tbuckley/cabot-search huggingface dataset:
Optimization of engraftment of human NK cells in NOD-Scid mice
Authors: Sebastien Dall'ozzo, Pari Antoniw, Jean-Francois Mirjolet, Francis Bichat
Journal: Cancer Research (2008)

1039  Background: The engraftment of human (hu) peripheral blood mononuclear cells (PBMCs) into mice with severe combined immune deficiency (SCID) has allowed the development of a system where aspects of human immune function may be examined in vivo. A valuable application would enable evaluation of the efficacy of human IgG1 antibodies in ablating tumour growth by antibody-dependent cell cytotoxicity (ADCC). NK cells are a key effector population for ADCC elicited by human IgG1 antibodies. NK cells have been shown to play a major role in the ADCC activity mediated by hu PBMCs and interact with human IgG1 molecules through binding to the FcγRIII receptor. The aim of this study was to establish optimal conditions for the engraftment of FcγRIII (CD16) positive hu NK cells in non-obese diabetic (NOD) SCID mice. The effect of whole body irradiation in combination with a murine NK cell-depleting antibody was examined and the engraftment monitored by determining the absolute number of hu NK cells in three organs/body compartments at two time-points.  Methods: NOD-SCID mice were whole body irradiated (1.8 Gy) on day 0 (D0), treated with a mouse NK cell-depleting antibody (TMβ-1) 3 days later (D3) and inoculated intraperitoneally with hu PBMCs the following day (D4). An unirradiated group also received antibody and PBMCs. Three donors of PBMCs were selected based upon the percentage of CD56+CD16+ NK cells and cells from each donor inoculated into both irradiated and non-irradiated groups. The engraftment of human NK cells in the peritoneal cavity, blood and spleen was analysed on D18 and D25 post-irradiation using 4-color flow cytometry (CD45, CD3, CD56 and CD16), and absolute cell numbers calculated per organ.  Results: Human NK cells were found in the peritoneal cavity, blood and spleen in both groups irrespective of the experimental conditions. At both D18 and D25, higher numbers of NK cells were recovered from irradiated mice compared to non-irradiated groups. A trend was also observed between the number of injected NK cells and the number of recovered NK cells at both time-points. Spleen weight significantly increased between D18 and D25 in both irradiated and non-irradiated mice, whilst the irradiated group exhibited a significant body weight loss between these time-points.Conclusions: Pre-treatment with irradiation resulted in higher numbers of human NK cells recovered from peritoneum, blood and spleen. The numbers of NK cells from blood donors was a key factor for the engraftment. The appearance of severe body weight loss in the irradiated group may predict earlier development of graft-versus-host disease compared to the non-irradiated group.
Arid1a Loss Drives Nonalcoholic Steatohepatitis in Mice Through Epigenetic Dysregulation of Hepatic Lipogenesis and Fatty Acid Oxidation
Authors: Austin Moore, Linwei Wu, Jen‐Chieh Chuang, Xuxu Sun, Xin Luo, Purva Gopal, Lin Li, Cemre Celen, Michael Zimmer, Hao Zhu
Journal: Hepatology (2018)

Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma. How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease. AT‐rich interactive domain‐containing protein 1A (ARID1A), a DNA‐binding component of the SWItch/sucrose nonfermentable adenosine triphosphate‐dependent chromatin‐remodeling complex, contributes to nucleosome repositioning and access by transcriptional regulators. Liver‐specific deletion of Arid1a (Arid1a liver knockout [LKO]) caused the development of age‐dependent fatty liver disease in mice. Transcriptome analysis revealed up‐regulation of lipogenesis and down‐regulation of fatty acid oxidation genes. As evidence of direct regulation, ARID1A demonstrated direct binding to the promoters of many of these differentially regulated genes. Additionally, Arid1a LKO mice were more susceptible to high‐fat diet–induced liver steatosis and fibrosis. We deleted Pten in combination with Arid1a to synergistically drive fatty liver progression. Inhibition of lipogenesis using CAT‐2003, a potent sterol regulatory element‐binding protein inhibitor, mediated improvements in markers of fatty liver disease progression in this Arid1a/Pten double knockout model. Conclusion: ARID1A plays a role in the epigenetic regulation of hepatic lipid homeostasis, and its suppression contributes to fatty liver pathogenesis. Combined Arid1a and Pten deletion shows accelerated fatty liver disease progression and is a useful mouse model for studying therapeutic strategies for NASH.
Childhood Asthma: Advances Using Machine Learning and Mechanistic Studies
Authors: Sejal Saglani, Adnan Custovic
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

A paradigm shift brought by the recognition that childhood asthma is an aggregated diagnosis that comprises several different endotypes underpinned by different pathophysiology, coupled with advances in understanding potentially important causal mechanisms, offers a real opportunity for a step change to reduce the burden of the disease on individual children, families, and society. Data-driven methodologies facilitate the discovery of "hidden" structures within "big healthcare data" to help generate new hypotheses. These findings can be translated into clinical practice by linking discovered "phenotypes" to specific mechanisms and clinical presentations. Epidemiological studies have provided important clues about mechanistic avenues that should be pursued to identify interventions to prevent the development or alter the natural history of asthma-related diseases. Findings from cohort studies followed by mechanistic studies in humans and in neonatal mouse models provided evidence that environments such as traditional farming may offer protection by modulating innate immune responses and that impaired innate immunity may increase susceptibility. The key question of which component of these exposures can be translated into interventions requires confirmation. Increasing mechanistic evidence is demonstrating that shaping the microbiome in early life may modulate immune function to confer protection. Iterative dialogue and continuous interaction between experts with different but complementary skill sets, including data scientists who generate information about the hidden structures within "big data" assets, and medical professionals, epidemiologists, basic scientists, and geneticists who provide critical clinical and mechanistic insights about the mechanisms underpinning the architecture of the heterogeneity, are keys to delivering mechanism-based stratified treatments and prevention.
Profiling of Gene Expression Biomarkers as a Classifier of Methotrexate Nonresponse in Patients With Rheumatoid Arthritis
Authors: Darren Plant, Mateusz Maciejewski, Samantha Smith, Nisha Nair, Kimme Hyrich, Daniel Ziemek, Anne Barton, Suzanne Verstappen
Journal: Arthritis & Rheumatology (2019)

Approximately 30-40% of rheumatoid arthritis (RA) patients who are initially started on low-dose methotrexate (MTX) will not benefit from the treatment. To date, no reliable biomarkers of MTX inefficacy in RA have been identified. The aim of this study was to analyze whole blood samples from RA patients at 2 time points (pretreatment and 4 weeks following initiation of MTX), to identify gene expression biomarkers of the MTX response.RA patients who were about to commence treatment with MTX were selected from the Rheumatoid Arthritis Medication Study. Using European League Against Rheumatism (EULAR) response criteria, 42 patients were categorized as good responders and 43 as nonresponders at 6 months following the initation of MTX treatment. Data on whole blood transcript expression were generated, and supervised machine learning methods were used to predict a EULAR nonresponse. Models in which transcript levels were included were compared to models in which clinical covariates alone (e.g., baseline disease activity, sex) were included. Gene network and ontology analysis was also performed.Based on the ratio of transcript values (i.e., the difference in log2 -transformed expression values between 4 weeks of treatment and pretreatment), a highly predictive classifier of MTX nonresponse was developed using L2-regularized logistic regression (mean ± SEM area under the receiver operating characteristic [ROC] curve [AUC] 0.78 ± 0.11). This classifier was superior to models that included clinical covariates (ROC AUC 0.63 ± 0.06). Pathway analysis of gene networks revealed significant overrepresentation of type I interferon signaling pathway genes in nonresponders at pretreatment (P = 2.8 × 10-25 ) and at 4 weeks after treatment initiation (P = 4.9 × 10-28 ).Testing for changes in gene expression between pretreatment and 4 weeks post-treatment initiation may provide an early classifier of the MTX treatment response in RA patients who are unlikely to benefit from MTX over 6 months. Such patients should, therefore, have their treatment escalated more rapidly, which would thus potentially impact treatment pathways. These findings emphasize the importance of a role for early treatment biomarker monitoring in RA patients started on MTX.
17β-Estradiol protects the esophageal epithelium from IL-13–induced barrier dysfunction and remodeling
Authors: Justin C. Wheeler, Simone Vanoni, Chang Zeng, Lisa Waggoner, Yanfen Yang, David Wu, Jazib Uddin, Rebekah Karns, Leah Kottyan, Vincent Mukkada, Marc E. Rothenberg, Simon P. Hogan
Journal: Journal of Allergy and Clinical Immunology (2018)
Tissue Derived Non-Classical Monocyte Derived Host Macrophages Protect Against Murine Intestinal Acute Graft-Versus-Host Disease
Authors: Duc Dung Le, Ana-Laura Jordán Garrote, Ranecky Maria, Katja J Ottmüller, Haroon Shaikh, Musga Qureischi, Lukas Scheller, Tim Steinfatt, Andreas Brandl, Julia Hartweg, Christian Brede, Carina Bäuerlein, Simone S Riedel, Nageswara Rao Tata, Anja Mottok, Hermann Einsele, Ehsan Vafadarnejad, Antoine Emmanuel Saliba, Amy J. Wagers, Natalio Garbi, Manfred B Lutz, Andreas Beilhack
Journal: Blood (2018)
Abstract 11631: Risk Score for Prognosis in Patients with Systolic Heart Failure and Mild Symptoms, and the Impact of Eplerenone at Different Levels of Risk
Authors: Timothy J Collier, Stuart Pocock, John J McMurray, Faiez Zannad, Henry Krum, Dirk J van Veldhuisen, Karl Swedberg, Harry Shi, John Vincent, Bertram Pitt
Journal: Circulation (2012)

Background: Our objective was to use EMPHASIS trial data to create a simple prognostic risk score for the composite endpoint (CEP) of cardiovascular death or hospitalisation for heart failure among...
Event-Free Survival As a Surrogate Endpoint for Overall Survival in Previously Untreated Acute Myeloid Leukemia: An Individual Patient-Level Analysis of Multiple Randomized Trials (Alliance A151614)
Authors: Jun Yin, Geoffrey L. Uy, Betsy Laplant, Elizabeth Storrick, Guido Marcucci, Hugo F. Fernandez, Zhuoxin Sun, Mark R. Litzow, Megan Othus, Frederick R. Appelbaum, Richard A. Larson, Richard M. Stone, Sumithra J Mandrekar
Journal: Blood (2018)
Outcome of Age-Adapted Approach to HLA-Identical Related Hematopoietic Stem Cell Transplantation in Severe Sickle Cell Disease: Saudi Experience
Authors: Mohsen Alzahrani, Moussab Damlaj, Mohammed Essa, Bader Alahmari, Ahmed Alaskar, Ayman Hejazi, Enas Basher, Rodaina Abujoub, Samer Ghazi, Khadega Abuelgasim, Hind Salama, Giamal Gmati, Abdulrahman Alsultan
Journal: Blood (2018)
Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases
Authors: Zeljka Trepotec, Eva Lichtenegger, Christian Plank, Manish K. Aneja, Carsten Rudolph
Journal: Molecular Therapy (2018)

Promising improvements in the field of transcript therapeutics have clearly enhanced the potential of mRNA as a new pillar for protein replacement therapies. Synthetic mRNAs are engineered to replace mutated mRNAs and to be immunologically inconspicuous and highly stable while maximizing protein expression. Approaches to deliver mRNA into the cellular cytoplasm safely and efficiently have been further developed so that two mRNA-based approaches replacing vascular endothelial growth factor (VEGF) and cystic fibrosis transmembrane conductance regulator (CFTR) have now made it into clinical trials. These studies bring mRNA therapeutics for protein replacement therapy closer to clinical realization. Herein, we provide an overview of preclinical and clinical developments of mRNA therapeutics for liver diseases.
Abstract 11574: Persistent or Worsened Mechanical Dyssynchrony After Cardiac Resynchronization Therapy is Associated With Risk for Ventricular Arrhythmias
Authors: Kristina H Haugaa, Josef J Marek, Mohammed Ahmed, Keiko Ryo, Evan Adelstein, Saba Samir, John Gorcsan
Journal: Circulation (2013)

Background: Cardiac resynchronization therapy (CRT) improves mortality in heart failure (HF) patients with wide QRS. However, effects on ventricular arrhythmias are less clear. We hypothesized that persistence or worsening of mechanical dyssynchrony is associated with ventricular arrhythmias after CRT. Methods: We studied 198 consecutive class III-IV CRT-D patients with QRS ≥120 ms and ejection fraction ≤35% (age 65±12 years, 53 (27%) female). Ventricular arrhythmias were defined as appropriate ICD therapy including anti tachycardia pacing and shock over 2 years. Mechanical dyssynchrony was defined as speckle tracking radial peak strain from anteroseptum to posterior wall delay ≥ 130ms, measured before CRT and 6 months after CRT. Four dyssynchrony groups were defined as: 1) No Dyssynchrony (<130ms) before or after CRT, 2) Improved Dyssynchrony ≥ 130 ms before CRT improved to < 130 ms after CRT, 3) Persistent Dyssynchrony ≥ 130 ms before and after CRT and 4) Worsened Dyssynchrony < 130 ms before increased ...
Abstract 12572: Safety and Efficacy of High Dose Spironolactone in Loop Diuretic Resistant Acute Decompensated Heart Failure
Authors: Chakradhar Velagapudi, Shweta Bansal, Kristina Munoz, Sonja Brune, Anand Prasad
Journal: Circulation (2018)

Introduction: Secondary hyperaldosteronism plays a key role in pathogenesis of volume overload and resistance to loop diuretics. However, Athena-HF trial failed to show response to high dose spiron...
A musical intervention for respiratory comfort during noninvasive ventilation in the ICU
Authors: Jonathan Messika, Yolaine Martin, Natacha Maquigneau, Christelle Puechberty, Matthieu Henry-Lagarrigue, Annabelle Stoclin, Nataly Panneckouke, Serge Villard, Aline Dechanet, Alexandre Lafourcade, Didier Dreyfuss, David Hajage, Jean-Damien Ricard
Journal: European Respiratory Journal (2018)

Discomfort associated with noninvasive ventilation (NIV) may participate in its failure. We aimed to determine the effect of a musical intervention on respiratory discomfort during NIV in patients with acute respiratory failure (ARF). An open-label, controlled trial was performed over three centres. Patients requiring NIV for ARF were randomised to either a musical intervention group (where they received a musical intervention and were subjected to visual deprivation during the first 30 min of each NIV session), a sensory deprivation group (where they wore insulating headphones and were subjected to visual deprivation during the first 30 min of each NIV session), or a control group (where they received NIV as routinely performed). The primary outcome was the change in respiratory discomfort before and after 30 min of the first NIV session. A total of 113 patients were randomised (36 in the musical intervention group, 38 in the sensory deprivation group and 39 in the control group). Median (interquartile range (IQR)) change in respiratory discomfort was 0 (−1; 1) between the musical intervention and control groups (p=0.7). Between groups comparison did not evidence any significant variation of respiratory parameters across time or health-related quality of life (HRQoL) at day-90. The Peri-traumatic Distress Inventory (PDI) at intensive care unit (ICU) discharge was reduced in musical intervention group patients. However, a 30 min musical intervention did not reduce respiratory discomfort during NIV for ARF in comparison to conventional care or sensory deprivation.
Abstract 18498: Genome-wide Analysis Identifies Genetic Variants Associated With a Novel Inflammatory Cardiovascular Biomarker, GlycA
Authors: Kristian C Becker, Alice Wang, Damian M Criag, Elizabeth Burns, Simon G Gregory, Robert W McGarrah, William E Kraus, Svati H Shah
Journal: Circulation (2017)

Background: GlycA, an aggregate biomarker of glycosylated acute phase proteins, is a novel inflammatory biomarker predictive of incident cardiovascular disease (CVD) events. The genetics of inter-individual heterogeneity in plasma glycA levels have not been evaluated. This study utilized a genome-wide association study (GWAS) to identify genetic determinants of plasma glycA levels. Methods: Our study included 2,541 sequential individuals evaluated for coronary artery disease from the CATHGEN biorepository (Durham, NC). Patient genotyping was performed by Illumina Omni1-Quad array. GlycA levels were measured in frozen, fasting plasma using NMR profiling to assess n-acetyl-methyl groups of N-acetylglucosamine residues. Race-stratified (AA and WH) and race-combined meta-analysis (MET) regression models were constructed for each SNP (additive and dominant models) to test for association between SNP and glycA levels, adjusting for age, sex, race and batch. Genome-wide significance was set at p < 1x10-6. Result...
Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of XmAb14045, a CD123 x CD3 T Cell-Engaging Bispecific Antibody: Initial Results of a Phase 1 Study
Authors: Farhad Ravandi, Asad Bashey, James M. Foran, Wendy Stock, Raya Mawad, William Blum, M. Wayne Saville, Chelsea M. Johnson, K. Gary J. Vanasse, Thomas Ly, Hagop M. Kantarjian, Bhavana Bhatnagar, Koichi Takahashi, Alice S. Mims
Journal: Blood (2018)
Prospective Multicenter Phase 3 Study Comparing 5-Azacytidine (5-Aza) Induction Followed By Allogeneic Stem Cell Transplantation Versus Continuous 5-Aza According to Donor Availability in Elderly MDS Patients (55-70 years) (VidazaAllo Study)
Authors: Nicolaus Kroeger, Katja Sockel, Christine Wolschke, Wolfgang Bethge, Richard F. Schlenk, Dominik Wolf‎, Michael Stadler, Guido Kobbe, Gerald Wulf, Gesine Bug, Kerstin Schäfer-Eckart, Christoph Scheid, Florian Nolte, Jan Krönke, Matthias Stelljes, Dietrich W. Beelen, Marion Heinzelmann, Detlef Haase, Hannes Buchner, Gabriele Bleckert, Uwe Platzbecker
Journal: Blood (2018)
Abstract 16245: The Impact of Delirium After Trans-catheter Aortic Valve Replacement
Authors: Chetan P Huded, Jill M Huded, Ranya N Sweis, Mark J Ricciardi, Hyde M Russell, Sukit C Malaisrie, Charles J Davidson, James D Flaherty
Journal: Circulation (2015)

Introduction: Delirium is associated with increased healthcare utilization, morbidity, and mortality. We assessed the impact of delirium on outcomes after trans-catheter aortic valve replacement (TAVR). Methods: We reviewed 294 consecutive cases of TAVR at a tertiary care academic medical center from June, 2008 to February, 2015. Delirium was identified by prospective confusion assessment method screening and retrospective chart review. The primary outcome was overall survival. Secondary outcomes included length of hospital stay, discharge destination, hospital re-admission within 30 days, and 30 day mortality. Results: Delirium was identified in 61 patients after TAVR (21%). Non-femoral access for TAVR was more common in delirious than non-delirious patients (41% vs 28%, P=0.04). There was no difference in the post-operative stroke rate between delirious and non-delirious patients (8% vs 6%, P=0.45). Post-TAVR respiratory failure was more common in delirious patients (21% vs 3%, P&lt;0.001). Of 13 delirious patients who developed respiratory failure, delirium preceded respiratory failure in 8 (62%). Median follow-up was 8.2 months. Delirious patients had decreased overall survival compared to non-delirious patients (figure, log-rank P&lt;0.01). After adjusting for Society of Thoracic Surgeons risk score and TAVR access type, delirium remained an independent predictor of overall survival (hazard ratio 1.97, 95% confidence interval 1.18 to 3.23, P&lt;0.01). Delirium was associated with longer mean length of hospital stay (13.3 +/- 9.5 days vs 6.7 +/- 3.8 days, P&lt;0.001) and higher rates of discharge to a rehabilitation facility (61% vs 27%, P&lt;0.001). There was no difference in 30 day hospital re-admission rates or 30 day mortality between groups. Conclusions: Delirium, a common syndrome after TAVR, is associated with decreased survival and increased healthcare utilization. Early detection of delirium after TAVR may help identify a high risk subset of patients.
Immunological methods for the diagnosis of oral mucosal diseases
Authors: S. Sun, B. Zhong, W. Li, X. Jin, Y. Yao, J. Wang, J. Liu, H. Dan, Q. Chen, X. Zeng
Journal: British Journal of Dermatology (2018)

Immunological methods, which have been widely used in autoimmune blistering diseases (AIBDs) of the oral mucosa, can also be adopted as auxiliary diagnostic tools in oral lichen planus (OLP) and discoid lupus erythematosus (DLE). AIBDs, characterized by autoantibodies against structural proteins of keratinocytes or the basement membrane zone, clinically present as blisters and erosions of the oral mucosa. When atypical lesions occur, OLP or DLE may be confused with AIBDs. The improvement of diagnostic accuracy is necessary due to the significant differences in treatment and prognosis among these diseases. A variety of immunological methods are used for qualitative and quantitative detection of target antigens and autoantibodies. These methods can evaluate efficacy of treatment, monitor diseases and guide treatment decisions. In this review, we discuss the application of immunofluorescence, biochemical tests, and protein microarrays for AIBDs, OLP and DLE, as well as the differential diagnostic methods using immunological tests.