tbuckley/cabot-search huggingface dataset:
Abstract 1676: An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma
Authors: Kazunori Kato, Atsushi Sakamoto, Taro Kojima, Toshio Hasegawa, Shigaku Ikeda
Journal: Cancer Research (2015)

Abstract EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in aggressive human cancers, including melanoma. Recently, EphA2 has been found to be integral player in cancer formation and expected as a target for antibody therapy. In this study, we have investigated the therapeutic effect of various anti-EphA2 mAbs that were recently established in our laboratory. Cell surface expression of EphA2 on melanoma cell lines was analyzed by flow cytometry and therapeutic effects of anti-EphA2 mAbs were investigated using cell proliferation, cell migration, invasion and antibody-mediated drug cytotoxicity assays. We found that human melanoma cell lines expressed EphA2 on their surface, while normal dermal fibroblasts and melanocytes were negative for EphA2. Recombinant human protein of EphrinA1 (a natural ligand for EphA2) and anti-EphA2 mAbs could not suppress melanoma cell proliferation, however, one of agonistic anti-EphA2 mAb, termed SHM16, inhibited metastatic potential such as migration and invasive properties of human melanoma. In contrast, an antagonistic anti-EphA2 mAb, SHM17, had no effect on migration and invasive assay. In addition, drastic growth inhibition and cell cytotoxicity were found in targeted delivery of immunotoxin by SHM16. In conclusion, these findings indicate a promising role for EphA2 as a target for antibody treatment in melanoma and enhance the therapeutic effect as an agonistic antibody to EphA2. Citation Format: Kazunori Kato, Atsushi Sakamoto, Taro Kojima, Toshio Hasegawa, Shigaku Ikeda. An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1676. doi:10.1158/1538-7445.AM2015-1676
466. Automated Generation of Genetically Modified Human CD34+ Cells in a Functionally Closed System
Authors: Constanze Lehmann, Samantha Scaramuzza, Kristina Reck, Mike Essl, Raisa J. Hernandez, Simona La Seta Catamancio, Chiara Bovolenta, Alessandro Aiuti, Ian C.D. Johnston
Journal: Molecular Therapy (2015)

Hereditary genetic disorders have been shown to be effectively treated by re-introduction of the wild-type gene product via viral modification of autologous CD34+ progenitor cells. However, current manufacturing processes are performed manually or at best by using semi-automated procedures. A standardized production of cellular therapeutic agents and their genetic modification is a major requirement to move cellular and gene therapies from their current translational setting into routine clinical use. A closed and highly automated manufacturing procedure would lead to large improvements in product performance, product safety and operator safety. We have recently developed a functionally closed and fully automated cell processing device, the CliniMACS Prodigy®, which enables complex cellular products to be manufactured. In this functionally closed system, the following steps have been automated: concentration and washing of blood products, magnetic labeling and enrichment of CD34+ cells, cultivation and pre-activation of the enriched CD34+ cells, transduction with lentiviral vectors and resuspension of the final cell product in buffer for infusion. Automated cell preparation, cell labeling and magnetic CD34+ cell separation was achieved from both mobilized and non-mobilized apheresis samples as well as bone marrow aspirates. CD34+ cells were enriched to purities exceeding 90%. Small scale experiments (10e5-10e7 purified CD34+ cells) performed with a newly developed automated transduction process, incorporating a single transduction cycle, resulted in high transduction efficiencies (up to 90%). A scale-up of the procedure was performed using larger numbers of cells (>10e7) enriched from mobilized apheresis material. CD34+ cells were transduced with a clinical-grade lentiviral vector using a two hit protocol already described in a clinical setting and used as standard for a control experiment run in parallel (Scaramuzza et al. 2013, Mol. Ther). Equivalent gene marking efficiencies were obtained. Moreover, gene modified cells maintained full engraftment potential as demonstrated by biodistribution studies in NSG mice. These preliminary data demonstrate that automated cell processing and genetic manipulation of haematopoetic progenitor cells can be efficiently performed in a closed system. Work in progress aims to further optimize this procedure and improve the efficiency of CD34+ cell transduction to levels superior to those currently achieved by manual protocols.
Polo-Like Kinase 1 (PLK1) Inhibition Reduces Cell Proliferation and Induces Apoptosis in Childhood Acute Lymphoblastic Leukemia
Authors: Stefanie A. Hartsink-Segers, Carla Exalto, Steven C. Clifford, Huib N. Caron, Rob Pieters, Monique L. Den Boer
Journal: Blood (2012)
Changes in Presentation of Celiac Disease in Ireland From the 1960s to 2015
Authors: Patricia Dominguez Castro, Grace Harkin, Mary Hussey, Brian Christopher, Clifford Kiat, Jun Liong Chin, Valerie Trimble, Deirdre McNamara, Padraic MacMathuna, Brian Egan, Barbara Ryan, David Kevans, Richard Farrell, Valerie Byrnes, Nasir Mahmud, Ross McManus
Journal: Clinical Gastroenterology and Hepatology (2017)
Hospitalization after hepatic artery embolization (HAE) for neuroendocrine tumors (NET).
Authors: S. Jaramillo, M. Lewis, L. R. Roberts, J. Rubin, A. Grothey
Journal: Journal of Clinical Oncology (2011)

e14553 Background: There is scant evidence to guide management of patients after hepatic artery embolization (HAE). We examined the length of stay (LOS), laboratory patterns, medication usage, morbidity, and mortality of patients hospitalized after HAE for metastatic NET. Methods: Data were gathered retrospectively from electronic medical records on: LOS; pre- and post-procedural liver function tests (LFTs); IV antibiotics and analgesia; peak temperature, bacteremia, and hepatic abscess formation; carcinoid crisis; and pre-HAE metastatic burden on CT and/or MRI. Results: From 2005-2009, 72 unique patients (57% male, age 30-80y, median 60y) underwent 174 HAEs for carcinoid (n=112) and islet cell (n=62) tumors. Median hospital stay was 4 days (range 1-8d). There was no correlation between height of peak LFTs and size of radiographic metastatic burden. Documented decline in LFTs was not uniform before dismissal; 25%, 37%, 30%, 53%, and 67% of patients were discharged before their respective AST, ALT, alkaline phosphatase, total and direct bilirubin levels had begun to decline, with no readmissions for acute hepatic failure. All patients received IV analgesia, and median use was 60 mg oral morphine equivalents (range 3-1,961 mg). Pre-HAE IV antibiotics were administered in 99% of cases, and post-HAE fever (temp ≥38.3ºC) occurred in 37% with no documented bacteremia. In 1 case, a hepatic abscess formed 1 month after HAE and an afebrile initial hospital course. There were 2 carcinoid crises, both within 48 hours of HAE. There was 1 in-hospital death associated with air in the portal venous system, a rare complication after HAE. Conclusions: Duration and intensity of in-hospital supportive care following HAE should be managed on a patient-by-patient basis. A downward trend in LFTs is not validated as a requirement for discharge. Modest median use of IV analgesia suggests that many patients could be converted to exclusively oral analgesics. Given the rarity of serious complications, many hospital stays could be shortened in favor of attentive outpatient care, thereby improving clinical practice by reducing costs and nosocomial risks.
400. CD269 (BCMA)-Specific CAR-Expressing T Cells Dramatically Eradicate Myeloma Cells from Bone Marrow of an Orthotopic Multiple Myeloma Mouse Model
Authors: Ryosuke Uchibori, Takeshi Teruya, Ken Ohmine, Masashi Urabe, Yasushi Saga, Hiroaki Mizukami, Junichi Mineno, Kazuto Takesako, Keiya Ozawa
Journal: Molecular Therapy (2016)

Introduction: Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells. During the past decade, overall survival rate of multiple myeloma have been improved. These improvements are linked to the induction of novel drugs with different mechanism of action such as proteasome inhibitors and immnomodulatory drugs. However, MM remains in most cases an incurable disease, and new therapeutic strategies are urgently required for radical cure or continued disease control. During recent years, some dramatic responses were reported using T cells expressing CD19-targeted chimeric antigen receptors (CAR). Therefore, CAR therapy could also be a promising new therapeutic strategy for MM. CD269 (also known as BCMA: B-cell maturation antigen) is a membrane protein that is selectively expressed on B-cell lineages and on plasma cells including myeloma cells. Our goal of this study is to verify whether treatment with CD269-specific CAR-expressing T cells can eradicate myeloma cells from bone marrow of tumor-bearing NOG mice. Methods: Firstly, we uniquely developed monoclonal antibodies against human CD269. Next, we designed and verified novel CD269-specific CAR. The CD269-CAR recombinant retroviral vector encodes the MoMLV (Moloney murine leukemia virus) retroviral backbone and the 3.3E-28z CAR. The 3.3E-28z CAR consists of an anti-human CD269 scFv that was derived from the 3.3E mouse hybridoma, a portion of the human CD28 molecule and the intracellular domain of the human CD3ζ molecule. Results: CD269-specific CAR-expressing T cells show redirected cytolysis toward CD269-positive U266 human MM-derived cells, but not CD269-negative K562 cells. Luciferase-expressing U266 cells that were injected into the cardiac chamber of NOG mice, selectively infiltrated to bone marrow. Six weeks after tumor inoculation, we injected saline, non-CAR gene-modified T cells, or CAR gene-modified T cells (GMCs) into the cardiac chamber of tumor-bearing mice. In the group of GMC injection, U266 cells were dramatically eradicated from bone marrow. Conclusion: Although the efficacy of BCMA-CAR has been demonstrated by previous study using intradermal models of MM, our challenge is the first report that presents with orthotopic models of MM. Our results are more appropriate for predicting the efficacy of CD269-CAR in the treatment of MM. We conclude that adoptive transfer of CD269-CAR-expressing T cells could be a promising option for patient with MM.
A Common Progenitor for Macrophages, Osteoclasts and Dendritic Cells Newly Discovered in Human Bone Marrow and Cord Blood Yields Dendritic Cells with T-Cell Priming Ability
Authors: Yanling Xiao, Joanna Aleksandra Grabowska, Riccardo Mezzadra, Maarten J. van Tol, Arjan C Lankester, Jannie Borst
Journal: Blood (2015)
Abstract LB-171: Collaborating mutations in gastrointestinal stromal tumor
Authors: Joshua Waterfall, J. Keith Killian, Yuelin Jack Zhu, C. Christopher Lau, Markku Miettinen, Lee J. Helman, Paul S. Meltzer
Journal: Cancer Research (2015)

Abstract Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract, is driven most commonly by activating mutations in the receptor tyrosine kinases KIT or PDGFRA. Alternatively, inactivating mutations of genes for the succinate dehydrogenase complex (SDH) constitute a distinct oncogenic mechanism in GIST. Using integrated genomic analyses we have recently reported that SDH deficiency in GIST may also arise from epigenomic inactivation of SDHC, reflected by coupled DNA methylation and expression silencing (1). SDHC epimutation is particularly frequent in, though not restricted to, patients with the cancer predisposition syndrome Carney Triad. It is well established that these primary driver mechanisms correlate with unique clinical, molecular, and epidemiological profiles. In order to identify collaborating oncogenic pathways associated with specific GIST subtypes we have extended our integrated genomic profiling of over 70 tumors enriched for SDH deficient cases. The primary focus is sequencing a panel of 200 cancer related genes for both somatic and inherited variants. We also include RNA expression arrays, DNA methylation arrays, and SNP arrays in this analysis. We have identified mutations in several known cancer associated genes including PTEN, KRAS, ARID1A, and TP53. In conclusion, collaborating mutations and deregulated pathways are identifiable in GIST and can increase our understanding of the underlying cancer biology as well as suggesting treatment possibilities for this malignancy. We acknowledge the contributions of the NIH Wild-Type GIST clinic investigators to this project. References 1. Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ, et al. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med. 2014;6:268ra177. Citation Format: Joshua Waterfall, J. Keith Killian, Yuelin Jack Zhu, C. Christopher Lau, Markku Miettinen, Lee J. Helman, Paul S. Meltzer. Collaborating mutations in gastrointestinal stromal tumor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-171. doi:10.1158/1538-7445.AM2015-LB-171
Abstract 2705: AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis
Authors: Wenting Mi, Qing Ye, Side Liu, Qing-Bai She
Journal: Cancer Research (2015)

Abstract The mTORC1 inhibitors, rapamycin and its analogs, have been used for the treatment of a variety of cancers, but the clinical performance of these drugs has fallen short of expectations due to only modest efficacy in tumors. The underlying mechanisms of rapamycin resistance remain largely elusive. Here, we found that activated AKT signaling is associated with rapamycin resistance in breast and colon cancers by sustained phosphorylation of the translational repressor 4E-BP1. Treatment of tumor cells with rapamycin or the AKT inhibitor MK2206 shows incomplete inhibition of 4E-BP1 phosphorylation, and is functionally manifest as cap-dependent translation, cell growth and motility. However, treatment with both drugs provides profound effects in vitro and in vivo. Mechanistically, we demonstrate that the combination treatment is required to effectively inhibit PRAS40 phosphorylation on both Ser183 and Thr246 mediated by mTORC1 and AKT respectively, and with the combined treatment, dephosphorylated PRAS40 binding to the raptor/mTOR complex is enhanced, leading to dramatic repression of mTORC1-regulated 4E-BP1 phosphorylation and translation. Knockdown of PRAS40 or 4E-BP1 expression markedly reduces the dependence of tumor cells on AKT/mTORC1 signaling for translational control of cell proliferation, survival and motility. Together, these findings reveal a critical role of PRAS40 as a key integrator of mTORC1 and AKT signaling for the translational regulation of tumor cell growth and motility, and highlight PRAS40 phosphorylation as a potential surrogate marker to evaluate the therapeutic response to mTOR inhibitors. Citation Format: Wenting Mi, Qing Ye, Side Liu, Qing-Bai She. AKT inhibition sensitizes tumor cells to rapamycin by enhancing the repressive function of PRS40 on mTORC1/4E-BP1 axis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2705. doi:10.1158/1538-7445.AM2015-2705
Quality and Safety in Health Care, Part XXI
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2016)

Congress provided for the formation of patient safety organizations (PSOs) so that physicians and other providers would come forward to improve the safety and quality of health care. Important legal safeguards for the providers and patients were put in place for PSOs. The Society for Vascular Surgery (SVS) PSO operates the Vascular Quality Initiative. The latter gathers information from certain commonly done vascular procedures. First, information is collected so a risk adjustment determination of each individual patient can be done. Then the details of every procedure are recorded for later analysis of the processes of the patient's care. In addition, outcome analysis from all procedures is carried out. This registry is an important source of data for research improving health care safety and quality.
Deletion 13, Detected by Metaphase Analysis, Is Not a Significant Prognostic Indicator In Myeloma
Authors: Fiona M. Ross, Laura Chiecchio, GianPaolo Dagrada, William J Tapper, Zoe J Konn, Kan Luk Cheung, Rebecca KM Protheroe, David M Stockley, Susan E Bell, Walter M Gregory, Alexander J Szubert, Gordon Cook, Roger G. Owen, Mark T. Drayson, Graham Jackson, Faith Davies, J. Anthony Child, Gareth J Morgan
Journal: Blood (2010)
GATA 1: pArg202Thr, a New GATA 1 Mutation Involved in a Severe Dyserythropoietic Phenotype
Authors: Serge Pissard, Chadia Mekki, Serge Hovhannisyan, Lydie M. Da Costa, Valentine Brousse, Carole Conejero, Stephane Giraudier, Mariane De Montalembert
Journal: Blood (2014)
13. Functional Role of Adenovirus Penton in Modulating In Vivo Properties of Liver-Targeted and Liver-Detargeted Adenovirus Variants
Authors: Svetlana Atasheva, Corey Emerson, Nelson C. Di Paolo, Eric Irons, Neetu Gulati, Phoebe Stewart, Dmitry M. Shayakhmetov
Journal: Molecular Therapy (2016)

Pharmacokinetic studies of adenovirus (Ad) vectors after intravascular delivery demonstrate that the majority of an administered virus dose is rapidly sequestered from the circulation by the liver. The molecular determinants that target Ad to the liver have been found on each of the virus capsid proteins, including hexon, penton, and fiber. The penton protein in the majority of Ad serotypes comprises a hypervariable loop containing an RGD motif that has been shown to interact with a number of cellular integrins upon virus entry into the cell. The binding of penton to integrins triggers virus internalization and relaxes the virus structure for subsequent endosomal disassembly. However, RGD motif interaction with integrins on tissue macrophages leads to production of inflammatory cytokines and significantly contributes to systemic Ad toxicity. Despite its importance for the virus entry into the cell, the penton is not well employed in the development of therapeutic Ad vectors. Therefore, in this study we evaluated strategies for modulating Ad penton interactions with cellular integrins. Ad vectors were created bearing substitutions of the RGD motif with mimetic non-RGD-containing peptides derived from extracellular proteins laminin 1 and laminin 3. These peptides are interacting with a different subset of integrins compared to those binging penton RGD motif. Unlike wild type (WT) Ad5, these penton-modified vectors were able to utilize β4 integrin for cell entry. The in vivo studies demonstrated that penton-modified Ads cannot activate a full inflammatory cascade and their in vivo toxicity, therefore, is dramatically reduced. Although the penton-mutated vectors were infecting a set of cancer cell lines in vitro and hepatocytes in vivo with a similar efficacy as the WT Ad5, interactions of virus with Kupffer cells and virus accumulation in the liver after intravascular vector delivery remain similar for penton-mutated and WT Ad vector. We also developed Ad vectors containing mutations abrogating virus interactions with all types of liver cells. Additionally to penton modifications, we introduced a T425A mutation in the hexon hyper variable loop HVR7 to completely abrogate virus interaction with blood coagulation FX and prevent transduction of hepatocytes. Furthermore, a set of mutations in the hexon HVR1 region were introduced to prevent Ad uptake by Kupffer cells. Due to penton modifications these vectors had very low toxicity and combinations of three mutations diverted the vector away from the liver. These data demonstrate that RGD loop modification represents a useful approach for introducing beneficial properties to the Ad vectors for greatly reducing their systemic toxicity and enable liver de-targeting. CryoEM analyses are currently underway to identify the structural differences in the capsid between the penton mutants and the wild type Ad.
Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study
Authors: Maarten Arends, Christoph Wanner, Derralynn Hughes, Atul Mehta, Daniel Oder, Oliver T. Watkinson, Perry M. Elliott, Gabor E. Linthorst, Frits A. Wijburg, Marieke Biegstraaten, Carla E. Hollak
Journal: Journal of the American Society of Nephrology (2016)

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00;
Differential T Cell Suppression by Two Different Pentostatin Conditioning Protocols for Nonmyeloablative Allogeneic Stem Cell Transplantation (NST).
Authors: Ugur Coskun, Robert G. Bociek, Zivko S. Pavletic, Charlie Kuszynski, Marcel Devetten, Laura Shafer, Lori Zobel, James E. Talmadge
Journal: Blood (2006)
ASPP2 Haploinsufficiency Promotes Tumor Formation in a Mouse Model.
Authors: Kerstin M. Kampa, Jared D. Acoba, Dexi Chen, Kelly Beemer, Joel Gay, Zhiyi Zhu, Emerson Padiernos, Alice Fan, Dean Felsher, Christopher Corless, Louie Naumovski, Charles D. Lopez
Journal: Blood (2006)
Updated European Association of Urology Guidelines Regarding Adjuvant Therapy for Renal Cell Carcinoma
Authors: Axel Bex, Laurence Albiges, Börje Ljungberg, Karim Bensalah, Saeed Dabestani, Rachel H. Giles, Fabian Hofmann, Milan Hora, Markus A. Kuczyk, Thomas B. Lam, Lorenzo Marconi, Axel S. Merseburger, Michael Staehler, Alessandro Volpe, Thomas Powles
Journal: European Urology (2016)
Fibromatosis Associated With Neuromuscular Choristoma
Authors: Stephen M. Broski, Benjamin M. Howe, Robert J. Spinner, Kimberly K. Amrami
Journal: Clinical Nuclear Medicine (2016)

Neuromuscular choristoma (NMC) is a rare benign peripheral nerve lesion consisting of mature skeletal muscle fibers admixed with nerve fascicles. Aggressive fibromatosis frequently develops in association with NMC, often after surgery or biopsy, but the exact pathogenesis is not known. We present a case of NMC complicated by aggressive fibromatosis evaluated by F-FDG PET/CT and examine the relationship of metabolic activity and MRI signal characteristics.