tbuckley/cabot-search huggingface dataset:
Role of Macrophage Migration Inhibitory Factor in Granulomatosis With Polyangiitis
Authors: Antoine G. Sreih, Rana Ezzedine, Lin Leng, Juan Fan, Jie Yao, Duncan Reid, Marta Piecychna, Simon Carette, David Cuthbertson, Paul Dellaripa, Gary S. Hoffman, Nader A. Khalidi, Curry L. Koening, Carol A. Langford, Alfred Mahr, Carol A. McAlear, Kathleen Maksimowicz‐Mckinnon, Paul A. Monach, Philip Seo, Ulrich Specks, E. William St.Clair, John H. Stone, Steven R. Ytterberg, Jeffrey Edberg, Peter A. Merkel, Richard Bucala
Journal: Arthritis & Rheumatology (2018)

Objective To examine the association between macrophage migration inhibitory factor ( MIF ) promoter polymorphisms and granulomatosis with polyangiitis ( GPA ) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis. Methods The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF −794 CATT 5−8 promoter microsatellite ( rs5844572 ). MIF promoter, CATT ‐length–dependent gene expression in response to β‐glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β‐glucan into wild‐type ( WT ) or Mif ‐knockout ( Mif ‐ KO ) C57 BL /6 mice and C57 BL /6 mice transgenically overexpressing Mif in lung epithelium ( Mif lung–Tg2.1). Mice were treated with a neutralizing anti‐ MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality. Results The percentage of human subjects carrying &gt;5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung–Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif ‐ KO mice. A significantly higher percentage of Mif lung–Tg2.1 mice, compared to Mif‐ KO or WT mice, died when injected with Candida albicans β‐glucan, and treatment of these mice with an anti‐ MIF monoclonal antibody protected against a lethal outcome. Levels of MIF ‐dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung–Tg2.1 mice. Conclusion Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung–Tg2.1 mice, while anti‐ MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA .
Infographic: Helping athletes make decisions on dietary supplement use
Authors: Ronald John Maughan
Journal: British Journal of Sports Medicine (2018)

Many athletes will go to great lengths—indeed almost any length—in the pursuit of success in their chosen sport. This includes training to the limits of what is tolerable and sometimes even beyond that. It is not surprising therefore that the search for anything that might confer even the smallest advantage is pursued assiduously. Some of the options chosen are of dubious benefit and some might even be harmful to the athlete’s health, performance and long-term career.

Nutrition offers many opportunities for performance enhancement, and the influence of nutrition on athletic performance has been documented extensively.1 Potential benefits include an ability to sustain a higher training load without succumbing to illness or injury and an enhanced responsiveness to the training stimulus as well as direct effects on competition performance itself. Athletes are aware that the food choices they make can have profound effects on all of these aspects of their sporting life, but most …
Author Correction: High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy
Authors: Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J Hartmann, Lukas M Weber, Reinhard Dummer, Mark D Robinson, Mitchell P Levesque, Burkhard Becher
Journal: Nature Medicine (2018)
Association of Inadequately Controlled Disease and Disease Severity With Patient-Reported Disease Burden in Adults With Atopic Dermatitis
Authors: Eric L. Simpson, Emma Guttman-Yassky, David J. Margolis, Steven R. Feldman, Abrar Qureshi, Tissa Hata, Vera Mastey, Wenhui Wei, Laurent Eckert, Jingdong Chao, Renée J. G. Arnold, Tiffany Yu, Francis Vekeman, Mayte Suárez-Fariñas, Abhijit Gadkari
Journal: JAMA Dermatology (2018)

Real-world data are limited on the patient-reported burden of adult atopic dermatitis (AD). To characterize the patient-reported burden of AD with regard to impact of disease severity and inadequate control in adults from clinical settings. In this cross-sectional study using data from 6 academic medical centers in the United States collected by a self-administered internet-based questionnaire, 1519 adult patients with AD were stratified by AD severity as mild or moderate/severe using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). Patients with moderate/severe disease using systemic immunomodulators/phototherapy were further stratified as having adequate or inadequate disease control. Strata were compared for all outcomes. Outcomes included validated measures and stand-alone questions assessing itch (pruritus numerical rating scale; PO-SCORAD itch visual analog scale), pain (numerical rating scale), sleep (PO-SCORAD sleep visual analog scale; sleep interference with function), anxiety and depression (Hospital Anxiety and Depression Scale), and health-related quality of life (Dermatology Life Quality Index). Among the 1519 adult patients with AD, relative to mild AD (n = 689, 64% women; mean [SD] age, 46.5 [18.0] years), patients with moderate/severe AD (n = 830, 66.8% women; mean [SD] age, 45.1 [16.9] years) reported more severe itching and pain, greater adverse effects on sleep, higher prevalence of anxiety and depression (417 [50.2%] vs 188 [27.3%]), and greater health-related quality-of-life impairment. The 103 patients with moderate/severe AD with inadequate disease control despite treatment with systemic immunomodulators or phototherapy (55.7%) reported higher burdens of itch and sleeping symptoms vs patients with controlled disease including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Sleep symptoms included trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]). Inadequate disease control was common among patients with moderate/severe AD, and was associated with a higher patient-reported burden than patients with controlled disease. Regardless of disease control, the burden of moderate/severe AD was higher than mild AD, suggesting a need for more effective therapies for moderate/severe disease.
US Department of Justice Investigations of Implantable Cardioverter-Defibrillators and Quality Improvement in Health Care
Authors: Paul A. Heidenreich
Journal: JAMA (2018)

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Incidence of Hospitalization for Heart Failure and Case-Fatality Among 3.25 Million People With and Without Diabetes Mellitus
Authors: David A. McAllister, Stephanie H. Read, Jan Kerssens, Shona Livingstone, Stuart McGurnaghan, Pardeep Jhund, John Petrie, Naveed Sattar, Colin Fischbacher, Soren Lund Kristensen, John McMurray, Helen M. Colhoun, Sarah H. Wild
Journal: Circulation (2018)

Recent clinical trials of new glucose-lowering treatments have drawn attention to the importance of hospitalization for heart failure as a complication of diabetes mellitus. However, the epidemiology is not well described, particularly for type 1 diabetes mellitus. We examined the incidence and case-fatality of heart failure hospitalizations in the entire population aged ≥30 years resident in Scotland during 2004 to 2013.Date and type of diabetes mellitus diagnosis were linked to heart failure hospitalizations and deaths using the national Scottish registers. Incidence rates and case-fatality were estimated in regression models (quasi-Poisson and logistic regression respectively). All estimates are adjusted for age, sex, socioeconomic status, and calendar-year.Over the 10-year period of the study, among 3.25 million people there were 91, 429, 22 959, and 1313 incident heart failure events among those without diabetes mellitus, with type 2, and type 1 diabetes mellitus, respectively. The crude incidence rates of heart failure hospitalization were therefore 2.4, 12.4, and 5.6 per 1000 person-years for these 3 groups. Heart failure hospitalization incidence was higher in people with diabetes mellitus, regardless of type, than in people without. Relative differences were smallest for older men, in whom the difference was nonetheless large (men aged 80, rate ratio 1.78; 95% CI, 1.45-2.19). Rates declined similarly, by 0.2% per calendar-year, in people with type 2 diabetes mellitus and without diabetes mellitus. Rates fell faster, however, in those with type 1 diabetes mellitus (2.2% per calendar-year, rate ratio for type 1/calendar-year interaction 0.978; 95% CI, 0.959-0.998). Thirty-day case-fatality was similar among people with type 2 diabetes mellitus and without diabetes mellitus, but was higher in type 1 diabetes mellitus for men (odds ratio, 0.96; 95% CI, 0.95-0.96) and women (odds ratio, 0.98; 95% CI, 0.97-0.98). Case-fatality declined over time for all groups (3.3% per calendar-year, odds ratio per calendar-year 0.967; 95% CI, 0.961-0.973).Despite falling incidence, particularly in type 1 diabetes mellitus, heart failure remains ≈2-fold higher than in people without diabetes mellitus, with higher case-fatality in those with type 1 diabetes mellitus. These findings support the view that heart failure is an under-recognized and important complication in diabetes mellitus, particularly for type 1 disease.
A Transferrin Triggered Pathway for Highly Targeted Delivery of Graphene‐Based Nanodrugs to Treat Choroidal Melanoma
Authors: Bingxin Zhao, Kalun Dong, Mimi Lin, Gongxian Dong, Suyan Shan, Tom Lawson, Lu Yan, Wenjing Zhang, Bingyang Shi, Shulei Chou, Mark S. Baker, Yong Liu
Journal: Advanced Healthcare Materials (2018)

Abstract The synthesis of transferrin (Tf)‐modified pegylated graphene (PG) and its application as a highly efficient drug delivery carrier for therapy of Ocular Choroidal Melanoma‐1 (OCM‐1) cells is presented. For the first reported time, nanoscaled PG is prepared using an environmentally friendly ball‐milling technique. The unique 2D nanostructure obtained using this PG synthesis approach offers considerable advantages in terms of drug loading and delivery, as well as the conjugation of Tf to PG providing a more targeted delivery vehicle. A highly efficient targeted pathway toward OCM‐1 cells triggered by an affinity between Tf and Tf receptors expressed on the surface of OCM‐1 cells is reported first here. PG‐Tf is observed to easily anchor anticancer drugs such as doxorubicin via π–π stacking. This work performs a Transwell two cells coculture experiment, a 3D in vitro tumor model, and an in vivo mouse model with OCM‐1 tumors to demonstrate the composite's therapeutic superiority over conventional systems for the targeted delivery and controlled release of antitumor drugs.
Combined MR Imaging of Oxygen Consumption and Supply Reveals Tumor Hypoxia and Aggressiveness in Prostate Cancer Patients
Authors: Tord Hompland, Knut Håkon Hole, Harald Bull Ragnum, Eva-Katrine Aarnes, Ljiljana Vlatkovic, A. Kathrine Lie, Sebastian Patzke, Bjørn Brennhovd, Therese Seierstad, Heidi Lyng
Journal: Cancer Research (2018)

Abstract The established role of hypoxia-induced signaling in prostate cancer growth, metastasis, and response to treatment suggests that a method to image hypoxia in tumors could aid treatment decisions. Here, we present consumption and supply-based hypoxia (CSH) imaging, an approach that integrates images related to oxygen consumption and supply into a single image. This integration algorithm was developed in patients with prostate cancer receiving hypoxia marker pimonidazole prior to prostatectomy. We exploited the intravoxel incoherent motion (IVIM) signal in diagnostic diffusion-weighted (DW) magnetic resonance (MR) images to generate separate images of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV). ADC and fBV correlated with cell density (CD) and blood vessel density (BVD) in histology and whole-mount sections from 35 patients, thus linking ADC to oxygen consumption and fBV to oxygen supply. Pixel-wise plots of ADC versus fBV were utilized to predict the hypoxia status of each pixel in a tumor and to visualize the predicted value in a single image. The hypoxic fraction (HFDWI) of CSH images correlated strongly (R2 = 0.66; n = 41) with pimonidazole immunoscore (HSPimo); this relationship was validated in a second pimonidazole cohort (R2 = 0.54; n = 54). We observed good agreement between CSH images and pimonidazole staining in whole-mount sections. HFDWI correlated with tumor stage and lymph node status, consistent with findings for HSPimo. Moreover, CSH imaging could be applied on histologic CD and BVD images, demonstrating transferability to a histopathology assay. Thus, CSH represents a robust approach for hypoxia imaging in prostate cancer that could easily be translated into clinical practice. Significance: These findings present a novel imaging strategy that indirectly measures tumor hypoxia and has potential application in a wide variety of solid tumors and other imaging modalities. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4774/F1.large.jpg. Cancer Res; 78(16); 4774–85. ©2018 AACR.
Molecular Analyses Support the Safety and Activity of Retroviral Replicating Vector Toca 511 in Patients
Authors: Daniel J. Hogan, Jay-Jiguang Zhu, Oscar R. Diago, Dawn Gammon, Ali Haghighi, Guangrong Lu, Asha Das, Harry E. Gruber, Douglas J. Jolly, Derek Ostertag
Journal: Clinical Cancer Research (2018)

Purpose: Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-grade glioma, we have performed extensive molecular analyses of patient specimens to track vector fate.Patients and Methods: Toca 511 and Toca FC (extended-release 5-fluorocytosine) have been administered to 127 high-grade glioma patients across three phase I studies. We measured Toca 511 RNA and DNA levels in available body fluids and tumor samples from patients to assess tumor specificity. We mapped Toca 511 integration sites and sequenced integrated Toca 511 genomes from patient samples with detectable virus. We measured Toca 511 levels in a diverse set of tissue samples from one patient.Results: Integrated Toca 511 is commonly detected in tumor samples and is only transiently detected in blood in a small fraction of patients. There was no believable evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes. Toca 511 sequence profiles suggest most mutations are caused by APOBEC cytidine deaminases acting during reverse transcription. Tissue samples from a single whole-body autopsy affirm Toca 511 tumor selectivity.Conclusions: Toca 511 and Toca FC treatment was not associated with inappropriate integration sites and clonal expansion. The vector is tumor-selective and persistent in patients who received Toca 511 injections. Clin Cancer Res; 24(19); 4680-93. ©2018 AACR.
Abstract 12605: Derivation and External Validation of a Cardiac Resynchronization Therapy Response Score
Authors: Eloi Marijon, Rui Providência, Kumar Narayanan, Sergio Barra, Simon Sporton, Pascal Defaye, Nicolas Sadoul, Olivier Piot, Vincent Algalarrondo, Didier Klug, Daniel Gras, Laurent Fauchier, Pierre Bordachar, Dominique Babuty, Jean-Claude Deharo, Anthony Chow, Christophe Leclercq, Pier Lambiase, Serge Boveda
Journal: Circulation (2015)

Introduction: In the last decade cardiac resynchronization therapy (CRT) has emerged as one of the most important advances in the treatment of patients with advanced heart failure. Unfortunately, almost tone third of patients do not have any benefit from this therapy. We aimed to derive and validate a CRT response score to improve the selection of patients for this intervention. Methods: The derivation cohort was composed of patients implanted with a CRT plus defibrillator in a multi-centric French registry. Clinical independent predictors of a favourable response to CRT (either clinical or echocardiographic) were assessed. A risk score was created based on the relative odds ratio of each of the variables. Three categories for predicting CRT response were defined: low (0 to 1), medium (2 to 3) and high (4 to 5) probability of response to CRT therapy. Endpoints assessed as true surrogates of lack of response to CRT-therapy were: all-cause mortality and all-cause mortality or heart transplant. Results: Among the 1,011 patients implanted with a de novo CRT-D, 75.8% were responders. Independent and significant predictors of CRT response in the first 6 months on multivariate logistic regression were: female gender (OR=2.08), New York Heart Association class ≤III (OR=2.71), left ventricle ejection fraction ≥ 25% (OR=1.75), QRS duration ≥ 150ms (OR=1.70) and estimated glomerular filtration rate &gt; 60ml/min (OR=2.01). All predictors were assigned 1 point. Likelihood of survival during 7,216 patient years in the derivation cohort was 52.9% in the low response, 75.2% in the intermediate and 90.7% in the high response group (log rank P &lt;0.001). External validation found similar results. Conclusion: We derived a clinical risk score, which appears to identify three different categories of patients with different likelihood of response to CRT therapy. This score may be of interest for prognostic assessment and treatment decisions, namely early referral for heart transplant.
The prebiotic inulin improves substrate metabolism and promotes short-chain fatty acid production in overweight to obese men
Authors: Christina M. van der Beek, Emanuel E. Canfora, Anna M. Kip, Stefan H.M. Gorissen, Steven W.M. Olde Damink, Hans M. van Eijk, Jens J. Holst, Ellen E. Blaak, Cornelis H.C. Dejong, Kaatje Lenaerts
Journal: Metabolism (2018)
Age-dependent health risk from ambient air pollution: a modelling and data analysis of childhood mortality in middle-income and low-income countries
Authors: Jos Lelieveld, Andy Haines, Andrea Pozzer
Journal: The Lancet Planetary Health (2018)

BackgroundWHO estimates that, in 2015, nearly 1 million children younger than 5 years died from lower respiratory tract infections (LRIs). Ambient air pollution has a major impact on mortality from LRIs, especially in combination with undernutrition and inadequate health care. We aimed to estimate mortality due to ambient air pollution in 2015, particularly in children younger than 5 years, to investigate to what extent exposure to this risk factor affects life expectancy in different parts of the world.MethodsApplying results from a recent atmospheric chemistry-general circulation model and health statistics from the WHO Global Health Observatory, combined in integrated exposure-response functions, we updated our estimates of mortality from ambient (outdoor) air pollution. We estimated excess deaths attributable to air pollution by disease category and age group, particularly those due to ambient air pollution-induced LRIs (AAP-LRIs) in childhood. Estimates are presented as excess mortality attributable to ambient air pollution and years of life lost (YLLs). To study recent developments, we calculated our estimates for the years 2010 and 2015.FindingsOverall, 4·55 million deaths (95% CI 3·41 million to 5·56 million) were attributable to air pollution in 2015, of which 727 000 deaths (573 000–865 000) were due to AAP-LRIs. We estimated that AAP-LRIs caused about 237 000 (192 000–277 000) excess child deaths in 2015. Although childhood AAP-LRIs contributed about 5% of air pollution-attributable deaths worldwide, they accounted for 18% of losses in life expectancy, equivalent to 21·5 million (17 million to 25 million) of the total 122 million YLLs due to ambient air pollution in 2015. The mortality rate from ambient air pollution was highest in Asia, whereas the per capita YLLs were highest in Africa. We estimated that in sub-Saharan Africa, ambient air pollution reduces the average life expectancy of children by 4–5 years. In Asia, all-age mortality increased by about 10% between 2010 and 2015, whereas childhood mortality from AAP-LRIs declined by nearly 30% in the same period.InterpretationMost child deaths due to AAP-LRIs occur in low-income countries in Africa and Asia. A three-pronged strategy is needed to reduce the health effects of ambient air pollution in children: aggressive reduction of air pollution levels, improvements in nutrition, and enhanced treatment of air pollution-related health outcomes.FundingNone.
Metastasis-free Survival — A New End Point in Prostate Cancer Trials
Authors: Julia A. Beaver, Paul G. Kluetz, Richard Pazdur
Journal: New England Journal of Medicine (2018)

The FDA’s approval of apalutamide for use in nonmetastatic castration-resistant prostate cancer (nmCRPC) was based on an improvement in metastasis-free survival. It was the first drug approval for nmCRPC and the first use of this primary end point to support drug approval.