tbuckley/cabot-search huggingface dataset:
Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells
Authors: Christin Riegel, Tina J. Boeld, Kristina Doser, Elisabeth Huber, Petra Hoffmann, Matthias Edinger
Journal: Leukemia (2019)

Abstract Acute graft-versus-host disease (aGvHD) is a frequent complication after allogeneic bone marrow/stem cell transplantation (BMT/SCT) induced by co-transplanted alloreactive conventional donor T cells. We previously demonstrated that the adoptive transfer of donor CD4 + CD25 + Foxp3 + regulatory T cells (Treg) at the time of BMT prevents aGvHD in murine models. Yet, the therapeutic potential of donor Treg for the treatment of established aGvHD has not yet been studied in detail. We now used in vitro expanded phenotypically and functionally stable murine Treg to explore their therapeutic efficacy in haploidentical aGvHD models. Upon transfer donor Treg ameliorate clinical and histologic signs of aGvHD and significantly improve survival. They migrate to lymphoid as well as aGvHD target organs, predominantly the gastrointestinal tract, where they inhibit the proliferation of conventional T cells, reduce the influx of myeloid cells, and the accumulation of inflammatory cytokines. Successfully treated animals restore aGvHD-induced tissue damage in target organs and lymphoid tissues, thereby supporting lymphocyte reconstitution. The therapeutically applied Treg population survives long term without conversion into pathogenic effector T cells. These results demonstrate that donor Treg not only prevent aGvHD, but are also efficacious for the treatment of this life-threatening BMT complication.
Results of Unrelated Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe on Behalf of Paediatric Diseases (PDWP) and Inborn Errors Working Parties (IEWP) of the EBMT
Authors: Eliane Gluckman, Josu de la Fuente, Barbara Cappelli, Graziana M. Scigliuolo, Fernanda Volt, Karina Tozatto-Maio, Vanderson Rocha, Tommaso Mina, Farah O'Boyle, Frans Smiers, Claudia Bettoni Da Cunha-Riehm, Elisabetta Calore, Sonia Bonanomi, Stelios Graphakos, Anna Paisiou, Michael H. Albert, Annalisa Ruggeri, Marco Zecca, Arjan C. Lankester, Selim Corbacioglu
Journal: Blood (2019)
RARE-27. UNUSUAL CASE OF TEENAGER WITH PRIMARY SPINAL GERMINOMA WITH INTRACRANIAL RELAPSE POST-THERAPY
Authors: Maria Kooken, Scott Wait, Carolina Fasola, Chad Jacobsen, David Gass
Journal: Neuro-Oncology (2019)

Abstract We present a case of a 14-year-old male who presented with back pain and difficulty walking and was found to have an intradural intramedullary germinoma in the thoracolumbar spine. After debulking, he was treated with four cycles of carboplatin and etoposide and then received local spinal radiotherapy (RT) to the initial area of disease with margin to 30 Gy in 17 fractions. Six months following completion of therapy, he was found to have an intracranial relapse. CLINICAL IMPORTANCE: Our patient is the second ever Hispanic and twelfth pediatric patient reported with primary spinal germinoma. We reviewed 54 total cases published in literature over last 35 years. Twenty-one patients (39%) were treated with surgery followed by local spinal RT (n=12) or CSI (n=9). Twenty-eight patients (52%) were treated with chemotherapy in addition to surgery and radiation. The remaining 5 patients (9%) either had surgery alone or details of their treatment plan were not reported. Six of the 54 patients experienced disease recurrence. None of the patients treated with CSI experienced disease recurrence after CSI. Ninety-six percent of patients were alive at last follow up. CLINICAL OUTCOME: Our patient had his relapsed disease resected and CSI to 23.4 GY in 13 fractions and focal boost to 21.6 Gy in 12 fractions was delivered to all sites of relapsed disease. He is undergoing surveillance of his tumor and there is no disease recurrence 3 months post-CSI. CONCLUSION: Primary spinal germinomas appear chemo responsive and radiosensitive; however, the optimal management to maximize disease control and minimize side effects is not clear. When using local spinal RT, close surveillance with brain and spine imaging seems indicated as relapses anywhere in the central nervous system are possible. Further study is needed to determine the optimum treatment approach to this tumor.
Is There a Role for Titre Monitoring in Kell Alloimmunized Pregnancies?
Authors: Evangelia Vlachodimtropoulou Koumoutsea, Maciej W Garbowski, Gareth Seaward, Rory Windrim, Johannes Keunen, Edmond Kelly, Tim VanMieghem, Nadine Shehata, Greg Ryan
Journal: Blood (2019)
Pooled Safety Analysis of Quizartinib Monotherapy in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Authors: Jorge E. Cortes, Siddhartha Ganguly, Alwin Krämer, Mark J. Levis, Giovanni Martinelli, Alexander E. Perl, Nigel H. Russell, Youngsook Choi, Jeanne Mendell, Ruth Namuyinga, Hoang Pham, Nabil Said, Yibin Wang, Tsvetomir Mitov, Ben Kim, Samer K. Khaled
Journal: Blood (2019)
O.04 Results from the IASLC Global Survey on Molecular Testing in Lung Cancer
Authors: M.V. Garcia, M. Smeltzer, M. Wynes, S. Lantuejoul, R.A. Soo, L. Dalurzo, E. Felip, K. Howell, K. Kerr, E. Kim, C. Mathias, P. Postmus, C. Powell, S. Ramalingam, K. Richeimer, M. Taylor, M. Tsuboi, I. Wistuba, K. Wood, G. Scagliotti, F. Hirsch
Journal: Journal of Thoracic Oncology (2019)
Results of the FUEL Trial
Authors: David J. Goldberg, Victor Zak, Bryan H. Goldstein, Kurt R. Schumacher, Jonathan Rhodes, Daniel J. Penny, Christopher J. Petit, Salil Ginde, Shaji C. Menon, Seong-Ho Kim, Gi Beom Kim, Todd T. Nowlen, Michael V. DiMaria, Benjamin P. Frischhertz, Jonathan B. Wagner, Kimberly E. McHugh, Brian W. McCrindle, Amanda J. Shillingford, Arash A. Sabati, Anji T. Yetman, Anitha S. John, Marc E. Richmond, Matthew D. Files, R. Mark Payne, Andrew S. Mackie, Christopher K. Davis, Shabana Shahanavaz, Kevin D. Hill, Ruchira Garg, Jeffrey P. Jacobs, Michelle S. Hamstra, Stacy Woyciechowski, Kathleen A. Rathge, Michael G. McBride, Peter C. Frommelt, Mark W. Russell, Elaine M. Urbina, James L. Yeager, Victoria L. Pemberton, Mario P. Stylianou, Gail D. Pearson, Stephen M. Paridon
Journal: Circulation (2019)

The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking.
Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms
Authors: Julian Baumeister, Nicolas Chatain, Annika Hubrich, Tiago Maié, Ivan G. Costa, Bernd Denecke, Lijuan Han, Caroline Küstermann, Stephanie Sontag, Kristin Seré, Klaus Strathmann, Martin Zenke, Andreas Schuppert, Tim H. Brümmendorf, Kamil R. Kranc, Steffen Koschmieder, Deniz Gezer
Journal: Leukemia (2019)
Three Cases of Patients with Complement Regulatory Factor Genetic Mutations and Acquired Thrombotic Thrombocytopenic Purpura (TTP)
Authors: Shebli Atrash, David Kent McKelvey, Appalanaidu Sasapu, Muthu Veeraputhiran, Soumya Pandey, Michele H. Cottler-Fox, Pooja Motwani
Journal: Blood (2016)
Medical Management of Ulcerative Colitis
Authors: G. Watkinson
Journal: BMJ (1961)

The medical management of ulcerative colitis is a diifficult and diffuse topic, and the assessment of any therapeutic agent is a most complex task in a disease which varies greatly in severity and extent, not only from patient to patient but also in the same individual from attack to attack.Carefully plainned controlled trials in colitic attacks of comparable severity are necessary for the evaluation of any remedy.No specific treatment has yet been found.The physician possesses a variety of drugs capable of inducing remission in perhaps half the cases treated and has no reliable means of predicting the therapeutic outcome in a particular instance.In treating the colitic patient the physician is faced with three duties; firstly, in terminating the acute fulminating attack or exacerbation of the colitis as speedily as possible ; secondly, in preventing recurrence by some form of maintenance therapy; and, thirdly, realizing that his efforts may fail at both these stages, knowing when to call in the surgeon.In this regard he should constantly be critically asking himself if his therapeutic efforts are adversely affecting the outcome of surgery or the long-term well-being of the patient.In trying to answer some of these problems I shall review the experiences of others, the results of the elegant therapeutic trials undertaken in colitis in recent years, and will draw on personal experience obtained in Leeds in the past ten years, where I have treated some 197 patients with colitis, who have received in all some 340 courses of treatment.The attacks of the disease were judged severe in two-thirds of the patients treated, and the clinical pattern of the illness was an acute fulminating attack in 36, chronic intermittent diarrhoea in 92, chronic continuous diarrhoea in 29, while 38 hiad a distal proctocolitis.Two cases resembling the non-specific enterocolitis described by Cooke and Brooke (1955) were included.
Immunophenotypic- and Molecular Analysis of Human Hematopoietic Stem and Progenitor Heterogeneity
Authors: Mikael Sommarin, Parashar Dhapola, Linda Geironson Ulfsson, Fatemeh Safi, Eva Erlandsson, Anna Konturek, Ram Krishna Thakur, Charlotta Boiers, David Bryder, Göran Karlsson
Journal: Blood (2019)
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Authors: Longchuan Bai, Haibin Zhou, Renqi Xu, Yujun Zhao, Krishnapriya Chinnaswamy, Donna McEachern, Jianyong Chen, Chao-Yie Yang, Zhaomin Liu, Mi Wang, Liu Liu, Hui Jiang, Bo Wen, Praveen Kumar, Jennifer L. Meagher, Duxin Sun, Jeanne A. Stuckey, Shaomeng Wang
Journal: Cancer Cell (2019)
PDTM-43. THERAPEUTIC TARGETS FROM BIG DATA: INTEGRATIVE DISCOVERY OF TREATMENTS FOR HIGH-RISK NEUROBLASTOMA
Authors: Elin Almstedt, Caroline Wärn, Ramy Elgendy, Neda Hekmati, Emil Rosén, Ida Larsson, Sven Påhlman, Daniel Bexell, Michael Vanlandewijck, Rebecka Jörnsten, Cecilia Krona, Sven Nelander
Journal: Neuro-Oncology (2019)

Abstract Despite major advances in the molecular exploration of pediatric cancers, approximately 50 % of children with high-risk neuroblastoma lack effective treatment. To identify new therapeutic options for this group of high-risk patients, we have combined integrative data analysis with experimental evaluation in patient-derived xenograft cells. We propose a new algorithm, TargetTranslator, which combines data from tumor biobanks, pharmacological databases, and cellular networks, to predict how particular targeted interventions will affect mRNA signatures associated with high patient risk. We find more than 80 known and novel targets to be associated with neuroblastoma risk and differentiation signatures. To evaluate these predictions, we performed RNA sequencing of drug-treated cell lines derived from high-risk patients and show that predicted compounds suppress risk signatures and malignant phenotypes. Using a xenograft model, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method (made available as a public tool, targettranslator.org) will enhance and expedite the discovery of risk-associated targets for pediatric and adult cancers.
CSIG-31. ALTERNATIVE RECEPTOR TYROSINE KINASE SIGNALING AS A RESISTANCE MECHANISM TO ERK INHIBITION IN HIGH-GRADE GLIOMAS
Authors: Ann-Catherine Stanton, Robert Koncar, Brian Golbourn, Michelle Wassell, Nishant Agrawal, Brittany Dey, Max Myers, Stephen Mack, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2019)

Abstract Pediatric High-Grade Gliomas (PHGG), which include Diffuse Midline Gliomas (DMG), are a leading cause of brain tumor death in children. Our recent work has identified extracellular signal-regulated kinase 5 (ERK5) as a critical mediator of cell survival in PHGG. Suppression of ERK5 genetically or pharmacologically leads to decreased cell proliferation and increased apoptosis both in vitro and in vivo in multiple PHGG and H3K27M mutant DMG cell lines. Mechanistically, we show that ERK5 directly stabilizes the proto-oncogene MYC at the protein level, providing rationale to clinically target ERK5. ERK5 contains both a kinase domain (KD) and a transactivation domain (TAD), unlike all other ERKs. Unexpectedly, we found that our ERK5 depleted cells could be partially rescued by an ERK5 kinase domain dead (ERK5-KDD) but TAD intact construct. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. To address this, we performed RNA sequencing of DMG cells, comparing control cells to ERK5 knockdown cells, and performed gene-ontology (GO) pathway analysis to identify transcriptional changes that occur in response to ERK5 depletion. We identified 105 differentially expressed genes, and GO analysis identified alternative receptor tyrosine kinase (RTK) gene-expression as one of the top biological processes upregulated in response to ERK5 loss. We validated our top targets at the RNA and the protein level. Our top targets were Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) and Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), both clinically actionable targets. Our future work will focus on functional validation of these RTKs as potential resistance mechanisms to ERK5 loss. Identification of resistance mechanisms to ERK5 loss will have both biological and translational relevance and may lead to effective therapeutic combinations.
Ectopic Corticotropin-Releasing Hormone–Secreting Pancreatic Neuroendocrine Tumor
Authors: Jingjing Zhang, Harshad R. Kulkarni, Richard P. Baum
Journal: Clinical Nuclear Medicine (2019)

Abstract Ectopic Cushing syndrome secondary to corticotropin releasing hormone (CRH)–secreting tumors or CRH and adrenocorticotropin hormone cosecreting tumors is extremely rare. We report here the case of a 54-year-old man who experienced CRH-secreting pancreatic neuroendocrine tumor causing Cushing syndrome, initially detected by SSTR (somatostatin receptor) scintigraphy, then significantly progressed with multiple liver metastases, demonstrating significantly increased SSTR expression on 68 Ga-DOTATOC PET/CT and a “mismatch” imaging pattern on 18 F-FDG PET/CT. The patient underwent peptide receptor radionuclide therapy with 177 Lu/ 90 Y-DOTATOC and demonstrated excellent response to the treatment.
Busulfan, Melphalan, and Bortezomib Compared to Single Agent High-Dose Melphalan As a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma: Long Term Follow up of a Novel Conditioning Regimen
Authors: Patrick Hagen, Anita D'Souza, Parameswaran Hari, Omar Davila, Mei-Jie Zhang, David H. Vesole, Scott E. Smith, Tulio E Rodriguez, Patrick J. Stiff
Journal: Blood (2019)
Pegasperagase Toxicity in Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Experience Comparing Patients Older and Younger Than 35 Years of Age
Authors: Jun H Choi, Jacques Azzi, Tsivia Hochman, Mary Lynn R. Nierodzik, Shella Saint Fleur-Lominy, Maher Abdul Hay
Journal: Blood (2019)
A Phase 2, Randomized, Open-Label, 2-Arm Study Comparing 2 Intermittent Dosing Schedules of Duvelisib in Patients with Indolent Non-Hodgkin Lymphoma (iNHL) (TEMPO)
Authors: Reem Karmali, Hagop Youssoufian, Kam Sprott, David T. Weaver, Narayana Narasimhan, Stephanie Lustgarten, Gloria Patrick, Alena Zalutskaya, Leo I. Gordon
Journal: Blood (2019)
Postoperative Infection—A Pervasive Mediator of Patient Mortality
Authors: Matthew R Woeste, William G. Cheadle
Journal: JAMA Surgery (2019)

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IgG:IgM Ratios of Liver Plasma Cells Reveal Similar Phenotypes of Primary Biliary Cholangitis With and Without Features of Autoimmune Hepatitis
Authors: Brian T. Lee, Yun Wang, Alexander Yang, Hyosun Han, Liyun Yuan, John Donovan, Neil Kaplowitz, Gary Kanel, Jeffrey Kahn, Lily Dara
Journal: Clinical Gastroenterology and Hepatology (2019)
GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis
Authors: Jan Best, Lars P. Bechmann, Jan-Peter Sowa, Svenja Sydor, Alexander Dechêne, Kristina Pflanz, Sotiria Bedreli, Clemens Schotten, Andreas Geier, Thomas Berg, Janett Fischer, Arndt Vogel, Heike Bantel, Arndt Weinmann, Jörn M. Schattenberg, Yvonne Huber, Henning Wege, Johann von Felden, Kornelius Schulze, Dominik Bettinger, Robert Thimme, Friedrich Sinner, Kerstin Schütte, Karl Heinz Weiss, Hidenori Toyoda, Satoshi Yasuda, Takashi Kumada, Sarah Berhane, Marc Wichert, Dominik Heider, Guido Gerken, Philip Johnson, Ali Canbay
Journal: Clinical Gastroenterology and Hepatology (2019)

The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH.We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development.The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC.In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.
SCIDOT-42. FT-2102 – A POTENT AND SELECTIVE BRAIN PENETRANT INHIBITOR OF MUTANT ISOCITRATE DEHYDROGENASE
Authors: Maria Ribadeneira, Sylvie Guichard, Lili Yao, Angela Toms, Sanjeev Forsyth, Blythe Thomson, Paul Ehrlich
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Iocitrate dehydrogenase mutations (mIDH1) are present in &gt;70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate (2-HG) causing DNA hypermethylation and promoting tumorigenesis. This abstract summarizes the structure-based design of FT-2102, a potent and selective inhibitor of mutated IDH1-R132 with brain distribution (Kpuu) that is in context of minimal effective concentrations required in brain to modulate 2-HG. METHODS The crystal structure of mutated IDH1 in complex with FT-2102 and NADPH cofactor (2.1A resolution) was determined via sitting-drop vapour-diffusion set-ups. HCT116/IDH1 R132H were implanted in Balb/c nude mice and FT-2102 was administered orally twice daily. FT-2102 and 2-HG levels in plasma and xenografts were determined by LC/MS. In silico and in vitro models were used to determine the extent of brain distribution and ex-vivo rat data was generated to validate the projected distribution into brain tissue (Kpuu). RESULTS In tumor Xenograft (HCT116/IDH1-R132H), FT-2102 inhibits tumor 2-HG production with an IC50 of 24nM which is consistent with its in vitro IC50 of 18nM. FT-2102 unbound plasma concentrations of 256nM in xenografted mice were found to achieve 90% reduction of 2-HG in tumor. Rat data showed that FT-2102 partitions into brain with a Kpuu of 0.45. Based on these data, the concentration of FT-2102 in brain to significantly reduce 2HG is predicted to be 115nM. Recent publications (Natsume, et al, ASCO19) propose 90% reduction of 2-HG (90%) is associated with tumor reduction in the brain. CONCLUSION The structure-based design of FT-2102 has facilitated CNS penetration in animal models and is undergoing evaluation in ongoing clinical trials including patients with CNS based IDH1m tumors (NCT: 03684811).