tbuckley/cabot-search huggingface dataset:
Antihistamines and Ovarian Cancer Survival: Nationwide Cohort Study and in Vitro Cell Viability Assay
Authors: Freija Verdoodt, Christian Dehlendorff, Marja Jäättelä, Robert Strauss, Anton Pottegård, Jesper Hallas, Søren Friis, Susanne K Kjaer
Journal: JNCI Journal of the National Cancer Institute (2019)

Antihistamines with cationic amphiphilic drug (CAD) characteristics induce cancer-specific cell death in experimental studies. Epidemiologic evidence is, however, limited. In a Danish nationwide cohort of ovarian cancer patients diagnosed during 2000-2015 (n = 5075), we evaluated the association between filled antihistamine prescriptions and cancer mortality. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer mortality. In an in vitro cell viability assay, we evaluated cell death in three ovarian cancer cell lines after treatment with clinically relevant doses of eight antihistamines. In our cohort study, CAD antihistamine use (≥1 prescription; n = 133) was associated with a hazard ratio of 0.63 (95% CI = 0.40 to 0.99) compared to use of non-CAD antihistamines (n = 304), and we found a tendency toward a dose-response association. In our cell viability assay, we found consistent and dose-dependent cytotoxicity for all CAD but not non-CAD antihistamines. In this nationwide cohort study, use of antihistamines with CAD characteristics is associated with a prognostic benefit in ovarian cancer patients.
How Morphologic Features Are Shaped By Underlying Somatic Genotype in MDS
Authors: Yasunobu Nagata, Ran Zhao, Hassan Awada, Cassandra M Kerr, Abhinav Goyal, Inom Mirzaev, Sunisa Kongkiatkamon, Aziz Nazha, Tomas Radivoyevitch, Jacob Scott, Mikkael A. Sekeres, Brian P. Hobbs, Jaroslaw P. Maciejewski
Journal: Blood (2019)
RARE-29. AZD8055 ENHANCES IN VIVO EFFICACY OF AFATINIB IN CHORDOMAS
Authors: Tianna Zhao, I-Mei Siu, Tara Williamson, Haoyu Zhang, Chenchen Ji, Peter Burger, Lucia Cottone, Adrienne Flanagan, Christine Hann, Gary Gallia
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Chordomas are rare, locally aggressive bone tumors that arise in cranial base, mobile spine, and sacrum. Currently, there are no FDA-approved therapies for chordoma patients, thus there is a high unmet need to develop effective treatments. In this study, we aim to evaluate the anti-tumor efficacy of small molecule inhibitors that target crucial oncogenic pathways in chordoma, as single agents or in combination, to identify novel therapies with the greatest translation potential. METHODS A panel of small molecule compounds that had exhibited in vitro efficacy against human chordoma cell lines or target known chordoma drivers was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and their efficacy was further evaluated using chordoma cell lines and xenograft models. RESULTS The in vivo activity of compounds identified in a NIH Chemical Genomics Center screen utilizing chordoma cell lines, together with inhibitors of c-MET and PDGFR, were evaluated in PDX models of chordoma that were previously described or recently established for this study. Inhibitors of EGFR (BIBX1382, erlotinib and afatinib), c-MET (crizotinib) or mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, co-inhibition of EGFR and mTOR also synergistically suppressed tumor growth in vivo, showing improved disease control. CONCLUSION Single inhibition of EGFR, c-MET or mTOR suppresses chordoma growth both in vitro and in vivo. Co-inhibition of EGFR and mTOR synergistically inhibits chordoma growth in a range of preclinical models. The insights gained from our study provide a novel combination therapeutic strategy for patients with chordoma.
Treatment Use Study of Platelet Components Treated with Amotosalen and Ultraviolet a Light in Response to Emerging Arboviruses in Puerto Rico - True Study Final Results
Authors: Salvador Rico, Susan L. Stramer, Richard J. Benjamin, Edgardo Cartagena, Axel Arroyo, Nelson Robles, Simon Carlo, L Vera, P Solivan-Ortiz, Norman Huang, Claudia Koontz, Travis Berry, Laurence Corash
Journal: Blood (2016)
Optimizing sequencing protocols for leaderboard metagenomics by combining long and short reads
Authors: Jon G. Sanders, Sergey Nurk, Rodolfo A. Salido, Jeremiah Minich, Zhenjiang Z. Xu, Qiyun Zhu, Cameron Martino, Marcus Fedarko, Timothy D. Arthur, Feng Chen, Brigid S. Boland, Greg C. Humphrey, Caitriona Brennan, Karenina Sanders, James Gaffney, Kristen Jepsen, Mahdieh Khosroheidari, Cliff Green, Marlon Liyanage, Jason W. Dang, Vanessa V. Phelan, Robert A. Quinn, Anton Bankevich, John T. Chang, Tariq M. Rana, Douglas J. Conrad, William J. Sandborn, Larry Smarr, Pieter C. Dorrestein, Pavel A. Pevzner, Rob Knight
Journal: Genome biology (2019)

As metagenomic studies move to increasing numbers of samples, communities like the human gut may benefit more from the assembly of abundant microbes in many samples, rather than the exhaustive assembly of fewer samples. We term this approach leaderboard metagenome sequencing. To explore protocol optimization for leaderboard metagenomics in real samples, we introduce a benchmark of library prep and sequencing using internal references generated by synthetic long-read technology, allowing us to evaluate high-throughput library preparation methods against gold-standard reference genomes derived from the samples themselves. We introduce a low-cost protocol for high-throughput library preparation and sequencing.
AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications
Authors: Chenjing Zhu, Yuquan Wei, Xiawei Wei
Journal: Molecular Cancer (2019)

Abstract Molecular targeted therapy for cancer has been a research hotspot for decades. AXL is a member of the TAM family with the high-affinity ligand growth arrest-specific protein 6 (GAS6). The Gas6/AXL signalling pathway is associated with tumour cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, monoclonal antibodies (mAbs), nucleotide aptamers, soluble receptors, and several natural compounds. In this review, we first provide a comprehensive discussion of the structure, function, regulation, and signalling pathways of AXL. Then, we highlight recent strategies for targeting AXL in the treatment of cancer.AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, are likely to improve the survival of many patients. However, future investigations into AXL molecular signalling networks and robust predictive biomarkers are warranted to select patients who could receive clinical benefit and to avoid potential toxicities.
DDIS-19. USING MATCHED PRIMARY AND RECURRENT PEDIATRIC BRAIN TUMOR ORTHOTOPIC MOUSE MODELS(PDOX) TO ILLUSTRATE THE GENETIC REVOLUTION AND TO INFORM NEW ANTI-RECURRENT PERSONALIZED THERAPIES
Authors: Yuchen Du, Mari Kogiso, Frank Braun, Lin Qi, Huiyuan zhang, Holly B Lindsay, Sibo zhao, Marcel Kool, Clifford Stephan, Xiaonan Li
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND AND PURPOSE Despite standard treatment largely benefits patients’ survival, tumors may recur as aggressive, therapy resistant relapses. It is imperative to obtain a better understanding of molecular changes that occur after primary tumor resection and treatment. We established a serial of PDOX models using patient tumor tissues procured at different time of patient clinical history. METHODS Dissociated tumor cells were cultured in vitro and transplanted into mouse brains. DNA and RNA were then extracted from tumor tissues or cells from patient and established xenografts. Whole genome methylation and transcriptomic profiling as well as histological phenotypes were examined. Standard therapies were conducted in xenografts. RESULTS Currently, three sets of matched primary and recurrent tumor xenografts (19850PNET, 100815GGG/GBM and 5958MB) were established. Tumor-take rate increased from 50–70% of primary tumors to 100% of recurrent tumors with decreased tumor onset time (6 months to 3 months), which demonstrated progressive phenotypes. RNA sequencing reveals preserved and newly changed genetic changes in recurrent tumors. High-throughput drug screening discovered a shared and a diverse panel of therapeutic targets that could be selected further for in vivo drug treatment especially for recurrent tumors. Tumor xenografts responded to standard therapy either same or different from clinic outcome, which might indicate the intrinsic or inducible evolutional molecular changes during cancer progression and treatment at different stages. CONCLUSION Three sets of matched primary and recurrent pediatric brain tumors, PNET/PNET, GGG/GBM and MB/MB, were successfully established in pediatric orthotopic mice tumor models (PDOXs) providing clinically-relevant and biologically-accurate animal model systems for development of novel therapeutic targets especially for recurrent tumors. Responses of primary and recurrent tumor xenografts to standard chemo-therapy were different possibly due to evolutionarily molecular changes in recurrent tumors during progression or induced by therapies.
SAT0205 Osteoporosis: a new method of screening
Authors: N Navarro, M Castellanos, MP Lisbona, C Galisteo, MC Garcia, MC Sanmartí, C Alegre
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> Usefulness of calcaneus densitometry as a method of screening in osteoporosis. <h3>Methods</h3> Study of 69 women with osteoporosis, with DMO (L2-L4, Ward) and a comparison of the results obtained with a calcaneus densitometry (photonic dual measure, Lunar PIXI model). We considered osteoporosis when we find -2.5 SD in DMO and -1.6 SD in the calcaneus densitometry. <h3>Results</h3> After comparing the DMO lumbar results and DMO Ward, individually, with results of calcaneus densitometry, we observed a coefficient correlation of 0.5 and 0.6 respectively. <h3>Conclusion</h3> In our study the measures of the calcaneus densitometry have a relation to DMO, then we could consider it as a method of screening with patients we suspect of a osteoporosis.
Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
Authors: Francesca Fioredda, Piero Farruggia, Andrea Beccaria, Antonino Trizzino, LuciaDora Notarangelo, Tiziana Lanza, Andrea Rotulo, Isabella Ceccherini, Angela Guarina, Alice Grossi, Federico Verzegnassi, Elena Mastrodicasa, Laura Luti, Angelica Barone, Giovanna Russo, Laura Porretti, Marta Pillon, Maurizio Miano, Carlo Dufour
Journal: Blood (2019)
Outcomes of Transplant-Eligible Newly Diagnosed Ultra-High Risk Myeloma Patients Treated in the NCRI Myeloma XI Trial Indicate the Need for Early Treatment Stratification and Novel Treatment Approaches
Authors: Martin F. Kaiser, Matthew Jenner, David Cairns, Charlotte Pawlyn, Andrea Paterson, Rebecca Mottram, Faith E. Davies, Mark T Drayson, Roger G. Owen, Gareth Morgan, Gordon Cook, Graham Jackson
Journal: Blood (2019)
Rituximab and Bendamustine for First-Line Treatment of Frail or Elderly Patients with Aggressive B-Cell Lymphoma: Final Results of the Prospective Phase-II Brenda Trial of GLA (German Lymphoma Alliance)
Authors: Florian Zettl, Friederike Braulke, Marita Ziepert, Andreas Viardot, Christoph Kahl, Gabriele Prange-Krex, Agnieszka Korfel, Martin H. Dreyling, Thomas Illmer, Josef Birkmann, Ulrich Wedding, Dietmar Reichert, Maike de Wit, Frank Hartmann, Hans-Juergen Hurtz, Norbert Schmitz, Mathias Witzens-Harig, Wolfram Klapper, Andreas Rosenwald, Viola Poeschel, Markus Loeffler, Gerald Wulf, Bettina Altmann, Lorenz Truemper
Journal: Blood (2019)
Durable and Robust Fetal Globin Induction without Anemia in Rhesus Monkeys Following Autologous Hematopoietic Stem Cell Transplant with BCL11A Erythroid Enhancer Editing
Authors: Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Aylin C. Bonifacino, Allen E. Krouse, Nathaniel S. Linde, Robert E. Donahue, Anne H. Shen, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Scot A. Wolfe, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell J. Weiss, Daniel E. Bauer, John F. Tisdale
Journal: Blood (2019)
Health economic evaluation of rivaroxaban in the treatment of patients with chronic coronary artery disease or peripheral artery disease
Authors: Martin R Cowie, André Lamy, Pierre Levy, Stuart Mealing, Aurélie Millier, Paul Mernagh, Olivier Cristeau, Kevin Bowrin, Jean-Baptiste Briere
Journal: Cardiovascular Research (2019)

Abstract Aims In the COMPASS trial, rivaroxaban 2.5 mg twice daily (bid) plus acetylsalicylic acid (ASA) 100 mg once daily (od) performed better than ASA 100 mg od alone in reducing the rate of cardiovascular disease, stroke, or myocardial infarction (MI) in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). A Markov model was developed to assess the cost-effectiveness of rivaroxaban plus ASA vs. ASA alone over a lifetime horizon, from the UK National Health System perspective. Methods and results The base case analysis assumed that patients entered the model in the event-free health state, with the possibility to experience ≤2 events, transitioning every three-month cycle, through acute and post-acute health states of MI, ischaemic stroke (IS), or intracranial haemorrhage (ICH), and death. Costs, quality-adjusted life-years (QALYs), life years—all discounted at 3.5%—and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic and probabilistic sensitivity analyses were conducted, as well as scenario analyses. In the model, patients on rivaroxaban plus ASA lived for an average of 14.0 years with no IS/MI/ICH, and gained 9.7 QALYs at a cost of £13 947, while those receiving ASA alone lived for an average of 12.7 years and gained 9.3 QALYs at a cost of £8126. The ICER was £16 360 per QALY. This treatment was cost-effective in 98% of 5000 iterations at a willingness-to-pay threshold of £30 000 per QALY. Conclusion This Markov model suggests that rivaroxaban 2.5 mg bid plus ASA is a cost-effective alternative to ASA alone in patients with chronic CAD or PAD.
Mutant U2AF1S34F and U2AF1Q157P Induce Distinct RNA Splicing and Hematopoietic Phenotypes In Vivo
Authors: Michael O. Alberti, Meng'ou Zhu, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jin J. Shao, Brian Wadugu, Cara Lunn Shirai, Matthew J. Walter
Journal: Blood (2019)
A Phase 1/2 Study of Umbralisib Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
Authors: Paul M. Barr, Brian T. Hill, Shuo Ma, Andrea M Baran, Andrew Bui, Philip J Meacham, Ashley Morrison, Jane L. Liesveld, Deborah A Mulford, Peter Sportelli, Hari P Miskin, Michael S Weiss, Jonathan W. Friedberg, Clive S Zent
Journal: Blood (2019)
Results from an Expanded Access Program of Anti-CD3/CD7 Immunotoxin Combination (T-Guard®) for the Treatment of Steroid-Refractory Acute Gvhd
Authors: Lenneke F J Groningen, Christoph Groth, Manita E J Bremmers, Eric G Hooren, Ypke V J M van Oosterhout, Nicole M A Blijlevens, Matthias Stelljes, Walter J F M van der Velden
Journal: Blood (2019)
Gain‐of‐function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway
Authors: Immacolata Andolfo, Barbara Eleni Rosato, Francesco Manna, Gianluca De Rosa, Roberta Marra, Antonella Gambale, Domenico Girelli, Roberta Russo, Achille Iolascon
Journal: American Journal of Hematology (2019)

Abstract Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca 2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain‐of‐function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca 2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP‐SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another “proof of concept” for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca 2+ overload, by the Ca 2+ ionophore A23187. There was strong down‐regulation of HAMP gene expression after this Ca 2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron‐loading anemias.
Role of Mutant p53 in the Progression of Chronic Lymphocytic Leukemia
Authors: Janani Ravikrishnan, Tzung-Huei Lai, Elizabeth Muhowski, Lindsey Brinton, Katie Williams, Alexandria Thompson, James S. Blachly, Hatice Gulcin Ozer, John C. Byrd, Rosa Lapalombella, Jennifer Woyach, Deepa Sampath
Journal: Blood (2019)
Whole Exome Sequencing Analysis in Chronic Lymphoproliferative Disorder of NK Cells (CLPD-NK) Patients Fails to Detect Significant Viral Load
Authors: Edoardo Giussani, Vanessa Rebecca Gasparini, Alessandro Coppe, Antonella Teramo, Andrea Binatti, Cristina Vicenzetto, Giulia Calabretto, Gregorio Barilà, Francesco Piazza, Gianpietro Semenzato, Stefania Bortoluzzi, Renato Zambello
Journal: Blood (2019)
Genetic Variants of ATM &amp; Non-Homologous End Joining Pathway Genes in Acute Myeloid Leukemia: A South India Case-Control Study
Authors: Sugunakar Vuree, Anuradha Cingeetham, Dunna Nageswara Rao, Manjula Gorre, Sudha Sinha, Raghunadharao Digumarthi, Vishnupriya Satti, Sadashivudu Gundeti
Journal: Blood (2019)
Vitamin D and Health Outcomes
Authors: Anika Lucas, Myles Wolf
Journal: JAMA (2019)

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Clinical Determinants of T-Cell Receptor Diversity after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia
Authors: David Ritchie, Eric Wong, Rachel Koldej, James Anton Kuzich, Piers Blombery, Georgina L Ryland, Yamuna Kankanige, Jerick Guinto
Journal: Blood (2019)
INNV-14. ADJUVANT CHEMOTHERAPY AFTER SEVERE MYELOTOXICITY DURING TEMOZOLOMIDE CHEMORADIATION IN GLIOMAS. IT IS FEASIBILE?
Authors: Veronica Villani, Alessandra Fabi, Paola Gaviani, Roberta Rudà, Giuseppe Lombardi, Giorgia Simonetti, Antonio Silvani, Edoardo Pronello, Giuseppe Minniti, Andrea Pace
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Malignant gliomas are aggressive primitive brain tumor in adults. Today, the standard of care is Temozolomide (TMZ) administered daily with radiation therapy, followed by adjuvant TMZ. TMZ treatment has been considered to have a low toxicity profile. However, during concomitant treatment some patient may develop a severe myelosuppression. This toxicity may be in some cases prolonged and lead to treatment discontinuation. METHODS We have retrospectively collected data from 5 Italian neuro-oncological centers, about glioma patients who developed severe and prolonged hematological toxicity during concomitant chemoradiotherapy with TMZ. The purpose of this study is to evaluate: percentage of patients receiving adjuvant chemotherapy after severe myelotoxicity; rate of toxicity observed during adjuvant chemotherapy. RESULTS 54 glioma patients who developed myelosuppression of grade 3 or 4 were considered. Histology was Glioblastoma in 45 patients (83%); 63% of patients were female. Myelotoxicity during concomitant phase occurred at a median of 4 weeks (range 1–8) from the start of treatment. After recovery of myelotoxicity 19 patients did not received any treatment while 35 (65%) were treated with chemotherapy (28 received standard TMZ, one TMZ with metronomic schedule, 2 lomustine and 4 other agents). Among patients treated with TMZ, 13 patients presented hematological toxicity grade 3–4 which required treatment discontinuation in 7 cases (20%). CONCLUSION the results of our study show that 80% of glioma patients presenting severe myelotoxicity during concomitant radiochemotherapy may be treated with maintenance TMZ after recovery of myelosuppression.
Clinical Characteristics and Outcome of Biphenotypic Acute Leukemia: 10 Cases Report and Literature Review
Authors: Jifeng Yu, Yingmei Li, Haizhou Xing, Hui Sun, Dingming Wan, Yanfang Liu, Xinsheng Xie, Chong Wang, Ling Sun, Kai Sun, Zhongxing Jiang
Journal: Blood (2019)