bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 745: HOXB7 renders breast cancer resistant to tamoxifen through activation of the HER2 pathway
Authors: Jin Kideok , Zhu Tao , Lundberg Goran , Sukumar Saraswati 
Published: June 2012

Abstract
Multiple factors, including long term treatment with tamoxifen, are involved in the development of selective estrogen receptor modulator (SERM) resistance of ERα positive breast cancer. It is well known in the endocrinology field that increased levels of ErbB/HER family members can also directly alter the cellular response to tamoxifen, but the mechanisms underlying increased expression of ErbB/HERs are not clear. In this studyreport we identifiedfound a number of HOXB7- specific binding sites throughout the genome in responsewith reaction to estrogen, through HOXB7 Chip on chip assay. We show that HOXB7 interacts with ERα and together they it bind to theharbors regulatory elements of ERα- regulated genes to enhance their transcription activity. Enforced expression of HOXB7 increases expression of ERα- regulated genes while knockdown of HOXB7 with siRNA reduces their expression. In addition, our work demonstrates that in order to mediate upregulation of HER2 in tamoxifen resistance, the HOXB7-ERα complex recruits ERα coactivators and promotes HER2 transcription activity through direct binding to the HER2 enhancer region. However, depletion of HOXB7 negatively affects the binding affinity of its cofactors to the HER2 enhancer element. Higher expression levels of HOXB7 significantly correlates with poorer disease free survival in ERα- positive breast cancer patients on adjuvant tamoxifen monotherapy. These findings implicate overexpression of HOXB7 as a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules, ERα and HER2, in the oncogene hieeirarchy. Therefore, fFunctional antagonism of HOXB7 has the potential tocould circumvent tamoxifen resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2011-745
Abstract 747: Tumor vaccine adjuvant effect of TLR7 agonist Imiquimod is limited by inducing immusuppressive cells
Authors: Dang Yushe , Wagner Wolfgang M. , Gad Ekram , Disis Mary L. 
Published: June 2012

Abstract
Toll-like receptor (TLR) agonists are immune stimulators and have been studied as potential vaccine adjuvants with great interest. We evaluated the adjuvant effects of the TLR7 agonist imiquimod as compared to GM-CSF, which is widely used as a vaccine adjuvant in clinical trials. We found that both topical imiquimod and intradermal GM-CSF effectively induced the accumulation and activation of dentritic cells in draining lymph nodes and equally enhanced OVA specific CD4+ and CD8+ T cell responses in an OVA-tg mouse model. We further evaluated the efficacy of tumor prevention of imiquimod and GM-CSF in a neu-transgenic (neu-tg) mouse model of human breast cancer which over-expresses both neu and IGFBP2 tumor associated antigens. The neu-tg mice were immunized with a vaccine composed of three immunogenic IGFBP2 peptides prior to being inoculated with syngeneic MMC tumor cells. The tumor growth was significantly inhibited in the groups which received GM-CSF as an adjuvant, but not in imiquimod-treated groups. We questioned whether imiquimod induces immune suppression in response to tumor associated antigens and assessed the frequencies of myeloid-derived suppressive cells (MDSC) and T regulatory cells (Treg) in the splenocytes after three immunizations. We found that both CD11c+GR1+ MDSC and CD4+FOXP3+Treg cells were significantly increased in imiquimod-treated mice, but did not increase in GM-CSF-treated group. Serum levels of IL-10 were also significantly increased in imiquimod-treated, but not in GM-CSF-treated group. IFN-gamma secretion in response to IGFBP2 antigen, on the contrary, was remarkably enhanced in the GM-CSF-treated mice, but not in the imiquimod-treated mice as tested by an IFN-gamma ELISPOT assay. Thus, the TLR7 agonist imiquimod, as a vaccine adjuvant did not achieve a protective effect on breast cancer growth. The limited anti-tumor effect observed is associated with elevated levels of immunosuppressive MDSC and Treg cells. These results may have significant implications in the future development of imiquimod as a vaccine adjuvant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 747. doi:10.1158/1538-7445.AM2011-747
Abstract 748: TLR3 agonist Ampligen® as an adjuvant inhibits the growth of breast cancer
Authors: Dang Yushe , Gad Ekram , Lai Vy , Rastetter Lauren , Salazar Lupe L. , Nicodemus Christopher F. , Disis Mary L. 
Published: June 2012

Abstract
A potent adjuvant is the key for a successful vaccine against tumor antigens. We evaluated the adjuvant effect of a TLR3 agonist, Ampligen® on the growth of breast cancer in a transgenic mouse model. Ampligen® [rintatolimod; poly(I)·poly(C12,U)] is a synthetic mismatched double strand RNA that specifically stimulates TLR3 (Hemispherx Biopharma, Philadelphia, PA). A neu-tg mice [strain name, FVB/N-TgN (MMTVneu) 202Mul] over-expressing both neu and IGFBP-2 tumor associated antigens (Park KH et al CR 2008) were used for this study. Three IGFBP2 peptides were used as immunogen. The mice were vaccinated with the peptides and Ampligen® three times, 2 weeks apart, with PBS, peptides alone, and Ampligen® alone as controls. Syngeneic MMC tumor cells were injected into the mice two weeks after the last vaccine, and the growth of tumors was monitored afterwards. Three other immune modulators (GM-CSF, TLR7 agonist Imiquimod and TLR9 agonist CpG ODN 2395) were also used to evaluate the efficacy of Ampligen® and combination adjuvant approaches. Our results indicate that peptides alone did not mediate an anti-tumor effect. Although Ampligen® alone at high concentration (100ug) had a weak anti-tumor effect as compared to the control with 23% tumor inhibition, vaccination with IGFBP2 antigen and Ampligen® remarkably inhibited tumor growth by 60%. A dose response of Ampligen® was observed with 20ug as the optimal dose. The analysis of the levels of multiplex cytokines (IL-12p70, IL-1a, IL-1b, IL-2, IL-5, IL-10, IL-17, IFNg and TNFa) in serum two days after last vaccine showed that the level of IL-12p70 was increased in peptides/Ampligen® treated mice as compared to control (5.9±0.9 vs. 3.1±0.8 pg/ml;n=5; p=0.041) or other adjuvants. The serum levels of other cytokines were not statistically different. We compared the adjuvant effect of Ampligen® with GM-CSF, Imiquimod and ODN 2395. Besides Imiquimod, all these adjuvants significantly inhibited tumor growth as compared with peptides alone (p&lt;0.002). Ampligen® was more effective than ODN2394 (p=0.02). The combination of Ampligen® with these other immunostimulators didn't further enhance the antitumor effect. In conclusion, Ampligen® as an adjuvant inhibited the growth of breast cancer with an increased level of Th1 cytokines and is a potent tumor vaccine adjuvant with the potential for clinical use.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 748. doi:10.1158/1538-7445.AM2011-748
Abstract 749: Cancer stem cell vaccination confers significant anti-tumor immunity by selectively targeting cancer stem cells
Authors: Ning Ning , Teitz-Tennenbaum Seagal , Yet Ji , Li Mu , Moyer Jeffrey S. , Ginestier Christophe , Wicha Max S. , Xu Yingxin , Prince Mark EP , Chang Alfred E. , Li Qiao 
Published: June 2012

Abstract
To date, the majority of cancer stem cell (CSC) studies have been confined to human tumors inoculated into severely immunosuppressed hosts (e.g. SCID mice), where adaptive immune responses are absent, and such hosts are therefore not suitable for immunologic evaluation. The lack of immunocompetent syngeneic animal tumor models where stem cells can be isolated has been the primary obstacle to evaluating the immunogenicity of CSCs. In this study, we identified CSC-enriched populations in two histologically distinct murine tumors (melanoma B16-D5 and squamous cell cancer SCC7). We found that a very small percentage (0.5-5%) of ALDEFLUOR/ALDH1+ cells exist in these tumors; as few as 500 sorted ALDEFLUOR+ cells could form tumors in syngeneic hosts. The stem cell nature of the ALDELFUOR+ cells was confirmed by their ability to form spheres in culture and to self-renew in vivo. We evaluated the protective anti-tumor responses induced by D5 cancer stem cell-based vaccination with dendritic cell in the syngeneic immunocompetent host (B6 mice) in a pulmonary metastatic setting. We found that enriched D5 CSCs are immunogenic and are significantly more effective as an antigen source compared with unselected D5 tumor cells in inducing protective anti-tumor immunity. CSC-induced protective antitumor immunity was confirmed in a second tumor model (SCC7) syngeneic to a genetically different immunocompetent host (C3H) in a subcutaneous tumor setting. Immune sera collected from D5 or SCC7 CSC-vaccinated hosts contain high levels of IgG and IgG2b which bound specifically to D5 CSCs or SCC7 CSCs, respectively. This binding resulted in the CSC lysis in the presence of complement. In addition, CTLs generated from PBMCs harvested from D5 or SCC7 CSC-vaccinated hosts selectively killed D5 or SCC7 CSCs efficiently. We provide the first direct experimental evidence that selective targeting of cancer stem cells by CSC-primed antibodies and T cells may represent the mechanisms involved in CSC vaccine-conferred anti-tumor immunity. The findings from these studies may help develop novel cancer stem cell-targeted immunological approaches for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2011-749
Abstract 760: Gene expression profiling in cancer vaccine: A new tool for cancer vaccine development
Authors: Matsueda Satoko , Sasada Tetsuro , Komatsu Nobukazu , Ioji Tetsuya , Shichijo Shigeki , Noguchi Masanori , Tashiro Kosuke , Kuhara Satoru , Itoh Kyogo 
Published: June 2012

Abstract
(Introduction) Recently, cancer vaccines have emerged as one of the promising therapeutic options. However, it is still difficult to predict clinical responses in vaccinated patients prior to vaccination. For further development of this field, it would be of critical importance to identify biomarkers for selecting patients adequate for cancer vaccination. To identify reliable biomarkers, we characterized gene expression profiles by the DNA microarray technology (Illumina) in PBMC from prostate cancer patients that showed better or worse responses to the personalized peptide vaccination (survival time &gt; 900 or &lt; 300 days, respectively; n = 20 each).
(Method) Total RNA was prepared from frozen-PBMCs prior to vaccination and hybridized. Detailed statistical analysis was performed to select genes that help predict patient clinical responses. In addition, to validate the result, 10 additional PBMC samples were analyzed in discriminant analysis.
(Result) A combination of genes was selected as a predictive biomarker. In discriminant analysis, the identified genes clearly discriminated long-term survivors from short-term survivors to the peptide vaccination.
(Conclusion) The identified gene set in PBMC may be useful as a biomarker in selecting patients adequate for personalized peptide vaccines. The detailed characterization of individual genes identified is currently underway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 760. doi:10.1158/1538-7445.AM2011-760
Abstract 781: Plasticity of human tumor-infiltrating Th17 cells
Authors: Ye Jian , Su Xinming , Hsueh Eddy C. , Zhang Yanping , Koenig Joyce M. , Hoft Daniel F. , Peng Guangyong 
Published: June 2012

Abstract
Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their function in human tumor immunity remains largely unknown. We have recently identified Th17 cells as an important component of human tumor-infiltrating lymphocytes (TILs) obtained from melanoma, breast, colon and ovarian cancer patients, but their stability and plasticity in the tumor microenvironment is still unclear. In this study, we generated Th17 clones from TILs. We showed that Th17 clones can differentiate into IFN-gamma-producing and FoxP3+ cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells (PBMCs). We further demonstrated that T cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-gamma and FoxP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Treg cells. We further demonstrated that the Th17-derived Treg cells, unlike naturally occurring CD4+CD25+ Treg cells, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human Th17 cells can differentiate into Treg cells and indicate the substantial developmental plasticity of Th17 cells, which may have clinical implications for the development of novel cancer immunotherapeutic approaches.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2011-781
Abstract 786: CEACAM1 regulates myeloid-cell-dependent tumor angiogenesis by inhibition of G-CSFR-Bv8 pathway
Authors: Lu Rongze , Shively John 
Published: June 2012

Abstract
Gr1+CD11b+ myeloid cells promote tumor angiogenesis and are refractory to VEGF antibodies treatment. Bv8, also known as Prokineticin 2, expressed in Gr1+CD11b+ cells and positively regulated by granulocyte colony-stimulating factor (G-CSF), has recently been shown to modulate Gr1+CD11b+ cells mobilization and tumor angiogenesis. Anti-Bv8 treatment reduced angiogenesis and growth. However, the signaling pathways in Gr1+CD11b+ to promote tumor angiogenesis are not fully understood. Carcinoembryonic antigen-related cell adhesion moclecule-1(CEACAM1) is highly expressed on Gr1+ myeloid cells, however the role of CEACAM1 in myeloid cells mediated tumor angiogenesis has not been investigated.
We have demonstrated that tumor growth and angiogenesis was significantly enhanced in Ceacam1−/− mice, which was independent on T and B cells by backcrossing Ceacam1−/− mice with Rag1−/− mice. Meanwhile Gr1+CD11b+ cells infiltration in tumor, spleen and blood was increased. Tumors coinjected with Gr1+CD11b+ cells from Ceacam1−/− mice exhibited increased angiogenesis compared to coinjection with Gr1+CD11b+ cells from control mice. Depletion of Gr1+ cells inhibited tumor growth and angiogenesis in control and Ceacam1−/− mice.
Gr1+CD11b+ cells from Ceacam1−/− mice expressed much higher Bv8 in vitro and in vivo. Further we have shown that CEACAM1 recruited Src-homology-phosphatase-1 (SHP-1) to attenuate granulocyte colony-stimulating factor receptor (G-CSFR)-Bv8 pathway in myeloid cells. Reconsititution of CEACAM1 into Ceacam1−/− bone marrow cells restored tumor growth and angiogenesis to normal level, and mutations of immunoreceptor tyrosine-based inhibitory motifs ITIMs abolished this restoration. Therefore, we identified CEACAM1, as an inhibitory regulator of G-CSFR-Bv8 pathway, negatively regulates myeloid cells dependent tumor angiogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 786. doi:10.1158/1538-7445.AM2011-786
Abstract 789: Cytokine interleukin-16 is an important growth-promoting factor for multiple myeloma
Authors: Atanackovic Djordje , Hildebrandt York , Reinhard Henrike , Templin Julia , Bokemeyer Carsten , Kröger Nicolaus 
Published: June 2012

Abstract
BACKGROUND: Multiple myeloma is a malignancy characterized by the expansion of a plasma cell clone that localizes to the human bone marrow. Myeloma cells and bone marrow stroma cells both produce soluble factors promoting the survival and progression of multiple myeloma. Interleukin-(IL)-16 is involved in regulating migration and proliferation of normal leukocytes, however, it has been unclear whether IL-16 also plays a role in the pathophysiology of human cancers.
METHODS: Using an antibody array we screened BM plasma of MM patients for the presence of a large number of cytokines/chemokines. We confirmed cytokine expression by myeloma cell lines and malignant plasma cells from MM patients applying real-time PCR, western blots, ELISA, and flow cytometry. We used transfection with inhibitory RNA to analyze cytokine function and we applied anti-cytokine antibodies to evaluate possible therapeutic options for MM.
RESULTS: We found IL-16 to be strongly overexpressed in the bone marrow of myeloma patients. Myeloma cell lines as well as primary tumor cells from myeloma patients constitutively expressed IL-16 and its receptors CD4 and/or CD9 and spontaneously secreted soluble IL-16. Silencing of IL-16 had an anti-proliferative effect on the tumor cells which was reversed by the addition of a recombinant C-terminal IL-16 peptide. Most importantly, the application of a monoclonal antibody directed against IL-16 had a strong growth-inhibiting influence on myeloma cells.
CONCLUSIONS: These findings suggest that cytokine IL-16 is an important growth-promoting factor in MM and might represent an important diagnostic and therapeutic target for this incurable human malignancy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 789. doi:10.1158/1538-7445.AM2011-789
Abstract 792: Tumor-induced thymic atrophy: Alteration in interferons and Jak/Stats signaling pathways
Authors: Lopez Diana M. , Carrio-Jardines Roberto , Torroella-Kouri Marta , Iragavarapu-Charyulu Vijaya 
Published: June 2012

Abstract
The thymus is the major site of T cell differentiation and a key organ of the immune system. Most important, it provides a specialized environment for the selection of rearranged clones that will function appropriately in the adaptive immune response. Thymic involution has been observed in several model systems; including graft-vs-host disease, aging, and tumor development, however, the mechanisms involved in this phenomenon remain to be elucidated. Previous results from our laboratory have reported that the severe thymic atrophy and impaired T cell development seen in mammary tumor bearers are associated with an arrest in at least two steps of T cell differentiation, changes in the levels of crucial cytokines expressed in the thymus microenvironment, and a progressive increase in apoptosis during the tumor development mainly due to downregulation of important molecules that control programmed cell death. Cytokines regulate numerous aspects of hematopoiesis via activation of the Jak/Stat pathways. In the present study we have used our mammary tumor model to investigate whether changes in the levels of cytokines in the thymus could affect the normal expression of the aforementioned pathways. RNA and protein analysis revealed an overexpression of the different interferons, a downregulation of most of the Jak/Stat pathways, and an increased expression of several suppressors of cytokine signaling (SOCS) in the thymuses of tumor bearers. Collectively, our data suggest a mechanism by which the impaired Jak/Stat signaling pathways observed in the whole thymus of tumor-bearing mice could be contributing to the abnormal T cell development and apoptosis observed during the tumor-induced thymic atrophy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 792. doi:10.1158/1538-7445.AM2011-792
Abstract 798: Measuring TK1 autoantibodies in the serum of cancer and non-cancer patients
Authors: LaPorte Wesley , Abegg-Lawrence Taylor , Alegre Melissa M. , Robison Richard A. , O'Neill Kim L. 
Published: June 2012

Abstract
One of the foremost problems in cancer is lack of a convenient, early detection method. Often malignancies are discovered too late, at stages that are so evolved that treatment becomes painful, expensive, or ineffective. Thymidine Kinase 1 (TK1) is an important nucleotide salvage pathway enzyme involved in DNA synthesis and repair. It has been shown that TK1 levels increase under normal cellular conditions typically during cell proliferation. However under malignant conditions, TK1 is over-expressed both in the cytosol of cancer cells and the serum of cancer patients. Consequently, serum TK1 levels (sTK1) are often used in cancer diagnosis and prognosis. We hypothesized that there may be autoantibodies against sTK1 in cancer patients because TK1 is generally intercellular and usually sequestered from the immune system. In order to investigate this hypothesis, we developed an ELISA in a 96 well plate format specifically to detect and measure the presence of autoantibodies against sTK1. Using purified TK1 as a capture antigen, we added serum from both pre-treatment cancer patients and age matched normal patients to detect any autoantibodies that interact with sTK1. Using two different types of primary, HRP conjugated antibodies, (Goat Anti-Human-HL & Goat Anti-Human-Fc) we were able to determine that there are antibodies to TK1 in the serum of both cancer and non-cancer patients. We eliminated the possibility that we were only detecting fragments of autoantibodies that were not true autoantibodies since our GAH-Fc antibody is specific to only intact antibodies. Furthermore, when we added TCEP (A common reducing agent which we used to remove the antibodies from the serum) to the serum, we saw a measurable signal reduction. Preliminary data suggest there are autoantibodies to TK1 in both cancer serum and normal serum. Further research is underway to elucidate the mechanisms responsible.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 798. doi:10.1158/1538-7445.AM2011-798