bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5290: ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data
Authors: Jongeneel Patrick , Lin Selena , Steffen Jamin , Jain Surbhi , Su Ying-Hsiu , Song Wei 
Published: July 2016

Abstract
The purpose of this study was to develop a computational method of extracting viral integration events from NGS data in an intuitive way that could accommodate access from users of all disciplines. Viral integration into the host genome is a characteristic of many pathogenic viruses, including the hepatitis B virus (HBV) and human papillomavirus (HPV). Gradual insertion of viral components near proto-oncogenes of the host genome over time can induce uncontrolled cellular proliferation, eventually leading to carcinogenesis. While increased availability of high-throughput next generation sequencing (NGS) has provided tools for researchers to discover these underlying host changes due to viral integrations, there is an emerging need for analytical support of this data. Here we present ChimericSeq, a user-friendly program that can quickly identify viral integration events from NGS data. To fully evaluate this program, we compared the functionality of ChimericSeq to other current viral integration programs. A number of synthetic data sets of HBV sequence fragments integrated into 100bp fragments of random human genomic DNA were created to mimic the nature of chimeric reads of NGS data. ChimericSeq was able to correctly identify reads containing at least 25bp of viral sequence at 100% accuracy. This was a major improvement over the current programs, VirusClip and ViralFusionSeq, which could not detect reads with only 25bp of viral sequence, and even had difficulty correctly identifying viral integration sites containing additional viral sequence. Furthermore, ChimericSeq could detect viral events nearly 10X and 100X faster than these current programs, respectively. Upon testing of NGS data from actual HBV-positive human tissue, we found that ChimericSeq was not only much faster, but was also able to detect more unique viral integration events than current viral integration tools. In conclusion, ChimericSeq expands NGS analytical support to a broader spectrum of the scientific community, being the first program of its kind to offer support in an intuitive graphical user interface (GUI) for commonly used operating platforms, such as Windows and Mac.
Citation Format: Patrick Jongeneel, Selena Lin, Jamin Steffen, Surbhi Jain, Ying-Hsiu Su, Wei Song. ChimericSeq: an easy-to-use program for discovery and analysis of integration events from NGS data. [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 5290.
Abstract 535: Deregulated Myc is an immunosuppressive switch
Authors: Kortlever Roderik M. , Sodir Nicole M. , Wilson Catherine H. , Burkhart Deborah L. , Swigart Lamorna , Littlewood Trevor D. , Evan Gerard I. 
Published: July 2016

Abstract
Early tumor evolution through sustained oncogene activity selectively bypasses the engagement of cell-intrinsic tumor-suppressor signaling and cell-extrinsic microenvironmental restrictions. How the immune system may be involved is virtually unknown. We describe here the contributions of a conditional and reversible low-level expression of Myc in a mouse model of KrasG12D-driven non-small cell lung cancer. Deregulated Myc activity results in highly expansive tumors that appear embedded in inflamed regions and leads to a rapid reduction of mouse survival. Myc activation imposes an immediate switch to an immunosuppressive and pro-angiogenic microenvironment, facilitated through IL23- and CCL9-associated recruitment of PD-L1 loaded macrophages and local exclusion of T-lymphocytes. Reversibly, blocking the activity of Myc-driven IL23 and CCL9 expression or withdrawal of deregulated Myc activity in tumors established by oncogene cooperation results in tumor cell death and regression, associated with a collapse of the established microenvironmental changes and re-engagement of cytotoxic T-cells. During oncogene cooperation with Ras, deregulated Myc directs a sufficient and necessary switch to a microenvironment that shields tumor growth and expansion from immune suppression.
Citation Format: Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Lamorna Swigart, Trevor D. Littlewood, Gerard I. Evan. Deregulated Myc is an immunosuppressive switch. [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 535.
Abstract 546: Impact of therapeutic EGFR inhibition on immune checkpoint blockade in head and neck squamous cell carcinoma
Authors: Rogers Laura M. , Espinosa-Cotton Madelyn M. , Simons Andrean L. , Weiner George J. 
Published: July 2016

Abstract
Patients with advanced recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) have few effective treatment options and a poor median survival of 6-8 months. Limited improvement in overall survival has been observed in HNSCC patients treated with EGFR inhibitors despite high expression of epidermal growth factor receptor (EGFR) in these tumors. Remarkable clinical results are emerging from immunotherapy targeting programmed death-1 (PD1) and its ligand programmed death ligand-1 (PDL1). Blockade of the PD1/PDL1 interaction is believed to enhance endogenous anti-tumor immunity by restoring T cell cytotoxic action. PDL1 is highly expressed in primary, recurrent, and metastatic HNSCC and phase 1 clinical trials are ongoing for monoclonal antibodies targeting the PD1/PDL1 axis in HNSCC.
We found that activation of EGFR in HNSCC cells by epidermal growth factor (EGF) significantly increases PDL1 expression in a dose dependent manner. EGFR inhibition using tyrosine kinase inhibitors (TKI) or cetuximab suppresses this EGF-induced PDL1 expression in cells with both wild type and constitutively active EGFR. This is consistent with published data that constitutively active EGFR in lung cancer cells correlates with higher PDL1 expression, and this can be reversed by EGFR inhibition. These results suggest there may be interactions between EGFR-targeted therapy and immunotherapy involving the PD1/PDL1 axis.
To evaluate potential therapeutic interactions, we used an immunocompetent, syngeneic mouse model of human EGFR-expressing TUBO cancer cells on a BALB/c background. The murine TUBO-EGFR cells are sensitive to human EGFR inhibitors both in vitro and in vivo. Initial studies show that treatment of tumors with EGFR inhibitor (erlotinib) results in increased intratumoral CD8+ T cell infiltration and tumor regression, suggesting that EGFR inhibition can impact the anti-tumor T cell response. We are currently evaluating the effects of EGFR inhibition on PDL1 expression and tumor response to PD1/PDL1 blockade using this model. Further, a clinical trial investigating the impact of cetuximab treatment on intratumoral expression of PDL1 in HNSCC patients is planned to open shortly. We conclude that signaling mediated by EGFR can impact expression of PDL1 by HNSCC. Understanding the interactions between EGFR inhibitors and immune checkpoint blockade could lead to new approaches to combining TKI and cancer immunotherapy.
Citation Format: Laura M. Rogers, Madelyn M. Espinosa-Cotton, Andrean L. Simons, George J. Weiner. Impact of therapeutic EGFR inhibition on immune checkpoint blockade in head and neck squamous cell carcinoma. [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 546.
Abstract 547: Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer
Authors: Petersen Sven H. 
Published: July 2016

Abstract
Apart from the cytotoxic effect of radiation- or chemotherapy it has become evident that these treatments are able to induce an immune response which can play an
additional and pivotal role in clearing tumours. This treatment-induced immunogenic tumour cell death (ICD) enables the host's immune system to recruit to the tumour and recognise and kill tumour cells which can even extend to yet untreated metastases, a phenomenon called “abscopal effect”. For the first time, we found evidence that radiation and/or chemo-treatment stimulates a pronounced up-regulation of both, PD-L1 and Galectin-9 on pre-apoptotic and apoptotic gastric tumour cells. Both these proteins exert immuno-modulatory signals which in turn may dampen the aimed immunogenicity of the treatment. PD-L1, which is the ligand to programmed cell death protein 1 (PD1) on T cells, and its upregulation is commonly used by cancer cells to evade immunity. PD-L1 causes T cell apoptosis and hence an inhibition of T cell driven anti-tumour immunity. Galectin-9 exerts immunoinhibitory functions and is, together with the immunostimulatory molecule HMGB1, a competitive binding partner for the receptor T-cell immunoglobulin domain and mucin domain 3 (Tim-3). Once engaged by its ligand, Tim-3 either exerts stimulatory or inhibitory effects, depending on ligand, cell type, maturation state and Tim-3 expression rate. Together with PD-L1, Galectin-9 enables a complex interplay between cancer cells and cells of the adaptive immune response expressing PD1 and Tim-3. Based on these results, we are investigating the mechanism responsible for PD-L1 and Galectin-9 upregulation and the effect on the efficacy of radio- as well as chemotherapy on tumour eradication. Additionally, due to their potentially enhancing effect on anti-tumour immunity, we are studying the therapeutic value of blocking Abs specific for human PD1 and/or Tim-3 in cancer immunotherapy.
Citation Format: Sven H. Petersen. Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric 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 547.
Abstract 548: Characterization of myeloid cells in bladder cancer
Authors: Mukherjee Neelam , Zhao Xiang Ru , Ji Niannian , Svatek Robert S. 
Published: July 2016

Abstract
Both cancer-associated inflammation and tumor-mediated immune suppression have been linked with expansion of myeloid cells in multiple tumor types, including bladder [1]. We previously observed a predominance of M2-like macrophages in mouse bladder tumors [2]. However, little is known about the characteristics of these myeloid cells in human bladder cancer. In this study, we analyzed myeloid cells from tumor tissues collected from patients with muscle-invasive bladder cancer. We used flow cytometry to characterize the different subsets of these myeloid cells.Myeloid cells were identified in the bladder tissue. Our results showed that bladder cancer patients have two major CD11b+CD33+ myeloid derived suppressor cell subsets: granulocyte-type HLADR−CD15+ cells and monocyte-type HLADR+CD14+ cells. Analysis of CD45+ CD11b+cells demonstrated that bladder tumors are dominated by phenotypical M2-like (CD163+ CD80lo) CD163+ M2 macrophages.
The primary treatment modality for bladder cancer is Bacillus Calmete-Guerin (BCG), a live attenuated mycobacterium that is instilled into the bladder via a urethral catheter [3]. This agent remains one of the most effective immune therapies to date. However, though it is effective in prevention of tumor recurrence, response is heterogeneous and tumor recurrence is observed in up to 50% of patients over time. The predominance of immunosuppressive myeloid cells subsets among TILs in human bladder cancer suggests myeloid cells could be potential targets for therapeutic intervention in bladder cancer. We investigated the role of macrophages in BCG therapy in the MB49 bladder cancer model. Depletion of macrophages by liposomal clodronate (LC) during MB49 tumor challenge resulted in decreased tumor growth compared to BCG monotherapy suggesting that macrophages have a critical role in BCG immunotherapy. This study characterizes these myeloid populations in bladder cancer patients and also investigates their potential role in bladder cancer development and therapeutic response.
References:
1.
Eruslanov, E., et al., Circulating and tumor-infiltrating myeloid cell subsets in patients with bladder cancer. International journal of cancer. Journal international du cancer, 2012. 130(5): p. 1109-1119.
2.
Svatek, R.S. et al., Sequential intravesical mitomycin plus Bacillus Calmette-Guérin for non-muscle-invasive urothelial bladder carcinoma: translational and phase I clinical trial. Clinical Cancer Research, 2015. 21(2): p. 303-11
3.
Askeland, E.J., et al., Bladder Cancer Immunotherapy: BCG and Beyond. Advances in urology, 2012. 2012: p. 181987.
Citation Format: Neelam Mukherjee, Xiang Ru Zhao, Niannian Ji, Robert S. Svatek. Characterization of myeloid cells in bladder 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 548.
Abstract 550: Evaluating changes in T cell activation by measuring expression of IL-2, CTLA-4, NFAT, and NF-kB in Jurkat cells
Authors: Bement Jacquelyn M. , Miyamoto Yuko J. 
Published: July 2016

Abstract
Insufficient stimulation of T cells due to activated checkpoint pathways can lead to ineffective clearance of tumor cells and thus, tumor growth and cancer. Developing methods to measure changes in the activation of such pathways are needed to evaluate the efficacy of immunotherapy approaches to treating cancer by altering T cell activation. Current methods that use measurments of IL-2 expression are limited by the fact that IL-2 is not specific to T cell activation and that it provides little insight into the mechanisms by which activation is affected. This project aims to address such limitations by determining whether changes in T cell activation can be effectively evaluated by measuring expression of CTLA-4, NFAT, and NF-kB, in addition to IL-2. Jurkat cells were cultured and activated with PMA (100 ng/mL) and ionomycin (500 ng/mL) for five hours. Staining for IL-2 and CTLA-4 with antibodies and transfection of the cells with genetic constructs that link NFAT and NF-kB to fluorescent proteins provided the means to link expression of fluorescence to expression of the molecules of interest. FACS analysis was then used to measure changes in the expression of the four signaling molecules in response to the induced changes in activation. Activation of the cells resulted in increased expression of all four molecules. Following activation, fluorescence due to CTLA-4, NFAT, and NF-kB expression changed by average fold increases of 2.58, 1.10 and 1.13, respectively. By measuring these key elements of T cell signaling pathways in addition to IL-2, these methods provide a potentially more effective alternative to current methods for evaluating the efficacy of immunotherapeutic treatments for cancer.
Citation Format: Jacquelyn M. Bement, Yuko J. Miyamoto. Evaluating changes in T cell activation by measuring expression of IL-2, CTLA-4, NFAT, and NF-kB in Jurkat cells. [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 550.
Abstract 571: Pregnancy associated plasma protein A (PAPP-A) is a potential novel therapeutic target in Ewing sarcoma
Authors: Heitzeneder Sabine , Shern John F. , Khan Javed , Mackall Crystal L. 
Published: July 2016

Abstract
Background: Ewing sarcoma (EWS) is the second most common bone malignancy in the pediatric population. Despite intensive treatment regimens, 5-year overall survival for patients with metastatic or relapsed disease is less than 20%, indicating a clear need for novel targeted therapies. The importance of IGF signaling in EWS is illustrated by activity of antagonistic targeting of IGF-1R in clinical trials, although this approach is plagued by rapid development of resistance. Pregnancy Associated Plasma Protein A (PAPP-A) anchors to cell surface proteoglycans and mediates metalloproteinase activity, that cleaves IGFs from IGFBP-4, IGFBP-2 and IGFBP-5, thus increasing local bioavailability of bioactive, free IGF. PAPP-A is expressed at high levels by placental trophoblasts, where it induces high levels of IGFs, which are required for fetal growth.
Methods: In an attempt to identify novel targetable cell surface antigens in EWS, we performed ribosomal depleted RNA sequencing in 122 EWS samples (49 cell lines and 73 tumor samples) and 96 normal samples of variable tissues.
Results: PAPP-A was identified as one of the top 5 membrane associated proteins overexpressed in EWS (&gt; than 4-fold) compared to normal tissue (p = 3.89E-30). PAPP-A showed substantial expression in tumors (median log2FPKM = 3.933, n = 122) and minimal expression in normal tissue (median log2FPKM = -1.564, n = 96). We confirmed cell surface expression of PAPP-A by flow cytometry on 10 EWS cell lines tested, and identified PAPP-A in the supernatant of 12 EWS cell lines, measured by ELISA. Targeting the PAPP-A locus in the EWS cell line EW8 utilizing CRISPR/Cas9 completely abrogated PAPP-A secretion in single cell clones and significantly diminished bioactive IGF-1 levels in EWS cultures, while increasing IGF-1 bound to IGFBP-4, results which confirm absent PAPP-A metalloproteinase activity. Gene knockout of PAPP-A in EW8 resulted in decreased cell growth in vitro.
Conclusions: We have identified PAPP-A as a novel potential cell surface target in Ewing sarcoma, characterized by high level tumor expression, limited normal tissue expression and biological significance in this tumor. Ongoing work is focused on studying growth of PAPP-A KO cell lines, and assessing whether PAPP-A neutralizing antibodies may mediate antitumor effects in EWS.
Citation Format: Sabine Heitzeneder, John F. Shern, Javed Khan, Crystal L. Mackall. Pregnancy associated plasma protein A (PAPP-A) is a potential novel therapeutic target in Ewing sarcoma. [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 571.
Abstract 572: A novel anti-PDL1 x anti-VEGFR2 bispecific antibody for enhanced antitumor immunity
Authors: Lu Dan , Polonskaya Zhanna , Zhang Haifan , Luna Xenia , Martomo Stella , Zhang Zhikai , Zhong Zhaojing , Wu Yan , Patel Jeegar , Tonra James , Witte Larry , Waksal Sam , Zhu Zhenping 
Published: July 2016

Abstract
The importance of VEGF/VEGFR2 signaling in cancer growth and metastasis has been clearly highlighted by the therapeutic benefits of bevacizumab (Avastin), a humanized antibody to VEGF, and Cyramza, a fully human antibody to VEGFR2, in multiple cancer treatment modalities. Recently, immune checkpoint antagonistic antibodies to PD1 and PDL1 have shown some success in a variety of clinical settings across multiple cancer types. The overall clinical efficacy of these individual antibody therapies has been, however, rather limited and, only evident in a fraction of patients. To this end, combinations of antibodies against both VEGF/VEGFR2 and PD1/PDL1 may represent promising approaches to further enhance the antitumor efficacy of individual antibody therapies. In this study, we engineered a bispecific anti-PDL1 x anti-VEGFR2 antibody using two fully human antibodies derived from antibody phage display libraries. In this bispecific format, a high affinity single chain antibody to PDL1 was genetically fused to the C-terminus of the heavy chain of a conventional IgG antibody against VEGFR2. The bispecific antibody was efficiently expressed in mammalian cells and could be purified to homogeneity via single step affinity chromatography. The bispecific antibody retained the binding activity of its parental antibodies to PDL1 and VEGFR2, and strongly blocked both VEGF/VEGFR2 and PDL1/PD1 interaction. Further, the bispecific antibody inhibited VEGF-stimulated VEGFR2 phosphorylation and proliferation of endothelial cells, and promoted proliferation of human T cells and secretion of cytokine such as IL2 and INFγ. The bispecific antibody is currently being evaluated in vivo in relevant animal models.
Citation Format: Dan Lu, Zhanna Polonskaya, Haifan Zhang, Xenia Luna, Stella Martomo, Zhikai Zhang, Zhaojing Zhong, Yan Wu, Jeegar Patel, James Tonra, Larry Witte, Sam Waksal, Zhenping Zhu. A novel anti-PDL1 x anti-VEGFR2 bispecific antibody for enhanced antitumor immunity. [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 572.
Abstract 582: Novel insights into the antitumor activity of an antibody specific for transferrin receptor 1 (ch128.1) in an in vivo model of human multiple myeloma
Authors: Leoh Lai Sum , Kim Yoon Kyung , Martinez-Maza Otoniel , Daniels-Wells Tracy R. , Penichet Manuel L. 
Published: July 2016

Abstract
The transferrin receptor 1 (TfR1), also known as CD71, is a type II transmembrane homodimeric protein involved in cellular iron uptake and regulation of cell growth. The high levels of TfR1 expression on cancer cells, its extracellular accessibility, and its central role in cancer pathology make it an attractive target for antibody-mediated cancer therapy. We have previously developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1), which exhibits direct cytotoxic activity against certain human malignant B cells in vitro through TfR1 degradation and iron deprivation. In addition, we showed that ch128.1 is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) against malignant B cells in vitro. Importantly, ch128.1 shows exceptional antitumor activity in xenograft models of disseminated multiple myeloma (MM) in immunosuppressed mice (SCID-Beige) in an early disease setting. Intriguingly, this activity is observed even in malignant cells that show no sensitivity to the direct cytotoxic activity of ch128.1 in vitro. In order to study the mechanism of the in vivo antitumor activity, we generated a ch128.1 mutant with abolished binding to FcγR and the complement component C1q (L234A/L235A/P331S). Interestingly, this antibody mutant exhibited a total lack of in vivo protection against MM. This lack of antitumor activity is not due to increased clearance as determined by bioavailability studies. If fact, the two antibodies showed comparable affinity for the mouse FcRn (the neonatal Fc receptor, also known as the Brambell receptor) as determined via surface plasmon resonance analysis. This result suggests a critical role for the antibody Fc fragment in ch128.1-mediated antitumor activity. However, preliminary in vivo studies showed that depletion of complement using cobra venom factor (CVF) does not decrease the antitumor activity of ch128.1, suggesting that CDC is not a relevant mechanism of action, at least in the model used. Furthermore, we recently found that treatment with ch128.1 also significantly increased survival in late MM disease. Further studies aiming to provide a better understanding of the in vivo activity conferred by this antibody are in progress. Our results suggest that ch128.1 can be effective in the therapy of incurable human B-cell malignancies such as MM.
Citation Format: Lai Sum Leoh, Yoon Kyung Kim, Otoniel Martinez-Maza, Tracy R. Daniels-Wells, Manuel L. Penichet. Novel insights into the antitumor activity of an antibody specific for transferrin receptor 1 (ch128.1) in an in vivo model of human multiple myeloma. [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 582.