tbuckley/cabot-search huggingface dataset:
Abstract 1022: DYRK1A kinase regulates mTOR signaling via modulating the TSC complex
Authors: Vijay R. Menon, Larisa Litovchick
Journal: Cancer Research (2015)

Abstract The Dual specificity Tyrosine-phosphorylation-Regulated Kinase 1A (DYRK1A) kinase is encoded on chromosome 21 and is involved in the pathogenesis of Down syndrome. Earlier studies have shown that DYRK1A is essential for cells to undergo growth arrest following serum starvation, at least in part by promoting the assembly of the DREAM repressor complex. However, the function of this important kinase is not fully understood. Using MudPIT MS/MS proteomic analysis of DYRK1A-interacting proteins followed by immunoprecipitation-Western blotting, we characterized the binding between DYRK1A and the subunits of the TSC tumor suppressor protein complex, a major regulator of the mTORC1 pathway. This interaction was mapped to the kinase domain of DYRK1A, suggesting that the TSC could serve as a substrate for DYRK1A phosphorylation. Indeed, overexpression of DYRK1A increased phosphorylation of both TSC1 and TSC2; this effect was fully reversed by the DYRK1A inhibitor, harmine. Functional studies revealed that loss of DYRK1A in two different cancer cell lines resulted in increased phosphorylation of mTORC1 substrates S6K1 and 4E-BP1. This effect of DYRK1A knockdown was inhibited by rapamycin, confirming the involvement of mTORC1 signaling. Thus, our work revealed novel function of DYRK1A in the regulation of mTOR signaling that controls cell growth, proliferation, and survival. Citation Format: Vijay R. Menon, Larisa Litovchick. DYRK1A kinase regulates mTOR signaling via modulating the TSC complex. [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 1022. doi:10.1158/1538-7445.AM2015-1022
FCGR3A and FCGR2A Polymorphisms Do Not Affect Response and Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab and Chemotherapy. A Study Based on 554 Patients Included in GELA (Groupe d'Etude des Lymphomes de l'Adulte) Prospective Multicentric Study LNH2003
Authors: Herve Ghesquieres, Fabrice Jardin, Sophie Pallardy, Aurélie Verney, Anne Laure Borrel, Nicolas Ketterer, Christian Recher, Richard Delarue, Andre Bosly, Bertrand Coiffier, Rene-Olivier Casasnovas, Olivier Fitoussi, Frederic Peyrade, Vincent Ribrag, Diana Zelenika, Herve Tilly, Corinne Haioun, Gilles Andre Salles
Journal: Blood (2011)
Thymoglobulin ® Rabbit Anti-Thymocyte Globulins (r-ATG) Induces Faster Platelet Recovery and Does Not Suppress Granulocyte Engraftment in a Non-Myeloablative Stem Cell Transplantation Setting.
Authors: Michael Y. Shapira, Igor B. Resnick, Benjamin Gesundeheidt, Menachem Bitan, Aliza Ackerstein, Simcha Samuel, Liliane Drey, Yuri Verkholevsky, Shimon Slavin, Reuven Or
Journal: Blood (2007)
Abstract 2168: BC-BET: an online bladder cancer biomarker evaluation tool
Authors: Garrett Dancik
Journal: Cancer Research (2015)

Abstract Cancer is a genetic disease whose biology is driven by mutated and abnormally expressed genes. In the past ∼15 years, the identification of diagnostic and prognostic biomarkers from genomic data has increased our understanding of cancer biology and has led to advances in the personalized treatment of many cancers. Despite these advances, however, there are no clinically approved biomarkers for the treatment of bladder cancer, which is the fourth most common cancer in males in the United States and one of the most expensive cancers to treat. Although gene expression profiles of bladder cancer patients are publicly available, their analysis is time-consuming and requires computational resources and bioinformatics expertise often not available to biologists or clinician-researchers. Here we describe BC-BET, an online Bladder Cancer Biomarker Evaluation Tool for evaluating candidate diagnostic and prognostic biomarkers in bladder cancer. The BC-BET database contains gene expression data collected from 11 publicly available patient cohorts (N = 1041). For a chosen gene, BC-BET evaluates whether the gene is differentially expressed (P &amp;lt; 0.05) between normal cells and tumors, between low-grade (LG) and high-grade (HG) tumors, and between non-muscle invasive (NMI) and muscle invasive (MI) tumors. Survival analysis is carried out to evaluate whether gene expression is significantly associated with survival in all patients, or in clinically important subsets of patients with NMI, LG tumors, or in patients with MI, HG tumors. Results are summarized graphically and can be downloaded in an Excel spreadsheet. A user can also look at the relative expression of a gene or the correlation between the expression of two genes across 40 bladder cancer cell lines. This tool is freely available to the cancer research community and will be updated as additional bladder cancer biomarker data becomes available. BC-BET is available from http://bioinformatics.easternct.edu. Citation Format: Garrett Dancik. BC-BET: an online bladder cancer biomarker evaluation tool. [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 2168. doi:10.1158/1538-7445.AM2015-2168
Abstract 3100: Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors
Authors: Indeewari K. Lindamulage, Hai-Yen Vu, Dr. Piyush Trivedi, Dr. Hoyun Lee
Journal: Cancer Research (2015)

Abstract Agents targeting colchicine-binding site are recognized as valuable lead compounds in the development of new anticancer drugs. Although colchicine can effectively inhibit cell proliferation, its use as an anticancer agent has not been approved by FDA due to its inherent toxicity. To develop colchicine-binding site targeting agents with low or no toxicity, we have created and examined several chalcone derivatives, from which we have identified CTR-17 and CTR-20 as promising leads. We have examined their anti-proliferative activities using three human breast cancer cell lines (MDA-MB-468, MDA-MB-231 and MCF-7) and two matching non-cancer breast cell lines (184B5 and MCF10A). In addition, we also examined their efficacy using one leukemic cell line (K-562) and one cervical cell line (HeLa). Data from this study showed that CTR-17 and CTR-20 preferentially kill cancer cells 10-100 times over non-cancer cells. Data obtained from flow cytometry, confocal microscopy and Western blotting showed that CTR-17 and CTR-20 induced prolonged mitotic arrest prior to killing cancer cells by apoptosis. We also found that both CTR-17 and CTR-20 inhibit tubulin polymerisation and bind to purified tubulin fibers with a dissociation constant of 3.4±1.7 μM and 5.9±1.9 μM, respectively. CTR-17 competitively inhibits the binding of colchicine to tubulin with an inhibitory concentration of 8.67 μM, suggesting that CTR-17 binds to tubulin at a site close to the colchicine binding site. Molecular docking studies confirmed this binding which occurs via three hydrogen bonds and Van der Waals interactions. In our xenograft model of the human breast cancer cells, the treatment of mice with CTR-17 or CTR-20 (30 mg/kg) twice per week for 30 days effectively inhibits tumor growth. The combination of CTR compounds (15 mg/kg/week) and paclitaxel (5 mg/kg/week) increases paclitaxel's anti-tumor activity by 40-60%. Most importantly, both CTR-17 and CTR-20, when used alone or in combination with paclitaxel, showed no notable toxicity to vital organs (spleen, liver, kidney and lung). Therefore, the novel CTR-17 and CTR-20 chalcone derivatives possess substantial potential as safe and effective anticancer drugs. This project was supported in part from the funds by the Northern Ontario Heritage Funds Corporation, Northern Cancer Foundation, and The City of Greater Sudbury Development Corporation. IKL is a recipient of the Ontario Trillium Scholarship. Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Dr. Piyush Trivedi, Dr. Hoyun Lee. Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors. [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 3100. doi:10.1158/1538-7445.AM2015-3100
MINI01.03: Phase (Ph) I Study of the Safety and Efficacy of the cMET Inhibitor Capmatinib (INC280) in Patients with Advanced cMET+ NSCLC
Authors: Todd M. Bauer, Martin Schuler, Rossana Berardi, Wan-Teck Lim, Robin Van Geel, Maja De Jonge, Analia Azaro, Maya Gottfried, Ji-Youn Han, Dae Ho Lee, Mira Wollner, David Hong, Arndt Vogel, Angelo Delmonte, Alexander Krohn, Yong Zhang, Matthew Squires, Monica Giovannini, Mikhail Akimov, Dong-Wan Kim
Journal: Journal of Thoracic Oncology (2016)
311. In Vivo Zinc Finger Nuclease-Mediated Targeted Integration of a Glucose-6-Phosphatase Transgene Enhances Biochemical Correction in Mice with Glycogen Storage Disease Type IA
Authors: Dustin J. Landau, Elizabeth D. Brooks, Pablo Pablo Perez-Pinera, Hiruni Amarasekara, Adam Mefferd, Songtao Li, Andrew Bird, Charles A. Gersbach, Dwight D. Koeberl
Journal: Molecular Therapy (2016)

Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) targeted to the ROSA26 safe harbor locus and a ROSA26-targeting vector containing a G6PC donor transgene, both delivered with adeno-associated virus (AAV) vectors, markedly improved survival of G6Pase knockout (G6Pase-KO) mice compared with mice receiving the donor vector alone (p<0.04) out to 8 months of age. Transgene integration has been confirmed by sequencing in the majority of the mice treated with both vectors. Surviving G6Pase-KO mice at 8 months of age had decreased glycogen content compared with young untreated G6Pase-KO controls, which correlated with the long-term survival of these mice that otherwise perish before weaning. A short-term experiment resolved difficulty observing biochemical differences between the dual-vector and single-vector groups, caused by a selective advantage for strongly-responding mice: 3-month-old mice receiving the ZFN had significantly reduced hepatic glycogen accumulation and improved G6Pase activity, compared with mice that received the donor vector alone. These data demonstrate that the use of ZFNs to drive integration of G6Pase at a safe harbor locus might improve transgene persistence and efficacy, and lower mortality in GSD Ia.
Abstract 4074: Cancer stem cells in tobacco-induced carcinogenesis and subsequent effect of ATRA-based chemoprevention
Authors: Subin Surendran, Christina Mimikos, Amritha Suresh, Wesley L. Hicks, Mukund Seshadri, Moni A. Kuriakose
Journal: Cancer Research (2015)

Abstract Introduction Chemoprevention is potentially the most effective method to lower the prevalence of head and neck squamous cell carcinomas (HNSCC), the sixth most common type of malignancy worldwide. The chemopreventive effects of retinoids against HNSCC have been previously reported. Retinoids however; relapse following cessation of medication is a critical problem that prevents its clinical use. The objective of this study was to determine the possible mechanism of retinoid resistance by exploring cancer stem cell mediated pathways. Experimental Procedures. In vitro cell line models of normal (NOK) and dysplastic oral keratinocytes (DOK) are being exposed to tobacco to assess the process of carcinogenic progression. The progression in the DOK and HOK cell lines will be assessed by proliferation, migration and invasion assays. The expression of stem cell markers/pathways (CD44/Hyaluronan, Wnt, Notch1, ALDH1A1) during the process of progression will be evaluated using QPCR and FACS. These cell lines will then be treated with ATRA and the subsequent effects on transformation and CSC-specific pathways further evaluated. Summary To this end, immunostaining of normal oral mucosa, potentially malignant lesions (n = 93) and malignant lesions (n = 48) for the stem cell marker CD44 was performed. CD44+ cells were found at a density of 58.57/hpf in normal mucosa, 61.56/hpf in mild dysplasia, 119.44/hpf in moderate dysplasia, and 107.6/hpf in severe dysplasia. The density of CD44+ cells in WDSCC, MDSCC and PDSCC were 183.4, 105 and 160/hpf respectively, indicates CSC cells may represent a marker of malignant progression The cell lines are currently under exposure to tobacco and the transformational changes being documented. Apart from the studies on the changes specific to CSCs, high throughput secretome and proteomic studies are also being planned to evaluate the global changes effected due to tobacco as well as due to subsequent treatment with ATRA. Conclusion This study hence attempts to provide novel insight into tobacco-induced carcinogenesis and mechanism of resistance to retinoid-based chemoprevention. Note: This abstract was not presented at the meeting. Citation Format: Subin Surendran, Christina Mimikos, Amritha Suresh, Wesley L. Hicks, Mukund Seshadri, Moni A. Kuriakose. Cancer stem cells in tobacco-induced carcinogenesis and subsequent effect of ATRA-based chemoprevention. [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 4074. doi:10.1158/1538-7445.AM2015-4074
Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice
Authors: Clara Jana‐Lui Busch, Tim Hendrikx, David Weismann, Sven Jäckel, Sofie M.A. Walenbergh, André F. Rendeiro, Juliane Weißer, Florian Puhm, Anastasiya Hladik, Laura Göderle, Nikolina Papac‐Milicevic, Gerald Haas, Vincent Millischer, Saravanan Subramaniam, Sylvia Knapp, Keiryn L. Bennett, Christoph Bock, Christoph Reinhardt, Ronit Shiri‐Sverdlov, Christoph J. Binder
Journal: Hepatology (2016)

Diet‐related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet‐induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low‐density lipoprotein receptor‐deficient mice on a Western‐type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo . MDA‐induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low‐density lipoprotein receptor‐deficient mice on a Western‐type diet. Conclusion : Accumulation of MDA epitopes plays a major role during diet‐induced hepatic inflammation and can be ameliorated by administration of an anti‐MDA antibody. (H epatology 2017;65:1181‐1195)
lncRNA Functional Networks in Oligodendrocytes Reveal Stage-Specific Myelination Control by an lncOL1 /Suz12 Complex in the CNS
Authors: Danyang He, Jincheng Wang, Yulan Lu, Yaqi Deng, Chuntao Zhao, Lingli Xu, Yinhuai Chen, Yueh-Chiang Hu, Wenhao Zhou, Q. Richard Lu
Journal: Neuron (2016)
b1 Integrin Deficiency in Both Erythroid Cells and Their Microenvironment Does Not Affect Basal Erythropoiesis but Critically Impairs Survival and Erythroid Response to Phenylhydrazine-Induced Stress in Adult Mice
Authors: Tatiana Ulyanova, Gregory V. Priestley, Yi Jiang, Stephen Padilla, Thalia Papayannopoulou
Journal: Blood (2008)
682. Correction of CTLs Cytotoxic Function Defect by SIN-lentiviral Mediated Expression of Munc13-4 in Type 3 Familial Hemophagocytic Lymphohistiocytosis
Authors: Tayebeh-Shabi Soheili, Ida Ricciardelli, Julie Riviere, Amandine Durand, Els Verhoeyen, Chantal Lagresle, Geneviève de Saint Basile, Persis Amrolia, Isabelle André-Schmutz, Marina Cavazzana
Journal: Molecular Therapy (2016)

Patients with mutations in UNC13D gene, coding for Munc13-4 protein, suffer from type 3 Familial hemophagocytic lymphohistiocytosis (FHL3), a life-threatening disorder of the immune system. Munc13-4 controls docking of lytic granules before they fused with the plasma membrane in cytotoxic T and NK lymphocytes and it's defect results in defective cytotoxic function of these cells. Hematopoietic stem and progenitor cell (HSPC) transplantation, which is the only curative treatment for FHL3 to date, is partially successful even when a compatible donor is available because of the important inflammatory background of patients. In this context gene therapy could be a promising therapeutic option especially for those patients without any compatible donor. As Munc13-4's function is to allow proper cytotoxic activity in mature cytotoxic CD8+ T cells we proposed that these laters may constitute target for gene correction. We constructed a self-inactivating HIV-1 derived lentiviral vector encoding human Munc13-4 in two different pseudotypes, the high tropism VSV-G and the measles virus glycoproteins (H/F) envelope which target more efficiently lymphoid cells through the signaling lymphocyte activation molecule (SLAM) as described by Verhoeyen et al. 2011. We demonstrated that both vectors are able to stably transduce FHL3 CD8+ T cells resulting in correction of defective degranulation capacity of these cells. However comparative analysis showed that H/F pseudotyped vector was more efficient than VSV-G vector to transduce FHL3 T cells. Adoptive transfer of the gene-corrected FHL3 T cells in SCID mice bearing autologous B-LCL lymphoma led to significant tumor regression due to an efficient homing into the tumor mass and long persistence of corrected T cells in peripheral blood as compared to non-corrected T cells receiving mice. Our study shows for the first time that a lentiviral mediating gene transfer in T cells could be proposed to treat a hemophagocytic lymphohistiocytosis disorder.
213. Treatment with MGN1601 Induces Immune Responses Against Tumor Associated Antigens in Patients with Renal Cell Carcinoma
Authors: Manuel Schmidt, Barbara Volz, Kerstin Kapp, Viktor Grünwald, Matthias Schroff, Burghardt Wittig
Journal: Molecular Therapy (2015)

The cell-based RCC tumor vaccine MGN1601 consists of two active pharmaceutical ingredients: allogeneic (human) cells gene-modified with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 combined with the synthetic DNA-based immunomodulator dSLIM®, a TLR-9 agonist. In a first in men, proof-of-principle, multi-center, open-label, single-arm, non-randomized phase 1/2 clinical trial (ClinicalTrials.gov: NCT01265368; EudraCT No.: 2009-016853-16) in patients with advanced RCC MGN1601 has shown a good safety profile and improved overall survival in the per-protocol (PP) treated patient population. In the ASET trial, MGN1601 – containing 10e7 gene-modified vaccine cells and 5 mg dSLIM® – was administered 8 times over 12 weeks with 3 weekly and 5 bi-weekly administrations (PP population). Specific immune responses of sera from patients before and after treatment with MGN1601 against a natural set of 17 known tumor associated antigens (TAA) expressed by the vaccine cells were evaluated ex-vivo in a translational research program using peptide arrays. Each TAA was represented on the array by overlapping peptides of 15 amino acids length with an overlap of 13 amino acids. The PP population comprised 10 of 19 heavily pre-treated patients with advanced RCC and of these the humoral immune response against TAA expressed on vaccine cells was evaluated. Within each antigen subsets of overlapping peptides were recognized by patient's sera with an abundant or clearly increased intensity after MGN1601 treatment indicating favoured immunogenic regions for an individual immune response. Such sets of peptides were identified within each antigen showing individual responses by sera from 2 to eight patients. Remarkably, some of these overlapping peptides were recognized by sera of more than one patient ("shared immunogenic regions"): In particular, 50 to 70% of treated patients shared response to immunogenic regions within survivin, stromelysin, c-myc, histone H1.2 and G1/S-specific cyclin-D1 indicating their comprehensive immunogenic potential. Within other TAA (e.g. p53, telomerase) shared immune responses to peptides were observed at lower rates (20 to 40% of patients), whereas within some of the antigens (e.g. MUC1, WT-1) no overlapping peptides recognized by sera of more than one patient were identified. The humoral immune response – assessed in patients treated with the tumor vaccine MGN1601 – revealed overlapping peptides within various TAA that induced an immune response shared by up to 7 of 10 patients, indicating comprehensive immunogenic regions within those TAA and their potential use as vaccine epitopes. The specific evaluation of immune response to those TAA remains to further studies.
Preventive distinction of patients with primary or secondary hypertension by discriminant analysis of chronobiologic parameters estimated on 24-hour blood pressure patterns.
Authors: Pietro Cugini, Terukazu Kawasaki, Loredana Di Palma, Sandro Antonicoli, Paola Battisti, Alessandro Coppola, Giuseppe Leone, Keiko Uezono
Journal: Circulation (1989)

This investigation deals with a statistical probatory that patients with primary (PH) or secondary (SH) hypertension may be correctly diagnosed by a discriminant analysis of the chronobiologic characteristics computed on the 24-hour blood pressure (BP) patterns. The methodology concerning non-invasive 24-h BP monitoring, chronobiologic analysis and the discrimination process is detailed. Substantial dissimilarities were found in the statistical distribution for systolic and diastolic BP rhythmometric parameters (mesor, amplitude and acrophase) by a retrospective assessment of two groups, consisting of 54 patients with PH and 16 patients with SH. The group-related distribution for rhythmometric parameters was found to be significantly different to generate a statistically significant intergroup discriminatory boundary. The discriminant analysis correctly diagnosed patients with PH and SH in a percentage of about 91% and 63%, respectively. The high incidence of success is convincing that the combination of 24-h BP monitoring/ chronobiologic analysis/ discrimination process can be a practical tool for confidently selecting patients with a presumable PH or SH.