bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 240: Amplification status of GAS41 and MDM2 in lung adenocarcinomas
Authors: Pikor Larissa , Lockwood William W. , Vucic Emily A. , Lam Wan L. 
Published: February 2011

Abstract
Background: Lung cancer is the leading cause of cancer death worldwide. High mortality rates are attributed to inefficient therapeutic strategies and a lack of screening for early detection. Identification of genes involved in lung cancer development may yield new molecular targets for diagnosis and treatment. It is well documented that the lung cancer genome harbors genetic alterations. We hypothesize that novel oncogenes can be discovered through characterization of chromosomal regions frequently amplified in lung adenocarcinoma.
Methods: A panel of 169 matched lung adenocarcinoma tumors was studied. Genetic profiles describing copy number alterations and gene expression were generated by whole genome array comparative genomic hybridization and Affymetrix platforms respectively, and visualized using SIGMA2 software. Regions of DNA amplifications were identified using the GISTIC algorithm and integrated with expression data to determine if amplification is associated with overexpression in tumors relative to matched normal tissue. An MTT assay was used to investigate the effect of cell proliferation after shRNA-mediated knockdown in a cell line with DNA amplification. Survival analysis using multiple independent data sets was also performed to assess the clinical significance of gene amplification and overexpression.
Results: A preliminary genome wide screen revealed Glioma Amplified Sequence 41 (GAS41) at 12q13-15 as frequently amplified and overexpressed in lung cancer. GAS41 suppresses cell cycle checkpoint genes p21 and p14, causing indirect repression of the p53 tumor suppressor, promoting tumorigenesis. Amplification of this gene has been reported in the earliest stages of glioma and astrocytoma. GAS41 is amplified in 16.57% of the lung adenocarcinoma tumors (28 of 169) analyzed and consistently overexpressed. Knockdown of GAS41 slowed cell proliferation, consistent with its biological function. Additionally, patients expressing high levels of GAS41 mRNA showed markedly poorer outcomes than those with lower expression.
Conclusions: Our data highlights the tumorigenic potential of GAS41, suggesting that amplification of this gene may be a critical alteration in lung cancer. GAS41 amplification and subsequent activation may represent a novel mechanism driving lung tumorigenesis. The association of GAS41 expression with survival and its demonstrated effect on cell proliferation make it a potential prognostic marker and therapeutic target in lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 240.
Abstract 2405: Treatment of human dendritic cells with Saccharomyces cerevisiae (yeast) reduces number and function of regulatory T cells (Tregs) and enhances the ratio of antigen-specific effectors to Tregs
Authors: Cereda Vittore , Vergati Matteo , Huen Ngar-Yee , di Bari Maria Giovanna , Gulley James L. , Franzusoff Alex , Schlom Jeffrey , Tsang Kwong Y. 
Published: February 2011

Abstract
It has been demonstrated that recombinant Saccharomyces cerevisiae yeast vector containing the transgene encoding carcinoembryonic antigen (yeast-CEA) activates human dendritic cells (DCs) and stimulates CEA-specific T-cell responses. Numerous studies have shown that regulatory T cell (Treg) function plays an important role in immune modulation. We compared the effects of yeast-treated DCs and CD40L-matured DCs on the number and functionality of CD4+CD25+CD127-FoxP3+ Tregs. Human DCs were treated with yeast or CD40L and cocultured with isolated autologous CD4+ T cells for 5 days, then the phenotype and function of the CD4+ T cells were analyzed. CD4+CD25+CD127- T cells isolated from the coculture of CD4+ T cells plus yeast-treated DCs had a lower expression of FoxP3 and decreased suppressive function compared to CD4+CD25+CD127- T cells isolated from the coculture of CD4+ T cells plus CD40L-treated DCs. Also, compared to the coculture of CD4+ T cells plus CD40L-treated DCs, the coculture of CD4+ T cells plus yeast-treated DCs showed increases in the ratio of CD4+CD25+ activated T cells to Tregs and in the production of Th1-related cytokines (IL-2, TNF-α, IFN-γ) and IL-6. In addition, yeast-treated DCs used as antigen-presenting cells (APCs) incubated with CEA enhanced the proliferation of CEA-specific CD4+ T cells in carcinoma patients compared to the use of CD40L-matured DCs used as APCs. This is the first study to report on the role of yeast-treated human DCs in reducing Treg frequency and functionality and thus enhancing antitumor immune response. These results provide a rationale for the use of yeast as a vector in cancer vaccines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2405.
Abstract 2407: Establishment of a clinically applicable human tyrosine hydroxylase DNA vaccine for anti-neuroblastoma immunotherapy
Authors: Shibina Anastasia , Nuebener Nicole , Seidel Diana , Stermann Alexander , Lode Holger N. , Gaedicke Gerhard 
Published: February 2011

Abstract
Background: Neuroblastoma (NB) is an aggressive neoplasm of the sympathetic nervous system in early childhood. Current treatment of high-risk NB consists of intensive myeloablative therapy followed by bone marrow transplantation. However, children with advanced stage disease or those with refractory disease have a poor prognosis. A promising adjuvant approach could be active immunotherapy with DNA vaccines encoding tumor-associated antigens, like tyrosine hydroxylase (TH), which is highly expressed on NB cells. We already established human TH (hTH) DNA vaccination in a syngeneic NB mouse model achieving complete remission of established mass disease and of metastasis. With regard to a clinical application important aspects of this xenogeneic TH DNA vaccination approach have to be readjusted for the use in humans.
Methods: For this purpose, hTHcDNA fused to mutated ubiquitin (Gly76[[Unsupported Character - [[Unsupported Character - &#61664;]]]]Ala76) was cloned into the FDA-approved, kanamycin encoding DNA plasmid pING. To examine the functionality of the new plasmid design, pING-hTH was transfected into HEK293 cells. Gene expression was verified by immunofluorescence and western-blot analysis. Furthermore, efficacy of the vaccine was tested in a syngeneic NB mouse model in a prophylactic setting employing attenuated Salmonella typhimurium SL7207 as DNA delivery system. Primary tumors were induced by s.c. injection of NXS2 NB cells and tumor growth was monitored over time. Furthermore, immunological mechanisms of tumor protection were evaluated.
Results: In vitro, functional hTH protein expression by the new plasmid design could be established in HEK293 cells. In vivo, xenogeneic TH DNA vaccination induced an anti-NB effect in mice receiving pING-hTH as indicated by a 48-52% reduction in s.c. tumor volume in contrast to empty vector controls. Immunization with hTH-pING DNA-vaccine further generated CTL-mediated responses against NXS2 NB cells and an increase in IFN-γ production. Furthermore, CD8+ T-cells presented at higher levels at primary tumor sites in hTH-vaccinated mice compared to controls.
Conclusion: The new vaccine design (hTH-pING) effectively induced an anti-NB immune response in vivo indicated by the suppression of s.c. primary tumors, which is mediated by NB-specific CTLs. Our findings open the possibility for developing a clinically applicable vaccination strategy for one of the most challenging childhood tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2407.
Abstract 241: A mutant DNA polymerase-delta associated with increased tumor progression causes random deletions in DNA
Authors: Loeb Lawrence A. , Schmitt Michael W. , Venkatesan Ranga N. , Pillaire Marie-Jeanne , Hoffmann Jean-Se'bastien 
Published: February 2011

Abstract
For many years, we have advanced the hypothesis that cancers exhibit a mutator phenotype. Recent support for this concept was gained by the increased frequency of random single-base substitutions measured in human tumors as well as by the large numbers of clonal mutations detected by DNA sequencing in a variety of human cancers. While these findings indicate that cancer cells accumulate large numbers of mutations, it remains unclear what types of alterations in the fidelity of DNA synthesis contribute most to the evolution of a tumor. In order to delineate the types of mutations that have the greatest impact on accelerating tumorigenesis, we studied the consequences of altered accuracy of synthesis by mutant DNA polymerases.
DNA polymerase δ (Pol δ) is responsible for replication of the lagging DNA strand during replication and functions in multiple DNA repair pathways. Based on homology to substitutions known to induce error-prone synthesis in other DNA polymerases, we constructed a series of single base substitutions at position L606 in the catalytic domain of human Pol δ. We found that Pol δ L606G introduces a high frequency of point mutations into DNA in vitro, but heterozygous mice expressing L606G do not exhibit a cancer phenotype. In contrast, Pol δ L606K synthesizes DNA in vitro with high accuracy; yet heterozygous mice expressing this mutant exhibit enhanced rates of tumor progression. Compared to either the wild type or L606G, the L606K mutant is defective in lesion bypass; cells expressing this mutant exhibit a decrease in the rate of fork progression. In addition, L606K cells exhibit an increase in spontaneous chromosomal aberrations, and comparative genomic hybridization analysis reveals an increased frequency of random deletions in tumors from mice expressing Pol δ L606K. These results indicate that mutations in a major replicating DNA polymerase can result in random deletions throughout the genome that have the potential to affect tumor progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 241.
Abstract 2410: Development of a genetically-optimized whole tumor cell vaccine for ovarian cancer using HSV-derived glycoprotein D
Authors: Hagemann Andrea R. , Leskowitz Rachel , Cohen Gary H. , Coukos George , Powell Daniel J. 
Published: February 2011

Abstract
Background: Dendritic cell (DC) vaccines offer a promising addition to standard treatment for ovarian cancer with surgery and chemotherapy. We have previously shown that treatment of whole tumor cells with replication-deficient herpes simplex virus (HSV) results in a potent, specific T-Cell response to ovarian tumors. We sought to improve vaccine efficiency by isolating and comparing two specific components of HSV-treated SK-OV-3-pulsed DCs: glycoprotein D (gD) and IL12p70.
Methods: SK-OV-3 cells were treated with HSV1716 or transfected with HSV-1-derived gD engineered to express a similar amount of surface of gD. We further engineered these cells to express IL12p70 by lentiviral transduction. Theses cells were UVB-irradiated and pulsed with DCs. ELISA was used to measure the kinetics of the IL12p70 burst of each tumor-pulsed DC, as well as to compare the naïve, autologous lymphocyte priming responses of each cell line.
Results: IL12p70 was increased 3-fold with gD-SKOV3 compared to HSV-SKOV3, while following the same kinetic curve (646 ± 45.2 pg/mL v. 234 ± 24.2 pg/mL; p &lt;0.01). gD-SKOV3 also resulted in a 2-fold higher priming response. Both the IL12p70 burst and priming response were blocked by treatment of SKOV3-gD cells with an antibody to gD. With the addition of IL12 to these cells, SKOV3-gD, but not SKOV3-HSV cells, resulted in significantly higher and more prolonged IL12 burst than that of SKOV3-IL12 cells alone.
Conclusions: Our in vitro results suggest a synergistic effect of IL12p70 and gD that is not seen with infection by intact HSV-1. We have isolated two key components from HSV, cytokine stimulation and gD-mediated blockade of immunosuppression, that in combination result in a more potent, specific immune response to ovarian cancer tumor cells. We can now utilize these key components to engineer a more efficient whole tumor cell vaccine for EOC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2410.
Abstract 2411: Intratumoral dendritic cell vaccine as neo-adjuvant immunotherapy of high-risk soft tissue sarcoma patients undergoing external beam radiation therapy (EBRT): Prospective phase I/II clinical trial
Authors: Iclozan Cristina , Finkelstein Steven E. , Ahmed Jamil , Bui Marilyn M. , Cotter Matthew J. , Ramakrishnan Rupal , Cheong David , Gonzalez Ricardo J. , Heysek Randy V. , Lenox Brianna C. , Sondak Vernon K. , Szekely Rosemary R. , Zager Jonathan S. , Letson G. Douglas , Antonia Scott J. , Gabrilovich Dmitry I. 
Published: February 2011

Abstract
Cell death inducing external beam radiation (EBRT) combined with experimental intratumoral injection of dendritic cells (DC) showed promise by initiating anti-autologous tumor-cell immune responses in mice. Here we performed first clinical trial testing this hypothesis in patients with large high-grade soft tissue sarcomas (STS). This type of cancer has a significant (&gt;50%) risk of progressing to distant metastases. Patients with clinical stage T2N0M0 or T3N0M0 high-grade STS of the extremity/trunk/chest wall were treated with standard neo-adjuvant EBRT 5040 cGy / 180 cGy coordinated with experimental DC therapy consisting of DC progenitor apheresis, ex-vivo expansion and culture, and 4 × intratumoral injections of 10 million DC. Autologous DC product was performed according to standardized GMP laboratory procedures. T cell function was assessed by EliSpot (measuring IFN-γ production) and proliferation (thymidine uptake) in addition to phenotyping of peripheral blood mononuclear cells by flow cytometry.
Clinically, targeted accrual was reached with eighteen patients completing neo-adjuvant EBRT with experimental intratumoral DC therapy. All patients have completed full immunologic assessment. Ten patients (56%) were induced to produce significant immune responses against autologous tumor cell lysates or/and survivin antigens as determined using ELISPOT assays or cell proliferation. Interestingly, some of these responses persisted even 30 weeks after start of treatment. Extensive post treatment T cell infiltration was detected within tumors. No clinical toxicity has been observed. Suggestive clinical outcome on 14 patients followed 1 year reveal progress in 1/7 patients with robust response (detected at more than one time point), and 4/7 patients with weak (detected at one time point at the beginning of the study) or no response respectively. Thus, this data is promising for planning future combined treatment approaches as radiation therapy/immunotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2411.
Abstract 2422: The trimeric engineered fusion protein with CD154 peptide mimetic (OmpC-CD154p), induced apoptotic signaling in B-NHL cell lines mediated by caspase 3 and caspase 8 activation
Authors: Martinez-Miguel Bernardo , Paniagua Melisa Martinez , Huerta-Yepez Sara , Gonzalez-Bonilla Cesar , Vega-Paredes Mario , Martinez-Maza Otoniel , Bonavida Benjamin 
Published: February 2011

Abstract
CD154 (CD40-ligand) is a critical transmembrane molecule with potent immune-stimulatory properties and is clinical applied in gene therapy for leukemia and lymphoma. The interaction between CD40, a member of the tumor necrosis factor superfamily, and its ligand CD154 is essential for the development of humoral and cellular immune responses. Selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically-based diseases and malignancies. Engagement of CD40-CD154 induces activation and proliferation of B lymphocytes and triggers apoptosis of carcinoma and B lymphoma cells. Several clinical trials have been reported targeting CD40 in cancer patients using recombinant CD154, mAbs and gene therapy, which were well tolerated and resulted in objective tumor responses. In addition to these therapies, CD154 mimetics have been considered with the objective to augment and potentiate the direct cytotoxic anti-tumor activity and for better accessibility to tumor sites. This approach was developed by us and we hypothesized that the genetic engineering of a fusion protein containing a CD154 peptide mimetic additional to be trimeric may be advantageous in that it may have a better affinity to CD40 on B cell malignancies and trigger cell death. The fusion partner may be a carrier targeting other surface molecules expressed on the malignant cells. This hypothesis was tested by the development of a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Trp140-Ser149 amino acid strand. This OmpC-CD154p fusion protein binds CD40 and triggers the CD40 expressing B cells. In this study, we demonstrate that OmpC-CD154p treatment inhibits cell growth and proliferation, on B-NHL cell lines Raji and Ramos. In addition, significant apoptosis was achieved and the extent of apoptosis was a function of the concentration used and time of incubation. The anti-tumor effect was specific as treatment with OmpC alone had no effect. OmpC-CD154p treatment induced activation of caspase 3 active and caspase 8. These findings establish the basis for the development of new fusion proteins specificity targeting the tumor cells directly and mechanism mediated by extrinsic pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2422.
Abstract 2442: VGX-100, a novel therapeutic monoclonal antibody targeting VEGF-C that inhibits tumor growth
Authors: Tester Angus , Phelan David , McColl Brad , Klupacs Robert , Baldwin Megan 
Published: February 2011

Abstract
Angiogenesis and lymphangiogenesis are important contributors to the growth and metastasis of a wide variety of tumor types. Therapeutic targeting of the angiogenic vascular endothelial growth factor (VEGF) is now an FDA-approved treatment for several cancers. Vascular endothelial growth factor-C (VEGF-C) has also been demonstrated to stimulate angiogenesis and lymphangiogenesis in a number of experimental systems, and is essential for development of the lymphatic system during embryogenesis. In addition, expression of VEGF-C drives tumor progression and metastasis in mouse models of cancer, and is associated with poor prognosis in many human cancers. Targeting VEGF-C is therefore a highly promising strategy for novel therapeutics, with the potential to disrupt both angiogenesis and lymphangiogenesis.
VGX-100 is a highly specific, fully human monoclonal antibody for VEGF-C that does not bind to other members of the VEGF family. In vitro testing demonstrates that VGX-100 blocks binding of VEGF-C to both VEGF receptor-2 and VEGF receptor-3, and inhibits the proliferation of blood vascular (HUVEC) and lymphatic endothelial cells in response to VEGF-C stimulation. Here we demonstrate anti-tumor efficacy through the use of xenograft models of human cancer, with VGX-100 treatment significantly inhibiting tumor growth in several models. These findings demonstrate that VGX-100 has great potential for development as a new cancer therapeutic, with potential clinical utility in combination with existing therapies or in patients refractory to existing anti-angiogenic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2442.
Abstract 2450: Surface molecule CD229 represents a possible target for the treatment of multiple myeloma
Authors: Atanackovic Djordje , Panse Jens , Hildebrandt York , Jadczak Adam , Luetkens Tim , Kobold Sebastian , Lajmi Nesrine , Zander Axel R. , Cao Yanran , Bokemeyer Carsten , Kroeger Nicolaus 
Published: February 2011

Abstract
BACKGROUND AND OBJECTIVES: The majority of patients with multiple myeloma (MM) will eventually relapse and succumb to their disease even after high dose chemotherapy and autologous stem cell transplantation, possibly due to the persistence of BM-residing myeloma stem cells. Therefore, new treatment strategies incorporating new therapeutic targets - ideally to be expressed by the bulk of end-stage myeloma cells and their dormant progenitors - are needed to improve the outcome of myeloma patients.
DESIGN AND METHODS: We screened myeloma cell lines for the presence of a large number of immunoreceptors and verified expression of potential target molecules on cell lines and patient samples. The function of the respective proteins was evaluated using gene knockdown and their potential as targets for antibody therapies was investigated using in vitro cytotoxicity assays.
RESULTS: Of all immunoreceptors analyzed, SLAM family member CD229 showed the strongest expression and was also found on myeloma precursors. Primary myeloma cells of myeloma patients uniformly evidenced CD229 surface expression while the molecule was absent from most healthy human tissues. Flow cytometric analysis of CD229 expression facilitated the detection of myeloma cells in the bone marrow. CD229 seemed to promote the survival of myeloma cells while CD229 silencing increased their susceptibility towards chemotherapy. Importantly, targeting CD229 with a monoclonal antibody resulted in specific lysis of the tumor cells.
CONCLUSIONS: These results suggest that CD229 might represent an attractive diagnostic and therapeutic target for the treatment of MM.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2450.