bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4: Hyper activation of poly(ADP-ribose) polymerase 1 initiates large-scale metabolic changes in a cellular model of glioblastoma
Authors: Wilk Anna M. , Fouquerel Elise , Johnston Bobbie , Trammell Samuel A.J. , Schambeau Lindsay , Andrews Joel F. , Pannell Lewis , Cooper Sara J. , Brenner Charles , Sobol Robert W. 
Published: July 2016

Abstract
PARP1 is a key enzyme of the Base Excision Repair (BER) pathway, facilitating the repair of base damage and single-strand DNA breaks. Activated PARP1 synthesizes poly (ADP-ribose) (PAR), triggering chromatin de-condensation to facilitate recruitment of BER proteins to complete repair. PARP1 activation is attenuated upon successful repair of the DNA lesion. However, unrepaired DNA breaks lead to continuous PARP1 activation and cell death. The molecular mechanism underlying PARP1 activation induced cell death was recently revealed as independent from NAD+ depletion. We have shown that PARP1 activation and PAR synthesis affect glycolysis by directly inhibiting the glycolytic enzyme, hexokinase 1 (HK1). Following on these discoveries, we decided to investigate global metabolic changes triggered by hyperactivation of PARP1. For this study, we used gas chromatography mass spectrometry (GC-MS) to quantify over 150 cellular metabolites and Multiple-Reaction Monitoring Liquid Chromatography Mass Spectrometry (MRM LC-MS) to measure NAD+ metabolites. As a model, we tested glioblastoma cells overexpressing methylpurine DNA glycosylase (MPG) to enhance the PARP1-activation response to DNA damage induced by the alkylating agent MNNG. Simultaneously, to monitor independence from the DNA damaging effect of NAD+ depletion, we utilized an inhibitor of NAD+ biosynthesis, FK866. We found that PARP1 activation leads to a strong accumulation of glucose, likely as a secondary effect of HK1 inhibition. In addition, we observed a significant change in the level of other metabolites including an increase in inosine, inosine monophosphate (IMP), cytidine and uridine levels upon PARP1 activation, suggesting an indirect effect of PARP1 activation on purine and pyrimidine metabolism. Ongoing studies will use these global approaches to unravel the complete metabolic response of cancer cells to genotoxic treatment.
Citation Format: Anna M. Wilk, Elise Fouquerel, Bobbie Johnston, Samuel A.J. Trammell, Lindsay Schambeau, Joel F. Andrews, Lewis Pannell, Sara J. Cooper, Charles Brenner, Robert W. Sobol. Hyper activation of poly(ADP-ribose) polymerase 1 initiates large-scale metabolic changes in a cellular model of glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4.
Abstract 4007: A novel immunotherapy, INT230-6, is able to induce high rates of complete response in mice through a cytotoxic T-cell-dependent mechanism
Authors: Walters Ian B. , Bloom Anja C. , Bender Lewis H. , Terabe Masaki , Berzofsky Jay A. 
Published: July 2016

Abstract
INT-230-6 is a combination of cisplatin, vinblastine and an amphiphilic cell penetration excipient that when administered intratumorally (IT) can induce complete regression in drug-injected and bystander established colon26 tumors. INT230-6 also has the ability to induce long term protection in mice against intravenous (IV) or subcutaneous (SC) re-inoculation of the cancer cells. This long term protection is dependent on induction of both CD4 and CD8 cells as evidenced by in vivo depletion prior to tumor re-inoculation. Previous studies had not elucidated whether the initial drug-injected tumor regression in naive mice was mainly due to the formulation's direct cytotoxicity or whether early tumor regression is dependent also on immune- based cell killing. To address this question, BALB/c mice were inoculated with 1×106 Colon26 cells SC. Tumors were grown to a mean of 300mm3. INT230-6 was administered intratumorally daily for 5 days (day 0 to 4). At the same time mice were treated either with an IgG control, or with rat anti mouse anti-CD4, anti-CD8 or both anti -CD4/CD8 on days 0,1,5,8,15. T cell subset depletion was confirmed by flow cytometry. In preliminary data, INT230-6 treatment resulted in regression from baseline in all mice with a complete regression of the large tumors in 40-80% of mice in the INT230-6 arm alone or the arm with IgG control. The CD4 depleted mice had a similar CR rate of 70%. However, in the CD8 depleted or the dual depleted (CD4/8) mice, tumors regrew after initial regression and no CR was observed. These results suggest that intratumoral administration of INT230-6 in addition to improving the direct cytotoxicity of cisplatin and vinblastine (data shown previously), also induces a potent CD8 tumor-specific T-cell response which participates in regression of the injected lesion, and may be able to similarly target distant lesions such as metastases.
Citation Format: Ian B. Walters, Anja C. Bloom, Lewis H. Bender, Masaki Terabe, Jay A. Berzofsky. A novel immunotherapy, INT230-6, is able to induce high rates of complete response in mice through a cytotoxic T-cell-dependent mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4007.
Abstract 4012: Improving radiotherapy abscopal effects with anti-PD1 and anti-CD137-based immunotherapy
Authors: Rodríguez-Ruiz MariaE. , Rodriguez Inmaculada , Garasa Saray , Barbes Benigno , Solorzano Jose Luis , Perez Gracia Jose Luis , Labiano Sara , Azpilikueta Arantza , Bolanos Elixabet , R. Sanchez-Paulete Alfonso , Aznar M. Angela , Rouzaut Ana , Jure-Kunkel Maria , Etxeberria Iñaki , Alfaro Carlos , Oñate Carmen , Ponz Mariano , Melero Ignacio 
Published: July 2016

Abstract
Radiotherapy is considered an efficacious local tool to erradicate or at least control cancer progression. However, recent lines of preclinical and clinical evidence indicate that proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lessions and on distant, non-irradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favourable effects on distant non-irradiated tumor lesions as observed on transplanted MC38 (colorectal cancer), B16OVA (melanoma) and 4T1 (breast cancer) models. Immunotherapy and radiotherapy synergized both when irradiation was given using external beams or provided with brachytherapy. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. The irradiation regimen induced immune infiltrate changes in the irradiated and non-irradiated lesions featured by reductions in the content of effector T cells, Tregs, and myeloid-derived supresor cells (MDSC), while effector T cells were expressing more intracellular IFN gamma in both the irradiated and contralateral tumors. Importantly, 48h following irradiation CD8+ TILs showed brighter expression of CD137 and PD-1 thereby displaying more target molecules for the activity of the corresponding monoclonal antibodies. Likewise, PD-1 and CD137 were induced on tumor infiltrating lymphocytes from surgically excised of human carcinoma lessions that were irradiated ex-vivo. These findings advocate for clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompained by radiotherapy strategies on treatable lesions, even if leaving disease outside the irradiation field.
Citation Format: MariaE. Rodríguez-Ruiz, Inmaculada Rodriguez, Saray Garasa, Benigno Barbes, Jose Luis Solorzano, Jose Luis Perez Gracia, Sara Labiano, Arantza Azpilikueta, Elixabet Bolanos, Alfonso R. Sanchez-Paulete, M. Angela Aznar, Ana Rouzaut, Maria Jure-Kunkel, Iñaki Etxeberria, Carlos Alfaro, Carmen Oñate, Mariano Ponz, Ignacio Melero. Improving radiotherapy abscopal effects with anti-PD1 and anti-CD137-based immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4012.
Abstract 4016: Personalizing the synergy of focal radiation and immunotherapy
Authors: Poleszczuk Jan , Luddy Kimberly , Pilon-Thomas Shari , Schoenfeld Jonathan , Enderling Heiko 
Published: July 2016

Abstract
Tumors grow within a host tissue that both facilitates progression by supplying nutrients and growth factors, and inhibits it through physical constraints and immune surveillance. Transformed cancer cells are confronted with this innate and adaptive immune surveillance, and tumors that develop to become clinically apparent have evolved to evade the immune system. This complex ecological system may be tipped back in favor of effective immune surveillance and tumor regression through novel immunotherapeutic strategies, particularly when used in concert with focal cytotoxic agents such as radiotherapy.
We developed a multi-scale mathematical model framework to simulate local tumor-immune interactions as well as systemic distribution patterns of T cells activated locally in each metastatic site. We simulate focal radiotherapy-induced cytotoxicity and subsequent activation of an adaptive immune response, which may propagate systemically to cause regression of unirradiated metastases, known as the abscopal effect. We simulate concurrent anti-CTLA4 immunotherapy to investigate synergy.
Model simulations suggest that systemic distribution of locally activated T cells is dependent on (i) the anatomical distribution of metastatic sites, (ii) the tumor volume of each metastasis, (iii) the site of focal therapy, (iv) the local therapy protocol of immune activation, and (v) the timing of concurrent immunotherapy. We find that irradiation of different metastatic sites has different likelihoods of inducing systemic tumor regressions.
The developed framework can identify combination therapy protocols that optimally harness the synergy of focal therapy-induced immunity with immunotherapy, and identify optimum treatment targets on a per patient basis.
Citation Format: Jan Poleszczuk, Kimberly Luddy, Shari Pilon-Thomas, Jonathan Schoenfeld, Heiko Enderling. Personalizing the synergy of focal radiation and immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4016.
Abstract 4047: Salmonella protein AvrA activates the STAT3 signaling pathway in colon cancer
Authors: Lu Rong , Wu Shaoping , Zhang Yong-Guo , Xia Yinglin , Zhou Zhongren , Tako Ikuko , Dong Hui , Bissonnette Marc , Sun Jun 
Published: July 2016

Abstract
Salmonella infection in humans can become chronic which leads to low grade persistent inflammation. These chronic infections increase the risk of several gastrointestinal diseases, including cancer. A recent study has shown that antibody against Salmonella flagellin was higher in colorectal cancer and pre-cancer cases than controls in two distinct populations in US and the Netherlands and that dietary intake is the one of the mediating factors, suggesting a potential link of Salmonella to colorectal cancer. Salmonella AvrA is a multifunctional protein that influences eukaryotic cell pathways by regulating ubiquitination and acetylation. In an animal model, we have demonstrated that infection with AvrA expressing Salmonella induces beta-catenin signals and enhances colonic tumorigenesis. Beta-catenin signaling is a key player in intestinal proliferation and tumorigenesis. The relative contributions of AvrA-induced proliferation and inflammation on tumorigenesis, however, are unknown. STAT3 is activated in chronically inflamed intestines in human inflammatory bowel diseases and in colitis-associated colon cancer. In the current study, mice were colonized with Salmonella AvrA-sufficient or AvrA-deficient bacterial strains. Then, inflammation-associated colon cancer was induced through the use of azoxymethane/dextran sulfate sodium. We determined that AvrA expressing bacteria activated the STAT3 pathway, which is predicted to increase inflammation, enhance proliferation, and promote tumorigenesis. Transcriptional activity of STAT3 and its target genes were up-regulated by Salmonella expressing AvrA, thus promoting proliferation and intestinal tumorigenesis. Our current findings provide new insights regarding a STAT3-dependent mechanism by which the specific bacterial product AvrA enhances the development of infection-associated colon cancer. Our observations also raise a note of caution regarding the use of mutant Salmonella organisms as vectors for ant-cancer therapy. Finally, these studies could suggest biomarkers (such as AvrA level in gut) to assess cancer risk in susceptible individuals and infection-related dysregulation of STAT/β-catenin signaling in colon cancer.
Citation Format: Rong Lu, Shaoping Wu, Yong-Guo Zhang, Yinglin Xia, Zhongren Zhou, Ikuko Tako, Hui Dong, Marc Bissonnette, Jun Sun. Salmonella protein AvrA activates the STAT3 signaling pathway in colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4047.
Abstract 4050: Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo
Authors: Gillet Nicolas , Hamaidia Malik , de Brogniez Alix , Gutierrez Geronimo , Renotte Nathalie , Reichert Michal , Trono Karina , Willems Luc 
Published: July 2016

Abstract
Bovine leukemia virus (BLV), a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1), induces lymphocytosis and B-cell leukemia/lymphoma in ruminants. Although the provirus undergoes transcriptional silencing during transformation, BLV-infected tumor cells massively express viral miRNAs from internal Pol III promoters. To understand the mechanisms involved, a provirus isogenic to a wild type molecular clone but devoid of miRNAs was inoculated into calves. High-throughput RNA-sequencing and bioinformatic analyzes indicated that BLV miRNAs modulate expression of genes involved in B-cell receptor signaling, apoptosis, cell activation and immune response (GZMA, FOS, PPT1, ANXA1, MAP2K1 and PIK3CG). Direct and indirect interactions within these regulatory pathways were validated by luciferase reporter assays. In vivo, the deletion of BLV miRNAs reduced proviral loads in the natural host, indicating their biological relevance in viral replication and persistence. Furthermore, oncogenesis was abolished in the ovine experimental model. These observations thus show that BLV miRNAs affect key signaling pathways, promote viral replication and drive oncogenesis.
Citation Format: Nicolas Gillet, Malik Hamaidia, Alix de Brogniez, Geronimo Gutierrez, Nathalie Renotte, Michal Reichert, Karina Trono, Luc Willems. Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4050.
Abstract 407: Functional analysis of discoidin domain receptor 2 mutation and expression in squamous cell lung cancer
Authors: Kobayashi-Watanabe Naomi 
Published: July 2016

Abstract
The treatment strategy for lung cancer has been rapidly progressed, especially in molecular targeted therapy. However, most treatments are established for adenocarcinoma of lung, but not squamous cell carcinoma (SQCC). SQCC occupies approximately 30% among entire lung cancer patients, but the prognosis is worse than that of adenocarcinoma patients. Discoidin domain receptor (DDR) 2 mutations have been recently reported as one of the candidates of molecular targets for lung SQCC, and they are associated with sensitivity to dasatinib, which is already applicable to treatment of chronic myeloid leukemia. However, precise roles of DDR2 on SQCCs of lung have not been clarified. We performed Sanger sequencing of DDR2 gene in a set of 44 primary lung SQCC samples and 7 lung SQCC cell lines, and identified a novel mutation (T681I) in a lung SQCC patient and a lung SQCC cell line, EBC-1. Endogenous protein expression level of DDR2 measured by Western blot technique was high in a lung SQCC cell line, PC-1. Overexpression of wild type and T681I of DDR2 promoted cancer cell invasion of a human lung SQCC cell line, H226B. In animal model, lung metastasis was enhanced and survival was shortened after transplantation of DDR2 wild type overexpressing cells into NOD/SCID/Jak3null (NOJ) mice, which exhibit deficiencies in NK cell activity, macrophage and dendritic cell function, and complement activation, as well as T and B cell deficiencies. Using the cDNA microarray and protein phosphorylation array assay, we found that ectopic expression of DDR2 induced TGF-β1 protein and mRNA expression accompanied with phosphorylation of c-Jun, p38 MAP kinase, and MMP1 elevation. During the process of metastasis, TGF-β pathway plays pivotal roles especially on disruption of basement membrane through induction of MMPs from fibroblasts mediated through both Smad and non-Smad pathways. Since phosphorylations of c-Jun and p38 MAPK were reported to be involved in non-Smad pathway, DDR2 would induce TGF-β mainly through non-Smad pathway, resulting in cancer invasion and metastasis. Taken together, elevation of DDR2 protein might contribute on tumor progression as well as some of DDR2 mutations in lung SQCC.
Citation Format: Naomi Kobayashi-Watanabe. Functional analysis of discoidin domain receptor 2 mutation and expression in squamous cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 407.
Abstract 4070: Carcinogen 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis is accelerated in Smad3 heterozygous mice compared to Smad3 wild type mice
Authors: Liu Zhengxue , Kundu Tanima R. , Matsuura Isao , Wang Guannan , Lin Yong , Lou You-Rong , Barnard Nicola J. , Wang Xiao-Fan , Huang Mou-Tuan , Suh Nanjoo , Liu Fang 
Published: July 2016

Abstract
Smad3 plays an important role in inhibiting cell proliferation and promoting apoptosis. Previous studies based on cell culture and xenograft animal models suggest that Smad3 has tumor suppressor function for breast cancer during early stages of tumorigenesis. Here we show that DMBA (7,12-dimethylbenz[a]anthracene), a chemical carcinogen, induces mammary tumor formation at a significantly higher frequency in the Smad3 heterozygous mice than in the Smad3 wild type mice. This is the first genetic evidence showing that Smad3 inhibits mammary tumorigenesis in a mouse model. Our findings provide strong support that Smad3 has important tumor suppressor function for breast cancer.
Citation Format: Zhengxue Liu, Tanima R. Kundu, Isao Matsuura, Guannan Wang, Yong Lin, You-Rong Lou, Nicola J. Barnard, Xiao-Fan Wang, Mou-Tuan Huang, Nanjoo Suh, Fang Liu. Carcinogen 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis is accelerated in Smad3 heterozygous mice compared to Smad3 wild type mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4070.
Abstract 4081: Stromal autophagy is required for the growth of cutaneous melanoma
Authors: Zhang Ran Ellen , Guo Natalie J. , Krishnan Nithya , Jelinek David , Uzunbas Gizem Karsli , Xie Xiaoqi , Gertych Arek , Mehnert Janice M. , Knudsen Beatrice , White Eileen , Coller Hilary A. 
Published: July 2016

Abstract
Through degrading bulk cytoplasmic materials into intermediate building blocks, autophagy refuels metabolism and maintains homeostasis under starvation and stress conditions. The context-dependent role of autophagy in cancer cells during tumorigenesis and tumor progression has been explored over the past decade; however, studies of autophagy in relation to the tumor microenvironment are still lacking. In this study, we investigated the role of autophagy in the cancer-associated fibroblasts (CAFs), a major component of the microenvironment that is important for the growth and development of cutaneous melanoma. Analysis of clinical biopsies revealed high levels of autophagy in fibroblasts that surrounded melanoma cells, but not in the non-tumor adjacent area. Fibroblasts co-cultured with any of multiple melanoma cell lines, but not melanocytes, also showed increased autophagic flux, which requires transforming growth factor beta (TGF-β) signaling. Knocking down autophagy-related (ATG) genes ATG5 or ATG7 in fibroblasts did not impair their proliferation in vitro, but inhibited the growth of co-engrafted melanoma cells in vivo. Further, by introducing intradermal melanoma allografts into mice that harbored fibroblast-specific Atg7 deletion, we observed remarkable tumor growth retardation. In order to mimic anti-autophagy therapy for patients, we generated mice that allowed conditional Atg7 depletion in their entire bodies, and found significant tumor growth suppression. Atg7 knockout mice contained elevated plasma levels of immune cell attractants, including CXCL9, CXCL10 and MCP-1. By inhibiting these cytokines/chemokines with atorvastatin, tumor growth in Atg7 knockout mice was completely rescued; while, there was no effect of atorvastatin on control mice. Taken together, our data show that through modulating the tumor microenvironment, stromal autophagy plays an important role during melanoma growth and development. Our findings indicate that stromal autophagy may represent a valuable therapeutic target that might induce less side effects and systemic toxicity.
Citation Format: Ran Ellen Zhang, Natalie J. Guo, Nithya Krishnan, David Jelinek, Gizem Karsli Uzunbas, Xiaoqi Xie, Arek Gertych, Janice M. Mehnert, Beatrice Knudsen, Eileen White, Hilary A. Coller. Stromal autophagy is required for the growth of cutaneous melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4081.