tbuckley/cabot-search huggingface dataset:
T Cell Epitope Predictions
Authors: Bjoern Peters, Morten Nielsen, Alessandro Sette
Journal: Annual Review of Immunology (2020)

Throughout the body, T cells monitor MHC-bound ligands expressed on the surface of essentially all cell types. MHC ligands that trigger a T cell immune response are referred to as T cell epitopes. Identifying such epitopes enables tracking, phenotyping, and stimulating T cells involved in immune responses in infectious disease, allergy, autoimmunity, transplantation, and cancer. The specific T cell epitopes recognized in an individual are determined by genetic factors such as the MHC molecules the individual expresses, in parallel to the individual's environmental exposure history. The complexity and importance of T cell epitope mapping have motivated the development of computational approaches that predict what T cell epitopes are likely to be recognized in a given individual or in a broader population. Such predictions guide experimental epitope mapping studies and enable computational analysis of the immunogenic potential of a given protein sequence region.
Fecal Microbiome Distinguishes Alcohol Consumption From Alcoholic Hepatitis But Does Not Discriminate Disease Severity
Authors: Ekaterina Smirnova, Puneet Puri, Mark D. Muthiah, Kalyani Daitya, Robert Brown, Naga Chalasani, Suthat Liangpunsakul, Vijay H. Shah, Kayla Gelow, Mohammed S. Siddiqui, Sherry Boyett, Faridoddin Mirshahi, Masoumeh Sikaroodi, Patrick Gillevet, Arun J. Sanyal
Journal: Hepatology (2020)

The role of the intestinal microbiome in alcoholic hepatitis is not established. The aims of this study were to (1) characterize the fecal microbial ecology associated with alcoholic hepatitis, (2) relate microbiome changes to disease severity, and (3) infer the functional relevance of shifts in microbial ecology.The fecal microbiome in patients with moderate alcoholic hepatitis (MAH) or severe alcoholic hepatitis (SAH) was compared with healthy controls (HCs) and heavy drinking controls (HDCs). Microbial taxa were identified by 16S pyrosequencing. Functional metagenomics was performed using PICRUSt. Fecal short chain fatty acids (SCFAs) were measured using a liquid chromatography-mass spectrometry platform. A total of 78 participants (HC, n = 24; HDC, n = 20; MAH, n = 10; SAH, n = 24) were studied. HDC had a distinct signature compared with HC with depletion of Bacteroidetes (46% vs. 26%; P = 0.01). Alcoholic hepatitis was associated with a distinct microbiome signature compared with HDC (area under the curve = 0.826); differential abundance of Ruminococcaceae, Veillonellaceae, Lachnospiraceae, Porphyromonadaceae, and Rikenellaceae families were the key contributors to these differences. The beta diversity was significantly different among the groups (permutational multivariate analysis of variance [PERMANOVA] P < 0.001). SAH was associated with increased Proteobacteria (SAH 14% vs. HDC 7% and SAH vs. HC 2%, P = 0.20 and 0.01, respectively). Firmicutes abundance declined from HDC to MAH to SAH (63% vs. 53% vs. 48%, respectively; P = 0.09, HDC vs. SAH). Microbial taxa did not distinguish between MAH and SAH (PERMANOVA P = 0.785). SCFAs producing bacteria (Lachnospiraceae and Ruminococcaceae) were decreased in alcoholic hepatitis, and a similar decrease was observed in fecal SCFAs among alcoholic hepatitis patients.There are distinct changes in fecal microbiome associated with the development, but not severity, of alcoholic hepatitis.
Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis
Authors: Florian J. Weisel, Steven J. Mullett, Rebecca A. Elsner, Ashley V. Menk, Nikita Trivedi, Wei Luo, Daniel Wikenheiser, William F. Hawse, Maria Chikina, Shuchi Smita, Laura J. Conter, Stephen M. Joachim, Stacy G. Wendell, Michael J. Jurczak, Thomas H. Winkler, Greg M. Delgoffe, Mark J. Shlomchik
Journal: Nature Immunology (2020)
Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm
Authors: Johanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurélie Plessier, Salma Merchant, Olivier Blanc-Brude, Michèle Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N. Hatem, Chloé James, Jean-Luc Villeval, Chantal M. Boulanger, Pierre-Emmanuel Rautou
Journal: Journal of Clinical Investigation (2020)

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.
Archived bone marrow smears are an excellent source for NGS-based mutation detection in acute myeloid leukemia
Authors: Adil S. A. Al Hinai, Tim Grob, François G. Kavelaars, Melissa Rijken, Annelieke Zeilemaker, Claudia A. J. Erpelinck-Verschueren, Kirsten J. Gussinklo, Mathijs A. Sanders, Kirsten van Lom, Peter J. M. Valk
Journal: Leukemia (2020)
Abstract 16757: Machine Learning-Based Classification of Echocardiographic Measurements Significantly Improves Accuracy in Predicting Mortality Over Standard Clinical Variables
Authors: Manar D Samad, Alvaro E Ulloa Cerna, Gregory J Wehner, Dustin N Hartzel, Christopher M Haggerty, Brandon K Fornwalt
Journal: Circulation (2017)

Introduction: Predicting patient outcomes (such as survival) following echocardiography is primarily based on ejection fraction (EF) and comorbid diagnoses. However, there may be a wealth of predic...
A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions
Authors: Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Greg J. Robinson, Melanie Rampton, Suzanne Elliott, Anand Odedra, David Khoury, Emma Ballard, Todd B. Shelper, Leonardo Lucantoni, Vicky M. Avery, Stephan Chalon, Joerg J. Moehrle, James S. McCarthy
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDInterventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naive individuals.METHODSHealthy, malaria-naive adults were enrolled in 2 studies to assess the safety, infectivity, and transmissibility of a new P. vivax isolate. Participants (Study 1, n = 2; Study 2, n = 24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes.RESULTSParasitemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Sixty-nine percent of participants (11/16) were infectious to Anopheles mosquitoes at peak gametocytemia. Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture.CONCLUSIONWe have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle.TRIAL REGISTRATIONACTRN12614000930684 and ACTRN12616000174482.FUNDING(Australian) National Health and Medical Research Council Program Grant 1132975 (Study 1). Bill and Melinda Gates Foundation (OPP1111147) (Study 2).
Autophagy and autophagy-related proteins in cancer
Authors: Xiaohua Li, Shikun He, Binyun Ma
Journal: Molecular Cancer (2020)

Abstract Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy.
Abstract 15777: Bronchoalveolar Lavage, Lung, and Mediastinal Lymph Node Biopsy Have a High Diagnostic Yield in Patients With Suspected Cardiac Sarcoidosis Regardless of Chest CT Findings
Authors: Bradley J Petek, David G Rosenthal, Jonathan M Keller, Bridget F Collins, Lawrence A Ho, Kristen K Patton, Richard K Cheng, Paco E Bravo, Carmen Mikacenic, Ganesh Raghu
Journal: Circulation (2017)

Background: The diagnosis of cardiac sarcoidosis (CS) is difficult to ascertain due to the insensitivity of endomyocardial biopsy and lack of other definitive interventions. Patients suspected to h...
Abstract P5-06-07: Desloratadine and loratadine increase breast cancer survival
Authors: Håkan Lars Olsson, Ildiko Fritz, Philippe Wagner
Journal: Cancer Research (2020)

Abstract Background: As tumors maintain an inflammatory microenvironment, anti-inflammatory medication can be used in cancer therapy. While H2-antihistamines have already shown effects as adjuvant anti-cancer drugs, H1-antihistamines have not been widely studied in this role, though they are among the most ubiquitously used medications globally, and have become increasingly sophisticated, affordable, and safe. Here, we aim to determine the effects of H1-antihistamines on breast cancer mortality. Methods: We investigated the effects of six H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) on breast cancer-specific and overall mortality in a nation-wide register-based study of all 61,627 Swedish women with newly diagnosed breast cancer July 1st 2005 - December 31st 2013. 14,711 women used H1-antihistamines. Both peri- and post-diagnostic antihistamine use was analyzed, using Cox regression models, and use in patient subgroups based on age or estrogen receptor status. Results: We found a consistently beneficial effect of desloratadine use (HR = 0·67; 95% CI 0·55-0·81, P &amp;lt; 0·001) on survival, as well as of loratadine use (HR = 0·80; 95% CI 0·67-0·95, P = 0·012), regardless of age or estrogen receptor status, or whether breast cancer-specific or overall survival was analyzed, and a consistently negative effect on survival of clemastine use (HR = 1·45; 95% CI 1·27-1·67, P &amp;lt;0·001). Conclusions: We suggest immediate trials of desloratadine and loratadine as adjuvant treatment of breast cancer. Especially promising is the results for ER-breast cancer. Further studies on the effects of ebastine and possibly fexofenadine may be merited, as well as further studies of H1-antihistamines, particularly desloratadine, as treatment options for other malignancies. Breast cancer survival adjusted for prognostic factorsTypeHRLow CIHighCIUp-valueCetirizin1.160.981.350.07clemasine1.341.131.590.0006desloratadine0.680.550.860.001ebastin0.490.270.860.01fexofenadin1.060.571.970.85loratadine0.780.620.960.02 Citation Format: Håkan Lars Olsson, Ildiko Fritz, Philippe Wagner. Desloratadine and loratadine increase breast cancer survival [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-07.
Our Wild Companions: Domestic cats in the Anthropocene
Authors: Sarah L. Crowley, Martina Cecchetti, Robbie A. McDonald
Journal: Trends in Ecology & Evolution (2020)

Cats share a long history with humans but are remarkable among domesticated species in largely retaining behavioural and reproductive independence from people. In many societies, the cat maintains liminal status as both a domestic and a wild animal. An adaptive push-and-pull between wild and domestic traits corresponds with dual roles as companions and pest controllers, and with conflicted treatment in husbandry, management, law, and public discourse. To move forward, we must proceed by understanding that cats are not exclusively pets or pests, but both a central component of human societies and an important, often adverse, influence on ecosystems. Developing a collaborative 'companion animal ecology', in which human-animal domestic relations link to ecological processes, will enable sustainable management of this wild companionship.
Abstract MS2-2: Targeting the cell cycle - Beyond CDK4/6 inhibition
Authors: R Jeselsohn
Journal: Cancer Research (2020)

Abstract Over the past several years three CDK4/6 inhibitors were approved for the treatment of metastatic ER+ breast cancer. This class of drug has had a major impact on patient outcomes and more recent analyses showed improvement in overall survival in addition to a significant delay in the need for chemotherapy and increase in progression free survival. Despite the remarkable clinical benefit, there are patients who have primary resistance to CDK4/6 inhibitors and the majority of patients will ultimately develop resistance to this class of drugs. Multiple pre-clinical studies and some clinical data have provided insights to the mechanisms of resistance to CDK4/6 inhibitors guiding the development of clinical trials after progression on a CDK4/6 inhibitor. In this presentation, I will review the mechanisms of resistance to CDK4/6 inhibitors and the ongoing clinical trials investigating novel therapeutic strategies to enhance responses to CDK4/6 inhibitors and for treatment after the acquisition of resistance to CDK4/6 inhibitors. Citation Format: R Jeselsohn. Targeting the cell cycle - Beyond CDK4/6 inhibition [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS2-2.
Hemopexin deficiency promotes acute kidney injury in sickle cell disease
Authors: Solomon Ofori-Acquah, Rimi Hazra, Oluwaseun O Orikogbo, Danielle Crosby, Bethany Flage, Ezekiel Bonwin Ackah, Diane Lenhart, Roderick J Tan, Dario A Vitturi, Vivian Paintsil, Ellis Owusu-Dabo, Samit Ghosh
Journal: Blood (2020)
Response to: ‘Corresponence on ‘Shared epitope defines distinct associations of cigarette smoking with levels of anticitrullinated protein antibody and rheumatoid factor’ by Ishikawa et al’ by Regueiro and Gonzalez
Authors: Yuki Ishikawa, Katsunori Ikari, Chikashi Terao
Journal: Annals of the Rheumatic Diseases (2020)

focusing on precise molecular mechanisms will be of particular interest.
Abstract OT2-04-01: A prospective, multicentre, open-label, randomized phase II study of PEmbroLizumab in combination with neo-adjuvant (F)EC-paclitaxel regimen in HER2-negative Inflammatory breast CANcer
Authors: Anthony Gonçalves
Journal: Cancer Research (2020)

Abstract Background: Inflammatory breast cancer (IBC) represents a rare but aggressive form of locally advanced BC. In spite of multimodality therapy including neoadjuvant chemotherapy (NAC), radical surgery and radiotherapy, prognosis remains poor, notably in HER2-negative subtypes. Whole-genome and gene expression profiling studies in IBC have identified an immune-enriched signature predicting for pathological complete response (pCR), suggesting a critical role for T-cell cytotoxicity in reaching complete tumor cell elimination after NAC. In addition, overexpression of programmed cell death ligand 1 (PD-L1) mRNA in IBC is more frequent than in non-IBC and has significant correlation with pCR. Pembrolizumab (PEM), an anti- programmed cell death 1 (PD 1) receptor antibody, inhibiting its interaction with PD-L1, is registered or in development across a large range of malignancies. PEM may boost anti-tumor immunity, eradicating residual tumor cells and thus improving pCR and outcome in HER2-negative IBC. Trial design: PELICAN-IPC 2015-016 trial (NCT03515798), sponsored by Institut Paoli-Calmettes with financial support of MSD, is a multicenter, randomized phase II, non-comparative study evaluating the addition of PEM to anthracyclines/taxanes NAC in non-metastatic HER2-negative IBC. Patients will receive 4 cycles of Q3W FEC100 (5FU 500 mg/m², Epirubicin 100 mg/m², Cyclophosphamide 500 mg/m²; non-triple negative) or 4 cycles of Q2W EC (Epirubicin 90 mg/m², Cyclophosphamide 600 mg/m²; triple-negative) followed by Q1W paclitaxel 80 mg/m² x 12, with (arm B) or without (arm A) Q3W IV PEM 200 mg started with C2 FEC/EC. The primary endpoint will be pCR in the experimental arm. The study also includes a run-in safety phase. Secondary endpoints include tolerance, invasive disease-free, event-free and overall survivals in each arms and collection of pre- and post-treatment tissue and blood samples for pharmacodynamics measurements and biological correlates. Following Simon’s 2-stage optimal procedure a total of 54 patients in arm B is required to reject the null hypothesis of a truly ineffective experimental arm (H0: p&amp;lt;= 20%) with 5% error risk and 90% power assuming a true pCR rate of 40%. 27 additional patients will be enrolled in the control arm A. Since June 2018, 7 patients have been enrolled in a single center and 13 additional centers are expected to open before the end of 2019. Citation Format: Anthony Gonçalves. A prospective, multicentre, open-label, randomized phase II study of PEmbroLizumab in combination with neo-adjuvant (F)EC-paclitaxel regimen in HER2-negative Inflammatory breast CANcer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-01.
Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design
Authors: Susann Winter, Saeed Shoaie, Shahram Kordasti, Uwe Platzbecker
Journal: Journal of Clinical Oncology (2020)

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the "immunome" is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.
Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development
Authors: Saireudee Chaturantabut, Arkadi Shwartz, Maija K. Garnaas, Kyle LaBella, Chia‐Cheng Li, Kelli J. Carroll, Claire C. Cutting, Nadine Budrow, Amrita Palaria, Daniel A. Gorelick, Kimberly D. Tremblay, Trista E. North, Wolfram Goessling
Journal: Hepatology (2020)

Background and Aims During liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions. Approach and Results Exposure of zebrafish embryos to 17β‐estradiol (E2) during liver development significantly decreased hepatocyte‐specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor (ESR) signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear ESR activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2 b ( esr2b ) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b−/− mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages, or vasculature. Significantly, E2‐stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, whereas loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development. Conclusions Our studies identify E2, esr2b , and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.