bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1937: Enhanced tumor control with adoptive transfer of TCR engineered T cells expressing Tcl1
Authors: Koya Richard C. , Mok Stephen , Chodon Thinle , Teitell Michael , Ribas Antoni 
Published: February 2011

Abstract
Advanced stage melanoma is associated with notable resistance to radio and chemotherapy, warranting intense research for new treatments. Immunotherapy with adoptive transfer of antigen-specific T cells has shown anti-tumor activity in melanoma, but questions remain regarding the biology of T cell responses, and the necessary enhancement strategies to achieve significant impact in the overall clinical outcome. The14 kDa protein T cell leukemia-1 (TCL1) has shown to augment the growth and survival of mature but not immature T cells through enhancement of signals that operate through the PI3K-Akt and protein kinase C (PKC)-MAPK- ERK pathways. Here we engineered TCL1 transgenic lymphocytes to express a T cell receptor (TCR) specific to ovalbumin antigen to be used in an adoptive transfer model for melanoma tumor control in vivo. A bicistronic MSCV-based retroviral vector was engineered to express the alpha and beta chains of a TCR (OT1) specific for SIINFEKL peptide of ovalbumin (OVA) presented on mouse MHC I (Kb). The transgenes were interspaced with picornavirus-derived highly efficient self-cleaving 2A-like sequences to allow balanced protein expression. Transduction of ex vivo activated primary murine T cells with retrovirus stocks demonstrated correct expression of specific TCR as analyzed by flow-cytometry with anti-Valpha2/Vbeta5.1+5.2 staining and OVA (SIINFEKL) tetramer assays, with transduction efficiency of 64.8-76% at M.O.I.=20. OT1 TCR-transduced murine splenocytes from TCL1 transgenic mice stimulated with ovalbumin-expressing murine EL4 lymphoma or B16 melanoma showed high and specific IFNgamma production (30,000 and 16,000 pg/ml/1e6cells/24h respectively) as assessed by ELISA. In vivo studies were carried out in C57BL6 mice implanted with syngeneic B16/OVA murine melanoma. Intravenously adoptive transferred OT1 TCR-transduced splenocytes from TCL1 transgenic mice lead to higher survival and tumor size control in comparison to OT1 TCR-transduced control syngeneic splenocytes (tumor volume: 221.65mm3 and 1095.48mm3, respectively at day 23 post-infusion, p&lt;0.05). In conclusion, TCL1 expression in mature T cells enhanced the potency of adoptively transferred T cells for treatment of melanoma.
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 1937.
Abstract 1948: Pvt1-encoded microRNA miR-1204 in tumorigenesis of human ovarian and breast cancer
Authors: Huang Jing , Collisson Eric A. , Gibb Bill , Jakkula Lakshmi , Martin Steven , Gray Joe w. 
Published: February 2011

Abstract
Amplification at chromosome 8q24 is one of the most frequent genomic abnormalities in human cancers and is associated with reduced survival duration in ovarian and breast cancers. Recently, microRNAs (miRNAs) at 8q24 have been identified in the PVT1 locus. Herein, we explored the biological functions of one miRNA, miR-1204, residing within the exon1B of PVT1. Mature hsa-mir-1204 is over-expressed in PVT1 amplified ovarian and breast cancer cell lines (HEY, OVCAR8, SUM-159PT and MDA-MB231). In vitro treatment with antagomir against hsa-mir-1204 inhibited cell proliferation and induced apoptosis in the four PVT1 amplified ovarian and breast cancer lines. Conversely, over-expression of miR-1204 promoted cell growth in PVT1 non-amplified ovarian and breast cancer lines (OV90 and MCF10A) and cooperated with c-Myc to potentiate Rat1A cell colony growth in soft agar assays. Since an inverse expression pattern is often present between miRNA and its target genes, we used computational approaches (miRanda, TargetScan, Pita) to identify distinct miR-1204 candidate target genes from two independent expression microarray datasets, one with significantly down-regulated genes by PVT1 copy number gain in 147 breast tumors and the other involving genes significantly repressed by miR-1204 overexpression and derepressed by silencing of miR-1204 in ovarian and breast cancer cells. Thirty putative target genes of miR-1204 were empirically verified by Q-RT-PCR method, and this group of genes was enriched with genes regulating cell death, cell growth and proliferation, cell cycle, cellular assembly and organization. Combined, these data suggest that human miR-1204 contributes to ovarian and breast tumor proliferation and survival and down-regulates distinct targets including multiple tumor suppressor genes and serves as a potential therapeutic target against tumors with 8q24 amplification.
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 1948.
Abstract 1949: Positive feedback regulation between EWS-FLI1 and miR-145 in Ewing's sarcoma
Authors: Ban Jozef , Mestdagh Pieter , Kauer Max , Jug Gunhild , Speleman Frank , Kovar Heinrich 
Published: February 2011

Abstract
The EWS-FLI1 chimeric protein is a potent tumor specific transcriptional regulator and the molecular cause of Ewing's sarcoma family of tumors (ESFT). We had previously hypothesized that, since EWS-FLI1 is the major driver of aberrant gene expression in ESFT, there should be an inverse correlation between the changes in gene expression observed in ESFT cell lines in response to RNAi-mediated EWS-FLI1 knockdown and the corresponding gene expression in primary tumors relative to the tissue of origin. We found that mesenchymal progenitor cells (MPC) fit this assumption best and established an ESFT specific EWS-FLI1 transcriptional signature on the mRNA level. Following the same approach, we now studied the EWS-FLI1 dependent regulation of microRNAs (miRNAs) in ESFT. Genome-wide miRNA analysis was performed after shRNA-mediated stable (5 cell lines) and inducible (1 cell line) EWS-FLI1 knockdown, as well as in 6 primary ESFT and 6 MPC samples using the stem-loop reverse transcription quantitative PCR platform. Among miRNAs consistently affected by EWS-FLI1 silencing and inversely expressed in primary tumors compared to MPCs was hsa-miR-145 which we found upregulated upon EWS-FLI1 silencing. Since several target sites exist for this miRNA within the FLI1 3′UTR, we asked if hsa-miR-145 is capable of modulating EWS-FLI1 expression in ESFT cells. Upon ectopic expression of pri-miR-145 in wildtype p53 ESFT cells, strong modulation of EWS-FLI1 protein levels, but not RNA levels, was observed. In p53 mutant cell lines this effect was less pronounced consistent with a recently reported role of p53 in miR-145 maturation. Preliminary studies suggest that hsa-miR-145 is indirectly regulated by EWS-FLI1 by a mechanism that may involve the NOTCH signaling pathway. Our results identify a positive feed-back loop between EWS-FLI1 and hsa-miR-145 expression in ESFT.
Supported by the 6th framework program of the European Commission, (STREP “E.E.T. Pipeline“ contract LSHC-CT-2006-037260) and grant P20665-B12 of the Austrian Science Fund FWF.
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 1949.
Abstract 195: Functional epigenetics identifies a protein phosphatase-1 regulatory subunit gene as a candidate tumor suppressor frequently silenced by promoter CpG methylation in multiple tumors
Authors: Leung Ching Hei , Ng Ka Man , Wong Ada Ho Yan , Ying Jian ming , Srivastava Gopesh , Leung Sing Fai , Chan Anthony Tak Cheung , Tao Qian 
Published: February 2011

Abstract
Protein Phosphatase 1 regulatory subunits (PPP1R) are a family of small molecules which modify the function and protein targeting of protein phosphatase-1 upon their interactions. Deregulated expression of PPP1R members could often be found in cancer cells. For example, ASPP family is well known for its necessity of p53 function while ASPP silencing leads to carcinogenesis or poor prognosis in cancer patients. Here, one of the PPP1R members (TUSC7) was identified which its role in tumor suppression had been investigated
Using semi-quantitative RT-PCR, expression profile of TUSC7 in cancer cell lines was obtained. TUSC7 was frequently silenced in cancer cells. Bisulfite treated tumor DNA was subjected to Methylation-specific PCR (MSP) using primers flanking across the ∼130bp CpG island of the TUSC7 promoter. It was revealed that silencing of TUSC7 was due to promoter hypermethylation in most of the corresponding cancer cell lines which had been further confirmed by bisulfite genomic sequencing (BGS). Treatment with azacytidine and trichostatin restored TUSC7 expression through demethylating the hypermethylated promoter. To quantitatively determine the extensiveness of cancer cell growth inhibition by TUSC7, colony formation assay was used. It was found that ectopic expression of TUSC7 could inhibit the proliferation of tumor cells, Caski (cervical carcinoma), HCT116 (colon carcinoma) and KYSE150 (esophageal squamaus carcinoma cells) by 40-50%. In addition, ectopic expression of TUSC7 increased the amount of phosphorylated GSK-3beta (pSer9-GSK-3beta) as shown in the western blot analysis. pSer-9 GSK-3beta is the inactive form of GSK-3beta. It has been reported that inactive GSK-3beta may affect p53 activities. To summarize, TUSC7 was found to be a tumor suppressor frequently silenced in cancer cells through epigenetic mechanism. TUSC7 may be significant in regulating the activity of GSK-3beta whose signaling is important in carcinogenesis.
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 195.
Abstract 1956: A novel mouse model of breast cancer metastasis to bone
Authors: Shaw Aubie K. , Johnson Rachelle , Sterling Julie , Mundy Greg , Moses Hal 
Published: February 2011

Abstract
Patients with advanced stage breast cancer develop bone metastasis, which leads to hypercalcemia, fractures, nerve compression, paralysis and pain. Breast cancer bone lesions can be osteolytic or osteoblastic, however osteolytic lesions are predominant. Currently, there is no experimental model available to examine osteotropism or trafficking of breast cancer cells to the bone from the primary tumor. TGFβ signaling has been suggested to be responsible for osteotropism. TGFβ stimulates Gli2 and PTHrP expression, which have been shown to be responsible for osteolysis. We have shown that MCF10A, AT-1 and CA1d human breast epithelial cells are responsive to TGFβ and express very high levels of Gli2 and PTHrP. Orthotopic grafting to the cleared fatpad of SCID mice shows that MCF10A and AT-1 cells do not form tumors, even when grafted with normal fibroblasts. CA1d carcinoma cells that are co-grafted with normal fibroblasts show rapid tumor formation with 100% incidence, whereas CA1d cells grafted alone rarely form tumors in the orthotopic site. The tumors can be localized real-time and non-invasively using optical imaging of GFP. X-ray imaging revealed loss of bone density in sacral/caudal vertebrae and hindlimbs. Ca1d grafts generate undifferentiated primary tumors that metastasize to lung and bone. Future studies will determine if CA1d cells stimulate osteolysis. This model may provide a valuable model to examine osteotropism of breast cancer 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 1956.
Abstract 1961: Ikzf1 haploinsufficiency contributes to the pathogenesis of BCR-ABL1 positive acute lymphoblastic leukemia
Authors: Collins-Underwood J Racquel , Miller Christopher B. , Downing James R. , Mullighan Charles G. 
Published: February 2011

Abstract
Expression of the constitutively active tyrosine kinase BCR-ABL1 is the hallmark of two diseases with distinct pathologic and clinical features: chronic myeloid leukemia (CML), an expansion of relatively mature granulocytes that typically responds well to kinase inhibition, and pre-B cell acute lymphoblastic leukemia (ALL), an aggressive malignancy of lymphoid progenitors that has a dismal prognosis. The basis for this dichotomy has been poorly understood. We recently identified a near-obligate deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) in de novo BCR-ABL1 positive ALL, and at the progression of CML to lymphoid blast crisis, suggesting that perturbation of IKAROS activity is a key event in the pathogenesis of BCR-ABL1 lymphoid leukemia. To test this hypothesis, we have examined the effect of Ikaros haploinsufficiency in a retroviral bone marrow transplant model of murine BCR-ABL1 B-progenitor ALL. Unmanipulated marrow from either Ikzf1 wild type mice or mice heterozygous for an Ikzf1 null allele was transduced with MSCV bicistronic retrovirus expressing GFP and p185 BCR-ABL1 and transplanted into lethally irradiated C57BL/6 recipients. Recipients of MSCV-GFP-p185 BCR-ABL1-transduced Ikzf1+/− marrow developed leukemia with markedly increased penetrance and reduced latency in comparison to recipients of wild-type marrow (46 vs. 122 d, P&lt;0.0001). The resulting leukemias resulted in bone marrow replacement by lymphoblasts, pancytopenia, extramedullary infiltration, and frequent clinical and histologic central nervous system involvement. The leukemias were of pre-B immunophenotype and uniformly transplantable into sublethally irradiated secondary recipients. Importantly, detailed enumeration of lymphoid subsets in Ikzf+/+ and +/− marrow did not demonstrate an expansion of lymphoid progenitors in Ikzf1+/− marrow, suggesting that the observed increased penetrance of B-ALL in Ikzf1+/− animals was not simply due to the expansion of targets of BCR-ABL1 transformation. Thus, Ikaros haploinsufficiency cooperates with BCR-ABL1 to induce an aggressive pre-B leukemia with clinical and pathologic features recapitulating human BCR-ABL1 ALL. These results support genomic analyses of human leukemia suggesting that IKAROS loss is important in the pathogenesis of this disease. Experiments evaluating the interaction of Ikzf1 loss with other targets of genomic alteration in BCR-ABL1 ALL (e.g. CDKN2A/B, PAX5), studies examining the role of Ikzf1 in responsiveness to kinase inhibitors, and genomic profiling studies are ongoing.
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 1961.
Abstract 1973: Targeting activated alleles of EGFR derived from glioma and lung cancer: Correlating kinase active-site occupancy with efficacy
Authors: Nicolaides Theodore P. , Barkovich Krister , Hariono Sujatmi , Garske Adam , Fan Qi Wen , Shokat Kevan , Weiss William A. 
Published: February 2011

Abstract
Introduction: The Epidermal Growth Factor Receptor (EGFR) features prominently in malignant glioma (MG), yet attempts to exploit this target in patients with MG have been somewhat disappointing. Unlike the highly sensitizing kinase site alleles of EGFR derived from patients with non-small cell lung cancer (NSCLCA), mutationally activated alleles of EGFR derived from patients with MG respond poorly to the currently available reversible clinical EGFR inhibitors. We hypothesize that the anti-tumor effects of EGFR inhibitors in MG-associated alleles of EGFR require more efficient blockade to achieve anti-tumor responses, in comparison with NSCLCA-associated alleles of EGFR, and that thisincreased efficiency can be achieved using irreversible inhibitors.
Methods: We generated glioma and fibroblast cell lines that expressed wild-type or tumor-associated alleles of EGFR derived either from MG (EGFRvIII) or NSCLCA (L858R or del 747-753). Using an EGFR affinity probe (an irreversible EGFR inhibitor tethered to a flourophore), we quantified occupancy of the kinase active site in response to erotinib, a clinical reversible inhibitor of EGFR, correlating occupancy with proliferation and apoptosis. Next, we repeated these measurements using the tool compound and irreversible EGFR inhibitor PD-168394.
Results: Using the affinity probe in pulse-chase experiments, we quantified active site occupancy of EGFR int response to increasing doses of inhibitors. In cells expressing MG-derived alleles, irreversible EGFR inhibitors were significantly more potent than reversible agents in abrogating signaling downstream of EGFR and in decreasing viability. Using the affinity probe, we found that irreversible inhibitors showed nearly complete occupancy of the active site, whereas treatment with reversible EGFR inhibitors resulted in only partial occupancy. Cells containing NSCLCA-derived EGFR alleles showed similar signaling and growth responses to both reversible and EGFR inhibitors, despite a large difference in EGFR kinase site occupancy with the two types of inhibitors. Flow cytometry studies correlating kinase site occupancy with downstream signaling in individual cells will also be presented.
Conclusions: Activated alleles of EGFR derived from MG require significantly higher levels of kinase site blockade to achieve an anti-proliferative threshold, as compared with activated alleles derived from NSCLCA. This higher degree of kinase site blockade can be achieved using irreversible inhibitors of EGFR. These studies support the initiation of clinical trials using irreversible inhibitors of EGFR in MG.
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 1973.
Abstract 1978: The poly-SUMO protein specific E3 ubiquitin ligase RNF4 is induced in multiple myeloma and reduces bortezomib-induced cell killing
Authors: Driscoll James J. , Gootenberg Jonathan , Amin Samir , Pelluru Dheeraj , Avet-loiseau Herve , Minville Stephane , Anderson Kenneth C. , Munshi Nikhil C. , Annunziata Christina M. 
Published: February 2011

Abstract
Multiple Myeloma (MM) is a fatal neoplasm of B-cell origin characterized by the clonal proliferation and accumulation of malignant plasma cells in the bone marrow. While recent advances in mechanistic understanding and treatment modalities have extended median survival to &gt;6 years and 10% of patients survive &gt;10 years, the vast majority of MM remains incurable with conventional, high dose therapy or stem cell transplantation. Bortezomib is a selective, reversible inhibitor of the 26S proteasome that inhibits protein degradation and is now FDA-approved for the treatment of newly diagnosed, relapsed and refractory MM. Though the catabolism of ubiquitinated substrates has been targeted therapeutically with significantly improved prognosis, patient response to bortezomib remains highly variable and cannot be predicted accurately. E3 ligases confer specificity on target selection for Ub+proteasome degradation. We therefore analyzed the expression of individual E3's using a microarray dataset obtained from MM patient tumor samples and found a striking variability in the expression level of individual E3 ligases between normal plasma cells and patients MM cells. RNF4, an E3 specific for poly-sumoylated proteins, was induced in MM patients and correlated with decreased patient response to the proteasome inhibitor bortezomib. Expression profiling of pretreatment tumor samples obtained from MM patients in independent clinical trials were used to generate a signature that correlated expression of SUMO+Ub+Proteasome pathway components with clinical outcome to predict patient response to bortezomib. Experimental validation by overexpression of RNF4-wt rendered myeloma cell lines relatively resistant to bortezomib while RNF4 depletion by shRNA enhanced sensitivity to bortezomib. Transfection of HA-tagged SUMO followed by bortezomib exposure led to the accumulation of HA-SUMO∼conjugates that were immunoreactive with Ub and proteasome components to further link the pathways. In summary, RNF4 an E3 ligase specific for SUMO-conjugates and induced in myeloma, modulates the cellular response to proteasome-based therapy and promotes bortezomib resistance. Our results support regulators of the sumoylation pathway as biomarkers to predict clinical response to bortezomib and provide evidence for targeting SUMO pathway to improve therapeutic outcome in myeloma in general and bortezomib specifically.
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 1978.