bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1917: Immunological Tumor Maps: a Landscape of Infiltrating Immune Cells in Colorectal Cancer Based on Complete Tissue Section Analyses
Authors: Halama Niels , Zoernig Inka , Foged Niels T. , Schirmacher Peter , Jaeger Dirk , Grabe Niels 
Published: February 2011

Abstract
In colorectal cancer (CRC) large scale tissue microarray (TMA) based quantitative immune cell counts using immune cell surface molecules (CD3, CD8, Granzyme B, and CD45RO) have identified the number of infiltrating immune cells to be potentially better predictors for patient survival than the classical TNM system. The spatial heterogeneity of immune cells may not be well reflected in the highly selected, and typically small (0,6-1 mm2) tissue cores of the TMA. This represents an obstacle in the individual prognosis prediction or classification of a single patient. To investigate this aspect, the localization and distribution of immune cell subpopulations based on the analysis of complete tissue sections by a dedicated novel staining and imaging system were performed. Using a specialized staining platform and whole slide imaging & analysis by virtual microscopy (VM), immunological “tumor maps” were generated. These tumor maps are based on cell densities in fields of 1mm2 size, visualizing intratumoral heterogeneity for the surface markers CD3, CD8, Granzyme B, and CD45RO. In total, an area of 867 mm2 was automatically evaluated with an average of 48 mm2 of evaluated tumor tissue per patient slide. Cell counts varied within a patient significantly, ranging from 0 to up to 2550 cells / mm2. Further analyses revealed, that sampling of single field counts within the tumor can only yield clear diagnostic decisions for a fraction of the analyzed patients, with ambiguous decisions for 11 out of 20 patients. Interestingly, the overall degree of heterogeneity also varied between patients, with lower heterogeneity found only in samples with lower cell counts. No samples with a homogeneous high cell density distribution were observed. The observed variability has implications for the individual prognosis prediction and represents the first spatial quantitative study of immune cells in a set of CRC primary tumors. The presented tumor maps therefore are a suitable tool to visualize heterogeneity. Furthermore, whole slide imaging & analysis by VM is essential in the identification of prognostic markers as well as in their subsequent application. In the future, spatial marker signatures could contribute to individual patient classification.
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 1917.
Abstract 192: Restoration of an epigenetically silenced tumor suppressor gene RASSF1A in human prostate cancer cells by a plant alkaloid, mahanine
Authors: Jagadeesh Shankar , Pal Bikas C. , Bhattacharya Samir , Banerjee Partha P. 
Published: February 2011

Abstract
The etiology of human prostatic carcinoma remains largely undefined. However, it is becoming clear that epigenetic inactivation of various tumor suppressor genes could play pivotal role in the development of various cancers including prostate cancer. One of such tumor suppressor is Ras-association domain family 1 (RASSF1) gene. Epigenetic inactivation of RASSF1A is probably the most frequently methylated gene described thus far in human cancer. Ectopic expression of RASSF1A in cancer cells that lack endogenous RASSF1A transcripts resulted in reduced growth of cancer cells in vitro and in nude mice supporting a role for RASSF1A as a tumor suppressor gene. Since, the restoration of RASSF1A expression in tumor cells impairs their tumorigenicity, factors that restore RASSF1A expression have immense importance in preventing tumor growth. In this investigation, we demonstrated that, mahanine, a plant derived carbazole alkaloid, restores RASSF1A expression in both androgen-responsive (LNCaP) and androgen-negative (PC3) prostate cancer cells by inhibiting DNA methyltransferase (DNMT) activity. Mahanine-induced expression of RASSF1A in turn significantly reduces cyclin D1 but not other cyclins. As a result of down-regulation of cyclin D1, cancer cells arrest at G0/G1 phase. To understand the inverse relationship between RASSF1A and cyclin D1, we observed that mahanine treatment down-regulates cyclin D1 and addition of RASSF1A siRNA prevents this inhibition. Inactivation of both Akt and CREB by mahanine and RASSF1A is associated with the down-regulation and translocation of cyclin D1. This study shows that mahanine can reverse an epigenetically silenced gene, RASSF1A in prostate cancer cells by inhibiting DNMT activity that in turn down-regulates a key cell cycle regulator, cyclin D1. Mahanine, therefore, promises an encouraging therapeutic choice for advanced prostatic cancer (Supported by NIH grant R01 CA131123).
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 192.
Abstract 1926: Adoptive γδ T cell transfer therapy for non-small cell lung cancer
Authors: Kakimi Kazuhiro , Murakawa Tomohiro , Fukami Takeshi , Goto Shigenori , Kaneko Toru , Yoshida Yukihiro , Takamoto Shin-ichi , Nakajima Jun 
Published: February 2011

Abstract
Human peripheral blood γδ T cells can recognize and kill tumor cells by their Vγ9Vδ2 T cell receptor and/or NKG2D. We have established large-scale ex vivo expansion of γδ T cells from peripheral blood mononuclear cells (PBMC) by zoledronate and IL-2. A clinical study of adoptive γδ T cell transfer therapy has been conducted for the treatment of non-small-cell lung cancer (NSCLC) patients to evaluate the safety profile and potential anti-tumor effects of γδ T cells. Prior to beginning the study, it was registered on a University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR : http://www.umin.ac.jp/ctr/index.htm) on March 1, 2006 (UMIN ID: C00000036).
PBMC were isolated from 67.5 ml of peripheral blood and stimulated with zoledronateand IL-2 for 14 days to obtain γδ T cells. The cultured cells on day 14 consisted mostly of γδ T cells. The predominant populations in fresh peripheral blood were cells with the CD45RA−CD27+ memory phenotype or a CD45RA+CD27− naïve phenotype. In contrast, most γδ T cells were shown to have the CD45RA−CD27− effector memory phenotype after 14 days culture. They expressed NKG2D and up-regulated the expression of activation marker CD69, and had cytotoxicity against allogeneic tumor cell lines. Upon stimulation, γδ T cells produced IL-2, TNF-α and IFN-γ. Though certain patients were refractory to zoledronate stimulation, γδ T cells from patients demonstrated comparable cytotoxic effector activity once they were successfully expanded.
Cultured cells were intravenously administered every 2 weeks for 6 injections. Fifteen patients who were resistant to current standard therapy were enrolled this study. The treatment was well tolerated and no severe adverse events related to γδ T cell therapy were observed. Two patients came off the study at the early stage of the treatment due to the aspiration pneumonia (grade 3) and radiation pneumonitis (grade3). The responses according to RECIST guideline were SD for 7 patients, PD for 6 patients and 2 inevaluable for response due to early drop off the study (The disease control rate was 46.7 %).
Transferred γδ T cells gradually accumulated in peripheral blood in patients who received more than 1×109 γδ T cells per injection and accounted for 10 % of PBMC even 2 weeks after the final injection. When PBMC were stimulated with PMA/ionomycin or zoledronate-pulsed Daudi cells, IFN-γ production and surface expression of CD107 were detected on γδ T cells, suggesting that transferred γδ T cells sustained their effector function in vivo.
These results indicated that γδ T cell therapy was well tolerated and feasible for the treatment of NSCLC.
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 1926.
Abstract 1930: Early post-operative adoptive multiple-cellular immunotherapy in gastric cancer: A 3-year follow-up report
Authors: Xu Yingxin , Qiao Zhi , Peng Zheng , Xia Shaoyou , Li Li , Wu Xin , Zhang Yanjun , Ning Ning , Li Jie , Li Rong 
Published: February 2011

Abstract
Objective Adoptive immunotherapy is an active approach, but efficacy is limited in the clinic for most solid tumor. We hypothesized that there are three factors might lead to improved clinical outcome in the patients with gastric cancer that include: 1) the combination of multiple immune cells, 2) more effector cells reaching at the site of the tumor by infusion in peritoneal cavity, 3) performing of immunotherapy as soon as possible after operation.
Patients & Methods 51 gastric cancer patients (stage III-IV 42/51) who underwent operation from September 2005 to March 2008 were retrospectively analyzed. Data were censored in 39 months (January 2009),Group A patients (n=22) received a course of immunotherapy which included autologous tumor lysate-pulsed dendritic cell (DC) via intradermic injection, cytokine induced killer cells (CIK) by iv, as well as DC-CIK by intraperitoneal injection in 11-14 days after operation, then a standard chemotherapy (18/22) and immunotherapy again. Group B patients (n=29) only received postoperative chemotherapy. Overall survival (OS) and disease-free survival (DFS) were calculated by the Kaplan-Meier method.
Results In total, 24 patients died, giving a median survival time of 25 months. The estimated 2-year OS and DFS of group A were 63.6% and 67.3%, while that of group B were 25.2% and 33.2%, respectively. Both of the estimated 3-year OS and DFS were significantly superior in group A (log-rank test, P&lt;0.01).
Conclusions Early post-operative adoptive multiple-cellular immunotherapy with infusion in peritoneal cavity significantly improved overall survival and disease-free survival in gastric cancer patients.
Key words gastric cancer; early; postoperative; adoptive cellular 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 1930.
Abstract 1940: Successful eradication of established peritoneal ovarian tumors in SCID-beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen
Authors: Chekmasova Alena A. , Thapi Dharmarao , Nikhamin Yan , Park Kay J. , Spriggs David R. , Brentjens Renier J. 
Published: February 2011

Abstract
Most patients diagnosed with ovarian cancer will ultimately die from their disease. For this reason, novel approaches to the treatment of this malignancy are needed. Adoptive transfer of a patients own T cells, genetically modified ex vivo through the introduction of a gene encoding an chimeric antigen receptor (CAR), an artificial T cell receptor, targeted to a tumor associated antigen, is a novel and promising approach to cancer therapy applicable to the treatment of ovarian cancer.
We have generated several CARs targeted to the retained extracellular domain of MUC16, termed MUC-CD, an antigen highly expressed on a majority of ovarian carcinomas. We investigate the in vitro biology of human T cells retrovirally transduced to express these CARs by co-culture assays on artificial antigen presenting cells (AAPCs) generated from NIH3T3 fibroblasts genetically modified to express the target MUC-CD antigen, as well as by cytotoxicity and proliferation assays utilizing the target human OV-CAR3(MUC-CD) ovarian tumor cell line. Finally, we assess the in vivo anti-tumor efficacy of human MUC-CD targeted T cells in a SCID-Beige orthotopic, xenogeneic OV-CAR3(MUC-CD) murine tumor model. CAR modified MUC-CD targeted T cells exhibited efficient in vitro cytolytic activity against cell lines which expressed the MUC-CD antigen and could be further expanded ex vivo through multiple cycles of co-culture on 3T3(MUC-CD/B7.1) AAPCs. Expanded MUC-CD targeted T cells infused into SCID-Beige mice bearing intraperitoneal human OV-CAR3(MUC-CD) tumors either delayed progression or fully eradicated tumor even in the setting of advanced disease.
These promising pre-clinical studies justify further investigation of MUC-CD targeted T cells as a potential therapeutic approach in the clinical setting treating patients with high risk MUC-16+ ovarian carcinomas.
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 1940.
Abstract 1944: In vitro analysis of suicide gene expression and function in human T lymphocytes transduced to express a tumor targeted chimeric antigen receptor
Authors: Park Jae , Yeh Raymond , Riviere Isabelle , Sadelain Michel , Brentjens Renier 
Published: February 2011

Abstract
Adoptive infusion of T cells genetically modified to express chimeric antigen receptors (CARs) targeted to tumor associated antigens (TAAs) is a promising novel approach to cancer therapy. However, in light of the fact that most TAAs targeted by such modified T cells are expressed, at least to some degree, by normal tissues as well as the fact that clinical experience with this technology is limited, safeguards are needed in the form of additional expression of transduced suicide genes by these T cells to allow for the efficient in vivo abrogation of infused T cells in the setting of unanticipated adverse events which may develop in the context of planned clinical trials.
Herein we report the in vitro function of 3 different suicide genes each initially inserted distal to a CAR gene and an IRES (internal ribosome entry site) element cloned into the SFG retroviral vector. Specifically, in this study we evaluated the herpes simplex virus thymidine kinase (HSV-TK SR39), E. coli derived nitroreductase (NTR), and inducible caspase-9 (iCasp-9). We initially found that all 3 suicide genes functioned sub-optimally in the second position of these IRES based bicistronic vectors. In order to enhance suicide gene expression we deleted the IRES elements replacing them with 2A linker peptides, which significantly improved gene expression and the cell growth inhibition upon the addition of respective substrate. In PG13 cells transduced with SFG 1928z. IRES. NTR we found 40% inhibition at 5mM of metronidazole (MTZ), but 90% in PG13 cells transduced with SFG 1928.2A.NTR. Similarly, PG13 (1928z.IRES.HSV-TK) fibroblasts exhibited 60% inhibition at 1µM of ganciclovir compared to 85% inhibition of PG13 (1928z.2A.HSV-TK) fibroblasts. Consistent with these findings, we found that human T cells transduced with either 1928z.2A.NTR or 1928z.2A.HSV-TK demonstrated 90% and 88% inhibition respectively at similar substrate concentrations.
In light of this encouraging in vitro data, we are currently in the process of assessing respective suicide gene function in vivo using a syngeneic, immune-competent mouse model recently developed in our laboratory. Ultimately we anticipate that these studies will allow us to rationally select the optimal suicide gene-prodrug combination to be incorporated into future clinical trials utilizing gene modified tumor targeted T cells.
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 1944.
Abstract 1946: Identification of miRNAs that contribute to melanoma brain metastasis
Authors: Gaziel Avital , Menendez Silvia , Segura Miguel F. , Zakrzewski Jan , Rose Amy , Kerbel Robert S. , Darvishian Farbod , Cohen Dalia , Osman Iman , Hernando Eva 
Published: February 2011

Abstract
Brain metastasis occurs in a large proportion of metastatic melanoma patients and is associated with a dismal prognosis. However, the molecular mechanisms that govern melanoma tropism to the brain remain poorly understood. MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, and have been recently shown to exert key roles during cancer metastasis. In this study we find that specific miRNAs may be important mediators of melanoma dissemination to the brain. First, we conducted a miRNA microarray analysis of metastatic melanoma tissues that revealed a subset of miRNAs differentially expressed in brain metastases (n=11) relative to other sites (n=48). A brain-specific signature comprised of seven miRNAs was further validated in an independent cohort of metastatic melanoma samples (n=36; 9 brain metastatic specimens). Then, we analyzed the trend of expression of those miRNAs during tumor progression by comparing their levels in primary tumors and their paired metastasis from patients with or without recurrence in the brain (n=18). Differential expression of some miRNAs was already evident at diagnosis in primary tumors that recurred in the brain, while for others it was acquired in the transition from primary to metastasis, suggesting that it may be a later event in tumor progression. Furthermore, in vitro modulation of specific signature miRNAs significantly altered the ability of melanoma cells to execute processes such as adhesion and transmigration through human brain endothelial cells and proliferation in human astrocytes conditioned media. Additionally, using an in vivo model of melanoma brain metastasis, we confirmed the capacity of specific miRNA alterations to promote melanoma cells’ competence to reach the brain. Finally, the analysis of potential downstream mediators of select miRNAs revealed the involvement of immuno-suppressive molecules, as well as inflammatory and chemotactic mediators in this process. Collectively, our results expand our understanding of the mechanisms that control melanoma brain metastasis, potentially revealing novel therapeutic avenues for patients for whom no viable approaches are currently available.
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 1946.
Abstract 1953: Functional identification of microRNA targets by integrated proteomics and microarray profiling: miR-193b in breast cancer
Authors: Leivonen Suvi-Katri , Rokka Anne , Östling Päivi , Kohonen Pekka , Corthals Garry , Perälä Merja , Kallioniemi Olli 
Published: February 2011

Abstract
MicroRNAs (miRNAs) regulate protein expression by targeting messenger RNAs (mRNAs) for cleavage or by inducing translational repression. Despite advances in bioinformatic predictions, it is a significant challenge to identify protein targets that the miRNAs regulate. Here, we applied a novel strategy combining functional data from quantitative proteomics using iTRAQ (isobaric tag for relative and absolute quantitation), gene expression microarray profiling and bioinformatic target predictions in order to characterize targets regulated by miRNAs. We focused on exploring the anti-cancer effects of miR-193b. According to our high-throughput functional studies (Leivonen et al., Oncogene, 2009), miR-193b induces cell cycle arrest and inhibition of estrogen-depedent growth when overexpressed in breast cancer cell lines.
Pre-miR-193b was over-expressed in MCF-7 breast cancer cells for 48 h, and the cell lysates were subjected to iTRAQ isobaric labelling followed by mass-spectrometric analyses. We identified over 600 proteins, of which 11 were repeatedly and significantly (p&lt;0.05) down-regulated, and 6 up-regulated by miR-193b as compared to controls. Three of the down-regulated proteins were predicted to be targeted by miR-193b by the TargetScan algorithm. Of the predicted miR-193b targets, two were also among the most prominently down-regulated genes at the mRNA level according to microarray profiling of miR-193b-transfected MCF-7 cells. These data were validated by western blotting and quantitative RT-PCR. The results indicated that miR-193b targets included proteins which have previously been linked to breast cancer progression and poor prognosis, such as 14-3-3ζ (YWHAZ), as well as mini-chromosome maintenance protein-7 (MCM7), which is associated with DNA replication and cell cycle control.
In conclusion, we demonstrate here that the combination of proteomic expression profiling and gene expression microarray profiling is a powerful strategy to functionally identify protein targets and mechanisms of action for miRNAs that have anti-cancer effects when transfected into breast cancer cells.
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 1953.