tbuckley/cabot-search huggingface dataset:
Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course
Authors: Herman T. den Dekker, Kimberley Burrows, Janine F. Felix, Lucas A. Salas, Ivana Nedeljkovic, Jin Yao, Sheryl L. Rifas-Shiman, Carlos Ruiz-Arenas, N. Amin, Mariona Bustamante, Dawn L. DeMeo, A. John Henderson, Caitlin G. Howe, Marie-France Hivert, M. Arfan Ikram, Johan C. de Jongste, Lies Lahousse, Pooja R. Mandaviya, Joyce B. van Meurs, Mariona Pinart, Gemma C. Sharp, Lisette Stolk, André G. Uitterlinden, Josep M. Anto, Augusto A. Litonjua, Carrie V. Breton, Guy G. Brusselle, Jordi Sunyer, George Davey Smith, Caroline L. Relton, Vincent W.V. Jaddoe, Liesbeth Duijts
Journal: European Respiratory Journal (2019)

Rationale We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. Methods We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV 1 ), FEV 1 /forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. Results We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5 , PAOX , LINC00602 , ABCA7 , PER3 , CLCA1 , VENTX , NUDT12 , PTPRN2 and TCL1A . Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. Interpretation Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.
Association between sensitization pattern and asthma, allergic rhinitis in 7-years-old children
Authors: Sohee Heo, Dong In Suh, So-Yeon Lee, Sungsu Jung, Jisun Yoon, Hyun-ju Cho, Young-Ho Kim, Song-I. Yang, Ji-Won Kwon, Gwangcheon Jang, Yonghan Sun, Sung-Il Woo, You Sook Youn, Kang Seo Park, Hwa Jin Cho, Myung-Hee Kook, Hye-Ryoung Yi, Hai Lee Chung, Ja Hyeong Kim, Hyung-Young Kim, Jin-A. Jung, Hyang-ok Woo, Jeom-Kyu Lee, Woo-Sung Chang, Soo-Jong Hong, Eun Lee
Journal: Journal of Allergy and Clinical Immunology (2019)
Prevalence of Comorbidities with Peanut Allergy: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial (PALISADE)
Authors: Douglas T. Johnston, Lawrence Sher, Stanley M. Fineman, Noelle M. Griffin, Rezi Zawadzki, Karin Rosén, Dareen D. Siri
Journal: Journal of Allergy and Clinical Immunology (2019)
Eosinophil peroxidase, GATA3, and T-bet as tissue biomarkers in chronic rhinosinusitis
Authors: Devyani Lal, Benjamin L. Wright, Kelly P. Shim, Matthew A. Zarka, James J. Lee, Yu-Hui Chang, Sergei I. Ochkur, Rohit Divekar, Alfred D. Doyle, Elizabeth A. Jacobsen, Hirohito Kita, Matthew A. Rank
Journal: Journal of Allergy and Clinical Immunology (2019)
Utility of restaging patients with stage II/III rectal cancer following neoadjuvant chemo/XRT: A systematic review.
Authors: Leah E. Hendrick, Renee L Levesque, David Shibata, Nathan M Hinkle, Justin J Monroe, Evan Scott Glazer, Jeremiah Lee Deneve, Paxton Vandiver Dickson
Journal: Journal of Clinical Oncology (2019)

495 Background: In the US, patients with clinical stage II/III rectal cancer typically receive neoadjuvant chemoradiation (chemo/XRT) over 5-6 weeks followed by a 6-10 week break before proctectomy. As this chemotherapy is delivered at radio-sensitizing doses, there is essentially a 3-month window during which potential systemic disease is untreated. Evidence regarding the utility of restaging patients prior to proctectomy is limited. Methods: PubMed, Scopus, Web of Science, and the Cochrane Library were searched for studies evaluating the utility of restaging patients with locally advanced rectal cancer after completion of long course chemo/XRT, and reporting changes in management after restaging. Studies that were non-English, included &lt; 50 patients, or examining the diagnostic accuracy of specific imaging modalities were excluded. Study quality was evaluated using the modified Newcastle Ottawa Scale. Results: Eight studies were identified including a total of 1251 patients restaged between completion of chemo/XRT and proctectomy. All studies were retrospective (6 single institution, 2 multi-institution). Restaging identified new metastatic disease in 72 (6.0%) patients, with 4 studies reporting specific sites: liver (n = 28), lung (n = 8), adrenal (n = 1), bone (n = 1), and multiple sites (n = 7). Overall, progression (distant or local) was detected in 85 (6.8%) patients and resulted in a reported change in management in 71 (5.7%) patients. One study identified an association of high-grade tumors with progression (p ≤ 0.05), however, this was not reported in any other study. Moreover, tumor-related prognostic characteristics were inconsistently reported among studies, precluding meta-analysis. Conclusions: Although restaging between completion of neoadjuvant chemo/XRT and proctectomy detects disease progression in only a small percentage of patients, findings may alter the treatment plan. A multi-institutional collaboration with analysis of well-defined prognostic variables may better identify a group of patients most likely to benefit from restaging.
Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
Authors: Daisuke Ennishi, Katsuyoshi Takata, Wendy Béguelin, Gerben Duns, Anja Mottok, Pedro Farinha, Ali Bashashati, Saeed Saberi, Merrill Boyle, Barbara Meissner, Susana Ben-Neriah, Bruce W. Woolcock, Adèle Telenius, Daniel Lai, Matt Teater, Robert Kridel, Kerry J. Savage, Laurie H. Sehn, Ryan D. Morin, Marco A. Marra, Sohrab P. Shah, Joseph M. Connors, Randy D. Gascoyne, David W. Scott, Ari M. Melnick, Christian Steidl
Journal: Cancer Discovery (2019)

Abstract We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. Significance: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination. See related commentary by Velcheti et al., p. 472. This article is highlighted in the In This Issue feature, p. 453
Efficacy of Granulocyte Colony‐stimulating Factor in the Management of Steroid‐Nonresponsive Severe Alcoholic Hepatitis: A Double‐Blind Randomized Controlled Trial
Authors: Saggere Muralikrishna Shasthry, Manoj Kumar Sharma, Varsha Shasthry, Apurva Pande, Shiv Kumar Sarin
Journal: Hepatology (2019)

Severe alcoholic hepatitis (SAH) is often a progressive disease with high mortality and limited steroid responsiveness. Management options of steroid nonresponsive SAH (day 7 Lille score &gt; 0.45) are limited. We assessed the efficacy and safety of granulocyte colony‐stimulating factor (G‐CSF) in steroid nonresponders. A randomized, double‐blind, single‐center trial (NCT01820208) was conducted between March 2013 and June 2016 in patients with histologically proven SAH, nonresponsive to 40 mg/day of prednisolone were randomized to G‐CSF (12 doses, 300 μg each in 28 days) or placebo. Responders were continued with prednisolone. Of the 430 patients with SAH, 132 received steroid therapy. Of these, 33 (25%) were nonresponders and were randomized to G‐CSF or placebo (14 in each group after exclusions). The baseline characteristics of both groups were comparable. The 28‐day mortality was comparable between the groups (21.4%, G‐CSF; 28.6%, placebo; P = 0.69). At 90 days, in the G‐CSF but not in the placebo group, the Model for End‐Stage Liver Disease reduced from 24.6 ± 3.9 to 19.4 ± 3.7 ( P = 0.002) and Maddrey’s discriminant function from 74.8 ± 22.8 to 57.4 ± 31 ( P = 0.26). Infections were less common (28% versus 71%; P &lt; 0.001) with lower 90‐day mortality (35.7% versus 71.4%; P = 0.04) in the G‐CSF than in the placebo group. On Cox regression analysis, receiving G‐CSF (hazard ratio, 0.37; SD, 0.14‐0.98; P = 0.04), and high baseline serum creatinine (hazard ratio, 4.12; SD, 1.7‐10.3; P = 0.002) predicted day‐90 outcomes in steroid nonresponsive SAH. Patients tolerated G‐CSF without any major adverse events. Conclusion: Approximately one‐quarter of patients with SAH do not respond to corticosteroid therapy. Administration of G‐CSF is safe and helps to reduce the disease severity and 90‐day mortality in these patients.
Experience of skin disease and relationships with healthcare providers: a qualitative study of Traveller women in Ireland
Authors: E. Gilhooley, S. Daly, O. Gallagher, M. Glacken, D. McKenna
Journal: British Journal of Dermatology (2019)

Significant health disparities exist between members of the Travelling community and those of the general population. Barriers to Traveller engagement with health services include the experience or perception of discrimination, and cultural and health literacy barriers. Experience of skin disease and interactions with healthcare providers has not been widely explored in this ethnic minority. The formation of positive relationships between the Travelling community and healthcare providers is important in the promotion of treatment adherence and improving health outcomes.To investigate Travellers' experience of skin disease and their relationships with healthcare providers.Focus groups were conducted with a purposive sample of female members of the Irish Travelling community with experience of skin health issues, between January 2018 and April 2018. Three focus groups were conducted at three separate locations with 10 participants in each group. Themes were identified from the focus group transcripts using an inductive thematic analysis framework.Emergent themes surrounding relationships between Travellers and healthcare providers included health literacy, discrimination, information inconsistency, trust and communication. Factors that were valued in the creation of positive relationships included an appreciation of varying degrees of health literacy, the provision of sufficient information tailored to an individual's needs and a demonstration of cultural competence.Dermatologists are well placed to provide practical, customized, treatment guidance and engage patients while integrating their culturally based beliefs.
Efficacy and safety of varlitinib, a reversible pan-HER tyrosine kinase inhibitor, in combination with platinum-based regimens in biliary tract cancers: A pooled analysis from three phase I studies.
Authors: Aaron C. Tan, Do-Youn Oh, Yee Chao, Chih-Yi Hsieh, Wei-Ling Chang, Fenny Isanto, Ying-Chen Chen, Mark McHale, Bertil Lindmark, Matthew C.H. Ng
Journal: Journal of Clinical Oncology (2019)

331 Background: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During Phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. Methods: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200-500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (Study 002); oxaliplatin and 5-FU/cape (Study 002SG); cisplatin and gemcitabine (Study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. Results: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. 002SG and 007 were still ongoing at data cut-off. 20 (46.5%) pts were male and the median age was 62 years (range 42-82). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the Ampulla of Vater (9.3%). 14 (32.6%) pts had received ≥ 1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥ 1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was -10.8% (range 49.5% to -87.1%). Of 43 pts, the most frequent (≥ 30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common Grade ≥ 3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. Conclusions: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1 st line BTC are ongoing. Clinical trial information: NCT02648425, NCT02435927, and NCT02992340.
Abstract P6-20-16: BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer
Authors: W Tang, X Huang, Z Ou, H Yan, J Gan, Q Dong, B Tan, Y Yang, Y Guo, S Li, B Thomas, J-C Yu
Journal: Cancer Research (2019)

Abstract Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. These two characteristics make Trop-2 a potential drug target. An antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, has recently been demonstrated to be effective in treating triple negative breast cancer (TNBC) and gastric cancer patients. Here we present a Trop-2 ADC, BAT8003, which contains an uncleavable linker and a maytansine derivative as the payload. An A114C mutation on antibody heavy chain was introduced to BAT8003 for site-specific conjugation, in order to generate a more homogeneous product for a better pharmacokinetics profile. BAT8003 is also completely devoid of fucose modification, to allow for enhanced ADCC effect. We show that BAT8003 is effectively internalized upon binding to Trop-2, and inhibits proliferation of Trop2-overexpressed tumor cells with IC50s of ˜1 nM. In a TNBC (MDA-MB-468 cell) mouse xenograft model, BAT8003 strongly inhibits tumor growth at a dose level as low as 5 mg/kg. BAT8003 also demonstrates potent activity in another TNBC (MX-1 cell) mouse tumor model, in which it shows the same inhibition activity as the naked antibody conjugated heterogeneously with almost two fold payload (DAR 3.5), suggesting the effect caused by site-specific conjugation. We are currently developing BAT8003 for clinical evaluation in TNBC and other cancer indications. Citation Format: Tang W, Huang X, Ou Z, Yan H, Gan J, Dong Q, Tan B, Yang Y, Guo Y, Li S, Thomas B, Yu J-C. BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-16.
EDA fibronectin–TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis
Authors: Alessandro Malara, Cristian Gruppi, Vittorio Abbonante, Daniele Cattaneo, Luigi De Marco, Margherita Massa, Alessandra Iurlo, Umberto Gianelli, Carlo L. Balduini, Maria E. Tira, Andrès F. Muro, Anil K. Chauhan, Vittorio Rosti, Giovanni Barosi, Alessandra Balduini
Journal: The Journal of Experimental Medicine (2019)

The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA+/+), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPOhigh). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPOhigh mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase.
Abstract A39: Characterizing the epigenetic effects of the histone 3.3 G34W mutation in giant cell tumors of bone
Authors: Shriya Deshmukh, Sima Khazaei, Dylan Marchione, Ashot Harutyunyan, Benjamin Garcia, Nada Jabado
Journal: Cancer Research (2018)

Abstract Introduction: Pediatric glioblastomas (pGBM) are malignant brain tumors associated with a dismal prognosis. A subset of pGBMs carry mutations of either the Lysine 27 or Glycine 34 (G34) amino acid residues of histone 3 variant genes. The same G34 residue is also mutated in 85-95% of giant cell tumors of bone (GCTs), albeit to Tryptophan (G34W) in GCTs rather than to Arginine or Valine (G34R/V) as in pGBMs. The G34 mutation is predicted to impede access of histone methyltransferases like SetD2 to the nearby Lysine 36 residue, thereby altering the epigenome and transcriptome. Methods: To elucidate the tumorigenic effect of G34 mutations, we used the gene-editing technology CRISPR/Cas9 to correct the G34W mutation to wild-type in 2 GCT cell lines. We then investigated CRISPR-edited cell lines using functional assays, proteomic, epigenomic, and transcriptomic analyses. Results: Correction of the G34W mutation to wild-type in CRISPR-edited GCT cells results in phenotypic and functional changes suggestive of reduced tumorigenicity. By mass spectrometry, G34W-mutant GCT cell lines display decreased level of Lysine 36 trimethylation (H3K36me3) on the mutant G34-peptide, similar to G34-mutated pGBM cell lines. However, unlike pGBMs, GCTs display increased levels of Lysine 36 dimethylation (H3K36me2) on the mutant G34W-peptide. Ongoing Experiments and Analyses: We are currently comparing the level and distribution of multiple histone marks by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) of CRISPR-edited wild-type clones relative to the parent G34W-mutant GCT line. We are also assessing differential gene expression by RNA-Seq and characterizing the methylation signature by 850K DNA methylation array of G34W-mutant GCTs and edited clones. Conclusion: The G34W-mutation clearly has an impact on tumorigenic potential, as evidenced by in vitro functional assays. The G34W-mutant peptide of GCT cell lines features a distinct profile of post-translational histone modifications compared to G34R- or G34V-mutant peptides of pGBM cell lines. Further investigation could elucidate the epigenetic mechanism(s) through which the G34W mutation confers its tumorigenic properties. Citation Format: Shriya Deshmukh, Sima Khazaei, Dylan Marchione, Ashot Harutyunyan, Benjamin Garcia, Nada Jabado. Characterizing the epigenetic effects of the histone 3.3 G34W mutation in giant cell tumors of bone [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A39.
Abstract 323: Metabolic Transformation of Fatty Acids Defines Resolving Versus Non-Resolving Inflammation in Obesity-Associated Heart Failure
Authors: Ganesh V Halade, Vasundhara Kain, Xavier de la Rosa, Paul C Norris, Kevin A Ingle, Sumanth D Prabhu, Charles N Serhan
Journal: Circulation Research (2017)

Whether and how fat intake contributes to persistent inflammation in obesity is unclear. Here, we report the differential metabolic transformation of fatty acids in heart failure (HF) pathology in the setting of obesity. We used permanent coronary ligation to induce myocardial infarction (MI) leading to acute (d1), healing phase (d5) and subsequent chronic HF phase (d28) in male C57BL/6J mice, while maintaining naïve controls at day (d)0. Prior to MI, 100 two month-old mice were subjected to n-6 fatty acids (safflower oil; SO; 22Kcal) for 3 months, with subsequent randomized allocation of 50 mice to docosahexaenoic acid (DHA; 22Kcal) enriched n-3 fatty acids for the next 2 months, while maintaining SO control in the remaining 50 mice. Both groups gained significant weight and fat mass independent of lean mass confirmed by magnetic resonance imaging. Post-MI survival and left ventricular (LV) function was decreased in SO-fed mice with downregulation of multiple inflammation resolution mechanisms in the spleen, infarcted LV, and kidney. DHA increased Ly6C low macrophages, MRC, Arg-1, YM1 and FFAR4 (GPR120) during the acute and resolving phase from d1 to d5 post-MI as compared with SO-fed mice. DHA-improved post-MI survival at d28, together with increased levels of D-series resolvins (RvD1, RvD2, RvD4, RvD5), maresin 1, and RvE3, and lower levels of prostaglandins (PGD 2 , PGE 2 , PGF2 α ), leukotriene B 4 (LTB 4 ), 20-OH-LTB 4 , thromboxane B2 and lipoxin A 4 in the resolving phase. During chronic HF at d28 post-MI, DHA increased CD4 + /CD127 - with increased expression of FOXp3 in the LV. DHA reduced FFAR1-3 , neprilysin activity and simultaneously increased FFAR4 in the kidney as compared with SO post-MI. In contrast, SO-induced overactivation of pro-inflammatory FFAR1 (GPR40) and reduction of anti-inflammatory FFAR4 tracked with increased serum creatinine and IL-1β, and decreased ALX/ FPR2 in kidney at d28 post-MI. Overall, DHA intake modulates the splenocardiac resolving phase with generation of proresolving mediators, augmentation of Ly6C low macrophages, and suppression of prostaglandins post-MI. Thus, the metabolic transformation of n-3 and -6 fatty acids can regulate resolution versus non-resolution of inflammation in HF post-MI in the setting of obesity.
Credo for optimality
Authors: Alan A. Stocker
Journal: Behavioral and Brain Sciences (2018)

Abstract Optimal or suboptimal, Rahnev &amp; Denison (R&amp;D) rightly argue that this ill-defined distinction is not useful when comparing models of perceptual decision making. However, what they miss is how valuable the focus on optimality has been in deriving these models in the first place. Rather than prematurely abandon the optimality assumption, we should refine this successful normative hypothesis with additional constraints that capture specific limitations of (sensory) information processing in the brain.