tbuckley/cabot-search huggingface dataset:
Unique epigenetic signature in T cell compartment after epicutaneous immunotherapy in peanut sensitized mice
Authors: Lucie Mondoulet, Vincent Dioszeghy, Camille Plaquet, Elodie Roche, Veronique Dhelft, Florence Busato, Christophe Dupont, Hugh A. Sampson, Jorg Tost
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 14759: Aggressive Risk factor REduction STudy: Implications for the Substrate for Atrial Fibrillation (ARREST-AF Substrate Study)
Authors: Rajeev K Pathak, Melissa E Middeldorp, Simon Stolcman, Scott Willoughby, Rajiv Mahajan, Dennis H Lau, Prashanthan Sanders
Journal: Circulation (2015)

Introduction: Cardiac risk factors (RF) such as hypertension, diabetes mellitus, obesity and sleep apnoea have been associated with structural and electrical remodeling of the atria that forms the substrate leading to the development and progression of atrial fibrillation (AF). We evaluated the impact of aggressive management of RFs on the AF substrate. Methods: 50 consecutive AF pts with BMI ≥ 27 kg/m2 and ≥1 cardiac risk factor were randomized to either RF management (RFM) or usual care (Control). The RFM group were managed in a physician-led clinic directed at RF control in accordance with AHA/ACC guidelines. Both the groups were studied with electrophysiological (EP) study, echocardiography, cardiac MRI, serum fibrosis and endothelial function markers at baseline and repeated at &gt; 6 mths later. Subjects in RFM group had &gt;10% weight loss at repeat study. Results: There were no differences in baseline characteristics or follow-up duration (15±3 mths) between the groups (p=NS). RFM resulted in greater reduction in weight (p&lt;0.001), systolic blood pressure (p=0.004), better glycaemic control (p=0.003) and lipid profile (p=0.04), reduced LA size (p=0.003) and total pericardial fat volume (p=0.001). The table presents the data showing that RFM resulted in marked reversal in atrial electrical parameters, reduced pro-inflammatory/fibrotic markers and improved endothelial/platelet function. Conclusion: Aggressive risk factor management reverses electrical and structural remodeling and results in a significant improvement in endothelial and platelet function underscoring its importance in AF management. (Trial registration: ACTRN12613000444785)
Gamma Tocopherol (γT) Supplementation Reduces Endotoxin-Induced Sputum Neutrophilia in Healthy Volunteers and Asthmatics Regardless of BMI or glutathione-S-transferase Mu1 (GSTM1) Genotype
Authors: Amika Sood, Allison J. Burbank, Kimberly Enders, Haibo Zhou, David B. Peden, Michelle L. Hernandez
Journal: Journal of Allergy and Clinical Immunology (2018)
Efficacy and Safety of Sacral and Percutaneous Tibial Neuromodulation in Non-neurogenic Lower Urinary Tract Dysfunction and Chronic Pelvic Pain: A Systematic Review of the Literature
Authors: Manuela Tutolo, Enrico Ammirati, John Heesakkers, Thomas M. Kessler, Kenneth M. Peters, Tina Rashid, Karl-Dietrich Sievert, Michele Spinelli, Giacomo Novara, Frank Van der Aa, Dirk De Ridder
Journal: European Urology (2018)
<i>Notes from the Field</i>: Legionellosis Outbreak Associated with a Hotel Aquatics Facility — Tennessee, 2017
Authors: Jane K. Yackley, David Sweat, Mary-Margaret A. Fill, Katie Garman, John R. Dunn
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

On June 26, 2017, the Tennessee Department of Health (TDH) was notified by CDC of two travel-associated cases of legionellosis.The patients resided in Florida and the United Kingdom but had a common hotel exposure in Memphis, Tennessee.On June 27, the Shelby County Health Department identified a third case in a Shelby County resident with the same hotel exposure.All three persons had positive Legionella urinary antigen tests and reported using the hotel hot tub.A joint state and local investigation was launched, which included environmental health, epidemiologic, and laboratory components.Shelby County environmental health specialists conducted an assessment of the hotel aquatics facility and identified improper water treatment monitoring and low chlorine residuals (0 ppm; acceptable range = 1-3 ppm).On June 28, TDH was notified of four additional travel companions with illness after exposure to the hotel aquatics facility, including two persons with confirmed Legionella, one of whom died.A public health directive was issued to the hotel on June 28, closing the aquatics facility and requiring consultation with an environmental engineering firm familiar with CDC Legionella reduction guidance for the assessment, testing, and remediation of the water distribution systems (1).Aquatics area water sampling was also conducted by a TDH environmental health specialist.Laboratory testing of the aquatics facility water samples identified three Legionella polymerase chain reactionpositive samples from the pool, pool sand filter, and hot tub sand filter, and isolated Legionella pneumophila serogroup 1 from the hot tub sand filter.The remediation firm isolated two nonpneumophila Legionella species, including an isolate from the aquatics facility sprinkler system.An online survey was created to capture epidemiologic and exposure information among hotel guests.A guest roster (including hotel guests before and after the official opening of the aquatics facility on May 27 [i.e., from May 15 to June 27]) was requested.On July 6, approximately 4,000 emails and 209 letters containing the survey link were sent to guests with available contact information.As of July 31, the survey end date, 983 responses were received.Through survey responses, CDC reciprocal notification of non-Tennessee cases, and calls received at the health department, 92 cases were identified,
Modulating transcriptional control of drug metabolism: A novel paradigm in drug therapeutics
Authors: Haiyan Huang, Hongwei Wang, Joseph Locker, Ganjam Kalpana, Sridhar Mani, Matthew R. Redinbo, Micheal Sinz, Mary Zoeckler
Journal: Cancer Research (2006)

893   Individual variation in drug metabolism is a major cause of treatment failures during cancer therapy. Because variations can lead to unpredictable and erratic drug side effects, there is a considerable need to modulate the pharmacodynamics of therapeutics to maximize efficacy and minimize side effects. Individual variations stem from differences in activity and abundance of drug metabolizing enzymes, including the cytochrome p450 family, whose expression is regulated at the level of transcription by orphan nuclear receptors. We have found that ketoconazole, a known inhibitor of p450 enzyme activity, represses the transcription of genes central to drug metabolism and transport by blocking the activation of nuclear receptors. Ketoconazole prevented the activation of endogenous as well as transiently transfected genes in cell lines and primary human and mouse hepatocytes. This inhibition was mediated by blocking the activation of nuclear receptors hPXR and CAR but not other nuclear receptors such as ERα or PPARγ. Ketoconazole disrupted the interaction between hPXR and co-activators in both mammalian two-hybrid assays and in co-activator dependent receptor ligand binding assays (CARLA). Furthermore, ketoconazole specifically inhibited PXR mediated gene transcription of cyp3a11, mdr1 and mrp2 in mice. Using LORR (Loss of Righting Reflex), we found that treatment of mice with ketoconazole inhibited the metabolism, and hence the functional consequences, of a CYP450 substrate-tribromoethanolamine. Finally, in wild type mice (n=6), we demonstrate that the pharmacokinetics of paclitaxel are normalized. Short term treatment with ketoconazole markedly reduces variation in treated population, and this effect coincides with decreased transcription of cyp3a11 and mrp2 in liver and mdr-1 in small bowel. These studies demonstrate for the first time that ketoconazole can inhibit the transcriptional activation of drug metabolism genes in vivo. Thus, ketoconazole has the potential to be used clinically to reduce individual variability in therapeutic responses.
Hepatocyte‐derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection
Authors: Dustin A. Cobb, Ok‐Kyung Kim, Lucy Golden‐Mason, Hugo R. Rosen, Young S. Hahn
Journal: Hepatology (2017)

Hepatitis C virus (HCV) is a global health concern that can cause severe liver disease, such as cirrhosis and hepatocellular carcinoma. Control of HCV requires vigorous T‐cell responses, yet CD4 + T cells in chronic HCV patients are dysfunctional. T follicular regulatory (Tfr) cells are a subset of regulatory T cells that suppress T follicular helper (Tfh) cells and the generation of high affinity antibody‐producing B cells. In this study, we examined the accumulation of Tfr cells in the liver compartment during chronic HCV infection and defined the cellular and molecular mechanisms underlying their expansion. Our analysis revealed a substantial population of Tfr cells in livers of chronic HCV patients that is absent in liver tissues from nonviral hepatitis or healthy subjects. Coculture of PBMCs from healthy subjects with HCV‐infected hepatoma cells resulted in preferential expansion of circulating Tfr cells, leading to suppression of Tfh cells. Additionally, coculture of tonsillar cells with infected hepatoma cells lead to an expansion of germinal center Tfr. Notably, expansion was mediated by transforming growth factor beta (TGF‐β)‐containing exosomes released from HCV‐infected hepatocytes given that blockade of exosome‐associated TGF‐β or inhibition of exosome release abrogated Tfr expansion. Conclusion : These results show that liver‐derived exosomes play a pivotal role in the accumulation of Tfr cells, likely leading to suppression of Tfh responses in HCV‐infected patients. Our study identifies a novel pathway in which HCV infection in hepatocytes exacerbates Tfr cell responses to subvert antiviral immunity. (H epatology 2018;67:71‐85)
A novel glycoproteomic approach for the discovery of carbohydrate-targeting serum tumor markers for lung cancer using Lectin-coupled ProteinChip system
Authors: Koji Ueda, Yataro Daigo, Yu Fukase, Toyomasa Katagiri, Nobuhisa Ishikawa, Shinji Irie, Taka-Aki Sato, Nobuoki Kohno, Mieko Shiwa, Yusuke Nakamura
Journal: Cancer Research (2008)

2433   Glycosylation is highly sensitive to the biochemical environment and is involved in various biological processes including differentiation, motility, and intracellular signaling, as well as oncogenesis and metastasis. Therefore the tumor specific alterations in protein glycosylation on the cell surface and in body fluids might be potential targets for the new cancer diagnostics and therapeutics. We here report our new approach to identification of carbohydrate-targeting serum tumor markers for lung cancer based on 3 key technologies: 1) removal of 14 abundant proteins from serum, 2) Lectin-coupled ProteinChip System, and 3) use of the acidic glycoprotein-compatible matrix for SELDI-TOF MS analysis. We pre-treated serum samples with immunodepletion-HPLC column to remove 14 abundant proteins (constituting 94% of serum protein), because only a limited number of proteins could be detected by previous ProteinChip-based approaches using crude serum samples. These low-abundant serum components were sequentially processed on Jacalin- or SNA-lectin chips, recognizing glycoproteins with pan-O-type glycans or Neu5Ac (α2, 6) Gal/GalNAc structures, respectively, followed by SELDI-TOF MS analysis. Since current SELDI-TOF MS analysis with general matrices (CHCA, DHB, SPA, etc.) has a major problem for the quantitative analysis of acidic glycoproteins due to heterolytic disassembly of neuraminic acid moieties, we overcame the problem by use of 2, 4, 6-Trihydroxyacetophenone in ammonium citrate solution as a matrix, which allowed quantitative and reproducible profiling of sialylated glycoproteins without decay of neuraminic acid moieties. In this study, we identified a protein peak with m/z = 9850 as a candidate carbohydrate-targeting tumor marker, in which significant loss of Neu5Ac (α2, 6) Gal/GalNAc structure was observed in 10 lung adenocarcinoma patients’ sera, but not in 10 healthy controls. We determined this candidate as Apolipoprotein C-III (APOC3) by MALDI-QIT-TOF MS/MS analysis, and successfully identified its O-glycosylation site by MALDI-QIT-TOF MS³ analysis. Further enzymatic and mass spectrometric experiments revealed that APOC3 protein had disialyrated and monosialyrated forms in human serum. Importantly APOC3 with the monosialyrated glycan structure was significantly more dominant in lung cancer patients’ sera than in normal sera. These results were validated by western blotting and mass spectrometry-based glycan structure analysis using the same set of serum samples. Our Lectin-coupled ProteinChip System will provide a wide range of applications with high-throughput and reproducible profiling of cancer-specific alterations of glycan structures on multiple serum proteins, which should be valuable for biomarker development and the study of variations in glycan structures in any type of human disease.
Phase I/II Study of Liposomal Doxorubicin (DOX) in Combination with Selinexor (SEL) and Dexamethasone (Dex) for Relapsed and Refractory Multiple Myeloma (RRMM)
Authors: Rachid Baz, Jeffrey A Zonder, Kenneth H Shain, Melissa Alsina, Jason B. Brayer, Mark Melody, Joel G. Turner, Jana L Dawson, Jongphil Kim, Daniel M Sullivan
Journal: Blood (2017)
ETS1 Expression Is Upregulated in Chronic Myeloid Leukemia (CML) and the ETS1 Transcriptional Program Correlates with Disease Progression Towards Blast Crisis
Authors: Christophe Desterke, Maud Voldoire, Nathalie Sorel, Marie Laure Bonnet, Sarah Pagliaro, Annelise Bennaceur-Griscelli, Emilie Cayssials, Jean-Claude Chomel, Ali G Turhan
Journal: Blood (2016)
Abstract SY19-01: Cell to cell variability in the responses of tumor cells to death ligands
Authors: Peter K. Sorger, Sabrina Spencer, Deborah Flusberg, Suzanne Gaudet
Journal: Cancer Research (2010)

Abstract Cell to cell variability in phenotype and fate is important for tissue homeostasis, the emergence of drug resistance and the evolution of tumors. I will discuss cell to cell variability in the responses of clonal populations of human cells to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic. Some TRAIL-treated human cells die within ~40 min, others only after 12 hr and some live indefinitely. During this variable delay initiator caspases (ICs) are active in processing substrates such as Bid and downstream effector caspases (ECs) but mitochondrial membrane permeablization (MOMP) does not occur and ECs are catalytically inactive. We have explored three explanations for cell to cell differences among members of a clonal and notionally uniform population: (i) genetic or epigenetic variation; (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation; (iii) difference in cell state such as position in the cell cycle or protein concentrations. To distinguish among these three possibilities we compared the fates of sister cells exposed to TRAIL using live-cell microscopy. Genetic and epigenetic factors are transmitted with near-perfect fidelity; reaction rates dominated by stochastic fluctuations are no more similar in sisters than in any two cells chosen at random and variability arising from differences in mRNA or protein levels should be transiently heritable (because division is a binomial process in which sister cells inherit roughly equal numbers of abundant cytosolic and nuclear factors but drift towards the population average over time). The later explanation is correct; natural fluctuations in protein levels dominate phenotypic heterogeneity in extrinsic apoptosis and cause transient phenotypic heritablility. Variability can be manipulated by protein over-expression and drugs and I will describe analytic methods for modeling these perturbations. Finally, I will show that natural variation is sufficient to cause some cells to follow one biochemical pathway to death (a MOMP-dependent Type II pathway) and another set of genetically identical cells to follow a fundamentally different pathway (a MOMP-independent Type I pathway). Citation Format: Peter K. Sorger, Sabrina Spencer, Deborah Flusberg, Suzanne Gaudet. Cell to cell variability in the responses of tumor cells to death ligands [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-01
Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma
Authors: Aly-Khan A. Lalani, Wanling Xie, Dylan J. Martini, John A. Steinharter, Craig K. Norton, Katherine M. Krajewski, Audrey Duquette, Dominick Bossé, Joaquim Bellmunt, Eliezer M. Van Allen, Bradley A. McGregor, Chad J. Creighton, Lauren C. Harshman, Toni K. Choueiri
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. <h3>Methods</h3> We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6&nbsp;weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. <h3>Results</h3> Median follow up was 16.6&nbsp;months (range: 0.7–67.8). Median duration on therapy was 5.1&nbsp;months (&lt;1–61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3–42.4) at baseline and 4.1 (1.1–96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6&nbsp;weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6&nbsp;weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (<i>p</i> &lt; 0.001) and OS (<i>p</i> = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes. <h3>Conclusions</h3> Early decline and NLR at 6&nbsp;weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.
Role for VGLUT2 in selective vulnerability of midbrain dopamine neurons
Authors: Thomas Steinkellner, Vivien Zell, Zachary J. Farino, Mark S. Sonders, Michael Villeneuve, Robin J. Freyberg, Serge Przedborski, Wei Lu, Zachary Freyberg, Thomas S. Hnasko
Journal: Journal of Clinical Investigation (2018)

Parkinson's disease is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). DA neurons in the ventral tegmental area are more resistant to this degeneration than those in the SNc, though the mechanisms for selective resistance or vulnerability remain poorly understood. A key to elucidating these processes may lie within the subset of DA neurons that corelease glutamate and express the vesicular glutamate transporter VGLUT2. Here, we addressed the potential relationship between VGLUT expression and DA neuronal vulnerability by overexpressing VGLUT in DA neurons of flies and mice. In Drosophila, VGLUT overexpression led to loss of select DA neuron populations. Similarly, expression of VGLUT2 specifically in murine SNc DA neurons led to neuronal loss and Parkinsonian behaviors. Other neuronal cell types showed no such sensitivity, suggesting that DA neurons are distinctively vulnerable to VGLUT2 expression. Additionally, most DA neurons expressed VGLUT2 during development, and coexpression of VGLUT2 with DA markers increased following injury in the adult. Finally, conditional deletion of VGLUT2 made DA neurons more susceptible to Parkinsonian neurotoxins. These data suggest that the balance of VGLUT2 expression is a crucial determinant of DA neuron survival. Ultimately, manipulation of this VGLUT2-dependent process may represent an avenue for therapeutic development.
Abstract 19507: Outcome of In-Hospital VT/VF Arrest by Time and Location When Using a Wearable Cardioverter Defibrillator
Authors: Chingping Wan, Steven J Szymkiewicz
Journal: Circulation (2016)

Introduction: Previous studies have shown that survival following an in-hospital sudden cardiac arrest (SCA) is worse during nighttime hours or on weekends, or in non-monitored areas. The wearable ...
Association of Surgical Practice Patterns and Clinical Outcomes With Surgeon Training in University- or Nonuniversity-Based Residency Program
Authors: Morgan M. Sellers, Luke J. Keele, Catherine E. Sharoky, Christopher Wirtalla, Elizabeth A. Bailey, Rachel R. Kelz
Journal: JAMA Surgery (2018)

Important metrics of residency program success include the clinical outcomes achieved by trainees after transitioning to practice. Previous studies have shown significant differences in reported training experiences of general surgery residents at nonuniversity-based residency (NUBR) and university-based residency (UBR) programs.To examine the differences in practice patterns and clinical outcomes between surgeons trained in NUBR and those trained in UBR programs.This observational cohort study linked the claims data of patients who underwent general surgery procedures in New York, Florida, and Pennsylvania between January 1, 2012, and December 31, 2013, to demographic and training information of surgeons in the American Medical Association Physician Masterfile. Patients who underwent a qualifying procedure were grouped by surgeon. Practice pattern analysis was performed on 3638 surgeons and 1 237 621 patients, representing 214 residency programs. Clinical outcomes analysis was performed on 2301 surgeons and 312 584 patients. Data analysis was conducted from February 1, 2017, to July 31, 2017.NUBR or UBR training status.Inpatient mortality, complications, and prolonged length of stay.No significant differences were observed between the NUBR-trained surgeons and UBR-trained surgeons in age (mean, 53.3 years vs 53.7 years), sex (female, 18.2% vs 16.9%), or years of clinical experience (mean, 16.5 years vs 16.5 years). Overall, NUBR-trained surgeons compared with UBR-trained surgeons performed more procedures (median interquartile range [IQR], 328 [93-661] vs 164 [49-444]; P < .001) and performed a greater proportion of procedures in the outpatient setting (risk difference, 6.5; 95% CI, 6.4 to 6.7; P < .001). Before matching, the mean proportion of patients with documented inpatient mortality was lower for NUBR-trained surgeons than for UBR-trained surgeons (risk difference, -1.01; 95% CI, -1.41 to -0.61; P < .001). The mean proportion of patients with complications (risk difference, -3.17%; 95% CI, -4.21 to -2.13; P < .001) and prolonged length of stay (risk difference, -1.89%; 95% CI, -2.79 to -0.98; P < .001) was also lower for NUBR-trained surgeons. After matching, no significant differences in patient mortality, complications, and prolonged length of stay were found between NUBR- and UBR-trained surgeons.Surgeons trained in NUBR and UBR programs have distinct practice patterns. After controlling for patient, procedure, and hospital factors, no differences were observed in the inpatient outcomes between the 2 groups.