bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4840: Blockade of IL-10 production in effector B cells significantly increases their therapeutic efficacy in cancer adoptive immunotherapy
Authors: Zheng Fang , Pan Qin , Egenti Martin , Chang Alfred E. , Li Qiao 
Published: August 2012

Abstract
We have previously reported the antitumor reactivity of adoptively transferred effector B cells and the mechanisms by which they mediate tumor regression in a spontaneous metastasis model. 4T1 breast cancer cells were inoculated into syngeneic Balb/c mice to prime tumor-draining lymph node (TDLN). TDLNs were subsequently harvested and B cells activated ex vivo. When adoptively transferred into mice inoculated with 4T1 tumor in the mammary fat pad, these activated B cells alone mediated the inhibition of spontaneous metastases to the lung. In this study, we used IL-10−/− Balb/c mice to generate IL-10−/− TDLN, and evaluated the antitumor immunity of IL-10−/− TDLN B cells. Adoptively transferred IL-10−/− TDLN B cells mediated significantly more effective antitumor immunity than equal numbers of WT TDLN B cells (p&lt;0.05). Activated IL-10−/− effector 4T1 TDLN B cells were capable of killing 4T1 tumor cells in a tumor antigen specific manner in in vitro cytotoxicity assays independent of antibody and complement. Adoptive transfer of IL-10−/− TDLN B cells resulted in the induction of host T and B cell antitumor immunity significantly more than adoptive transfer of WT TDLN B cells (p&lt;0.05). This was evident by significantly modulated cytokine production (e.g. up-regulated IFN-gamma and IL-2 production by host T cells, but down-regulated IL-10 production by host B cells). In addition, adoptively transferred IL-10−/− TDLN B cells increased the production of IgG which bound to 4T1 tumor cells. Furthermore, IL-10−/− TDLN B cell infusion significantly increased tumor cell lysis (CTL) activity mediated by host B cells as well as T cells in an immunologically specific fashion. The molecular and cellular pathways involved in the direct killing of 4T1 tumor cells by IL-10−/- 4T1 TDLN effector B cells and by host B cells subjected to IL-10−/- 4T1 TDLN effector B cell adoptive transfer is under active investigation in our lab. While the role played by B cells in the host immune response to cancer is complex and controversial, our results indicate that removal of IL-10-producing B cell subsets may represent an effective strategy to augment the therapeutic efficacy of TDLN B cells used in adoptive immunotherapy. Mechanistically, adoptive transfer of B cells depleted of IL-10-producing subsets destroys tumor cells directly and confers greater host cellular and humoral antitumor immunity by shifting cytokine production to a Type 1 profile and by producing tumor-reactive antibodies respectively.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4840. doi:1538-7445.AM2012-4840
Abstract 4841: Lysis of cancer cells by highly purified T regulatory cells engaged via an EpCAM/CD3-bispecific BiTE antibody
Authors: Münz Markus , Murr Alexander , Hoffmann Petra , Edinger Matthias , Baeuerle Patrick A. , Kufer Peter , Raum Tobias 
Published: August 2012

Abstract
BiTE antibodies are single-chain bispecific antibody constructs with dual specificity for CD3 on T cells and a surface antigen on target cells. By bridging cytotoxic T cells and cancer cells, BiTE antibodies are capable to temporarily mount a polyclonal T cell response that is not restricted by T cell receptor specificity, presence of MHC class I, generation and presentation of peptide antigen, or the need for T cell co-stimulation. Examples are the CD19/CD3-bispecific BiTE antibody blinatumomab, which has shown high response rates and durable remissions in leukemia and lymphoma patients, and EpCAM/CD3-bispecific BiTE antibody solitomab (MT110), which is in a dose-escalating phase 1 study in patients with solid tumors. CD8+ and CD4+ effector memory T cells were found to be the most potent effector cells for BiTE antibodies. Here, we have assessed whether highly purified T regulatory cells (T regs) can also serve as effector cells for BiTE antibody MT110, despite multiple reports suggesting that T regs rather suppress the anti-tumor activity of cytotoxic T cells. T regs were purified from human peripheral blood mononuclear cells (PBMC) using anti-CD25 magnetic beads and fluorescence-activated cell sorting (FACS) for expression of CD4 and CD45RA markers, followed by expansion in the presence of IL-2 (Hoffmann P. et al., Methods Mol. Biol. 677:15-30, 2011). Purified naïve CD4+/CD25high/CD45RA+/FOXP3+ T regs had a purity of 96-99.6%, and contained no detectable CD8+ T cells. In co-culture experiments, a small fraction of purified T regs up-regulated the expression of granzyme B and perforin when stimulated with MT110 in the presence of EpCAM+ target cells. As shown by chromium release assay and phase contrast microscopy, T regs caused a MT110 dose-dependent, redirected lysis of target cells. No target cell lysis was observed with a BiTE antibody solely binding to CD3 on T cells, and by T regs alone. We then tested the activity of T regs against spheroids formed in vitro from colorectal cancer stem cells. Only in the presence of MT110, T regs could significantly reduce the size and integrity of spheroids. In that respect, T regs had a similar activity as PBMC. Our study suggests that T regs, which often are associated with immune escape of tumors, can be effectively engaged for redirected cancer cell lysis by a BiTE antibody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4841. doi:1538-7445.AM2012-4841
Abstract 4907: Effect of arsenic trioxide on cholangiocarcinoma: Use of an in vitro test and an in vivo xenograft model
Authors: Kim Eun Young , Roh Seon Ae 
Published: August 2012

Abstract
Objective: Arsenic trioxide (As2O3), an ingredient of many traditional Chinese medicines, has been shown to be active against many types of tumors. To assess whether local application of As2O3 inhibited cholangiocarcinoma development, we assayed the in vitro and in vivo effects of the chemical on human cholangiocarcinoma cancer cells of the CC-t6 line. Materials and methods: The effect of As2O3 on CC-t6 cell survival was determined using MTT assays and the mechanism of action was evaluated by flow cytometry following Annexin V-PI staining. The in vivo effect of As2O3 on tumor volume was explored using a nude mouse xenograft model. Results: In the MTT assay, As2O3 inhibited CC-t6 cells more strongly than did than cisplatin or adriamycin. As2O3 reduced CC-t6 cell proliferation via G0/G1 phase arrest and caused dose-dependent induction of apoptosis. Injection of As2O3 into CC-t6-induced tumors in nude mice inhibited the growth of subcutaneous tumor xenografts. Conclusions: As2O3 treatment dose-dependently inhibited the proliferation of CC-t6 cells via G0/G1 phase arrest and retarded tumor growth in nude mice, suggesting that As2O3 may be effective in the treatment of cholangiocarcinoma. Keywords: arsenic trioxide (As2O3), cholangiocarcinoma, intratumoral injection, tumor xenografts
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4907. doi:1538-7445.AM2012-4907
Abstract 4908: The apoptotic response of the triple negative breast cancer cell line HCC1806 to chemotherapeutics
Authors: Rorie Checo J. , King Jamie , Bryant Relena , Gurley Kashenya 
Published: August 2012

Abstract
Triple negative breast cancer is characterized by the loss or low expression of estrogen receptor, progesterone receptor, and HER2 proteins which have been targeted and established as somewhat effective therapy regiments in other breast cancer subtypes including luminal breast cancer. Since triple negative tumors are missing these established drug targets, there has been little advancement in the establishment of drug therapies to specifically target this breast cancer subtype. Triple negative breast cancer is described as aggressive due to its invasiveness and metastatic properties. One potential mediator of triple negative breast cancer aggressive behavior may be due to the fact that this breast cancer subtype may have as high as an 80% p53 tumor suppressor gene mutation rate. While the p53 gene may be mutated at high rates, it may be possible to design drugs to target some of the downstream genes that p53 transactivates, including the cyclin dependent kinase inhibitor p21 and the pro-apoptotic gene PUMA, in order to inhibit the further growth of the triple negative breast cancer cells. We previously reported that classic chemotherapeutics including actinomycin-D, staurosporine, and doxorubicin, were effective in eliciting apoptosis in breast cancer cell lines. We initially stressed breast cancer cell lines with all three chemotherapeutics listed above. We showed that all of the cell lines underwent significant apoptosis by 24hrs. Interestingly, the “normal” breast cancer cell line AG11132 had a delayed apoptosis response to doxorubicin treatment as compared to the breast cancer cell lines HCC1806, HCC70 and HCC1500. Therefore, we treated the breast cancer cell lines with a titration of various doxorubicin concentrations. Here we show that even at lower doxorubicin concentrations, a significant amount of apoptosis was measured at 24hrs in all of the cell lines including the triple negative breast cancer cell line HCC1806. We measured apoptosis by the physical characteristics as observed under light microscopy and by using the cell viability assay. We are currently monitoring the p53 tumor suppressor pathway network in all of these cells to determine the network's integrity and whether there is a direct or indirect involvement of p53 on the apoptosis responses. We are also further analyzing the chemotherapeutic agents to determine their effectiveness in killing breast cancer cells with limited cytotoxic effects to normal breast cells at various time-points.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4908. doi:1538-7445.AM2012-4908
Abstract 4913: A quantitative integrated systems biology approach for modeling cell cycle pathways in normal and tumor cells
Authors: Tummala Hemanth , Khalil Hilal S. , Goszcz Katarzyna , Tupone Maria Grazia , Stoyanova Vili , Nikolova Ekaterina , Mitev Vanio , Zhelev Nikolai 
Published: August 2012

Abstract
We have developed a novel biological system for quantitative analysis of biochemical pathways in normal and tumour human cells. The system is based on cells growing in tissue culture media where the concentrations of growth factors, hormones and other components of the media are precisely defined and continuously monitored. Quantitative immunoblotting and luminescence-based reporter assays are then used to measure the cellular concentration of key cell cycle regulatory proteins and their activity in real time in live cells. This technology resulted in accurate measurement of cellular concentration of a number of key cell cycle regulatory proteins such as Cyclins, CDKs and CDK inhibitors during the cell cycle. The data are being utilized in the development of a quantitative integrated systems biology approach to the cell cycle. The approach consists of a comprehensive network of the molecular interaction pathways regulating cell cycle in normal and tumor cells and a model which incorporates the activity of key molecular species in a single dynamical system which can be solved using genetic algorithms designed to match experimental data, both qualitative and quantitative, to the model kinetics. The model could be utilized for the development of new drug targets and would be capable of consistently measuring the effects of existing drugs (either single or in combination) and opens up a methodology for establishing the effectiveness of these drugs with clear implications for cost/benefit assessment. Major impact is expected on clinical research where the model can be a tool in determining intervention strategies in the molecular pathways concerned. Apart from the development of new drug targets the model will be capable of consistently measuring the effects of existing drugs (either single or in combination) and opens up a methodology for establishing the effectiveness of anti-cancer drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4913. doi:1538-7445.AM2012-4913
Abstract 4926: Modeling the transcriptome landscape of HER2+ breast cancer
Authors: Kalari Krishna R. , Chai High-Seng , Asmann Yan W. , Tang Xiaojia , Rossell David , Baheti Saurabh , Nair Asha , Baker Tiffany R. , Necela Brian M. , Carr Jennifer M. , Hart Steve N. , Sun Zhifu , Kachergus Jennifer M. , Younkin Curtis S. , Kocher Jean-Pierre A. , Thompson Aubrey E. , Perez Edith A. 
Published: August 2012

Abstract
Motivation: Overexpression of HER2 (the product of the ERBB2 gene) occurs in about 15% of all breast tumors. We have undertaken to use next generation transcriptome sequencing technology to identify genomic features that are unique to HER2+ tumors. Interactome mapping was then used to integrate the genes associated with these features into a transcriptome landscape model, with a view towards identifying nodes of interaction that might be targeted in HER2+ tumors. Methods: We performed 50nt paired-end RNA-sequencing for 24 breast tumors: 8 each HER2+, ER+, triple negatives (TN). In addition to breast adenocarcinomas, we also sequenced 8 early passage non-transformed HMEC cell lines as normal controls. Reads from RNA sequencing were aligned to the genome and exon junctions using TopHat software. Gene counts were summarized and annotations were performed using our in-house programs. Tukey's test was used to obtain genes or transcripts that are specific to HER2 tumor group compared to other tumors/normal. A combination of bioinformatics softwares and algorithms were used to identify SNVs. Results: Only 13527 genes with median gene count greater than 16 reads in at least one of the 4 groups were considered for differential gene expression and splicing analysis. Some 696 genes were differentially expressed in HER2+ tumors compared to ER+, TN tumors and HMECs. We identified 272 alternately spliced transcripts for which the HER2+ tumors exhibited a mean transcript expression ratio significantly different from the means of other tumor groups. We also identified 4735 expressed single nucleotide variants that are uniquely associated with HER2+ tumors compared to other tumors/normal groups. Among these 3579/4735 sequence polymorphisms were not present in the 1000 genome germline sequence database or in the dbSNP132 database of naturally occurring germline polymorphisms. Integration of all the genes obtained from genomic feature analyses (differential expression, alternative splicing, single nucleotide variance) has been carried out to indentify biological processes that are specific to the HER2+ tumor subtype. Key nodes and pathways that are specific to HER2+ tumors will be evaluated for association with clinical outcome in a large series of patients who have received HER2-targeted therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4926. doi:1538-7445.AM2012-4926
Abstract 4931: Biomarker discovery in a large panel of cell lines shows different sample size requirement for prediction of response across a set of compounds
Authors: Nebozhyn Michael , Cristescu Razvan , Liu Yaping , Feldman Igor , Lezhnin Sergey , Zhang Theresa , Zawel Leigh , Fawell Stephen , Dai Hongyue , Li Jing , Loboda Andrey 
Published: August 2012

Abstract
A panel of more than 600 cell lines from 17 tumor types has been profiled and sensitivity to a set of FDA approved compounds with different mechanisms of action has been tested. Comparison of gene expression profiles with overlapping set of publicly available profiles showed 100% accuracy of cell line identity prediction using nearest neighbor classifier. Similar analysis of CNV data had 80% accuracy due to relatively little CNV perturbation in some of the cell lines. Significant gene expression signatures have been detected for 80% of compounds. De-novo agnostic classification based on 50% train/test split and a linear classifier resulted in significant prediction on the test set for about 40% of the compounds, such as dasatinib, 5FU, paclitaxel, but failed to produce a significant prediction for others, such as doxorubicine, irinotecan, and vinblastine. For most of the compounds, the prediction of response is complex, with multiple distinct molecular features contributing to a classification algorithm. This inherent complexity requires integration of gene expression, CNV and mutation data as well as a large cell line sets for development of accurate classification algorithms. We defined functional CNV and SNV events using gene expression based modules as a functional readout. Predictive models that incorporate prior knowledge of mechanism of action of the compounds and rely on functional SNV and CNV events out perform completely agnostic methods of prediction.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4931. doi:1538-7445.AM2012-4931
Abstract 4932: Exploration of EMT-related microRNAs using function-based screening with expression analysis of E-cadherin in Panc1 line
Authors: Harazono Yosuke , Kozaki Ken-ichi , Muramatsu Tomoki , Kurasawa Yasuhiro , Uzawa Narikazu , Amagasa Teruo , Inazawa Johji 
Published: August 2012

Abstract
Recently, epithelial-mesenchymal transition (EMT) has been demonstrated to contribute to malignant transformation during cancer progression. To perform the function-based screening of EMT-related microRNAs (miRNAs), we first generated an in vitro model using a pancreatic cancer cell line, Panc1, in which a transcriptional reporter construct containing E-cadherin promoter region and a reporter gene, GFP, was transfected. After the selection of independent clones by the limiting dilution and the examination of GFP-upregulation in response to overexpression of ectopic miR-200b/a, we successfully established a stable transfectant clone, Panc1-EPG8. Then, we performed function-based screening with expression analysis of GFP in Panc1-EPG8 cells 4 days after ectopic transfection of 470 synthetic miRNAs. We further reexamined the expression level of E-cadherin after ectopic transfection with selected candidate miRNAs in Panc1-EPG8 cells by Western blotting and qRT-PCR, resulting in the identification of a novel miRNA as a candidate EMT-related miRNA. Our findings strongly suggest that this miRNA may play a crucial role during EMT in cancer progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4932. doi:1538-7445.AM2012-4932
Abstract 4936: Network signatures of survival in glioblastoma multiforme
Authors: Patel Vishal , Gokulrangan Giridharan , Chowdhury Salim , Chen Yanwen , Sloan Andrew , Koyuturk Mehmet , Barnholtz-Sloan Jill , Chance Mark 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and also the most aggressive, with a median survival time of approximately 1 year. Differences in age and pathology have long been recognized as key factors in determining prognosis, and, more recently, comprehensive mRNA profiling has been undertaken to establish the molecular basis underlying prognosis. Though early mRNA expression-based gene sets represented unbiased queries into molecular differences in gliomas, they only uncovered differences in survival ex post facto1, 2. Newer gene sets capitalize upon advances in technology, yet they suffer for their unwieldy size and ambiguous biological meaning3. Though the myriad gene sets proposed share little overlap with each other, recent work has demonstrated that the use of interaction networks can consolidate these differences. To determine the molecular basis of prognostic differences in GBM directly, we employed an existing computational framework, CRANE, to exhaustively search protein interaction networks and identify molecular signatures distinguishing short-term (&lt;225 days) and long-term (&gt;635 days) survivors of GBM in The Cancer Genome Atlas gene expression microarray dataset. Using CRANE, we identified a 50 gene subnetwork signature of survival in GBM, which we validated in an independent dataset of 91 patients (80% classification accuracy). We further hypothesized that the use of interaction networks consolidates variation in mRNA expression into more stable features at higher phenotypic levels. To test this hypothesis, we examined protein expression levels of the 50 network targets in an independent cohort of 16 patients (10 patients: survival&lt;9 months; 6 patients: survival&gt;18 months) using label-free proteomics. Of the 17 network targets identified in common with our 50 subnetwork signature genes, 8 were significantly differentially expressed between short-term and long-term survivors, and expression levels of 3 of the proteins (STAT3, Calnexin, and HSPA9) predicted phenotype (LTS vs. STS) with 75% or more accuracy (12 or 13 correct out of 16). Our conclusion is that data integration using interaction networks can drive discovery of a stable subnetwork signature exhibiting clear differences in protein expression. This manageable subset of proteomic targets will prove invaluable in the design of cost-effective clinical assays (e.g. IHC) suitable for retrospective analysis from FFPE tumor tissue in existing biobanks, as well as for prospective studies predicting patient survival - a much desired endpoint for clinicians and patients alike.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4936. doi:1538-7445.AM2012-4936