bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2021: ONO-WG-307, a novel, potent and selective inhibitor of Bruton's tyrosine kinase (Btk), results in sustained inhibition of the ERK, AKT and PKD signaling pathways
Authors: Yasuhiro Tomoko , Yoshizawa Toshio , Daub Henrik , Weber Christoph , Narita Masami , Kawabata Kazuhito 
Published: August 2012

Abstract
Purpose: Btk is a key regulator of B cell receptors (BCR) which play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. BCR signaling is implicated in the survival of malignant B cells and recent studies indicate that targeting Btk may be effective in the treatment of B-cell lymphoma. Response between cell survival and BCR signaling is implicated in different types of B-cell lymphoma. Therefore, we evaluated the inhibitory effect of ONO-WG-307 on Btk-dependent signal transduction by large-scale and quantitative phosphoproteome analysis to a depth of more than 10,000 phosphorylation sites. Methods: Two tumor cell lines (sensitive and non-sensitive) were treated with ONO-WG-307. After 72h, cell viability was determined by the CellTiter-Glo Luminescent Cell Viability Assay. P-Btk was used as a marker for Btk activity determined by Western blot and Flow Cytometry. Quantitative phosphoproteomics were enabled by differential SILAC labeling of lymphoma cells. After 1 hr incubation with ONO-WG-307, the total cellular proteins were digested and phosphopeptides were enriched by a combination of strong cation exchange and immobilized metal affinity chromatography. Site-specific phosphorylations were identified and by LC-MS analysis on a LTQ-Orbitrap-Velos mass spectrometer followed by bioinformatic processing. Results: Btk is potently and selectively inhibited by ONO-WG-307 in an in vitro Btk kinase assay, with an IC50 in the subnanomolar range whereas IC50 values for other tyrosine kinases (Lck, Lyn and Fyn) were above 1 µM. The concentration required for growth inhibition for the sensitive cells was 3.59 nmol/L (IC50), whereas considerably higher concentrations were required to suppress growth of non-sensitive cells. Surprisingly, inhibition of cellular Btk and ERK phosphorylation by ONO-WG-307 levels of P-Btk and P-ERK were similar in both sensitive and non-sensitive cells. However, our quantitative phosphoproteome studies revealed selective suppression of Akt-mediated signaling and cellular protein kinase D activity in sensitive compared to non-sensitive cells.Conclusion: These results suggest that the selective ONO-WG-307 inhibition of “responder” cell growth might be due to a critical role of Btk-mediated signaling through Akt and protein kinase D. These data shed new light on the cellular mode-of-action of Btk inhibition and support the potential clinical utility of ONO-WG-307 in B cell malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2021. doi:1538-7445.AM2012-2021
Abstract 2101: Differential mtDNA sequence variants in primary tissues of colorectal adeno-polyps
Authors: Adams Gregory , Mehrabi Sharifeh , Vatcharapijarn Yupha , Akwe Joyce A. , Yao Xuebiao , Aikhionbare Felix O. 
Published: August 2012

Abstract
Introduction: Increasing evidence suggest that mitochondrial alterations involved in cellular signal pathways have been associated with tumorigenesis. Differentially diagnosing progressive stages of colorectal adenomatous polyps is important for therapeutic intervention and surveillance. We hypothesized that Mitochondrial DNA (mtDNA) variants in colorectal adenomatous polyps are stage-specific genetic changes. We aimed to identify the genetic mtDNA mutations present in the early stages of colorectal cancer. Methods: MtDNA sequence variants among the different types of colorectal adenomatous polyps: Tubular, Tubulovillous and Villous adenomatous were analyzed from sixty-four tissue samples (33 tumor 31 matched surrounding normal tissue (NST)) with patients mean age 57.1±7. Two mtDNA regions were screened from each sample with two primer pairs spanning 8282-to-10107 and 11673-to-13950bp comprised of the MT-NC7, MT-TK, MT-ND3, ATPase 6, ATPase 8, COX III, ND3, ND4L, ND4 and ND5 genes. The presence of polymorphisms and other sequence variants of mtDNA were also evaluated using the high-resolution restriction endonucleases and PCR based sequencing. Results: Forty-two variants were observed of which 18 of 42 (42%) were not previously reported in the MITODAT reference database. The distribution of observed mutations included, 31% (13/42) Tubular, 52% (22/42) Tubulovillous, 45% (19/42) Villous, 45% (19/42) colorectal cancer (including FAP and JVP). Notably, unreported germline variant, G8573A, in the ATPase 8 gene region was found in 100% tubulovillous adenomas, but not any other samples. A heteroplasmic variant A11873G, in the MTND4 gene was detected in 67% tubular, 78% tubulovillous, 71% villous and 38% cancer subtypes. Given that mutations in ATPase 8 genes inhibits the production of ATP from ADP, and mutations in MTND4 genes prevent the normal interactions of complex I with ubiquinone, affecting the generation of ATP, these observed variants may influence the early stages of colorectal tumor. Conclusion: Therefore, our findings suggest that certain mtDNA sequence variants may contribute as a framework for further differentiation studies of stages of colorectal adeno-polyps.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2101. doi:1538-7445.AM2012-2101
Abstract 2142: Dietary grape polyphenol resveratrol regulates Rac activity to increase mammary tumor growth and metastasis
Authors: Castillo-Pichardo Linette , Cubano Luis A. , Dharmawardhane Suranganie 
Published: August 2012

Abstract
Resveratrol is a natural compound from grapes and peanuts that is structurally similar to estrogen and can act as an estrogenic or antiestrogenic compound, depending on the concentration. In vitro, high concentrations of resveratrol can have proapoptotic, antigrowth, anti-inflammmatory, antiangiogenic, and anti-invasive properties in cancer cells. However, we reported that resveratrol at low, physiologically relevant, concentrations acts similar to estrogen and promotes breast cancer cell migration via actin cytoskeletal changes regulated by Rac; a small GTPase that plays a pivotal role in cancer cell migration/invasion, and thus, metastasis. Herein, we investigated the effects of dietary resveratrol on mammary tumor growth and metastasis in immunocompromised mouse models of cancer metastasis. Interestingly, our findings suggest promotion of mammary tumor growth and metastasis to lung, liver, and kidney by resveratrol in tumors derived from the low metastatic estrogen receptor (ER)α(−), ERα(+) MDA-MB-231 and the highly metastatic ER(-) MDA-MB-435 cancer cell lines. To determine the role of Rac in resveratrol-mediated mammary tumor progression, the activity of Rac was measured in tumors from resveratrol-treated mice. Our results show a significant increase in tumoral Rac activity, consistent with the concentration of resveratrol that induced the highest metastatic efficiency. Taken together, our findings demonstrate a cancer-promoting role for dietary concentrations of resveratrol in metastatic cancer via Rac activation. Therefore, this study illuminates the importance of further delineating resveratrol's concentration dependent molecular mechanisms, particularly in breast cancer, before it can be tested in the clinic or used as a dietary supplement for cancer patients. This study was supported by DoD/BCRP W81XWH-08-1-0258 to LCP, DoD/BCRP W81XWH-07-1-0330 to SD, the UCC Pilot Project Program, and the UCC Postdoctoral Program sponsored by the PR Science, Technology and Research Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Universidad Central del Caribe or the PR Science, Technology and Research Trust.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2142. doi:1538-7445.AM2012-2142
Abstract 2259: Oncolytic attenuated measles virus exploits autophagy for its replication and spreads by suppressing Rig-1 like receptors (RLRs) in non-small cell lung cancer cells
Authors: Xia Mao , Gonzalez Patrick , Li Chunyan , Meng Gang , Wang Hongwei , Luehl Nike , Beltinger Christian , Wei Jiwu 
Published: August 2012

Abstract
Both autophagy and RLRs are involved in response to microbial infection, including oncolytic attenuated measles viruses, which are being tested in several clinical trials in advanced cancer patients. As little is known about the role of autophagy in measles virus infection and oncolytic activity as well as the crosstalk with RLRs, these mechanisms require further investigation. In this study, we show for the first time that measles virus of the Edmonston strain (MV-Edm) exploits autophagy for its replication and spreads by suppressing RLRs in non-small cell lung cancer cells (NSCLCs). MV-Edm rapidly induced autophagosomes formation in NSCLCs. Inhibition of autophagy by RNAi led to a hampered viral replication/spread accompanied by robustly increased production of type-I interferons. Conversely, overexpression of autophagic genes massively reduced production of type-I interferons and enhanced viral replication. Expression of RIG-I and MDA5 was enhanced in MV-Edm infected NSCLCs and massively increased when autophagy was concomitantly inhibited, suggesting that virus-induced autophagy participated in modulating RLR-mediated anti-viral response. As enhancing viral replication and spread within tumors could improve oncolytic efficiency, our work may lead to improve clinical therapeutic efficacy of oncolytic MV-Edm when combined with autophagy inducers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2259. doi:1538-7445.AM2012-2259
Abstract 2381: ApoStreamtm, an antibody independent platform, captures circulating tumor cells in patients with hepatocellular carcinoma
Authors: Poklepovic Andrew , Roberts John D. , Quigley Maria , Melnikova Vladislava , Woo Jacky , Wu Weigou , Davis Darren 
Published: August 2012

Abstract
Biopsies of HCC can be technically difficult, given the vascular nature of the liver and underlying liver disease. Many HCC patients do not get biopsies, and molecular characterization of these tumors is not possible. Capture of CTCs from blood allows for analysis of cancer cells in metastatic dissemination. The use of EpCAM-based enrichment platforms limits the type of tumor cells that can be recovered, as it selects only for cells which express the antigen of interest. Nonselective methods of CTC analysis are needed. An ongoing study is evaluating the recovery of CTCs in HCC patients with elevated serum alpha-fetoprotein (AFP) using the novel antibody-independent ApoStream™ platform, which utilizes the principle of dielectrophoretic field-flow fractionation to position cells in a hydrodynamic flow profile for sorting. Paired blood samples from HCC patients were analyzed by CellSearch and ApoStream™. Collected cells were immunophenotyped using antibodies against Cytokeratin (CK), CD45, DAPI, and AFP, and analyzed by quantitative laser scanning cytometry. In comparison with the CellSearch platform, ApoStream™ isolated higher number of CK+/CD45-/DAPI+ CTCs in HCC cancer patients. A majority of the CK+/CD45-/DAPI+ CTCs enriched by the ApoStream™ platform (62-98%) were AFP+. ApoStreamTM also isolated AFP+, putative CTCs with the CK-/CD45-/DAPI+ phenotype (9-85 cells), and cells with CK+/CD45+/DAPI+ phenotype (1-978 cells). Conclusion: The ApoStreamTM CTC enrichment platform successfully isolated a greater number of CTCs from HCC patients. ApoStream™ CTC analysis is also being used for pharmacodynamic analysis in an ongoing phase I study of the combination of sorafenib and vorinostat in patients with advanced HCC. In preclinical models, the combination synergistically induces tumor cell death through activation of CD95. In this study, CTC analysis will compare the expression of CD95 and other markers prior to and after drug combination exposure.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2381. doi:1538-7445.AM2012-2381
Abstract 2528: 3C23K: an anti-human Müllerian inhibiting substance type II receptor humanized monoclonal antibody for ovarian cancer targeted therapy
Authors: Jacquet Alexandra , Kersual Nathalie , Garambois Véronique , Fontayne Alexandre , Pujols Fanny , Fournier Nathalie , Pugnière Martine , Chavanieu Alain , de Romeuf Christophe , Prost Jean-François , Urbain Rémi , Pèlegrin André , Gaucher Christine , Teulon-Navarro Isabelle 
Published: August 2012

Abstract
Asymptomatic in early stages, ovarian cancer is a “silent killer” representing the fifth leading cause of female deaths in western countries. Every year 56,967 women in Europe and USA die as a consequence of this disease. The incidence of ovarian cancer is forecast to undergo a 13 % increase in the next eight years in the seven major developed countries to reach about 72,000 annual cases in 2019. Due to the limitations of the current therapeutic approaches, there is a strong need for novel, more efficient, therapies. For this reason, we have produced a humanized monoclonal antibody 3C23K targeting the human Müllerian Inhibiting Substance type II Receptor (MISRII), expressed on most ovarian cancer subtypes, including epithelial ovarian cancer (EOC) representing more than 90% of ovarian cancers. This monoclonal antibody derives from the murine monoclonal antibody 12G4 and displays a particular glycosylation profile known to favor effector recruitment (EMABling®) as previously demonstrated in vitro. In vivo, we also showed that 3C23K exhibited a significant effect on tumor growth against several ovarian tumor xenografted models derived from patient primary EOC tumors. In this study, we first confirmed by peptide microarray that the epitope of 3C23K antibody was strictly identical to that of 12G4 antibody and a 3D-model of the full MISRII molecule was generated in order to better localize the 3C23K epitope. Furthermore, SPR studies demonstrated cross-reactivity of 3C23K with MISRII of rabbit, dog, pig, cow and primate. In vivo, antitumor activity of 3C23K against xenografted EOC tumor models was confirmed with various concentrations and treatment schedules. Moreover, interestingly, we constructed a mutant form of 3C23K harboring two mutations in the Fc region (G236R/L328R) in order to prevent binding to both murine and human FcαRs, and demonstrated that such a modification abolished antitumor activity. This data confirmed in vivo that recruitment of effectors is essential for 3C23K efficacy. Finally, in order to anticipate clinical treatment of ovarian cancers, 3C23K was tested in vivo in combination with carboplatin. Combination, when compared with treatment of each product alone, resulted in more than additive antitumor activity. Altogether these data showed that humanized monoclonal antibody 3C23K represents a promising candidate for ovarian cancer immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2528. doi:1538-7445.AM2012-2528
Abstract 2531: Reduction of In Vivo Tumor Growth and Angiogenesis by a Humanized IgG4 Monoclonal Antibody to SEMA4D
Authors: Jonason Alan S. , Fisher Terrence L. , Torno Sebold , Bussler Holm , Doherty Michael A. , Winter Laurie A. , Reilly Christine , Kirk Renee , Howell Alan , Huang He , Caplan Jeff , Kenney Patrick , Scrivens Maria , Pandina Tracy , Croy Leslie , Evans Elizabeth E. , Paris Mark , Watkins Raymond , Zauderer Maurice , Leonard John E. , Smith Ernest S. 
Published: August 2012

Abstract
Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including metastasis, tumor invasion, and neovascularization. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells activates RhoA and AKT signaling pathways, which promotes formation of new blood vessels and tumor growth in vivo. SEMA4D is over-expressed in a wide array of tumor types, and is also produced by inflammatory cells recruited to the tumor microenvironment, such as tumor-associated macrophages. In addition to its effects on endothelial cells, the interaction of PLXNB1 with MET and ERBB2 can lead to SEMA4D-mediated transactivation of these membrane receptor kinases with a direct effect on tumor cell migration and invasive growth. Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated inflammatory cells, functions as a crucial factor in tumor metastatic potential, and that expression of SEMA4D and/ or its high affinity receptor in tumors induces neovascularization and increases overall tumor aggressiveness. Antibody neutralization of SEMA4D represents a new therapeutic strategy for cancer treatment. We selected a humanized IgG4 antibody, VX15/2503, that binds with roughly 3 nM affinity to rat, mouse, primate, and human SEMA4D. We utilized cellular collapse, flow cytometric and other in vitro functional assays to demonstrate that this antibody blocks SEMA4D interaction with PLXNB1. Using both this antibody and its mouse IgG1 equivalent, MAb 67-2, we have demonstrated that antibody-mediated SEMA4D neutralization blocks tumor growth in CT26 tumor grafts with a tumor growth delay (TGD) of 42% and BCA34 (TGD 18%) tumor grafts, as well as RIP-Tag2, with a tumor growth inhibition (TGI) of 56%, and Tyr:NRAS (TGD 52%) spontaneous tumor models. In summary, we demonstrate that antibody mediated neutralization of SEMA4D in vivo inhibits tumor growth and tumor angiogenesis in a variety of tumor models. The humanized antibody, VX15/2503, has successfully completed IND-enabling toxicology testing and a Phase I trial is currently being conducted in adult patients with advanced solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2531. doi:1538-7445.AM2012-2531
Abstract 2600: SLX4 mutation in hereditary breast cancer
Authors: Shah Sohela , Lach Frank , Kim Yonghwan , Sarrel Kara , Rau-Murthy Rohini , Hansen Nichole , Rendleman Justin , Kirchhoff Tomas , Joseph Vijai , Offit Kenneth , Smogorzewska Agata 
Published: August 2012

Abstract
SLX4 is a DNA repair protein that serves as a docking platform for three structure-specific endonucleases. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi Anemia (FA-P). Monoallelic defects in several Fanconi Anemia genes are known to confer susceptibility to breast and ovarian cancer. Therefore, we resequenced the entire SLX4 coding region in 739 (288 Ashkenazi Jewish and 480 Non-Ashkenazi Jewish) breast cancer patients with 3 or more family members affected by breast cancer and no known BRCA1/BRCA2 mutations, to determine if SLX4 is involved in breast cancer susceptibility. We found a novel nonsense (p.W823*) mutation in one patient. We are sequencing the gene in the breast tumor from the patient to determine the status of the wild-type allele. In addition we also found 8 novel, 33 rare (MAF&lt;1%), and 3 common (MAF&gt; 0.5) missense variants, of which 12 (5 novel and 10 rare) are predicted as damaging by Polyphen2. Functional analysis of these missense mutations is being performed to determine their role in the pathogenicity of the SLX4 gene. Acknowlegements- This project was funded by The Starr Cancer Consotium (Agata Smorgorzewska and Kenneth Offit), The Rita Allen Foundation Scholars Program Grant (Agata Smorgorzewska) and Burroughs Wellcome Fund Career Award for Medical Scientists (Agata Smorgorzewska). We would like to thank the Geoffrey Beene Translational Oncology and Diagnostic Molecular Genetics laboratories for their help with the study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2600. doi:1538-7445.AM2012-2600
Abstract 2648: Gene-asbestos interaction and lung cancer risk from a genome-wide association study
Authors: Liu Chen-Yu 
Published: August 2012

Abstract
Occupational asbestos exposure has been found to increase lung cancer risk based on epidemiologic studies. In order to clarify the respective roles of genetic factors and asbestos exposure on lung cancer risk, we conducted the asbestos exposure-gene interaction analyses. The first discovery stage included 745 Caucasian cases and 839 Caucasian controls using Illumina Human 610-Quad BeadChips. Several independent populations were included in the second replication stage. Cumulative lifetime asbestos exposure score (AES), which was previously developed and validated in our study population, was calculated from self-reported duration and intensity of occupational and nonoccupational exposures. We have found several suggested interesting / significant regions that might be associated with lung cancer risk in our SNP-asbestos exposure interaction tests, especially on 2p25.3, which has been replicated in another independent population. Further replication is still in process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2648. doi:1538-7445.AM2012-2648