tbuckley/cabot-search huggingface dataset:
Studying the Exposome to Understand the Environmental Determinants of Complex Liver Diseases
Authors: Angela C. Cheung, Douglas I. Walker, Brian D. Juran, Gary W. Miller, Konstantinos N. Lazaridis
Journal: Hepatology (2019)

Cheung, Angela C.; Walker, Douglas I.; Juran, Brian D.; Miller, Gary W.; Lazaridis, Konstantinos N. Author Information
Clinical, Immunophenotypic and Genetic Characteristics of Aggressive (non-Burkitt) B-Cell Lymphoma in a Real Life Cohort
Authors: Louise Roulin, Jean-Philippe Jais, Alina Nicolae, Elsa Poullot, Cyrielle Robe, Francois Lemonnier, Fabien Le Bras, Alizee Maarek, Karim Belhadj, Jehan Dupuis, Elodie Scherman, Mohammad Hammoud, Taoufik El Gnaoui, Sebastien Mule, Emmanuel Itti, Asma Beldi-Ferchiou, Marie Helene Delfau Larue, Philippe Gaulard, Corinne Haioun, Christiane Copie
Journal: Blood (2019)
Disease trajectories in childhood atopic dermatitis
Authors: A.D. Irvine, P. Mina‐Osorio
Journal: British Journal of Dermatology (2019)

Eczema (also known as atopic dermatitis or AD) is a complex skin condition that generally develops in early childhood, affecting 15 to 20% of children worldwide. Although it clears by itself in some children, it persists into adulthood in many children, contrary to popular belief. Many children develop related allergic diseases such as asthma, allergic rhinitis and eosinophilic oesophagitis (allergic inflammation of the oesophagus), a pathway known as the “atopic march”. The authors, based in Ireland and the U.S.A., aimed to find reproducible patterns (i.e. clinically relevant characteristics) that could help doctors predict whether childhood AD will clear or progress, by surveying several recent studies with large patient cohorts (groups studied). These studies show that most atopic children, in fact, do not follow the classical “atopic march” but can follow various disease courses. Although the data came from different sources or were described in different ways, the authors identified common characteristics of early‐childhood AD that may help estimate risk of developing persistent disease (i.e. that progresses into adulthood) and related allergic diseases. They found that children who get severe AD at a very young age and who have parents with a history of related diseases, have a higher risk of disease progression. Genetic factors, allergies, and living in an urban environment also increase this risk. The authors provide a practitioner's guide that could help doctors to identify children with AD at higher risk of disease progression and to decide on the best course of action for their treatment, such as regular check‐ups or referring them to a specialist for further testing or treatment.
SM09419, a Novel, Small-Molecule CDC-like Kinase (CLK) Inhibitor, Demonstrates Strong Inhibition of the Wnt Signaling Pathway and Antitumor Effects in Mantle Cell Lymphoma Models
Authors: Heekyung Chung, Emily Creger, Lauren Sitts, Kevin Chiu, Chi-Ching Mak, Sunil KC, Betty Tam, Gail Bucci, Josh Stewart, Timothy Phalen, Steven Cha
Journal: Blood (2019)
MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect
Authors: Daniel Esposito, Jochen Weile, Jay Shendure, Lea M. Starita, Anthony T. Papenfuss, Frederick P. Roth, Douglas M. Fowler, Alan F. Rubin
Journal: Genome biology (2019)

Multiplex assays of variant effect (MAVEs), such as deep mutational scans and massively parallel reporter assays, test thousands of sequence variants in a single experiment. Despite the importance of MAVE data for basic and clinical research, there is no standard resource for their discovery and distribution. Here, we present MaveDB ( https://www.mavedb.org ), a public repository for large-scale measurements of sequence variant impact, designed for interoperability with applications to interpret these datasets. We also describe the first such application, MaveVis, which retrieves, visualizes, and contextualizes variant effect maps. Together, the database and applications will empower the community to mine these powerful datasets.
TMOD-23. PRECLINICAL DRUG EVALUATION IN A GENETICALLY ENGINEERED MINIPIG MODEL OF NEUROFIBROMATOSIS TYPE 1
Authors: Sara Osum, Anat Stemmer-Rachamimov, Brigitte Widemann, Eva Dombi, Jeremie Vitte, Sonika Dahiya, Tilat Rizvi, Nancy Ratner, Ludwine Messiaen, David Gutmann, Marco Giovannini, Christopher Moertel, David Largaespada, Adrienne Watson
Journal: Neuro-Oncology (2019)

Abstract We have employed gene-editing technology to create a Neurofibromatosis Type 1 (NF1) minipig that replicates the broad spectrum of disease that develops in NF1 patients and meets the National Institute of Health’s diagnostic criteria for NF1. The NF1 boars are fertile and the NF1 mutant allele is transmitted at a Mendelian rate with no reduction in fitness of offspring that inherit this allele. To date, we have observed 100% penetrance of café au lait macules, a phenotype that occurs in nearly every NF1 patient, but has never been demonstrated in any other animal model. The NF1 minipig develops cutaneous neurofibromas and optic pathway glioma, that histologically resemble human tumors. Additionally, we have observed other NF1-associated phenotypes including Lisch nodules, tibial dysplasia, white matter decompaction, hypopigmentation, and freckling of the skin. The FDA has emphasized the need for development and testing of new therapies in large animal disease models prior to human studies. Therefore, we have conducted pharmacological studies in our NF1 swine to look at the pharmacokinetic and pharmacodynamic properties MEK inhibitors, currently in clinical trials for NF1. We have demonstrated that oral administration of the MEK inhibitors results in clinically relevant plasma levels of the drug and inhibition of Ras signaling, and that certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. We envision this large animal model of NF1 will become a standard in the evaluation of the safety and efficacy of new drugs prior to Phase I clinical trials. Further, an NF1 minipig may enable researchers to better understand the biological and genetic mechanisms underlying this complex disease, detect NF1-related tumors earlier, identify biomarkers, discover novel drug targets, and test new drugs and combination therapies for safety and efficacy.
STEM-18. DISTINCT BUT PREDICTABLE MECHANISMS DRIVE GENETIC VS. EPIGENETIC RESISTANCE TO TARGETED THERAPY
Authors: Joshy George, Yaohui Chen, Nourhan Abdelfattah, Keiko Yamamoto, Scott Adamson, Bradley Rybinski, David Baskin, Jeffrey Chuang, Kyuson Yun
Journal: Neuro-Oncology (2019)

Abstract Emergence of therapy resistance greatly reduces long-term utility of effective targeted therapies, including SMO/SHH pathway inhibitors. SHH signaling is activated in ~25% of human medulloblastomas (MB) and FDA approved SMOi (to treat basal cell carcinoma (BCC)) are currently in clinical trials for MBs and acute myeloid leukemia (AML). Accumulating clinical experience suggests that a significant number of BCC patients treated with SMOi develop acquired resistance over time and some show de novo resistance. A similar pattern is observed in MB patients, indicating the need to elucidate resistance mechanisms, particularly those driving de novo vs. acquired resistance, and develop new strategies to overcome both de novo and acquired resistance to SMOi. We report that we have discovered a novel, epigenetic mechanism of therapy resistance to SMOi that underlie de novo resistance. Using two different mouse models of SHH MB, we tested our original hypothesis that the selective pressure on cancer stem cells (CSCs), but not bulk tumor cells, will determine the resistance mechanism at the molecular level. We show that acquired mutations in the SHH pathway genes (previously reported mechanism of resistance) occur only in tumors that contain CSCs that depend on the SHH pathway. In tumors where only the bulk tumor cells, but not CSCs, depend on SHH signaling, no acquired mutations in the SHH pathway genes are detected. Instead, in these tumors, epigenetic reprogramming through selective degradation of specific histone modifiers results in global changes in the epigenetic cell state and gene expression patterns. Importantly, we can predict the mechanism of resistance in individual tumors prior to treatment based on CSC phenotypes. Finally, we also report biomarkers that can be used to identify tumors with CSCs that are independent of SHH pathway, which can be exploited to design anticipatory combination therapies in the future.
The Increase on Th1 and CD8+T Levels While a Decrease on Treg Level after Dasatinib Treatment Indicate a Better Therapeutic Response to Dasatinib and Deeper Clinical Remission in Chronic Myelogenous Leukemia Patients
Authors: Jingying Dai, Hong Zheng, Xiaobing Huang, Xi Yang, Xiaodong WANG
Journal: Blood (2019)
RTHP-38. THE FEASIBILITY OF PSYCHOLOGICAL INTERVENTIONS FOR REDUCE THE NEED OF ANESTHESIA DURING RADIOTHERAPY IN &lt; 5 YR PEDIATRIC PATIENTS WITH CNS MALIGNANCIES
Authors: Linbo Cai, Juan Li, Mingyao Lai, Qingjun Hu, Xing Zhang
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVES The aim of this study was to explore the psychological intervention to reduce the use of sedatives in children when undergoing radiotherapy. METHODS From January 2017 to December 2018, 53 pediatric patients, without limited consciousness, from 3 to 5 years old diagnosed with brain tumors and admitted to radiotherapy at the oncology centers of Guangdong Sanjiu Brain Hospital, received the systematic intervention (including desensitization, simulation play practice, distraction, etc.) to reduce medical fear for radiotherapy. A case-control study of semi-structured and play-based interventions was undertaken for psychological preparation of young children during radiotherapy. RESULTS After receiving interventions, 49 children were willing to cooperate with treatment, with the success rate of 92.45%. There were 19 children behaving cooperative in the 3-year-old group, while there were both 17 patients showing compliance in the 4-year-old group and 5-year-old group. Compared with the success rate of the 3-year-old group (84.21%), psychological interventions were more appropriate for the 4-year-old group (94.12%) and 5-year-old group (100%). For those failed cases, 2 children aged 3 used anesthesia during the whole radiotherapy sessions; 2 children aged 3 and 4 took sedatives in the early session of radiotherapy. CONCLUSION This study suggested that psychological intervention was able to improve the adherence of pediatric patients to the whole treatment course and reduce the occurrence of drug resistance due to non-compliance.
Phosphatidylinositol 3-Kinase (PI3K) Inhibitors-Related Hematological Toxicities in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma
Authors: Bradley J. Grant, Anita Sultan, Nicholas D'Cunha, Chandler Graf, Sriman Swarup, Myint Aung Win, Ei Moe Phyu, Thura Win Htut, Myat Min Han, Yin Mon Myat, Nimesh Adhikari, Nyein Htway Yu, Donald P. Quick, Kyaw Zin Thein
Journal: Blood (2019)
Phase I Trial of Escalating Doses of the Bcl-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction and High Dose Cytarabine Consolidation in Previously Untreated Adults with Acute Myeloid Leukemia ( AML)
Authors: Richard M. Stone, Daniel J. DeAngelo, Ilene Galinsky, Caroline Kokulis, Jeremy M. Stewart, Michael McGinnis, Lillian Werner, Anthony G. Letai, Marina Y Konopleva, Marlise Luskin
Journal: Blood (2019)
A Phase I Study of Asciminib (ABL001) in Combination with Dasatinib and Prednisone for Untreated BCR-ABL1-Positive ALL in Older Adults
Authors: Marlise Luskin, Mark A. Murakami, Kristen E. Stevenson, Martha Wadleigh, Malgorzata McMasters, Peter Winter, David M. Weinstock, Richard Stone, Daniel J. DeAngelo
Journal: Blood (2019)
TMIC-03. UPREGULATION OF THE NLRC4 INFLAMMASOME CONTRIBUTES TO POOR PROGNOSIS IN GLIOMA PATIENTS
Authors: Jaejoon Lim, Youngjoon Park, Minjun Kim, Juwon Ahn, KyuBum Kwack, Kyunggi Cho
Journal: Neuro-Oncology (2019)

Abstract Inflammation in tumor microenvironments is implicated in the pathogenesis of tumor development. In particular, inflammasomes, which modulate innate immune functions, are linked to tumor growth and anticancer responses. However, the role of the NLRC4 inflammasome in gliomas remains unclear. Here, we investigated whether the upregulation of the NLRC4 inflammasome is associated with the clinical prognosis of gliomas. We analyzed the protein expression and localization of NLRC4 in glioma tissues from 11 patients by immunohistochemistry. We examined the interaction between the expression of NLRC4 and clinical prognosis via a Kaplan-Meier survival analysis. The level of NLRC4 protein was increased in brain tissues, specifically, in astrocytes, from glioma patients. NLRC4 expression was associated with a poor prognosis in glioma patients, and the upregulation of NLRC4 in astrocytomas was associated with poor survival. Furthermore, hierarchical clustering of data from the Cancer Genome Atlas dataset showed that NLRC4 was highly expressed in gliomas relative to that in a normal healthy group. Our results suggest that the upregulation of the NLRC4 inflammasome contributes to a poor prognosis for gliomas and presents a potential therapeutic target and diagnostic marker.
QOLP-05. PREDICTING SURVIVAL WITH THE HEIDELBERG PROGNOSTIC MODEL AFTER SALVAGE STEREOTACTIC RADIOSURGERY OF PREVIOUSLY IRRADIATED PROGRESSIVE HIGH-GRADE GLIOMAS
Authors: Federico Ampil, Troy Richards, Nestor dela Cruz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The concept of repeat radiotherapy for previously irradiated, progressive high-grade gliomas (PHGG) is intuitively rational for a disease that has the potential to be a life-threatening illness and seriously affect the quality of remaining life. Recently, a simplified method of prognosis prediction (the Heidelberg prognostic model/HPM) was developed to evaluate survival after re-irradiation of PHGGs. OBJECTIVE This retrospective study aimed to assess whether salvage stereotactic radiosurgery (SSRS) is worthwhile in patients with PHGGs, and to determine which individuals are likely to benefit from retreatment using the HPM. METHODS Three hundred eighty-three people were diagnosed with intracranial glioma between 2000 and 2010 at our institution. From this population, 25 patients (7%) who had a history of prior irradiation and underwent SSRS for PHGGs formed the subjects of this clinical audit. In the HPM system, scores were assigned for clinicopathological features such as age, histology and interval duration between treatments. There were five and 20 patients with HPM determined low and high prognostic scores, respectively. The mean follow-up period was 9.9 months. RESULTS Overall median survival (MS) was 7 months, and the 6, 12- and 24-months crude survival rates (CSR) were 60%, 28% and 16%, respectively. The MS and CSRs for the low scoring patients were 20 months, 100%, 100% and 20%, respectively; for the 20 high-scoring individuals, the corresponding findings were 8 months, 75%, 35% and 10%, respectively. Among the evaluable 11 people, the quality of life was acceptable in approximately half of the cases. Local recurrence rate after SSRS was 12%. Adverse-related events were not observed. CONCLUSION A trend towards improved survival was observed in the HPM low-scoring patients. More documentation of favorable effects is required to support the useful role of SSRS as second line treatment of PHGGs.
NIMG-65. PREDICTING PROGNOSIS AND CANCER HOTSPOT MUTATIONS USING QUALITATIVE MR IMAGING ANALYSIS IN GLIOBLASTOMA
Authors: Maikel Verduin, Inge Compter, Sergey Primakov, Sander van Kuijk, Maarten te Dorsthorst, Elles Revenich, Mark ter Laan, Sjoert Pegge, Anton Meijer, Jan Beckervordersandforth, Ernst Jan Speel, Arthur Jochems, Wendy de Leng, Monique Anten, Martijn Broen, Linda Ackermans, Olaf Schijns, Marc Vooijs, Vivianne Tjan-Heijnen, Philippe Lambin, Danielle Eekers, Linda Jacobi-Postma, Ann Hoeben
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Tumor heterogeneity poses one of the major limitations in improving the treatment for glioblastoma (GBM), which calls for new clinically relevant predictive models. This study aims to investigate non-invasive diagnostic methods, including patient characteristics and qualitative imaging analysis as a prognostic classifier and predictor for druggable oncogenes. METHODS We performed a retrospective analysis on 143 GBM patients (discovery cohort). Diagnostic MRIs were re-analyzed for qualitative imaging features (VASARI features). DNA was extracted from formalin-fixed, paraffin-embedded GBM tissue of the discovery cohort for next-generation sequencing (Ion Torrent Cancer Hotspot panel v2Plus), TERT-promoter mutation and MGMT-methylation analysis. Multivariable regression analysis was used to determine the prognostic and predictive value of VASARI features. RESULTS Of the 143 patients, median age was 61.4 years (range 15.5–84.6) with a median overall survival of 12 months (range 0–142). We observed IDH1 R132H mutation in 8.5%, MGMT-promotor methylation in 26.1%, TERT-promotor mutation (C250T;C228T) in 69.5%, EGFR mutation in 20.3% and EGFR amplification in 37.5% of all patients. A set of eight VASARI features was identified to be associated with overall survival (p&lt; 0.001), which is currently being validated in an external dataset (n= 184). Interestingly, VASARI features appeared to be associated with IDH1-mutation (four features, p=0.004), TERT-promotor mutation (five features, p-value &lt; 0.001), EGFR mutation (five features, p-value &lt; 0.001) and EGFR amplification (seven features, p-value &lt; 0.001) but not with MGMT-methylation (two features, p-value=0.054). Additional cancer hotspots are currently being analyzed and internal validation is ongoing. CONCLUSION AND FUTURE PERSPECTIVES We propose an integrated prognostic classifier comprising MRI features, also associated with GBM-specific molecular alterations. Additionally, quantitative MRI radiomics features are being extracted from the discovery and validation set and incorporated in the prognostic classifier. Subsequently, radiomics and VASARI features will be correlated to intratumoral heterogeneity, assessed by tissue micro-array analysis of the discovery cohort.
Bleeding peptic ulcer.
Authors: A. Banning, A. Baron, H. Kopelman, K. L. Lam, P. Warren
Journal: BMJ (1965)

crash into our textbooks of physiology and of information theory.But most thinking neurologists look askance at all cerebral diagram-makers and cartographers, whether they tell of cortical architectonics, motor homunculi, suppressor bands, or linguistic schemata.Mindful of the fate of phrenology, modern neurology has but little respect for cere- bral mosaics.How then should we judge Gall to-day, after we have divorced the accomplishments of the man from the record of his phrenological votaries?Gall represents a "great though misguided, and perhaps even slightly ridiculous, figure in the rise of a progressive science."This, according to Temkin, was the verdict of the historians of philosophy, Littr6 and Leaves.Perhaps they were a little too hard.To contemporary neuro- logists Gall was a great man.May I, in conclusion, quote that inspiring anatomist, the mentor of so many of us older medical scientists?" The time has come," he wrote, " for a juster appreciation of the important part played by Gall, and a more adequate recogni- tion of his achievements than has been made in the past.If he was responsible for certain speculations, which in the hands of irresponsible followers have been used for meretricious purposes, it must not be forgotten that Gall's work brought to an end a barren system of philosophy which seriously impeded progress.His contributions to the anatomy of the central nervous system are of far-reaching importance, and to the physiology of the brain and to psychological theory he gave a new orientation and a new inspiration."These were the words of Elliot Grafton Smith, with which you and I might perhaps agree.
<i>Grp78</i> Loss in Epithelial Progenitors Reveals an Age-linked Role for Endoplasmic Reticulum Stress in Pulmonary Fibrosis
Authors: Zea Borok, Masafumi Horie, Per Flodby, Hongjun Wang, Yixin Liu, Sivagini Ganesh, Amy L. Firth, Parviz Minoo, Changgong Li, Michael F. Beers, Amy S. Lee, Beiyun Zhou
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Alveolar epithelial cell (AEC) injury and dysregulated repair are implicated in the pathogenesis of pulmonary fibrosis. Endoplasmic reticulum (ER) stress in AEC has been observed in idiopathic pulmonary fibrosis (IPF), a disease of aging.
Sensitive Monitoring of BCR-ABL1 Kinase Domain Mutations By Next Generation Sequencing for Optimizing Clinical Decisions in Philadelphia-Positive Acute Lymphoblastic Leukemia in the Graaph-2014 Trial
Authors: Jean-Michel Cayuela, Francois Lay, Yves Chalandon, Philippe Rousselot, Xavier Thomas, Violaine Havelange, Francoise Huguet, Patrice Chevallier, Anne Thiebaut-Bertrand, Sylvain Chantepie, Nicolas Boissel, Norbert Vey, Martine Escoffre-Barbe, Franciane Paul, Celine Berthon, Isabelle Plantier, Mathilde Hunault, Carlos Graux, Veronique Lheritier, Sylvie Chevret, Hervé Dombret
Journal: Blood (2019)
Transcriptomic and Metabolomic Profiling Identifies Calcium-Dependent Signaling Mechanisms As a Novel and Exploitable Target to Overcome Anti-CD20 Resistance in Non-Hodgkin Lymphoma (NHL)
Authors: Ravi Dashnamoorthy, Saheli Sarkar, Afshin Beheshti, Maisarah Mokhtar, Tali Konry, Michael Levin, Andrew M. Evens
Journal: Blood (2019)
Observation on the Efficacy of Consolidation Chemotherapy Combined with Allogeneic Natural Killer Cell Infusion in the Treatment of Low and Moderate Risk AML
Authors: Hao Jiang, Xiaojun Huang, Chunjian Wang, Lizhong Gong, Jinsong Jia, Xiaohong Liu, Yu Wang, Chenhua Yan, Yingjun Chang, Xiaosu Zhao, Hongxia Shi
Journal: Blood (2019)
In-Hospital Complications and Outcomes of Autologous Stem Cell Transplantation in Multiple Myeloma Patients Older Than 65-Years Old in the United States: National Inpatient Sample Analysis, 2011-2015
Authors: Veli Bakalov, Amy Tang, Hira G. Shaikh, Shrunjal Shah, Zena Chahine, Robert B. Kaplan, John Lister, Santhosh Sadashiv
Journal: Blood (2019)