tbuckley/cabot-search huggingface dataset:
Abstract 4338: Clinical significance of soluble CD26 in malignant pleural mesothelioma
Authors: Nobukazu Fujimoto, Kei Ohnuma, Keisuke Aoe, Osamu Hosono, Taketo Yamada, Takumi Kishimoto, Chikao Morimoto
Journal: Cancer Research (2015)

Abstract There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM. Citation Format: Nobukazu Fujimoto, Kei Ohnuma, Keisuke Aoe, Osamu Hosono, Taketo Yamada, Takumi Kishimoto, Chikao Morimoto. Clinical significance of soluble CD26 in malignant pleural 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 4338. doi:10.1158/1538-7445.AM2015-4338
Evaluation of NIH-Defined Chronic Graft-Versus-Host-Disease in a Rapamycin-Based Haploidentical Stem Cell Transplantation: Analysis of 113 Consecutive Patients with High Risk Haematological Malignancies
Authors: Maria Teresa Lupo-Stanghellini, Alessandra Forcina, Daniela Clerici, Attilio Bondanza, Andrea Assanelli, Matteo Carrabba, Magda Marcatti, Sarah Marktel, Elena Guggiari, Francesca Lunghi, Simone Claudiani, Giorgia Levati, Claudio Bordignon, Consuelo Corti, Massimo Bernardi, Chiara Bonini, Jacopo Peccatori, Fabio Ciceri
Journal: Blood (2012)
A Phase I/II Study of Escalating Doses of Thalidomide (Thal) in Conjunction with Bortezomib (Vel) and High Dose Melphalan (Mel) As A Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation (PBSCT) in Patients with Advanced Multiple Myeloma (MM).
Authors: Sung H Hong, David S Siegel, Michele L Donato, David H. Vesole, Andrew L Pecora, Joshua R. Richter, Emily Brown, Kathryn Buttner, Marie DelFavero, Daniel Kim, Andrea Ortega, Scott D Rowley
Journal: Blood (2012)
Abstract B53: The integrin αvβ6 is a promising therapeutic target for treating PDAC
Authors: Sabari Vallath, Claire Reader, Jennifer Morton, Owen Sansom, Jeff Evans, Andrew Biankin, Simon T. Barry, Hemant Kocher, John F. Marshall
Journal: Cancer Research (2016)

Abstract Integrins are expressed on the surface of all nucleated cells and permit bi-directional communication for cells with their extracellular environment. The integrin αvβ6 is not usually expressed on adult cells unless they are undergoing tissue remodeling, as αvβ6 activates TGFβ, the cytokine that orchestrates wound healing. We find that αvβ6 is not expressed by normal pancreas but is upregulated on over 90% of PDAC. In vitro experiments show αvβ6 promotes cell survival, adhesion, migration and invasion through Matrigel. Treatment with αvβ6-blocking antibody 264RAD of xenografts of human PDAC cell line CfPac1 co-injected with stellate cells stopped tumor growth. In combination with Gemcitabine 264RAD shrank established (100mm3) tumors significantly (p&amp;lt;0.001). In separate studies we treated novel transgenic mice (Pdx1-Cre; LSL-KRasG12D/+; LSL-Dusp6-/-; developed by Prof. S. Keays) with Gemcitabine or 264RAD+Gemcitabine once they had developed PDAC. The Gemcitabine alone group all died within 17 days but the combination therapy group lived significantly longer, the last animal dying at 59 days. Immunohistological analysis shows that the 264RAD-treated tumors had significantly reduced pErk and Ki67 suggesting reduced growth signaling and proliferation. Additionally strongly reduced endomucin and SMA suggest reduction in angiogenesis and myofibroblast activity in the microenvironment. This may be due to reduced TGFβ signaling since pSMAD3 and nuclear SMAD4 levels were also strongly suppressed. Thus 264RAD suppressed PDAC development by targeting both the pancreatic cancer cells and the microenvironment. These studies have resulted in the funding of a Phase I trial for 264RAD therapy of PDAC patients, sponsored by Cancer Research UK in collaboration with AstraZeneca-Medimmune. Citation Format: Sabari Vallath, Claire Reader, Jennifer Morton, Owen Sansom, Jeff Evans, Andrew Biankin, Simon T. Barry, Hemant Kocher, John F. Marshall.{Authors}. The integrin αvβ6 is a promising therapeutic target for treating PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B53.
MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2
Authors: Rajdeep Das, Philip A. Gregory, Rayzel C. Fernandes, Iza Denis, Qingqing Wang, Scott L. Townley, Shuang G. Zhao, Adrienne R. Hanson, Marie A. Pickering, Heather K. Armstrong, Noor A. Lokman, Esmaeil Ebrahimie, Elai Davicioni, Robert B. Jenkins, R. Jeffrey Karnes, Ashley E. Ross, Robert B. Den, Eric A. Klein, Kim N. Chi, Hayley S. Ramshaw, Elizabeth D. Williams, Amina Zoubeidi, Gregory J. Goodall, Felix Y. Feng, Lisa M. Butler, Wayne D. Tilley, Luke A. Selth
Journal: Cancer Research (2016)

Serum levels of miR-194 have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion, and epithelial-mesenchymal transition in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR-194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo Mechanistic investigations identified the ubiquitin ligase suppressor of cytokine signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194-driven metastatic phenotypes, whereas overexpression of a nontargetable SOCS2 reduced miR-194-stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacologic inhibition of ERK and JAK/STAT pathways reversed miR-194-driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer. Cancer Res; 77(4); 1021-34. ©2016 AACR.
Activating <i>ESR1</i> Mutations Differentially Affect the Efficacy of ER Antagonists
Authors: Weiyi Toy, Hazel Weir, Pedram Razavi, Mandy Lawson, Anne U. Goeppert, Anne Marie Mazzola, Aaron Smith, Joanne Wilson, Christopher Morrow, Wai Lin Wong, Elisa De Stanchina, Kathryn E. Carlson, Teresa S. Martin, Sharmeen Uddin, Zhiqiang Li, Sean Fanning, John A. Katzenellenbogen, Geoffrey Greene, José Baselga, Sarat Chandarlapaty
Journal: Cancer Discovery (2016)

Abstract Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen-independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from more than 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g., L469V, V422del, and Y537D). Although many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo. Correspondingly, tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants. Significance: A diversity of activating ESR1 mutations exist, only some of which confer resistance to existing ER antagonists that might be overcome by next-generation inhibitors such as AZD9496. Cancer Discov; 7(3); 277–87. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 235
Abstract 4690: Next-generation screen for integrative subtyping and target discovery for KRAS-mutant cancer
Authors: Tina L. Yuan, Rachel Bagni, Ming Yi, Arnaud Amzallag, Shervin Afghani, Katie Beam, William Burgan, Nicole Fer, Leslie Garvey, Brian Smith, Andrew Waters, Robert Stephens, Cyril Benes, Frank McCormick
Journal: Cancer Research (2015)

Abstract Mutations in the small GTPase, KRAS, are found in ∼140,000 new cases of cancer every year in the United States. This heterogeneous class of cancers manifests primarily as adenocarcinomas of the lung, colon and pancreas. These cancers display a wide spectrum of KRAS-dependency and differentially activate downstream effector signaling. The tumors further diverge in their array of co-occurring secondary mutations, expression signatures and KRAS mutant allele. Ultimately, the sole trait these cancers share in common is an obstinate resistance to chemo- and targeted-therapies, making identification of effective treatments an urgent need. To identify treatments for such a heterogeneous class of cancers, we developed a strategy to stratify KRAS-mutant cell lines into subtypes by integrating next-generation RNAi screening and “Omics” database mining. Each subtype is characterized by unique biomarkers and distinct patterns of effector dependency, both of which represent potential targets for personalized therapeutic strategies. Our RNAi screen systematically evaluates sensitivity to siRNA-mediated knockdown of 40 KRAS effector nodes in a panel of 135 lung, colorectal and pancreatic cancer cell lines. Data is analyzed on the single cell level, through the simultaneous measurement of 5 functional parameters. This single-cell, multi-dimensional approach allows for a comprehensive assessment of cellular homeostasis, with unprecedented depth and dynamic range that allows robust classification of cell lines by similarity. We identify subtypes of KRAS-mutant cell lines that rely on particular effector pathways such as the RAL, RSK, MTOR and autophagy pathways, which are not engaged by all KRAS-mutant cell lines, and thus may represent targets for personalized treatment. We further identify widely shared dependencies such as on the RAF, glycolytic and cell cycle pathways. Through integrative data mining of exome, transcriptome and drug/siRNA sensitivity databases for each KRAS-mutant subtype, we can identify unique biomarkers that will serve to stratify patients in the clinic and recommend personalized treatment strategies. Citation Format: Tina L. Yuan, Rachel Bagni, Ming Yi, Arnaud Amzallag, Shervin Afghani, Katie Beam, William Burgan, Nicole Fer, Leslie Garvey, Brian Smith, Andrew Waters, Robert Stephens, Cyril Benes, Frank McCormick. Next-generation screen for integrative subtyping and target discovery for KRAS-mutant cancer. [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 4690. doi:10.1158/1538-7445.AM2015-4690
RARE-20TUMOR-ASSOCIATED MACROPHAGES ASSOCIATE WITH CEREBROSPINAL FLUID INTERLEUKIN-10 AND SURVIVAL IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL)
Authors: Junichi Sakata, Takashi Sasayama, Kazuhiro Tanaka, Takashi Mizowaki, Hiroaki Nagashima, Satoshi Nakamizo, Hirotomo Tanaka, Masamitsu Nishihara, Katsu Mizukawa, Takanori Hirose, Tomoo Itoh, Eiji Kohmura
Journal: Neuro-Oncology (2015)
Abstract 2560: The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis
Authors: Shaoqing Shi, Qiong Wang, Jennings Xu, Mabel T. Padilla, Toru Nyunoya, Chengguo Xing, Lin Zhang, Yong Lin
Journal: Cancer Research (2015)

Abstract Because chemoresistance is the major hurdle of anticancer therapy, sensitizing cancer cells to chemotherapy is a main challenge for improving survival in cancer patients. Combined therapy by using drugs with distinct functioning mechanisms may increase anticancer efficacy. We have recently identified the novel chalcone derivative chalcone-24 (Chal-24) as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this study, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beklin1 pathway for autophagy activation, it strongly triggered Chal-24-induced proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, cisplatin induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a dual mechanism for potentiation of anticancer activity with combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIP degradation. Altogether, our work suggests that combination of Chal-24 and cisplatin could be employed for improving chemotherapy efficacy. (Supported by R01ES017328 (NIEHS/NIH) and DE-FG02-09ER64783 (DOE). Citation Format: Shaoqing Shi, Qiong Wang, Jennings Xu, Mabel T. Padilla, Toru Nyunoya, Chengguo Xing, Lin Zhang, Yong Lin. The cisplatin and Chal-24 combination synergistically kills cancer cells through IAP and c-FLIP degradation, Ripoptosome formation and autophagy-mediated apoptosis. [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 2560. doi:10.1158/1538-7445.AM2015-2560
Safety and Efficacy of Thiotepa-Based Conditioning Therapy for Allogeneic Transplantation in Acute Myeloid Leukemia - a Survey from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation
Authors: Sandra Eder, Myriam Labopin, Jurgen Finke, Donald W. Bunjes, Attilio Olivieri, Stella Santarone, Alessandro Rambaldi, Lothar Kanz, Giuseppe Messina, Arnon Nagler, Mohamad Mohty
Journal: Blood (2014)
Correction: Clinical Correlates of <i>NRAS</i> and <i>BRAF</i> Mutations in Primary Human Melanoma
Journal: Clinical Cancer Research (2011)

In this article (Clin Cancer Res 220011;17:229–35), which was published in the January 15, 2011 issue of Clinical Cancer Research (1), the alignment of Table 4 is incorrect. The correct table is shown below.
Abstract 4986: Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2
Authors: Mathieu Joseph François Crupi, Piriya Yoganathan, Leslie N. Bone, Eric Lian, Andrew Fetz, Costin N. Antonescu, Lois M. Mulligan
Journal: Cancer Research (2015)

Abstract The RET receptor tyrosine kinase is an important contributor to kidney and enteric nervous system development. In normal development, RET signaling regulates cell proliferation, migration, survival and differentiation, but RET is also implicated in growth and spread of several human cancers. Activating mutations of RET are drivers of inherited and sporadic thyroid cancers, while expression of wildtype RET receptors in breast and pancreatic cancers has been associated with enhanced tumor invasion, metastasis and poor disease prognosis. RET is expressed as two major isoforms, RET9 and RET51, that have unique 9 or 51 amino acid C-terminal tails, respectively. These isoforms induce unique phosphorylation patterns on intracellular tyrosine residues, differentially bind downstream signalling proteins, and possess different intrinsic abilities to cause cellular transformation. We have previously shown that RET isoforms are internalized from the cell surface into endosomal compartments in response to glial cell line derived neurotrophic factor (GDNF) ligand stimulation, but the specific mechanisms of RET trafficking remain to be elucidated. Here, we used total internal reflection fluorescence microscopy to demonstrate that RET internalization occurs through clathrin coated pits (CCPs). Activated RET receptors colocalize with clathrin, but not caveolin, at sites of CCPs. The RET51 isoform is rapidly and robustly recruited to CCPs upon GDNF stimulation, while RET9 recruitment occurs more slowly and is less pronounced. We showed that the clathrin-associated adaptor protein complex 2 (AP2) is important for RET internalization. Our data establish that interactions with the AP2 complex promote RET receptor internalization via clathrin-mediated pathways but that RET9 and RET51 have distinct internalization kinetics that may contribute to the functional differences between RET isoforms which are critical to regulating RET's contribution to tumorigenesis and normal development. These data may also have clinical importance, as they characterize key regulatory events for an important oncogene that may in future indicate biologically relevant targets for therapeutic interventions in RET-associated tumors. Citation Format: Mathieu Joseph François Crupi, Piriya Yoganathan, Leslie N. Bone, Eric Lian, Andrew Fetz, Costin N. Antonescu, Lois M. Mulligan. Distinct temporal regulation of RET isoform internalization: Roles of clathrin and AP2. [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 4986. doi:10.1158/1538-7445.AM2015-4986
Polyphosphate nanoparticles on the platelet surface trigger contact system activation
Authors: Johan J. F. Verhoef, Arjan D. Barendrecht, Katrin F. Nickel, Kim Dijkxhoorn, Ellinor Kenne, Linda Labberton, Owen J. T. McCarty, Raymond Schiffelers, Harry F. Heijnen, Antoni P. Hendrickx, Huub Schellekens, Marcel H. Fens, Steven de Maat, Thomas Renné, Coen Maas
Journal: Blood (2017)
500. Triple AAV Vectors Expand AAV Cargo Capacity in the Retina
Authors: Andrea Maddalena, Pasqualina Colella, Ivana Trapani, Renato Minopoli, Alberto Auricchio
Journal: Molecular Therapy (2015)

We have recently shown that dual AAV vectors expand AAV cargo capacity in the retina up to 9kb thus allowing their application to the therapy of inherited blinding conditions like Stargardt disease or Usher syndrome type IB (USHIB). However, for several other inherited blinding conditions the size of the coding sequence to be transferred would not fit into dual AAV vectors and would require a triple AAV vector system. We have generated triple AAV vectors encoding a reporter EGFP-DsRed fusion protein under the transcriptional control of the ubiquitous CMV promoter. The expression cassette was split in three parts and packaged in three distinct AAV vectors. In order to favour the directional concatemerization upon co-infection, highly recombinogenic sequences were added to the constructs which would then be eliminated from the mature transcript by the inclusion of flanking splicing signals (Figure 1). Triple AAV 2/2 vectors were used to infect HEK293 cells in vitro and AAV 2/8 vectors in vivo by subretinal administration in C57Bl/6 mice. Direct fluorescence analysis showed EGFP and DsRed colocalization in HEK293 cells; full length protein expression was confirmed by Western Blot analysis of HEK293 cell lysates. Fundoscopy analysis of C57Bl/6 mice up to 2 months after subretinal delivery shows signal compatible with EGFP-DsRed expression. Western-blot analysis of retinal lysates supports the production of the full length protein. Our results suggest that AAV DNA cargo capacity can be increased up to 12kb in the retina by triple AAV vectors. This bodes well for gene therapy of retinal diseases which require a high DNA cargo capacity.