tbuckley/cabot-search huggingface dataset:
Cysteinyl leukotriene receptor 1 expression identifies a subset of neutrophils during the antiviral response that contributes to postviral atopic airway disease
Authors: Dorothy S. Cheung, Jerome A. Sigua, Pippa M. Simpson, Ke Yan, Syed-Rehan A. Hussain, Jennifer L. Santoro, Erika J. Buell, Desire A. Hunter, Michelle Rohlfing, Deepa Patadia, Mitchell H. Grayson
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 15265: Exercise Inhibits High-Fat Diet-Induced Upregulation of Endothelin-1 and Endothelin Receptor Type A and Restores Flow-Induced Arteriolar Dilation in Mice
Authors: Abeer M Mahmoud, Mohamed M Ali, Varadarajan Sudhahar, Masuko Ushio-Fukai, Tohru Fukai, Shane A Phillips
Journal: Circulation (2016)

High-fat diet (HFD) promotes insulin resistance and subsequent development of vascular dysfunction (VD). The purpose of this study was to examine the effect of HFD on endothelial function with an e...
Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage Regeneration <i>In Vitro</i>
Authors: Lucienne A. Vonk, Sanne F. J. van Dooremalen, Nalan Liv, Judith Klumperman, Paul J. Coffer, Daniël B.F. Saris, Magdalena J. Lorenowicz
Journal: Theranostics (2017)

Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available.Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA.Increasing evidence suggests that therapeutic efficacy of MSC depends on paracrine signalling.Here we investigated the role of extracellular vesicles (EVs) secreted by human bone marrow derived MSC (BMMSC) in human OA cartilage repair.Methods: To test the effect of BMMSC-EVs on OA cartilage inflammation, TNF-alpha-stimulated OA chondrocyte monolayer cultures were treated with BMMSC-EVs and pro-inflammatory gene expression was measured by qRT-PCR after 48 h.To assess the impact of BMMSC-EVs on cartilage regeneration, BMMSC-EVs were added to the regeneration cultures of human OA chondrocytes, which were analyzed after 4 weeks for glycosaminoglycan content by 1,9-dimethylmethylene blue (DMMB) assay.Furthermore, paraffin sections of the regenerated tissue were stained for proteoglycans (safranin-O) and type II collagen (immunostaining).Results: We show that BMMSC-EVs inhibit the adverse effects of inflammatory mediators on cartilage homeostasis.When co-cultured with OA chondrocytes, BMMSC-EVs abrogated the TNF-alpha-mediated upregulation of COX2 and pro-inflammatory interleukins and inhibited TNF-alpha-induced collagenase activity.BMMSC-EVs also promoted cartilage regeneration in vitro.Addition of BMMSC-EVs to cultures of chondrocytes isolated from OA patients stimulated production of proteoglycans and type II collagen by these cells.Conclusion: Our data demonstrate that BMMSC-EVs can be important mediators of cartilage repair and hold great promise as a novel therapeutic for cartilage regeneration and osteoarthritis.
Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement From the American Heart Association
Authors: Shakira F. Suglia, Karestan C. Koenen, Renée Boynton-Jarrett, Paul S. Chan, Cari J. Clark, Andrea Danese, Myles S. Faith, Benjamin I. Goldstein, Laura L. Hayman, Carmen R. Isasi, Charlotte A. Pratt, Natalie Slopen, Jennifer A. Sumner, Aslan Turer, Christy B. Turer, Justin P. Zachariah
Journal: Circulation (2017)

Adverse experiences in childhood and adolescence, defined as subjectively perceived threats to the safety or security of the child’s bodily integrity, family, or social structures, are known to be associated with cardiometabolic outcomes over the life course into adulthood. This American Heart Association scientific statement reviews the scientific literature on the influence of childhood adversity on cardiometabolic outcomes that constitute the greatest public health burden in the United States, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. This statement also conceptually outlines pathways linking adversity to cardiometabolic health, identifies evidence gaps, and provides suggestions for future research to inform practice and policy. We note that, despite a lack of objective agreement on what subjectively qualifies as exposure to childhood adversity and a dearth of prospective studies, substantial evidence documents an association between childhood adversity and cardiometabolic outcomes across the life course. Future studies that focus on mechanisms, resiliency, and vulnerability factors would further strengthen the evidence and provide much-needed information on targets for effective interventions. Given that childhood adversities affect cardiometabolic health and multiple health domains across the life course, interventions that ameliorate these initial upstream exposures may be more appropriate than interventions remediating downstream cardiovascular disease risk factor effects later in life.
Abstract 11370: Coronary Artery Calcium Incidence Varies by ASCVD Risk: Insights From the Dallas Heart Study
Authors: Anurag Mehta, Parag Joshi, Colby Ayers, Khurram Nasir, Jarett Berry, Anand Rohatgi, Amit Khera
Journal: Circulation (2016)

Introduction: Absence of coronary artery calcium (CAC=0) is associated with favorable cardiovascular outcomes and can be useful for down-classifying risk in middle-aged asymptomatic individuals. Identifying predictors of incident CAC can inform preventive measures. Hypothesis: We hypothesized that in a young, multi-ethnic, population-based cohort, increasing atherosclerotic cardiovascular disease (ASCVD) risk would be associated with incident CAC on repeat scanning. Methods: Participants of the Dallas Heart Study (DHS) underwent CAC scanning at baseline (EBCT) and at follow up (MDCT), after a mean interval of 6.9 years. Participants with baseline CAC=0 were included, and those with clinical ASCVD or on statin therapy were excluded. Incident CAC was analyzed as CAC &gt;0 as well as CAC &gt;10 at follow up. ASCVD risk was calculated using the 2013 AHA/ACC risk estimator. Results: Among 2,272 participants with baseline and follow up CAC measurements, 756 participants meeting exclusion criteria had absent CAC (CAC=0) at baseline, with a mean age of 42 years, 65.6% women, and 42.2% blacks. Of these individuals, incident CAC occurred in 23.8% using CAC &gt;0 and in 8.3% using CAC &gt;10. Risk markers associated with incident CAC &gt;0 included baseline 10-year ASCVD risk, family history of coronary heart disease, low density lipoprotein particle concentration, diabetes and statin use at follow up. In fully adjusted analyses, only baseline 10-year ASCVD risk was associated with incident CAC &gt;0. The prevalence of CAC &gt;0 at follow up by baseline 10-year ASCVD risk categories of &lt;5%, ≥5 to &lt;7.5%, and &gt;7.5% was 21.2%, 41.5%, and 51.4%, respectively (p-trend&lt;0.01). The prevalence of CAC &gt;10 was 7%, 12.2%, and 27.1% respectively. Conclusions: In this young cohort, one in four individuals with absent CAC developed incident CAC after approximately 7 years. Reassessing risk, including consideration of repeat CAC measurement in those with higher baseline 10-year ASCVD risk, may be warranted.
Bioinformatics and Proteomics Evaluations to Consider IgE Binding Assays for Potential Cross-Reactivity Between House-Cricket ( Aceta domesticus ) Used in Food, Crustaceans and Cockroaches
Authors: Mohamed Abdelmoteleb, Lee K. Palmer, Natalia Pavlovikj, Justin T. Marsh, Philip E. Johnson, Richard E. Goodman
Journal: Journal of Allergy and Clinical Immunology (2018)
Assessment of the Diameter of Pigmented Skin Lesions With and Without a Ruler
Authors: Harshitha Mannam, Andrew Choi, Saya Jacob, Michael Kwa, Shuai Xu, June K. Robinson
Journal: JAMA Dermatology (2017)

This analysis of survey results examines the accuracy with which medical students, internal medicine residents, and dermatology residents, fellows, and faculty can estimate the diameter of skin lesions in clinical photographs.
Anti-EGFRvIII TandAbs recruiting either T- or NK-cells as bispecific therapeutic antibody candidates for the treatment of EGFRvIII+ tumors.
Authors: Martin Treder, Jens-Peter Marschner, Kristina Ellwanger, Stefan Knackmuss, Michael Weichel, Thorsten Gantke, Uwe Reusch, Ivica Fucek, Narendiran Rajasekaran, Xing Zhao, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2016)

e14008 Background: EGFRvIII is the most prevalent tumor-specific variant of the EGFR family and represents an attractive tumor target such as in glioblastoma, head and neck or lung cancer. EGFRvIII is highly tumor specific and several approaches to target this receptor variant are in clinical development: rindopepimut, a vaccine in combination with bevacizumab, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Bi-specific antibodies recruiting immune effectors for targeted destruction of antigen-positive tumor cells represent another option for highly specific and effective treatments. Methods: We developed tetravalent, bi-specific TandAbs (tandem antibodies) that recognize EGFRvIII, and recruit either T-cells via CD3 or NK-cells via CD16A. The selected TandAbs demonstrated very high specificity towards EGFRvIII using several assays. Results: No binding was observed to recombinant EGFR or to EGFR presenting cells. Both, T-cell and NK-cell recruiting TandAbs were highly cytotoxicity towards EGFRvIII+ cell lines with EC50 values in the low picomolar range. No cytotoxicity was observed on EGFRvIII- target cells or cells expressing EGFRwt. Importantly, TandAb-induced cytotoxicity and effector cell proliferation both require the presence of the EGFRvIII target. In vivo pharmacodynamics for anti-EGFRvIII TandAbs was investigated in a mouse xenograft model and respective results will be presented. EGFRvIII expression by tumor and healthy tissues were evaluated by immunohistochemistry. Whilst the antigen is expressed by glioblastoma and several other solid tumors, EGFRvIII was not detectable in healthy tissues. Conclusions: EGFRvIII/CD3 and EGFRvIII/CD16A TandAbs are highly attractive therapeutic antibody candidates. Due to the tumor specific expression of EGFRvIII and the highly specific binding of TandAbs to this target, TandAbs have the potential to effectively destroy tumor cells with a favorable safety profile.
The Value of Established Relationships Between Primary Care Clinicians and Specialists
Authors: Larry R. Kaiser, Verdi J. DiSesa
Journal: JAMA Surgery (2017)

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Survival of Cancer Stem-Like Cells Under Metabolic Stress via CaMK2α-mediated Upregulation of Sarco/Endoplasmic Reticulum Calcium ATPase Expression
Authors: Ki Cheong Park, Seung Won Kim, Jeong Yong Jeon, A. Ra Jo, Hye Ji Choi, Jungmin Kim, Hyun Gyu Lee, Yonjung Kim, Gordon B. Mills, Sung Hoon Noh, Min Goo Lee, Eun Sung Park, Jae-Ho Cheong
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca2+-dependent apoptosis during glucose deprivation. Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) gene knockdown, and investigated the role of nuclear factor kappa B (NFκB) in CSCs during time-dependent Ca2+-mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFκB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone. Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFκB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677–90. ©2017 AACR.
High-efficiency transduction of spinal cord motor neurons by intrauterine delivery of integration-deficient lentiviral vectors
Authors: Sherif G. Ahmed, Simon N. Waddington, Maria Gabriela Boza-Morán, Rafael J. Yáñez-Muñoz
Journal: Journal of Controlled Release (2017)

Integration-deficient lentiviral vectors (IDLVs) are promising gene delivery tools that retain the high transduction efficiency of standard lentiviral vectors, yet fail to integrate as proviruses and are instead converted into episomal circles. These episomes are metabolically stable and support long-term expression of transgenes in non-dividing cells, exhibiting a decreased risk of insertional mutagenesis. We have embarked on an extensive study to compare the transduction efficiency of IDLVs pseudotyped with different envelopes (vesicular stomatitis, Rabies, Mokola and Ross River viral envelopes) and self-complementary adeno-associated viral vectors, serotype-9 (scAAV-9) in spinal cord tissues after intraspinal injection of mouse embryos (E16). Our results indicate that IDLVs can transduce motor neurons (MNs) at extremely high efficiency regardless of the envelope pseudotype while scAAV9 mediates gene delivery to ~ 40% of spinal cord motor neurons, with other non-neuronal cells also transduced. Long-term expression studies revealed stable gene expression at 7 months post-injection. Taken together, the results of this study indicate that IDLVs may be efficient tools for in utero cord transduction in therapeutic strategies such as for treatment of inherited early childhood neurodegenerative diseases.
Early Markers of Sickle Nephropathy in Children With Sickle Cell Anemia Are Associated With Red Cell Cation Transport Activity
Authors: John Brewin, Sanjay Tewari, Anke Hannemann, Halima Al Balushi, Claire Sharpe, John S. Gibson, David C. Rees
Journal: HemaSphere (2017)

Abstract The early stages of sickle cell nephropathy (SCN) manifest in children with sickle cell anemia (SCA) as hyperfiltration and proteinuria. The physiological conditions of the renovascular system are among the most conducive to hemoglobin S polymerization in the body and will magnify small changes in red cell volume thus crucially modulating intracellular concentrations of hemoglobin S. This large cross‐sectional study of children with sickle cell anemia measured glomerular filtration rates and microalbuminuria to report prevalence, clinical correlates and uniquely, association with key red cell cation transport mechanisms. One hundred and twelve patients (mean age 10.7 ± 4.1) were recruited. The prevalence of hyperfiltration and microalbuminuria was 98% and 15.1%, respectively. Glomerular filtration rates did not vary with age, but proteinuria became more prevalent with increasing age. Both features associated with markers of hemolysis, while elevated hemoglobin F was protective, but no association was seen with systolic or diastolic blood pressure. In multivariate analysis, both Gardos channel (β = 0.476, P &lt; 0.001) and KCl co‐transporter (KCC; β = −0.216, P = 0.009) activity, alongside age (β = 0.237, P = 0.004), remained independently predictive for microalbuminuria. Increased activity of Gardos channel and P sickle positively associated with microalbuminuria, while increased KCC activity associated with a reduction in microalbuminuria. This study demonstrates a direct link between the abnormally active red cell cation transport systems in sickle cell disease and sickle organopathy. Small variations in the activity of these transport mechanisms predict for SCN and measurement of them may help identify those at risk, while pharmaceutical manipulation of these excessively active systems may ameliorate their risk.
Multi-trait analysis of genome-wide association summary statistics using MTAG
Authors: Patrick Turley, Raymond K. Walters, Omeed Maghzian, Aysu Okbay, James J. Lee, Mark Alan Fontana, Tuan Anh Nguyen-Viet, Robbee Wedow, Meghan Zacher, Nicholas A. Furlotte, Patrik Magnusson, Sven Oskarsson, Magnus Johannesson, Peter M. Visscher, David Laibson, David Cesarini, Benjamin M. Neale, Daniel J. Benjamin
Journal: Nature Genetics (2017)
Abstract 16520: Treatment Persistence With New Oral Anticoagulants for Non-Valvular Atrial Fibrillation: The Quebec Observational Study
Authors: Samy Suissa, Janie Coulombe, Thomas Evers, Christel Renoux
Journal: Circulation (2016)

Introduction:  Continuous use of oral anticoagulant therapy is essential to reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF). To date, no study has compared real world treatment persistence patterns between users of new oral anticoagulants (NOACs) and warfarin, before and after the introduction of NOACs in 2011   Objective:  To compare treatment persistence between NOACs and warfarin users with NVAF.   Methods:  A retrospective cohort of patients 40 years of age or older with a first inpatient or outpatient diagnosis for NVAF during 2006-14 was identified using the healthcare databases of the Regie de I′assurance-maladie du Quebec (RAMQ). Patients were followed until the emigration date, end of prescription drug coverage, death or December 31, 2014. Treatment persistence was defined from dispensed prescriptions that follow each other with a gap of no more than 20% of the duration of the previous prescription. Kaplan-Meier curves were used to describe the cumulative probability of persistence of the initiating treatment. Cox proportional hazards models were used to estimate hazard ratios (HRs) of discontinuation of NOACs relative to VKAs, after adjustment for baseline confounders.   Results:  The cohort included 154,101 patients with NVAF, of which 74,000 were diagnosed before January 2011 (54,000 on VKA) and 70,119 after (22,458 on VKA and 16,637 on NOAC). Patients initially treated with VKAs were slightly older and had more comorbidity, including prior bleeding events, cardiovascular diseases as well as other chronic and acute conditions. At twelve months following treatment initiation, persistence was 36% for patients on NOACs compared with 14% for patients on VKAs before and after January 2011. A similar pattern was seen for rivaroxaban versus VKA. After adjustment, the probability of NOAC treatment discontinuation was half that of VKA (HR 0.50; 95% CI: 0.49-0.51). Sensitivity analyses using a longer grace period of 60 days to define persistence confirmed a higher one-year persistence of 80% for NOACs versus 60% for VKAs (HR of discontinuation 0.50; 95% CI: 0.48-0.52).   Conclusions:  This real world study shows that twice as many patients initiated on NOACs, including rivaroxaban, remain on therapy than those initiating VKAs.
IFN-γ and TNF-α Pre-licensing Protects Mesenchymal Stromal Cells from the Pro-inflammatory Effects of Palmitate
Authors: Lauren Boland, Anthony J. Burand, Alex J. Brown, Devlin Boyt, Vitor A. Lira, James A. Ankrum
Journal: Molecular Therapy (2017)

The use of mesenchymal stromal cell (MSC) therapy for the treatment of type 2 diabetes (T2D) and T2D complications is promising; however, the investigation of MSC function in the setting of T2D has not been thoroughly explored. In our current study, we investigated the phenotype and function of MSCs in a simulated in vitro T2D environment. We show that palmitate, but not glucose, exposure impairs MSC metabolic activity with moderate increases in apoptosis, while drastically affecting proliferation and morphology. In co-culture with peripheral blood mononuclear cells (PBMCs), we found that MSCs not only lose their normal suppressive ability in high levels of palmitate, but actively support and enhance inflammation, resulting in elevated PBMC proliferation and pro-inflammatory cytokine release. The pro-inflammatory effect of MSCs in palmitate was partially reversed via palmitate removal and fully reversed through pre-licensing MSCs with interferon-gamma and tumor necrosis factor alpha. Thus, palmitate, a specific metabolic factor enriched within the T2D environment, is a potent modulator of MSC immunosuppressive function, which may in part explain the depressed potency observed in MSCs isolated from T2D patients. Importantly, we have also identified a robust and durable pre-licensing regimen that protects MSC immunosuppressive function in the setting of T2D. The use of mesenchymal stromal cell (MSC) therapy for the treatment of type 2 diabetes (T2D) and T2D complications is promising; however, the investigation of MSC function in the setting of T2D has not been thoroughly explored. In our current study, we investigated the phenotype and function of MSCs in a simulated in vitro T2D environment. We show that palmitate, but not glucose, exposure impairs MSC metabolic activity with moderate increases in apoptosis, while drastically affecting proliferation and morphology. In co-culture with peripheral blood mononuclear cells (PBMCs), we found that MSCs not only lose their normal suppressive ability in high levels of palmitate, but actively support and enhance inflammation, resulting in elevated PBMC proliferation and pro-inflammatory cytokine release. The pro-inflammatory effect of MSCs in palmitate was partially reversed via palmitate removal and fully reversed through pre-licensing MSCs with interferon-gamma and tumor necrosis factor alpha. Thus, palmitate, a specific metabolic factor enriched within the T2D environment, is a potent modulator of MSC immunosuppressive function, which may in part explain the depressed potency observed in MSCs isolated from T2D patients. Importantly, we have also identified a robust and durable pre-licensing regimen that protects MSC immunosuppressive function in the setting of T2D.
Development and validation of the parent-reported drug hypersensitivity quality of life questionnaire
Authors: Nisarat Chantaravisarut, Thatchai Wirodwanich, Wipa Jessadapakorn, Pasuree Sangsupawanich, Tippawan Liabsuetrakul, Araya Yuenyongviwat
Journal: Journal of Allergy and Clinical Immunology (2018)