tbuckley/cabot-search huggingface dataset:
Abstract 3577: Targeting localization and function of the RNA helicase DDX5/p68 with 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902)
Authors: Judit Remenyi, Mi Young Yang, Young Bok Lee, Deog Joong Kim, Frances V. Fuller-Pace
Journal: Cancer Research (2015)

Abstract The DEAD box RNA helicase DDX5/p68 is aberrantly expressed and post-translationally modified in several cancers. Several studies have indicated that p68 plays important roles in cell proliferation and tumor progression; in particular, p68 that is phosphorylated on Tyr593 has been shown to be associated with cell transformation, epithelial mesenchymal transition and cell migration. Therefore, p68 may be a promising target for novel anti-cancer therapeutics. We previously reported that 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902) inhibits the growth cancer cell lines by interacting and interfering with the function of phosphorylated p68 at low nanomolar concentrations, and inhibit tumor growth in several human xenograft models in nude mice. Although p68 is largely a nuclear protein, it has been found to shuttle between the nucleus and cytoplasm in cells, a function that appears to be critical for its role in epithelial-mesenchymal transition. Furthermore, our previous work demonstrated that the nuclear localization of p68 alters during the cell cycle suggesting that alterations in localization of p68 may also be important for cell cycle control and proliferation. We therefore investigated the effect of RX-5902 on the cellular localization of phosphorylated p68 in cancer cell lines. Our results suggest that treatment with RX5902 results in a significant alteration in the localization of phosphorylated p68, providing a possible mechanism(s) by which RX-5902 may affect phosphorylated p68 function. Further ongoing studies are aimed at examining the effect of RX-5902 on cellular motility in wound healing assays to determine whether RX-5902 could additionally affect the potential function of phosphorylated p68 in cell migration. Citation Format: Judit Remenyi, Mi Young Yang, Young Bok Lee, Deog Joong Kim, Frances V. Fuller-Pace. Targeting localization and function of the RNA helicase DDX5/p68 with 1-(3,5-dimethoxyphenyl)-4-[(6-fluoro-2-methoxyquinoxalin-3-yl) aminocarbonyl] piperazine (RX-5902). [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 3577. doi:10.1158/1538-7445.AM2015-3577
150. Further Development of an Allele-Specific Gene Silencing Strategy to Correct a Dominant-Negative Mutation Causing Collagen VI-Related Muscular Dystrophy
Authors: Véronique Bolduc, Katherine Sizov, Apurva Sarathy, Yaqun Zou, Carsten G. Bönnemann
Journal: Molecular Therapy (2016)

Collagen VI-related congenital muscular dystrophies (COL6-RD), caused by mutations in any of the three genes coding for collagen type VI (COL6A1, COL6A2, COL6A3), underlie a spectrum of disorders ranging from severe life-threatening early onset Ullrich muscular dystrophy via intermediate phenotypes to the milder Bethlem type, typically presenting with generalized muscle weakness, proximal joint contractures, and respiratory failure. At present, there are no treatment options available for individuals affected with these diseases. The fact that the majority of COL6-RD cases are carriers of inherited or de novo dominant mutations, acting as dominant-negative, poses a challenge for the development of targeted therapies. In contrast to gene replacement, allele-specific silencing has the potential to treat these disorders, as it would convert the dominant-negative state into a clinically asymptomatic haploinsufficient state. Therefore, in the laboratory we aim at exploring targeted RNA interference (RNAi) approaches as a potential therapeutic approach for dominant COL6-RD. We have previously demonstrated the allele-specificity and efficacy of siRNA oligos to downregulate the expression of a mutant COL6A3 transcript in vitro in patient-derived fibroblasts. In preparation of in vivo testing we have now extended our study to cells isolated from a mouse model of the disorder, which carries the most frequent dominant-negative mutation, a deletion of exon 16 on Col6a3. We transfected a series of small interfering RNA (siRNA) oligonucleotides into Col6a3del16+/- fibroblast cells, isolated from skin and muscle. To assay efficacy we used outcome measures such as unsaturated PCR, quantitative RT-PCR, and immunofluorescence. In addition, we performed in vivo electroporation of siRNA oligonucleotides in FDB muscles of Col6a3del16+/- mice. We found that siRNA oligonucleotides were effective in Col6a3del16+/- cells, to specifically knockdown the expression from the mutant allele and to restore the production of a collagen VI matrix in culture. This study provides further proof-of-concept of the use of RNAi as a potential treatment for COL6-RD.
Reconciling evidence-based medicine and precision medicine in the era of big data: challenges and opportunities
Authors: Jacques S. Beckmann, Daniel Lew
Journal: Genome Medicine (2016)

This era of groundbreaking scientific developments in high-resolution, high-throughput technologies is allowing the cost-effective collection and analysis of huge, disparate datasets on individual health. Proper data mining and translation of the vast datasets into clinically actionable knowledge will require the application of clinical bioinformatics. These developments have triggered multiple national initiatives in precision medicine-a data-driven approach centering on the individual. However, clinical implementation of precision medicine poses numerous challenges. Foremost, precision medicine needs to be contrasted with the powerful and widely used practice of evidence-based medicine, which is informed by meta-analyses or group-centered studies from which mean recommendations are derived. This "one size fits all" approach can provide inadequate solutions for outliers. Such outliers, which are far from an oddity as all of us fall into this category for some traits, can be better managed using precision medicine. Here, we argue that it is necessary and possible to bridge between precision medicine and evidence-based medicine. This will require worldwide and responsible data sharing, as well as regularly updated training programs. We also discuss the challenges and opportunities for achieving clinical utility in precision medicine. We project that, through collection, analyses and sharing of standardized medically relevant data globally, evidence-based precision medicine will shift progressively from therapy to prevention, thus leading eventually to improved, clinician-to-patient communication, citizen-centered healthcare and sustained well-being.
Haploidentical/Mismatched Hematopoietic Stem Cell Transplantation for Nonresponders to Immunosuppressive Therapy Compared with First-Line Rabbit Antithymocyte Immunoglobulin Treatment Against Acquired Severe Aplastic Anemia
Authors: Limin Liu, Xiuli Wang, Song Jin, Lin Hao, Yanming Zhang, Xingxia Zhang, Wu Depei
Journal: Blood (2015)
Characterization of the Role of Regulatory T Cells (Tregs) in Inducing Progression of Multiple Myeloma
Authors: Yawara Kawano, Michele Moschetta, Katsutoshi Kokubun, Pavlo Lukyanchykov, Esilida Sula Karreci, Salomon Manier, Shokichi Tsukamoto, Satoshi Takagi, Jiantao Shi, Michaela R. Reagan, Daisy Huynh, Antonio Sacco, David M. Dorfman, Marta Chesi, Peter Leif Bergsagel, Aldo M Roccaro, Jamil Azzi, Irene M. Ghobrial
Journal: Blood (2015)
Daunorubicin Induces Procoagulant Activity of Cultured Endothelial Cells through Phosphatidylserine Exposure and Microparticles Release
Authors: Yueyue Fu, Huibo Li, Wen Li, Xiushuai Dong, Jinxiao Hou, Rui Xie, Chunyan Gao, Xue Yang, Jin Zhou, Gary E. Gilbert, Jialan Shi
Journal: Blood (2010)
BMS-936564 (MDX1338): A Fully Human Anti-CXCR4 Antibody Induces Apoptosis in an in Vitro Model of Stromal – Leukemia Cell Interaction for Chronic Lymphocytic Leukemia.
Authors: Manoj Kumar Kashyap, Deepak Kumar, Harrison Jones Jones, Michael Y. Choi, Johanna Melo-Cardenas, Michelle R. Kuhne, Peter Sabbatini, Lewis Cohen, Suresh Shelat, Pina M Cardarelli, Thomas J. Kipps, Januario E. Castro
Journal: Blood (2012)
Outcome of Aplastic Anemia in Children. A Survey On Behalf of the SAA and PDWP of the EBMT
Authors: Carlo Dufour, Marta Pillon, Rosi Oneto, Genny Franceschetto, Andrea P Bacigalupo, Jakob R. Passweg, Gerard Socie, Antonio M. Risitano, Andre Tichelli, Regis Peffault de Latour, Alicia Rovó, Hubert Schrezenmeier, Christina Peters, Mahmoud Aljurf, Judith C Marsh
Journal: Blood (2012)
Abstract 3877: The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers
Authors: Seung-Hyun Jung, Min Sung Kim, Youn Jin Choi, Shinn Young Kim, Sun Shin, Nam Jin Yoo, Yeun-Jun Chung, Sug Hyung Lee
Journal: Cancer Research (2015)

Abstract Early gastric cancers (EGCs) precede advanced gastric cancers (AGCs), with a favourable prognosis compared to AGC. To understand the progression mechanism of EGC to AGC, it is required to disclose EGC and AGC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (five EGCs and four AGCs) and eight MS-stable (MSS) gastric cancers (four EGCs and four AGCs). In the cancers, we observed well-known driver mutations (TP53, APC, PIK3CA, ARID1A, and KRAS) that were enriched in cancer-related pathways, including chromatin remodelling and tyrosine kinase activity. The MSI-H genomes harboured ten times more mutations, but were largely depleted of copy number alterations (CNAs) compared to the MSS cancers. Interestingly, EGC genomes showed a comparable level of mutations to AGC in terms of the number, sequence composition, and functional consequences (potential driver mutations and affected pathways) of mutations. Furthermore, the CNAs between EGC and AGC genomes were not significantly different in either MSI-H and MSS. Evolutionary analyses using somatic mutations and MSI as molecular clocks further identified that EGC genomes were as old as AGC genomes in both MSS and MSI-H cancers. Our results suggest that the genetic makeup for gastric cancer may already be achieved in EGC genomes and that the time required for transition to AGC may be relatively short. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful in the clinical settings for the molecular diagnosis and therapeutics of gastric cancer patients. Citation Format: Seung-Hyun Jung, Min Sung Kim, Youn Jin Choi, Shinn Young Kim, Sun Shin, Nam Jin Yoo, Yeun-Jun Chung, Sug Hyung Lee. The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers. [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 3877. doi:10.1158/1538-7445.AM2015-3877
Abstract 3907: Differential effects of 1α, 25-dihydroxyvitamin D3 dose on keratinocyte proliferation and ΔNp63α stabilization
Authors: Natasha T. Hill, Jin Zhang, Mary K. Leonard, Miryoung Lee, Madhavi Kadakia
Journal: Cancer Research (2015)

Abstract 1α, 25-dihydroxyvitamin D3 (VD3) is a secosteriod that has been explored as an anti-cancer agent, but has also been shown to promote cell survival. Its receptor, Vitamin D Receptor (VDR), is a direct target of the oncogene ΔNp63α, which is overexpressed in non-melanoma skin cancers. The interconnection between VDR/VD3 signaling and ΔNp63α, led us to examine whether VDR/VD3 signaling promotes keratinocyte proliferation by regulating ΔNp63α levels. We show that VDR regulates ΔNp63α expression at both the transcript and protein level. Interestingly, while low doses of VD3 led to an increase in ΔNp63α protein levels and keratinocyte proliferation, high doses of VD3 failed to increase ΔNp63α protein levels and resulted in reduced proliferation. Increased levels of ΔNp63α by low dose VD3 was shown to be VDR dependent and critical for the pro-proliferative effects of VD3. Furthermore, VD3 mediated increases in ΔNp63α protein levels occur via p38 activation. Analysis of squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and precursors to invasive SCC demonstrated a significant correlation between p63 and VDR levels when compared to normal skin samples. In this study we demonstrated a differential dose effect of VD3 on ΔNp63α stability, which directly resulted in differential effects on cell growth. Delineation of the mechanisms by which VD3 exerts its effect on ΔNp63α will be critical for determining the future of VD3 in cancer therapies. Citation Format: Natasha T. Hill, Jin Zhang, Mary K. Leonard, Miryoung Lee, Madhavi Kadakia. Differential effects of 1α, 25-dihydroxyvitamin D3 dose on keratinocyte proliferation and ΔNp63α stabilization. [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 3907. doi:10.1158/1538-7445.AM2015-3907
Response to Open Peer Commentaries on “A Framework for Unrestricted Prenatal Whole-Genome Sequencing: Respecting and Enhancing the Autonomy of Prospective Parents”
Authors: Stephanie C. Chen, David T. Wasserman
Journal: The American Journal of Bioethics (2016)

We are gratified that our target article (Chen and Wasserman 2017) generated so much commentary from thoughtful scholars. We take this opportunity to clarify our framework, address some misundersta...
Abstract 3944: High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma
Authors: Masaki Nasu, Sandra Pastorino, Hugh Luk, Erin Flores, Francine Baumann, Amy Powers, Shreya Kanodia, Giovanni Gaudino, Yu-an Zhang, Adi Gazdar, Haining Yang, Harvey I. Pass, Mitsuru Emi, Michele Carbone
Journal: Cancer Research (2015)

Abstract Background: Malignant mesothelioma (MM) is a lethal tumor whose pathogenesis results from complex interactions between host genetics and environmental carcinogens. BAP1 mutations were reported in 22% and 23% of sporadic MM in two US Caucasian studies whereas BAP1 mutations were found in 61% of sporadic MM in a Japanese study. The significant discrepancy in frequency of BAP1 mutations suggested either a possible influence of ethnicity or differences related to the methodological approaches. Methods: To investigate this apparent discrepancy, we carried out comprehensive genomic analyses using multiple techniques in order to detect somatic alterations of the BAP1 gene in tumors of 22 US Caucasian MM patients. Results: Six mutations were detected by Sanger sequencing, gross gene alterations were found in 7 MM specimens by Multiplex Ligation-Dependent Probe Amplification and copy number analysis, and a new splice variant was identified by cDNA sequencing. Changes in methylation were not observed in our study. Immunohistochemistry (IHC) revealed nuclear BAP1 staining in the 8 MM tumors containing wild-type BAP1 while tumor cells in the 14 biopsies with mutated BAP1 did not show any nuclear staining. We extended our BAP1 IHC analysis to an independent cohort of MM samples from the National Virtual Mesothelioma Bank and we found loss of BAP1 nuclear staining in 46 out of 67 biopsies. Moreover we found similar frequency of BAP1 loss across different MM histological subtypes. Conclusions: We identified somatic alterations of the BAP1 gene in 73.7% of Caucasian MM tumors in two independent cohorts of somatic MMs, underscoring the need to apply integrated genomic analyses to scrutinize the BAP1 gene for its alterations. Immunohistochemistry was the most reliable technique to detect BAP1 mutations in MM biopsies. The high incidence of alterations establishes BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or histological subtype. Citation Format: Masaki Nasu, Sandra Pastorino, Hugh Luk, Erin Flores, Francine Baumann, Amy Powers, Shreya Kanodia, Giovanni Gaudino, Yu-an Zhang, Adi Gazdar, Haining Yang, Harvey I. Pass, Mitsuru Emi, Michele Carbone. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. [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 3944. doi:10.1158/1538-7445.AM2015-3944
Does Concomitant Methotrexate (MTX) and GM-CSF Administration after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Predispose to Thrombotic Microangiopathy (TMA)?.
Authors: Jayesh Mehta, H. Kwaan, L. Gordon, A. Evens, S. Singhal, J. Winter, S. Williams, J. Rowe, A. Goldstone, M. Tallman
Journal: Blood (2004)
Histamine Monitoring in Patients with CML during Treatment with Imatinib: Comparison to Monitoring by Cytogenetics and BCR/ABL.
Authors: Hermine Agis, Susanne Herndlhofer, Hans Semper, Hendrati Pirc-Donoewenater, Oskar Haas, Christine Mannhalter, Harald Esterbauer, Wolfgang R. Sperr, Klaus Geissler, Peter Valent
Journal: Blood (2005)
179. Helper-Dependent Adenovirus-Mediated Gene Transfer of an LDL Receptor/Transferrin Chimeric Protein Reduces Aortic Atherosclerosis in LDL Receptor-Deficient Mice
Authors: Eleonora Leggiero, Giuseppe Labruna, Laura Iaffaldano, Martina Esposito, Dalila Savoia, Lucia Sacchetti, Lucio Pastore
Journal: Molecular Therapy (2016)

Familial hypercholesterolemia (FH) is a well-characterized genetic hyperlipidemia due in most of the cases to mutations in the LDL receptor (LDLR) gene; FH is characterized by elevated concentration of plasma LDL cholesterol (LDL-C) with consequent deposition of LDL-C in tendons, skin and arteries. Statins can lower cholesterol levels but are not effective in all patients whose prognosis is still quite poor. In the past, we have developed safe and effective gene-therapy strategies for hepatocytes transduction and consequent expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We have recently devised a therapeutic strategy for reducing LDL using a secreted protein that can potentially be expressed in non-hepatic tissues used as bioreactors. At this aim, we developed an HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDLR fused with transferrin (LDLR/Tf). We evaluated the efficacy of LDLR/Tf in cellular models such as CHOldla7 in which we restored the cell ability to uptake of labeled LDL; subsequently, we administered intravenously 1X10E11 vp/kg of the HD-Ad vector expressing LDLR/Tf in LDLR-deficient mice and demonstrated the efficacy of the above-mentioned vector in reducing total and LDL cholesterol levels; in addition, expression of LDLR/Tf significantly reduced aortic atherosclerotic lesions in treated LDLR-deficient mice compared to controls 1.78±0.48 vs. 5.38±0.54 sq.mm.). We therefore demonstrated the efficacy of serum secretion of LDLR/Tf in reducing aortic atherosclerosis in FH mice. These results will allow the evaluation of HD-Ad vector-mediated expression of LDLR/Tf in non-hepatic tissues using alternative routes of administration in order to develop safer gene transfer protocol more compatible with clinical applications.
Cellular and Molecular Mechanisms of Sensitivity and Resistance of Hematopoietic Malignant Cells to Treatment with ch128.1Av, An Antibody-Avidin Fusion Protein Specific for Human Transferrin Receptor 1 (CD71).
Authors: Jose A Rodriguez, Gustavo Helguera, Tracy R Daniels, David Casero Diaz-Cano, Elizabeth Ortiz-Sanchez, Giovanni Coppola, Matteo Pellegrini, Otoniel Martinez-Maza, Manuel L Penichet
Journal: Blood (2008)
511. Enhanced-Affinity NY-ESO-1-Specific T Cells Exhibit Extended Functionality without Exhaustion in a Pattern of Effector and Memory Programming in Multiple Cancer Indications
Authors: Luca Melchiori, Daniel D. Williams, Gwendolyn K. Binder-Scholl, Ryan Wong, Martin Kreutz, Helen K. Tayton-Martin, Edward Stadtmauer, Dan T. Vogl, Melinda Merchant, William Tap, Sandra D'Angelo, Eduardo Davila, Marylene Fortin, Yoav Peretz, Aaron P. Rapoport, Crystal Mackall, Bent K. Jakobsen
Journal: Molecular Therapy (2015)

It is now well established that human tumors express unique antigens, however immunosuppressive mechanisms prevent natural immune responses. We hypothesized that infusion of T cells that have been genetically modified to express affinity-optimized tumor antigen-specific TCRs may overcome these barriers. We initiated several ongoing clinical studies to evaluate T cells engineered with an affinity-enhanced TCR specific for the NY-ESO-1 and LAGE-1 cancer testis antigens (NY-ESOc259-T), in synovial sarcoma (SS) and multiple myeloma (MM) patients with antigen-positive tumors. Here we report the initial findings from these correlative studies. Post infusion PBMCs were analyzed by flow cytometry evaluating memory and exhaustion markers (e.g. CD45RA, CCR7, PD-1) and polyfunctionality/cytotoxicity markers (e.g. IFN-γ and Granzyme B). NY-ESOc259-T cells were detected by pentamer staining and their phenotype was correlated with the clinical response. Once infused, NY-ESOc259-T rapidly expanded, peaking around day 21 and subsequently decreasing in frequency but remaining detectable up to one year after infusion. In MM, NY-ESOc259-T cells transitioned from a central memory phenotype to an effector phenotype, up-regulating markers of polyfunctionality and cytotoxicity. These markers decreased at later time points as the cells acquired an effector memory phenotype. In SS, NY-ESOc259-T also up-regulated these antitumor markers, but transitioned toward a phenotype closely related to T stem cell memory (see figure). In all clinical settings, no T regulatory NY-ESOc259-T cells were observed. Exhaustion markers analysis revealed no simultaneous expression of PD-1, LAG-3 and TIM-3 even at later time points, indicating that NY-ESOc259-T cells successfully clear the tumor without becoming exhausted. This correlated with up-regulation of anti-tumor molecules upon stimulation. These data show for the first time that affinity-enhanced, TCR transduced T cells exhibit robust expansion, durable persistence without exhaustion, and follow a natural immune expansion and contraction pattern consistent with an antigen-driven mechanism of action. Moreover the ability of the cells to respond to antigen even up to one year after tumor clearance indicates the onset of a functional memory that mimics a physiologic response to a pathogen.