bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2390: Serotonin signal transduction in human endothelial cells
Authors: Zamani Ali , Roy Anshu , Zhai Ling , Li Rangbao , Qu Zhican 
Published: February 2011

Abstract
Angiogenesis is a highly regulated biological complex process, which consist of endothelial cells proliferation, migration, and tubulogenesis as key cellular steps to form new blood capillaries from preexisting vessels. Imbalance in angiogenesis contributes to a variety of human diseases. Tumor growth depends on angiogenesis and antiangiogenic agents have been developed as effective anti-cancer medicine. Recently, we have demonstrated that serotonin (5-HT), a well-recognized neurotransmitter, has a promoting effect on endothelial cells proliferation, migration and tubulogenesis, suggesting serotonin plays a role in regulation of angiogenesis. To study the role of serotonin in angiogenesis, we examined the expression of serotonin receptor isoforms in human endothelial cells. Real time PCR studies have showed that, serotonin receptor 1B (HTR1B), 1D (HTR1D), 1A (HTR1A) and 2B (HTR2B) are expressed in primary human endothelial cell lines. Blocking serotonin 1B receptor had significant inhibitory effect on endothelial cells proliferation and tubulogenesis. We have further explored the 1B-mediated signal transduction in endothelial cells. The results have revealed that the serotonin 1B receptor as a G protein-coupled receptor (GPCR) is coupled to Gi protein and decreased intracellular cAMP level upon its receptor binding. Both serotonin and 1B receptor agonist were able to activate ERK, p38, Akt, RhoA, Rac1 and PYK2/FAK signaling in endothelial cells. In contrast, a selective antagonist for serotonin 1B receptor blocks the serotonin-stimulated Akt and PYK2/FAK activation. Experiments with pertussis toxin (general Gi blocker) further demonstrated that heterotrimeric Gi-protein is required for the activation of Akt and PYK2/FAK by serotonin. These findings suggest that Akt and PYK2/FAK are involved in signaling transduction in serotonin-activated endothelial 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 2390.
Abstract 2401: IGF-IR peptide vaccine inhibits tumor growth via IFN-g-dependent biologic remodeling of the tumor
Authors: Cecil Denise L. , Park Kyong Hwa , Gad Ekram , Disis Mary L. 
Published: February 2011

Abstract
The insulin-like growth factor (IGF) pathway plays an important role in breast cancer growth and metastasis. The majority of breast tumors overexpress the IGF-I receptor (IGF-IR). Increased IGF-IR signaling in breast cancer is correlated with a poor prognosis and is associated with disease that is resistant to chemotherapy, radiotherapy, and biologic therapy. Thus, therapeutically targeting the IGF-IR signaling pathway is a promising approach to treat breast cancer. We have determined that the IGF-IR is immunogenic in breast cancer. Furthermore, vaccination with MHCII IGF-IR-specific peptides p384-398, p575-589, p951-965, and p1122-1136 induces a CD4+ T cell-dependent anti-tumor immune response in Neu-transgenic mice. Preliminary data suggests that IGF-IR specific immunization results in both decreased proliferation and increased apoptosis of tumor cells. Antigen specific CD4+ T cells secrete IFN-g and we have demonstrated that the inhibition of tumor growth with the IGF-IR vaccine is dependent on IFN-g. We questioned the mechanism whereby IFN-g-secreting CD4+ T cells targeting IGF-IR could inhibit tumor growth. Studies suggest that tumor-associated IGF-IR activation is decreased in tumors from vaccinated mice, with concomitant upregulation in SOCS-3, which has been shown to be modulated by IFN-g. In addition, IFN-g stimulation of the tumor cell line derived from the Neu-transgenic mouse decreased IGF-IR activation and induced SOCS-3 expression. Thus, active immunization targeting IGF-IR may induce both immunologic and biologic effects resulting in inhibition of breast cancer growth.
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 2401.
Abstract 2404: A DNA vaccine encoding the androgen receptor ligand binding domain elicits anti-tumor immune responses in vivo
Authors: Olson Brian M. , Johnson Laura E. , McNeel Douglas G. 
Published: February 2011

Abstract
The androgen receptor (AR) is a nuclear receptor that plays a critical role in both androgen-dependent and -independent prostate cancer, and remains the primary target of therapy for metastatic prostate cancer. We have shown that the AR may be a potential immunological target antigen, identifying some prostate cancer patients that have concurrent antibody and cellular immune responses specific for the AR ligand-binding domain (LBD). We have also identified that some patients have cytotoxic T lymphocytes (CTL) that are specific for ARLBD-derived HLA-A2 epitopes, some of which can lyse prostate tumor cell lines. Moreover, we demonstrated that these epitope-specific CTL could be elicited in HLA-A2 transgenic mice by means of a DNA vaccine encoding the ARLBD (pTVG-AR). In this report, we sought to evaluate whether this DNA vaccine could elicit anti-prostate tumor responses in relevant rodent models in which the ARLBD is expressed as a “self” antigen. First, Copenhagen rats immunized with the pTVG-AR vaccine four to six times at 14-day intervals were challenged with a syngeneic prostate tumor cell line subcutaneously implanted. These animals were found to develop T-cell responses specific for the ARLBD and have a significant delay in tumor growth compared with control vaccinated animals (p=0.018). In a separate autochthonous model, HLA-A2 transgenic mice were crossed with TRAMP mice and the resulting transgenic hybrid (A2/TRAMP) expressed HLA-A2 and developed prostate tumors driven by the SV40 large T antigen under a prostate-specific promoter. A2/TRAMP mice were similarly immunized with pTVG-AR, or control vector, at 14-day intervals and evaluated at 16 weeks of age. Mice immunized with pTVG-AR were found to develop HLA-A2 epitope-specific CD8+ T cell responses, and had fewer well-differentiated adenocarcinomas compared with control immunized mice. Finally, A2/TRAMP mice were immunized repetitively over time and followed for survival. Mice immunized with pTVG-AR (n=8) had a median survival of 218 days, compared with a median survival of 198 days for control (n=7) immunized animals (p=0.040, log-rank test). These combined data show that not only can the ARLBD be safely targeted in vivo (none of the immunized animals had any sign of autoimmunity or overt toxicity), but more significantly that vaccines targeting the ARLBD can elicit an anti-prostate tumor responses in separate animal models. These findings suggest that the ARLBD is a potentially attractive immunological target antigen for the treatment of human prostate cancer.
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 2404.
Abstract 2408: Selective delivery of NY-ESO-1 antigen protein by cholesteryl pullulan (CHP) to CD8α+ dendritic cells in the draining lymph node for cross-presentation
Authors: Harada Naozumi , Muraoka Daisuke , Tajima Kazuo , Shiku Hiroshi 
Published: February 2011

Abstract
Exogenous protein antigens per se poorly stimulate CD8+ T cells when used as immunogens. Hence, this could be a major drawback of cancer vaccines with protein antigens. To overcome the problem, we developed cholesteryl pullulan (CHP) as a delivery system for protein antigens. A series of in vitro and in vivo experiments and clinical studies confirmed that a therapeutic cancer vaccine containing the complex of CHP and protein antigen such as NY-ESO-1 or HER2 efficiently stimulated not only CD4+ T cells but also CD8+ T cells. To understand the mechanism underlying such effect of CHP, we investigated the tissue distribution of NY-ESO-1 protein complexed with CHP (CHP-NY-ESO-1) after its subcutaneous injection into mice by tracing the protein using NY-ESO-1-specific sandwich ELISA or FACS analysis with fluorescently labeled protein. By sandwich ELISA, NY-ESO-1 protein was detected only in the skin at the injection site, and its content was significantly higher with CHP-NY-ESO-1 than with NY-ESO-1 alone, indicating that CHP would make NY-ESO-1 protein antigen more persistent in vivo. In FACS analysis, fluorescence-positive cells which incorporated NY-ESO-1 protein were detected only in the draining lymph node among the lymphoid tissues such as draining/non-draining lymph nodes, spleen and peripheral blood mononuclear cells. Interestingly, the percentage of fluorescence-positive cells in the whole lymphocytes of this tissue was much higher with CHP-NY-ESO-1 (6.4%) than with NY-ESO-1 alone (0.9%). The lymphocytes capably incorporated fluorescence were CD11b+ cells and CD11c+ cells that include professional antigen-presenting cells such as macrophages and dendritic cells, respectively. In the mice received CHP-NY-ESO-1, the percentages of fluorescence-positive CD11b+ cells and CD11c+ cells were 53% and 66% at the highest, respectively, while these values in the mice with NY-ESO-1 alone were around 10%. Among the CD11c+ cells, as well as other dendritic cell subsets, the fluorescence was detected in the CD8α+ cells which are known to be capable to efficiently cross-present protein antigens. These results suggest that CHP would be an “immunotransporter” which efficiently delivers protein antigens to the antigen-presenting cells in draining lymph nodes. Hence, CHP may facilitate the presentation of protein antigens to both CD8+ T cells and CD4+ 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 2408.
Abstract 2414: Comparable effect of p53 peptide vaccine in adjuvant or pulsed on dendritic cells in ovarian cancer patients: A gynecologic oncology group study
Authors: Rahma Osama , Achtar Ed , Czystowska Malgorzata , Szajnik Marta E. , Wieckowski Eva , Bernstein Sarah , Herrin Vincent E. , Steinberg Seth M. , Merino Maria , Gooding William , Visus Carmen , DeLeo Albert B. , Berzofsky Jay A. , Whiteside Theresa L. , Wolf Judith K. , Bell Jeffrey G. , Khleif Samir N. 
Published: February 2011

Abstract
Purpose: Peptide antigens have been administered by different approaches in cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by the wild-type (wt) p53 vaccine using two approaches.
Experimental Design: Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received subcutaneous wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells intravenously. Interleukin-2 (IL-2) was administered in both cohorts in alternative cycles. The immunologic response was assessed by ELISPOT and tetramer assays.
Results: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B had an immunologic response. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively.
Conclusion: We demonstrated that using either vaccination approach could generate comparable specific immune responses against the wt p53 peptide with minimal toxicity. Accordingly, our findings support the utilization of the less demanding subcutaneous method. Furthermore, as IL-2 may add toxicity and induce T regulatory cells, which can suppress the immune response, therefore, it may not be needed in future trials.
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 2414.
Abstract 2424: Synergistic induction of apoptosis in human solid cancer cells by Lexatumumab and cisplatin in a caspase-dependent manner
Authors: Xiuxian Wu , Inui Masashi , Sugimoto Mikio , Kakehi Yoshiyuki 
Published: February 2011

Abstract
Introduction and Objectives: Mapatumumab and Lexatumumab are human agonistic antibodies against TNF-related apoptosis-inducing ligand (TRAIL)-receptor 1 (TRAIL-R1) and TRAIL-R2, respectively, which induce apoptosis specifically in cancer cells. Here, we investigated whether chemotherapeutic agents enhance Mapatumumab- or Lexatumumab-mediated apoptosis against various solid cancer cells.
Methods: Cytotoxicity and synergy was assessed by MTT and isobolograpic analyses, respectively. TRAIL-R2 expression was detected by real-time RT-PCR, flow cytometry, and Western blotting. Apoptosis was assessed by DNA Ladder and caspase assays.
Results: Treatment of ACHN human renal cell carcinoma (RCC) cells with cisplatin combined with Mapatumumab did not overcome resistance to these agents. However, treatment with cisplatin in combination with Lexatumumab had a synergistic cytotoxicity. Synergy was also achieved in six primary RCC cell cultures. Lexatumumab and cisplatin also synergistically enhanced apoptosis. Pretreatment with cisplatin followed by Lexatumumab resulted in high cytotoxicity compare with the reverse sequence. Cisplatin significantly increased TRAIL-R2 expression at both mRNA and protein levels. Furthermore, the combination of Lexatumumab and cisplatin significantly enhanced caspase-8 activity, Bid cleavage, up-regulation of Bax, cytochrome c release, and caspase-9, caspase-6, and caspase-3 activities. Importantly, the activation of capase-8 was significantly abrogated by the specific inhibitors of caspase-9, caspase-6, and caspase-3. Furthermore, combination-induced cytotoxicity was significantly suppressed by DR5: Fc chimeric protein and the specific inhibitors of caspase-8, caspase-9, caspase-6, and caspase-3. Similar effect was observed in prostate cancer, bladder cancer, lung cancer, and cervical cancer cells.
Conclusions: Cisplatin sensitizes solid cancer cells to Lexatumumab-induced apoptosis by potentiation of the extrinsic and intrinsic apoptotic pathways that lead to enhancement of caspase activation, particularly caspase-8. These results suggest that combination of cisplatin plus Lexatumumab is promising against solid cancers.
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 2424.
Abstract 243: Characterization of CDK5RAP3 in hepatocellular carcinoma
Authors: Mak Grace W.Y. , Ng Irene O.L. , Ching Y.p. 
Published: February 2011

Abstract
CDK5 regulatory subunit associated protein 3 (CDK5RAP3, also called C53 and LZAP) is a novel cyclin-dependent kinase 5 (CDK5) activator interacting protein that has been shown to regulate apoptosis induced by genotoxic stress. More recently, CDK5RAP3 has also been found to regulate p53 and NF-κB signaling. Here, we have characterized the role of CDK5RAP3 in hepatocellular carcinoma (HCC) cell lines. Using real-time quantitative RT-PCR, we found that 58% (39/67) of human HCC samples had significantly higher expression (at least 2-fold) of CDK5RAP3 transcripts as compared to their corresponding nontumorous livers. The overexpression of CDK5RAP3 was statistically correlated with clinicopathological feature of more metastatic phenotype. Using stable expression clones, we demonstrated that knockdown of CDK5RAP3 in HCC cell line inhibited anchorage-independent growth and tumorigenicity of cells while overexpression of CDK5RAP3 remarkably promoted tumorigenicity of cells. Our western blotting data indicated that knockdown of CDK5RAP3 in HCC cell line SMMC-7721 resulted in an upregulation of p14ARF. Using luciferase reporter assay, we showed that ectopic expression of CDK5RAP3 suppressed p14ARF promoter activity in a dose-dependent manner. Taken together, our data provide the first evidence that CDK5RAP3 is overexpressed in HCC and overexpression of CDK5RAP3 may contribute to the development of HCC via downregulation of p14ARF. In summary, CDK5RAP3 is a potential oncoprotein in promoting hepatocarcinogenesis, the regulation behind may attribute to its regulation on p14ARF expression.
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 243.
Abstract 2430: Gastric cancer cell lines with c-Met gene amplification are sensitive to growth inhibition by the bivalent c-Met antibody LA480
Authors: Tetreault Jonathan , Xia Jinqi , Zeng Wei , Wortinger Mark , Cunningham Jason , Feroze Farhana Mohammed , Yu Kun , Chow Chi-Kin , Lu Jirong , Denning Irene , Vaillancourt Peter , Davies Julian , Liu Ling 
Published: February 2011

Abstract
Gastric cancer is common in Asia, and advanced disease is typically incurable. Development of effective treatments for gastric cancer is thus a high priority to address this highly unmet clinical need. c-Met gene amplification resulting in c-Met overexpression and pathway activation has been highly linked to tumor progression and metastasis. It has been reported that approximately 10-20% of gastric tumors have increased copy numbers of the MET gene. c-Met- amplified gastric cancer cell lines that are dependent on an activated c-Met pathway for cell growth have been reported to be highly sensitive to growth inhibition by small molecule inhibitors of c-Met. We report that LA480, a humanized monoclonal antibody specific for c-Met, can directly inhibit HGF-independent in vitro cell proliferation of three c-Met- amplified Asian gastric cell lines (MKN45, SNU-5, and NUGC-4), in a dose-dependent manner. After 48 hours of treatment with LA480, 60-70% percent inhibition of 3H-thymidine incorporation was observed. For one of these gastric lines (NUGC-4), sensitivity to LA480 increases with continuous passage of the culture. This increased sensitivity to LA480 over time appears to be associated with increased expression of cell surface c-Met and increased constitutive phospho-Met expression. In addition to inhibiting proliferation of c-Met- amplified Asian gastric lines, LA480 also directly inhibited proliferation of a c-Met- amplified gastric cell line (Hs 746T) from a Caucasian patient. These data suggest that targeting c-Met amplification with LA480 may be a promising treatment for gastric cancer.
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 2430.
Abstract 2434: Novel primate-crossreactive BiTE antibodies that eliminate cancer cells expressing cMet, IGFR-1, FAP-alpha, PSCA, Endosialin, CAIX or Her2/neu
Authors: Raum Tobias J. , Rau Doris , Kischel Roman , Bluemel Claudia , Hausmann Susanne , Steiger Carola , Meier Petra , Ebert Evelyn , Mangold Susanne , Hoffmann Patrick , Strasser Susanne , Cierpka Ronny , Kvesic Majk , Baeuerle Patrick A. , Kufer Peter 
Published: February 2011

Abstract
BiTE antibodies are designed to transiently connect target cells with T cells of patients for induction of potent redirected lysis of cancer cells. Clinical proof-of-concept has been obtained with CD19/CD3-bispecific BiTE antibody blinatumomab (MT103), which showed a high response rate in patients with relapsed/refractory non-Hodgkin's lymphoma and acute B-lymphocytic leukemia. An EpCAM/CD3-bispecific BiTE antibody called MT110 currently is in a dose-escalating phase 1 study in patients with lung or gastrointestinal cancers, and BiTE antibodies targeting carcinoembryonal antigen (CEA), EGFR, CD33 or melanoma chondroitin sulfate proteoglycan (MCSP) are in earlier stages of development. Here, we have generated a series of novel BiTE antibodies for cancer therapy that are based on our novel BiTE antibody platform, which is human in sequence and cross-reactive between human and non-human primate antigens.
One set of target antigens selected for new BiTE generation is also targeted by conventional monoclonal antibodies that are in various stages of clinical development. These are mesenchymal-epithelial transition factor (cMet), insulin-like growth factor receptor type I (IGFR-1), prostate-specific stem cell antigen (PSCA), carboanhydrase type IX (CAIX) and Her2/neu. These targets are all expressed by cancer cells of solid tumors, and some also by their so-called cancer stem cells. By targeting fibroblast activating protein alpha (FAP-alpha), a first BiTE antibody was generated that not only targets sarcoma cells but also stromal fibroblasts, which constitute the stromal tissue of many human cancers. By targeting endosialin (CD248), a first BiTE antibody was generated targeting cancer blood vasculature.
We show that various single-chain antibodies specific for the seven target antigens cMet, IGFR-1, FAP-alpha, PSCA, CAIX, Her2/neu and endosialin could in each case be used to construct novel BiTE antibodies. All BiTE antibodies showed bispecific binding, cross-reactivity between human and Cynomolgus monkey antigens, and, most importantly, potent redirected lysis of CHO cells expressing the respective target antigen. This shows that new T cell-engaging BiTE antibodies can be made specific for a great variety of potential tumor-associated and also for stromal antigens.
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 2434.