bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4745: TLR8 agonist and Doxil chemotherapy potently activate human antitumor immune response in a human immune system mouse model
Authors: Facciabene Andrea , Malykhin Alexander , Mathews Maura , Fang Chungyun , Dietsch Greg , Hershberg Rob , Coukos George 
Published: June 2012

Abstract
Because of differences between mouse and human immune systems, many of the effects of immunomodulatory drugs cannot be fully studied in syngeneic mouse models. We thus generated a novel tumor-bearing mouse model with human immune system (HIS) to study interactions between chemotherapy and immune modulatory therapy. We tested the individual effects and the interactions between doxorubicin, a drug which induces immunogenic tumor cell death and activates antigen-presenting cells, and VTX-2337, a novel small-molecule TLR8 agonist, which induces potent activation and type 1 polarization of human myeloid DCs but is inactive on murine leukocytes. Nod/SCID/ILRγc knock out (NSG) mice were inoculated with human CD34+ cord blood cells from HLA-A2+ human donors; transplanted s.c. with human HLA-A2+ OVCAR5 ovarian cancer tumors; and treated with pegylated liposomal doxorubicin (Doxil); VTX-2337; or a combination. NSG-HIS mice exhibited a full human hematopoietic system, including human monocytes, macrophages and plasmacytoid and myeloid DCs as well as T and B cell subsets. In NSG-HIS mice, VTX-2337 induced dose-dependent activation of human Monocytes CD14+ and CD11c+ cells with upregulation of CD80, CD86, CD83, CD40 and MHCII within 6 hrs. Transient, dose-dependent upregulation of human Th1 cytokines but also IL-10 was observed in the plasma of treated mice, reaching peaks within 6 hrs and subsiding within 24 hrs. Doxil induced mild activation of CD11c+ DCs and mild upregulation of Th1 cytokines. The combination of two drugs induced potent activation of CD11c+ DCs and marked increase in Th1 cytokines with significant decrease of IL-10. HLA-A2+ OVCAR5 tumors were successfully engrafted, exhibiting infiltration by human leukocytes. VTX-2337 and Doxil treatment independently induced tumor-infiltrating lymphocytes and restricted growth of human ovarian tumor xenografts in a dose-dependent manner, while the combination of the two drugs induced the highest frequency of Leukocytes (hCD45) and potently restricted growth of ovarian tumors. Combined activation of innate and adaptive immunity by VTX-2337 and Doxil, as well sensitization of tumor cells by Doxil to adaptive and innate immune effector mechanisms was at the basis of the observed interactions suppressing tumor growth. We conclude that the NSG-HIS provided a suitable tool to establish potent interactions between TLR8 agonist and Doxil chemotherapy, which warrant clinical testing.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2011-4745
Abstract 4748: Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation
Authors: Yamaguchi Hideki , Fukami Kiyoko , Sakai Ryuichi 
Published: June 2012

Abstract
Degradation of extracellular matrix (ECM) that is present in the basement membrane and tumor stroma is essential for local invasion and formation of metastatic sites by malignant cancer cells. Invadopodia are ECM-degrading protrusions formed by a variety of invasive cancer cell types and are thought to function in cancer invasion and metastasis. Many components of invadopodia, such as proteins involved in actin polymerization, cell signaling, and ECM degradation, have been reported to date. However, signaling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that produce D-3 phosphoinositides. PI3Ks mediate the signal transduction of extracellular stimuli and regulate diverse cellular events. Uncontrolled activation of the PI3K signaling pathway leads to several pathological phenomena, including tumorigenesis and tumor malignancy. We investigated the role of PI3K signaling during invadopodia formation. We found that in human breast cancer cells, both invadopodia formation and degradation of a gelatin matrix was blocked by treatment with PI3K inhibitors or sequestration of the PI3K product phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3]. Mammals have 8 PI3K enzymes that are subdivided into three general classes (I-III) on the basis of their domain structures and substrate specificities. Functional analyses revealed that among the PI3K family proteins, the class I PI3K catalytic subunit p110α is selectively involved in invadopodia formation. p110α is encoded by the PIK3CA gene, which is one of the most frequently amplified and mutated genes identified in human cancers. Clinical studies revealed that activating mutations of PIK3CA are associated with the development of invasive and metastatic phenotypes and poor patient prognosis. The expression of p110α with the activating mutations promoted invadopodia-mediated invasive activity. Furthermore, knocking down PDK1 and Akt, the downstream effectors of PI3K signaling, suppressed invadopodia formation induced by the p110α mutants. These data suggest that the PI3K signaling pathway via p110α regulates invadopodia-mediated invasion of breast cancer cells. Targeting p110α may be a potential therapeutic approach for controlling invasion of malignant cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4748. doi:10.1158/1538-7445.AM2011-4748
Abstract 4754: Targeting of Ewing sarcoma by CAR-reengineered GD2-specific T cells
Authors: Kailayangiri Sareetha , Altvater Bianca , Meltzer Jutta , Leuchte Katharina , Hotfilder Marc , Juergens Heribert , Rossig Claudia 
Published: June 2012

Abstract
Primary metastatic Ewing sarcoma involving the bone and/or bone marrow has remained largely incurable. Relapses after intensive multimodal treatment regimens are attributed to a rare subpopulation of residual cells capable of reinitiating tumor growth. Cellular immunotherapy with chimeric antigen receptor (CAR) transduced T cells is a promising strategy to eradicate minimal residual disease and prevent relapse. Based on the observation that Ewing sarcoma cells express the ganglioside antigen GD2, we have explored the capacity of T cells transduced with GD2-specific CARs to functionally interact with Ewing sarcoma cells.
Surface GD2 expression was detected on 10 of 11 Ewing sarcoma cell lines by flow cytometry analysis, and on 11 of 12 primary Ewing tumor samples by immunofluorescence staining. To obtain GD2-specific effector T cells, CD3/CD28 stimulated T cells from five healthy donors were retrovirally transduced with the second generation GD2-specific CAR 14.G2aCD28ζ, resulting in CAR surface expression in 83.8±2.7% (81.1-87.8%) of the cells. Ewing sarcoma cell lines expressing various levels of GD2 were used as target cell lines for 14.G2aCD28ζ-mediated cytolysis in a 51Cr release assay. Both GD2hi VH-64 and GD2intermediate Cado-ES-1 cells were efficiently lysed by gene-modified T cells (36.6±7.7% and 25.3%±8.2 lysis at a 40:1 effector-to-target cell ratio) in the absence of background cytolysis of GD2-negative tumor cells and by non-transduced T cells. Moreover, efficient and antigen-specific granzyme B secretion was found after coincubation of various Ewing sarcoma cell lines and a primary Ewing sarcoma cell culture with CAR gene-modified T cells. 14.G2aCD28ζ T cells further eradicated Ewing sarcoma cells in a serum-free spheroid model for anchorage-independent micrometastatic tumor growth. Functional activation of CAR-expressing T cells in response to GD2 positive Ewing sarcoma cells was further demonstrated by significant secretion of IFN-γ and TNFα and significant proliferative responses to various cell lines expressing low, intermediate or high levels of GD2.
Thus, GD2 is a promising target antigen for the redirected antitumor activity of T cells not only in neuroblastoma and melanoma, but also in Ewing sarcoma. To address the preclinical in vivo efficacy of 14.G2aCD28ζ T cells, we have now established an in vivo model of disseminated disease by intravenous transfer of Ewing sarcoma cells to sublethally irradiated NOD/scid mice. Magnetic resonance imaging allows to visualize metastatic tumor manifestations in xenotransplanted mice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4754. doi:10.1158/1538-7445.AM2011-4754
Abstract 4760: Molecular classification and risk-stratification in medulloblastoma using an integrative genomic approach
Authors: Cho Yoon-Jae , Tamayo Pablo , Tsherniak Aviad , Meyerson Matthew , Mesirov Jill P. , Pomeroy Scott L. 
Published: June 2012

Abstract
Purpose. Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors.
Patients and Methods. We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density SNP array and miRNA analysis on 115 and 98 of these, respectively. Unsupervised clustering analysis of mRNA expression data was used to identify molecular subgroups of medulloblastoma and DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We then developed a Bayesian cumulative log odds model for predicting outcome, starting with ‘evidence’ provided by clinical features (metastasis and histology), then incrementally adding genomic evidence representing disease-subtype independent and dependent features. We then validated our results on independent test cohorts.
Results. We identify 6 molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event free and overall survival. Moreover, we show that integration of high-level clinical and genomic risk factors, including molecular subtype, can yield more comprehensive, accurate and biologically interpretable prediction models for outcome in medulloblastoma. We introduce a novel Bayesian nomogram indicating the amount of evidence that each feature contributes on a patient-by-patient basis.
Conclusion. Our results detail the complex genomic heterogeneity of medulloblastomas, identify a previously unrecognized molecular subgroup with particularly poor clinical outcome and propose a Bayesian outcomes prediction model that outperforms the current clinical classification schema and previously published molecular markers proposed for medulloblastoma risk stratification.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4760. doi:10.1158/1538-7445.AM2011-4760
Abstract 4762: Genistein and Indole 3 carbinol induced apoptosis in endometrial cancer cell through DR5 mediated pathway
Authors: Cho Chi-Heum , Shin So-Jin , Kwon Sang-Hoon , Cha Soon-Do , Kim Yong-Man 
Published: June 2012

Abstract
Objective: To address the growth inhibitory effects of Genistein and Indole 3 carbinol in endometrial cancer cell growth and evaluate its effect on apoptosis using ishikawa endometrial cancer cell line.
Methods: Human endometrial cancer cells ishikawa were cultured and treated with various concentrations of Genistein and Indole 3 carbinol alone and in combination. Cell proliferation and growth arrest were evaluated by MTS assay and FACS analysis, respectively. The apoptosis induced was analyzed by DNA fragmentation and western blotting.
Results: Combination of Genistein and Indole 3 carbinol significantly inhibited the proliferation of ishikawa cells in dose dependent manner. Cell cycle analysis indicated the increased proportion of cell arrest in sub G1 phase. DNA fragmentation, up regulation of DR5, down regulation of c-Flip, cleavage of caspase-8 and PARP revealed apoptotic progression.
Conclusion: Genistein and Indole 3 carbinol synergistically inhibited the growth of endometrial cancer cell. Significant induction of apoptosis is associated with DR5 regulated death dependent pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4762. doi:10.1158/1538-7445.AM2011-4762
Abstract 4765: Investigation of omega-3 docosahexaenoic acid (DHA)-induced apoptosis in human triple negative breast cancer
Authors: Xiong Ailian , Yu Weiping , Sanders Bob G. , Kline Kimberly 
Published: June 2012

Abstract
Omega-3 fatty acid enriched diets especially diets rich in docosahexaenoic acid (DHA) have long been associated with a lower incidence of a variety of cancers. Both in vivo and in vitro studies have indicated that DHA exerts anticancer actions via inducing tumor cells to undergo programmed cell death or decreasing cell proliferation. In this study, we investigated the anticancer actions of DHA in human triple negative breast cancer (TNBC) cells in vitro. Data indicate that DHA induces apoptosis in MDA-MB-231 and BT-20 human p53 mutant TNBC cells by activating both intrinsic and extrinsic death-mediating pathways. Activation of apoptosis is associated with induction of endoplasmic reticulum (ER) stress, and increased levels of phosphorylated JNK (pJNK), and CHOP and DR5 protein levels; as well as, reduced levels of pIκB and NF-κB downstream mediators: c-FLIP, Survivin and Bcl-2. DHA induces ROS generation and antioxidants, RRR-alpha tocopherol (αT) and N-acetyl-Cysteine (NAC) block DHA-induced apoptosis, ER stress and upregulation of pJNK/CHOP/DR5. Taken together, our data demonstrate that DHA induces apoptosis in p53 mutant TNBC via activation of ROS mediated ER stress and suppression of NF-kB mediated anti-apoptotic factors. Since p53 mutant TNBCs are associated with poor prognosis and limited treatment options, these studies suggest DHA may be a successful adjuvant treatment strategy. Research is supported by the Clayton Foundation for Research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4765. doi:10.1158/1538-7445.AM2011-4765
Abstract 4768: Receptor interacting protein (RIP) and Sirtuin-3 (SIRT3) on opposite sides of anoikis resistance and promotes tumorigenesis
Authors: Kamarajan Pachiyappan , Alhazzazi Turki , D'Silva Nisha , Verdin Eric , Kapila Yvonne 
Published: June 2012

Abstract
Anoikis-apoptotic cell death triggered by loss of extracellular matrix (ECM) contacts is disregulated in many chronic debilitating and fatal diseases. Regulating crosstalk between anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like autoimmune diseases and cancer. Previously, we showed that anoikis activates a CD95/Fas-mediated signaling pathway regulated by receptor-interacting protein (RIP), a kinase that shuttles between Fas-mediated cell death and integrin/FAK-mediated survival pathways in a variety of cell systems. Since sirtuin 3 (SIRT3), an NAD-dependent deacetylase, is known to regulate longevity, cell survival, metabolism, and tumorigenesis, we hypothesized that SIRT3, might engage in crosstalk with Fas/RIP/integrin/FAK survival-death pathways. Specifically, we examined the roles of RIP and SIRT3 in oral squamous cell carcinoma (OSCC) anoikis resistance and tumorigenesis. Using immunohistochemical staining, immunoblotting, human tissue micro arrays, and overexpression and suppression approaches we examined the roles of RIP and SIRT3 in this context. RIP and SIRT3 have an opposite expression profile in OSCC cells and tissues. Stable suppression of RIP by RIP-targeted shRNA enhances SIRT3 levels, whereas, stable suppression of SIRT3 by SIRT3-targeted shRNA does not impact RIP levels in OSCC cells. Forced expression of RIP in RIP null cells downregulates SIRT3. As OSCC cells become anoikis-resitant they form multicellular aggregates in suspension conditions and their expression of SIRT3 increases as their expression of RIP decreases. Anoikis-resistant cells with high SIRT3 and low RIP levels induce an increased tumor burden and incidence in mice unlike their adherent OSCC cell counterparts, which express low SIRT3 and high RIP levels. OSCC cells with SIRT3 suppression fails to form multicellular aggregates in suspension conditions. Taken together, these data demonstrate that RIP is an upstream negative regulator of SIRT3 in anoikis resistance and anoikis resistance contributes to a more aggressive phenotype in OSCC development and progression (Supported by NIH grant R01DE014429 and NIH grant 2R56DE014429 to YLK).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4768. doi:10.1158/1538-7445.AM2011-4768
Abstract 4778: Resveratrol suppresses constitutive activation of AKT via generation of reactive oxygen species and induces apoptosis in diffuse large B cell lymphoma cell lines
Authors: Jehan Zeenath , Hussain Azhar R. , Ahmed Maqbool , Ahmed Saeeda O. , Al-Dayel Fouad , Bavi Prashant , Uddin Shahab , Al-Kuraya Khawla S. 
Published: June 2012

Abstract
We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in the pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer agents that can be utilized to target these deregulated pathways, we found that Resveratrol (trans-3,4′, 5-trihydroxystilbene) is a naturally occurring polyphenolic compound that has an antioxidant and chemopreventive effects on various cancer cells. In the current investigation, we therefore investigated the role of resveratrol-mediated chemopreventive effect on various DLBCL cell lines. Resveratrol caused a dose dependent inhibition of cell viability in DBCL cell lines. To see whether this inhibition was due to cell cycle arrest or apoptosis, we found that resveratrol induced apoptosis in all DLBCL cell lines. We next investigated the action of resveratrol on PI3-kinase/AKT pathway and found that resveratrol treatment resulted in inhibition of constitutively activated AKT and its downstream targets, p-FOXO1, p-GSK3 and p-Bad via generation of reactive oxygen species (ROS). Inactivation of Bad led to conformational changes in Bax protein causing loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This led to activation of caspase-9, caspase-3, and poly-(ADP)-ribose polymerase cleavage leading to caspase-dependent apoptosis. In addition, resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; however, this up-regulation did not result in apoptosis. Finally, co-treatment of DLBCL with sub-toxic doses of TRAIL and resveratrol induced efficient apoptosis. Altogether, these data suggest a novel function for resveratrol, acting as a suppressor of AKT/PKB pathway via generation of ROS in DLBCL cells, and raise the possibility that this agent may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway either alone or in combination with other chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2011-4778
Abstract 4779: TNF-induced Cofilin 1 phosphorylation by LIMK in colorectal tumor cells
Authors: Ivanovska Jelena , Ettle Benjamin , Benderska Natalya , Chakilam Saritha , Gandesiri Muktheshwar , Ziesché Elisabeth , Hartmann Arndt , Agaimy Abbas , Fischer Thomas , Gohla Antje , Fabry Ben , Schneider-Stock Regine 
Published: June 2012

Abstract
Objectives: Recently, we have shown that the pro-inflammatory cytokine TNF induces apoptosis in HCT116 colorectal tumor cells. Among the first apoptotic signs is a drastic change in cell morphology through modulation of the cytoskeleton. In order to identify and to characterize phosphorylation events and kinase targets associated with early cytoskeletal reorganization after TNF-treatment, we performed a peptide array screen.
Methods: HCT116 tumor cells were cultured for 6h to 72 hours in either normal or TNF- conditioned medium, and radioactive labelled lysates were hybridized to a PepChip kinase full slide array for screening the phosphorylation status of over 400 proteins at over 1400 potential phosphorylation sites. For verification, cell lysates were collected and co-immunoprecipitated. The precipitated proteins were analyzed by western blotting. We verified the subcellular localization of proteins by co-immunofluorescence.
Results: Pepscan array and western blotting revealed that cofilin 1 is markedly phosphorylated on Serine 3 (pCofSer3) after 24 and 48 hours of TNF-treatment. A potential up-stream kinase of cofilin is LIMK1, a serine/threonine protein kinase known to be involved in actin cytoskeleton reorganization through phosphorylation and inactivation of cofilin 1. Interaction between LIMK/Cofilin1/pCofSer3 was verified by co-immunoprecipitation and co-immunofluorescence. F-actin, cofilin1 and LIMK colocalized in membrane ruffles and lamellipodia, consistent with a cofilin-dependent actin cytoskeletal remodelling after TNF treatment. The effects were reversed by ROCK 1 inhibition.
Conclusion: Our data show that TNF-treatment in HCT116 tumor cells induces the formation of a LIMK/Cofilin1/pCofSer3 protein complex that is localized in membrane ruffles and lamellipodia, suggesting that TNF-induced cytoskeletal alterations early during apoptosis are regulated through cofilin signalling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4779. doi:10.1158/1538-7445.AM2011-4779