.I. Salgado, A.R.C. Romacho, M.J. Álvarez-Ossorio, J. Hernández-Quero, J.M. Pascasio, N. Espinosa, C. Delgado, F.G.D.A. Clotilde, J. De Juan, A. Poyato, F.M. Jimenez, B.B. Carral, F.G. Garcia
Journal: Journal of Hepatology (2018)
Why don9t we give chest patients dietary advice
Authors: G Devereux, A Seaton
Journal: Thorax (2001)

Dietary vitamin E, IgE concentrations, and atopy

A Fogarty, S Lewis, S Weiss, J Britton

Vitamin E inhibits IgE responses to allergic stimuli in animals. We investigated the relation between dietary vitamin E intake and serum IgE concentrations and atopy, measured as allergen skin sensitisation, in a random sample of 2633 adults. Higher concentrations of vitamin E intake were associated with lower IgE concentrations and a lower frequency of allergen sensitisation. These findings may explain the beneficial effect of dietary vitamin E on the incidence of asthma. ( Lancet 2000;356:1573–4)

The introductory article by Fogarty and colleagues showed what at first glance might be thought an implausible association.1 Is it likely that what we eat as adults can have any bearing on what is widely regarded as a genetically determined propensity to allergic disease? The answer is yes. In this paper we shall review the now quite extensive literature on associations between diet and obstructive airway diseases and point to intriguing new evidence that an unbalanced diet may be an important determinant of allergic disease. From this it follows that we should, as chest physicians, pay more attention to what our patients eat.

There is good evidence that oxidant/antioxidant imbalance is important in the pathogenesis of chronic obstructive pulmonary disease (COPD); cigarette smoke contains oxidants and free radicals that, by generating oxygen radicals, damage cellular lipids, proteins and nucleic acids. The neutrophils and macrophages associated with the COPD inflammatory response also release oxygen radicals.2 These radicals have been implicated in the pathogenesis of COPD because of their ability to induce oxidative inactivation of antiproteinases, tissue damage, sequestration of neutrophils, and the generation of inflammatory mediators. However, other factors must influence the development of COPD because individuals vary in their susceptibility to the effects of cigarette smoke; only a proportion …
CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs
Authors: Ole Audun W. Haabeth, Marte Fauskanger, Melanie Manzke, Katrin U. Lundin, Alexandre Corthay, Bjarne Bogen, Anders A. Tveita
Journal: Cancer Research (2018)

Abstract Tumor-specific CD4+ T cells have been shown to mediate efficient antitumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)–expressing tumor cells, or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4+ T cells reactive against an epitope within the Ig light chain variable region of a murine B-cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II–restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II–expressing tumor cells was essential both for the priming and effector phase of CD4+ T-cell–driven antitumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen–specific CD4+ T cells in vivo. These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4+ T-cell–mediated rejection and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4+ T cells. Significance: Elimination of tumors by CD4+ T cells recognizing secreted tumor neoantigens can occur in the absence of tumor cell-intrinsic MHC II expression, highlighting the potential clinical relevance of indirect antigen recognition by tumor-infiltrating APC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4573/F1.large.jpg. Cancer Res; 78(16); 4573–85. ©2018 AACR.
Hypoallergenic casein hydrolysate for peptide-based oral immunotherapy in cow's milk allergy
Authors: Hiroshi M. Ueno, Teruhiko Kato, Hidenori Ohnishi, Norio Kawamoto, Zenichiro Kato, Hideo Kaneko, Naomi Kondo, Taku Nakano
Journal: Journal of Allergy and Clinical Immunology (2018)
TCT-719 Clinical Impact of Baseline Right Bundle Branch Block in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Euihong Ko, Sun Hack Lee, Sangwoo Park, Yong-Hoon Yoon, Sang Yong Om, Minsoo Kim, Hanbit Park, Sang-Cheol Cho, Kyusup Lee, Osung Kwon, Do-yoon Kang, Pil Hyung Lee, Jung-Min Ahn, Soo-Jin Kang, Duk-Woo Park, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Frequency of Plaque Dislodgement and Embolization in Transradial vs Transfemoral Approaches for Left-Sided Cardiac Catheterization
Authors: William C. Roberts, Jeffrey M. Schussler
Journal: JAMA Cardiology (2018)

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Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102
Authors: Noah Kornblum, Fengmin Zhao, Judith Manola, Paula Klein, Bhuvaneswari Ramaswamy, Adam Brufsky, Phillip J. Stella, Brian Burnette, Melinda Telli, Della F. Makower, Puneet Cheema, Cristina I. Truica, Antonio C. Wolff, Gamini S. Soori, Barbara Haley, Timothy R. Wassenaar, Lori J. Goldstein, Kathy D. Miller, Joseph A. Sparano
Journal: Journal of Clinical Oncology (2018)

Purpose The mammalian target of rapamycin inhibitor everolimus targets aberrant signaling through the PI3K/AKT/mammalian target of rapamycin pathway, a mechanism of resistance to anti-estrogen therapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that everolimus plus the selective ER downregulator fulvestrant would be more efficacious than fulvestrant alone in ER-positive metastatic breast cancer resistant to aromatase inhibitor (AI) therapy. Patients and Methods This randomized, double-blind, placebo-controlled, phase II study included 131 postmenopausal women with ER-positive, human epidermal growth factor receptor 2-negative, AI-resistant metastatic breast cancer randomly assigned to fulvestrant (500 mg days 1 and 15 of cycle 1, then day 1 of cycles 2 and beyond) plus everolimus or placebo. The study was designed to have 90% power to detect a 70% improvement in median progression-free survival from 5.4 months to 9.2 months. Secondary end points included objective response and clinical benefit rate (response or stable disease for at least 24 weeks). Prophylactic corticosteroid mouth rinses were not used. Results The addition of everolimus to fulvestrant improved the median progression-free survival from 5.1 to 10.3 months (hazard ratio, 0.61 [95% CI, 0.40 to 0.92]; stratified log-rank P = .02), indicating that the primary trial end point was met. Objective response rates were similar (18.2% v 12.3%; P = .47), but the clinical benefit rate was significantly higher in the everolimus arm (63.6% v 41.5%; P = .01). Adverse events of all grades occurred more often in the everolimus arm, including oral mucositis (53% v 12%), fatigue (42% v 22%), rash (38% v 5%), anemia (31% v. 6%), diarrhea (23% v 8%), hyperglycemia (19% v 5%), hypertriglyceridemia (17% v 3%), and pneumonitis (17% v 0%), although grade 3 to 4 events were uncommon. Conclusion Everolimus enhances the efficacy of fulvestrant in AI-resistant, ER-positive metastatic breast cancer.
420Relationship between CHA2DS2 VASc score, serum pentraxine 3 and left atrial appendage tissue doppler velocity in patients with non-valvular atrial fibrillation
Authors: AHMED Abdel-Galeel, AYMAN Hassan Galal, AMR Ahmed Aly Youssef, SALWA Dimitry
Journal: Cardiovascular Research (2018)

Background: Atrial fibrillation (AF) is a common arrhythmia with high risk for systemic embolism.This depends on left atrial (LA) mechanical and haematological factors.The inflammation enhances platelet activation, endothelial damage and interaction between platelets and neutrophils.Inflammatory markers as pentraxin 3 (PTX3) are elevated in patients with dilated LA with poorly functioning left atrial appendage (LAA).Many clinical schemes were proposed to assess risk of stroke as CHA2DS2-VASc.However, they need to be refined with incorporation of some echocardiographic and laboratory parameters.Objectives: To compare the sensitivity and specificity of CHA2DS2-VASc score alone, with addition of serum PTX3 and with addition of serum PTX3 and LAA tissue Doppler velocity.Patients and Methods: The study included 80 patients with non-valvular AF (NVAF) were enrolled.CHA2DS2-VASc score was calculated for every patient.Serum PTX3 was measured within 1 week before the transesophageal echocardiographic examination.LA size and volume and LAA tissue Doppler velocity were measured by trans-thoracic echocardiography (TTE).LAA thrombi were reported by trans-esophageal echocardiography (TEE).Results: The mean age was 59.268.3 years with 47 patients (58.8%) were males.By TEE, 13 patients (16.25%) were found to have LAA thrombi.Using ROC statistic, a cut-off value of 11.98 mg/dl for serum PTX3 (sensitivity: 92%, specificity: 55%) and 8.4 cm/sec.for LAA tissue Doppler velocity (sensitivity: 53.8%, specificity: 88%) were set.According to CHA2DS2-VASc score, 31 patients (38.75%) were considered to be at high risk for stroke (sensitivity: 92%, specificity: 55%).Combining the above three parameters improves both sensitivity (99%) and specificity (100%).Conclusion: Adding some echocardiographic and laboratory parameters as serum PTX3 to the clinical risk score CHA2DS2-VASc will improve both sensitivity and specificity in predicting high risk patients.This will better guide anti-thrombotic therapy in NVAF patients.