bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2447: Transient lymphocyte decrease due to adhesion & migration following treatment with catumaxomab (anti-EpCAM x anti-CD3) in vivo
Authors: Eberhardt Andrea , Dettmar Kirsten , Atz Judith , Lindemann Carsten , Schroeder Petra , Kluge Michael 
Published: February 2011

Abstract
Catumaxomab is a trifunctional, bispecific antibody targeting EpCAM and CD3 which redirects T-cells to EpCAM expressing tumor cells and is able to evoke T-cell cytotoxic responses. The hybrid Fc region of catumaxomab provides a third functional binding site, which is able to bind and activate Fcγ receptor (FcγR)-positive accessory cells.
In clinical trials a transient decrease in peripheral blood lymphocyte counts was observed following i.p. administration of catumaxomab. Lymphocyte decrease may be a result of either decreased production or increased destruction of lymphocytes, redistribution of lymphocytes or various unknown / multifactorial pathogeneses.
We determined whether the observed transient decrease in patients might be due to antibody induced adhesion of lymphocytes to endothelial cells or to migration of lymphocytes into the tissue. Therefore, we investigated the influence of catumaxomab on adhesion of human T cells to endothelial cells in vitro. Catumaxomab physiologically activated T-cells by increasing expression of the activation marker CD69 and induced the release of cytokines, including TNFα and IFNγ. TNFα increased expression of adhesion molecules CD54 and CD62E on endothelial cells.
Furthermore, catumaxomab dose-dependently increased adhesion of T cells to endothelial cells, and the adhesion was further increased when the endothelial cells were preactivated with TNFα. Thus, catumaxomab increases adhesion of T-cells to endothelial cells, which is due to antibody mediated upregulation of adhesion molecules on T-cells and production of cytokines that upregulate endothelial cell adhesion molecules.
Furthermore, we showed that treatment of BALB/c mice with the related trifunctional antibody BiLu (anti-human EpCAM x anti-mouse CD3), that binds to mouse CD3, also resulted in a dose-dependent transient decrease in CD3+ T-cells (both CD4+ and CD8+) that returned to the normal range within 48 h.
These results provide a rationale for the transient and reversible decrease in peripheral lymphocyte counts observed following catumaxomab administration in clinical studies, which is likely to be due to redistribution of lymphocytes and not due to depletion of circulating lymphocytes or stem 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 2447.
Abstract 2453: P16, a novel monoclonal antibody specifically recognizing human placental growth factor (PLGF), blocks PLGF-VEGFR1 interaction in vitro and inhibits angiogenesis and tumor growth in vivo
Authors: Xu Yiqing , Hu Hong-Qun , Luo Shi-Ping , Sun Ya-Nan , Zhou Qing , Chen Zui , Song Xiao-Qi , Zhou Qunmin 
Published: February 2011

Abstract
Placental growth factor play (PLGF) is a homolog of vascular endothelial growth factor (VEGF) and binds to VEGF receptor-1. Previous studies have indicated its synergistic role with VEGF in angiogenesis, while a recent study suggested its independent role in promoting growth and metastasis of VEGF-inhibitor-resistant tumors. In order to further investigate the role of PLGF in tumor angiogenesis in relationship to VEGF, we have generated a novel PLGF-specific monoclonal antibody (mAb). Hybridomas secreting PLGF-specific mAbs were obtained by fusing splenocytes from mice immunized with yeast-derived recombinant human PLGF protein with Sp/20 myeloma cells; the mAb clone that showed highest binding affinity, designed as P16, was selected for further study. This P16 mAb recognizes human PLGF, in both native and denatured forms, but not VEGF-A, VEGF-B or VEGF-D. P16 mAb is of IgG1-kappa type. Sequence analysis of cDNA encoding the heavy and light chains of P16 mAb showed novel variable regions. Using P16 mAb in immunohistochemical staining assay, increased levels of PLGF protein were found in a number of human tumors from lung, breast and colon. PLGF proteins were also detected in a wide variety of normal human tissues including lung, stomach, colon and kidney, contrary to previous reports. Importantly, P16 mAb blocked the binding of PLGF to VEGFR-1 in a dose-response manner, and inhibited the PLGF-mediated endothelial cell line growth in vitro. Treatment of human tumor xenografts (A673 rhabdomyosarcoma) in nude mice with P16 mAb resulted in marked inhibition of tumor growth, which is similar in degree to the tumor inhibition by VEGF-specific antibody Bevacizumab. A humanized form of P16 mAb was constructed and showed similar inhibition of tumor growth in xenograft nude mice model. In conclusion, P16 mAb is a novel mAb specifically recognizing human PLGF but not VEGF and blocks the binding of PLGF to its receptor. It inhibits angiogenesis and tumor growth, suggesting an important and independent role of PLGF in tumor growth. Further studies on its mechanisms of action and its clinical applications are under way.
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 2453.
Abstract 2457: The MUC1 membrane-bound mucin is an actor in renal clear-cell carcinoma
Authors: Bouillez Audrey , Gnemmi Viviane , Hémon Brigitte , Seuningen Isabelle Van , Zini Laurent , Leroy Xavier , Aubert Sébastien , Perrais Michael 
Published: February 2011

Abstract
MUC1, an O-glycoprotein membrane-bound mucin, is overexpressed in renal clear-cell carcinomas (CRCC) with correlation to two major prognostic factors, Tumor-Node-Metastasis stage and nuclear Fürhman grade. Previously (Aubert et al., Cancer Res 2009), we have shown that (i) MUC1 was significantly overexpressed in metastatic CRCC vs non-metastatic CRCC and (ii) MUC1 is a target gene of HIF-1 transcription factor which is a part of the hypoxia pathway, the main renal carcinogenetic pathway. To better understand the roles of MUC1 in CRCC, we used two renal cell lines expressing MUC1 (Caki-2 cells) or not (ACHN cells). Caki-2 cells were stably transfected with shRNA targeting MUC1 and ACHN cells with an expressing vector containing MUC1 cDNA. Proliferation, migration and invasion properties were studied in vitro in the different cellular clones using Boyden chambers coated with Matrigel, wound healing assay and MTS cell proliferation assay, respectively. Our results showed that (i) MUC1 expression was associated with an increase of invasion and migration properties of renal carcinoma cells whereas no effect on proliferation and apoptotic rate was observed and (ii) levels of phospho-JNK were higher in MUC1 expressing cells. Results of (i) transcriptomic analysis on 44K Agilent microarrays, (ii) signaling pathway screening and (iii) subcutaneous xenografts will be presented. Our results show that MUC1 plays a role in biological properties of renal cancer cells suggesting important function for this mucin in tumour progression and confirms its potential as a therapeutic target in this type of cancer.
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 2457.
Abstract 2462: Overexpression of prostaglandin E2 EP4 receptor enhances mouse skin tumorigenesis
Authors: Simper Melissa S. , Bowen Rebecca A. , Surh Inok , Fischer Susan M. 
Published: February 2011

Abstract
Chronic inflammation has recently been suggested to be involved in cancer development, and cyclooxygenase-2 (COX-2), a key mediator of the inflammatory response, is known to be upregulated in several cancers. COX-2 is responsible for the production of prostaglandins, and prostaglandin E2 (PGE2) is the major prostaglandin involved in inflammation. PGE2 binds to four receptors (EP1-EP4), and the EP4 receptor has recently been shown to be important in carcinogenesis depending on the tissue in which it is expressed. To determine the role of EP4 in skin carcinogenesis, transgenic mice were generated that overexpress EP4 in the basal layer of the skin under the control of the bovine keratin 5 promoter (BK5.EP4). Using a two-stage chemical carcinogenesis protocol, the BK5.EP4 mice were shown to develop both papillomas and squamous cell carcinomas earlier than wild type (WT) mice. However, a tumor observed before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment on one BK5.EP4 mouse suggested that TPA was not necessary for the promotion of the tumors. Therefore a 7,12-dimethylbenz[a]anthracene (DMBA)-only carcinogenesis protocol was performed, and by 30 weeks, the BK5.EP4 mice again developed more carcinomas compared to none on the WT mice. Immunohistochemistry performed on DMBA-treated mice demonstrated that the BK5.EP4 epidermis began to detach 48 hours after treatment with total detachment occurring 5 days after treatment, while WT mice had only increased epidermal thickening. By 7 to 10 days after DMBA treatment, patches were observed on the BK5.EP4 skin where it appeared the hair and epidermis were detaching, which were not seen on the WT mice. MMP-9, MMP-7, and E-cadherin expression also were upregulated in the BK5.EP4 mice at the same time detachment of the epidermis was occurring. However, no differences in proliferation, stem cell numbers, or CYP1A1 and CYP1B1 expression have been observed. These data suggest that overexpression of EP4 in the mouse skin can increase tumorigenesis, possibly through the wounding of the skin and the subsequent inflammation and epidermal regeneration acting as a tumor promoter. Supported by CA100140.
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 2462.
Abstract 2471: Immunosuppressive effect of elevated epidermal ornithine decarboxylase activity
Authors: Keough Martin P. , DeFeo Karen , Hayes Candace S. , Gilmour Susan K. 
Published: February 2011

Abstract
Tumor promoting agents, such as phorbol esters, promote tumorigenesis via induction of inflammation and hyperplasia. However, the immunosuppressive/immunomodulating properties of tumor promoting agents may play a relevant role in tumor promotion as well. Because elevated polyamine biosynthesis is sufficient to promote skin tumorigenesis, we hypothesized that increased activity of epidermal ornithine decarboxylase (ODC), a key regulatory enzyme in polyamine biosynthesis, may suppress the cutaneous immune response in addition to stimulating proliferation. To investigate the role of ODC in the control of cutaneous inflammation, a well-known model of T cell mediated inflammation was used. A contact hypersensitivity (CHS) response was elicited in the ears of both ODC transgenic mice, in which ODC is targeted to the epidermis, and their normal littermates by topical sensitization and challenge with oxazolone. Unlike in normal littermate mice, ear swelling was dramatically reduced in ODC transgenic mice after elicitation of CHS. Flow cytometric and immunohistochemical analyses of the infiltrating immune cells revealed fewer infiltrating immune cells, especially neutrophils, in the elicited ears of ODC transgenic mice. The specific ODC inhibitor, α-difluoromethylornithine, abrogated the suppressive effects of ODC in CHS reactions. Adoptive transfer of sensitized lymphocytes from either ODC transgenic or normal littermate mice to naïve ODC transgenic or wild-type mice indicated that elevated epidermal ODC activity suppress both the sensitization and elicitation phases of CHS. Cytokines are central mediators of immune functions associated with inflammatory reactions. The cytokine profile of ex vivo stimulated lymphocytes isolated from draining lymph nodes showed reduced levels of IL-6 and IL-10 in sensitized and challenged ODC transgenic mice. In vivo labeling of dendritic cells by topical application of fluorescein isothiocyanate (FITC) showed fewer FITC-labeled dendritic cells in the draining lymph nodes of ODC transgenic mice compared to normal littermates. Vascular permeability was assessed using Evans blue extravasation assays during the elicitation phase of CHS. At 24 hours after induction of CHS, there was 45% less plasma extravasation of Evans blue dye into the ear skin of ODC transgenic mice compared to normal littermates. Collectively these data indicate elevated epidermal ODC activity can suppress a number of functions associated with cutaneous inflammatory reactions. In addition to promoting cellular proliferation, the immune suppression mediated by increased epidermal ODC activity may provide an environment conducive to tumor growth. This work was supported by NIH grant CA070739.
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 2471.
Abstract 2477: The effect of dissociated glucocorticoids on 12-O-tetradecanoylphorbol-13-acetate (TPA) induced skin inflammation in SENCAR mice
Authors: Kowalczyk Piotr , Sosnowska Renata , Kowalczyk Magdalena , Tolstykh Olga , Junco Jacob , Walaszek Zbigniew , Slaga Thomas J. , Hanausek Margaret 
Published: February 2011

Abstract
Glucocorticoids are very effective in preventing carcinogen- and tumor promoter-induced skin inflammation, hyperplasia, and mouse skin tumor formation when applied to skin together with a carcinogen. Their control of cellular functions is mediated by a well-known transcription factor, glucocorticoid receptor (GR). GR acts via two different mechanisms: transcriptional regulation that requires DNA-binding and protein-protein interaction between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1), which is independent of DNA binding. We hypothesize that only the transrepression activities of the GR are sufficient to suppress skin tumor development. To test our hypothesis, we have synthesized two glucocorticoids (RU24858 and RU24782) that induce only transrepression activities of the GR. These two compounds are able to bind to the GR with high affinity and repress the AP-1 and NF-κB activity while showing reduced transactivation activities in vitro. Different doses (0.001, 0.01 and 0.1 mg) of RU24858, RU24782, desoxymethasone (DES) and fluocinolone acetonide (FA) or acetone were applied to the dorsal skin of female SENCAR mice 20 min. prior to TPA application (2 μg), two times per week for two weeks. Keratinocytes proliferation rates were estimated by measuring epidermis thickness and BrdU incorporation index. Immunohistochemistry and RT-PCR techniques were also used to evaluate expression level of genes involved in inflammation and cell cycle regulation. All studied compounds did not influence keratinocytes proliferation when applied alone. Application of DES, FA and RU24858 reversed TPA induced hyperplasia, in dose-depended manner, while RU24782 treatment had no effect on epidermis thickness or the BrdU incorporation index in TPA treated skins. All tested compounds were able to decrease c-jun mRNA level both in acetone and TPA-treated skins. DES, FA and RU24858 were also able to decrease elevated by TPA mRNA level of IL-6, COX-2 and iNOS. RU24782 did not influence mRNAs levels of these genes. These findings suggest that RU24782 had no effect on TPA-induced inflammation and hyperplasia in SENCAR mice, while RU24858 was able to reduce all tested inflammation markers, having only slight effect on epidermal hyperplasia. Supported by NIH grants CA 0796065-06 and P30 CA 54174-16S1.
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 2477.
Abstract 2482: Effect of L-isoleucine and L-leucine at early stage of rat bladder carcinogenesis
Authors: Kanagawa Akihiro , Xie Xiaoli , Yamano Shyotaro , Wei Min , Wanibuchi Hideki 
Published: February 2011

Abstract
We previously demonstrated the promotion effects of L-isoleucine and L-leucine on N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder carcinogenesis when supplemented in AIN-93G diet in a 29-week bioassay. However, little is known about the mechanism underlying the promotion effects. The aim of the present study is to evaluate the effects of L-isoleucine and L-leucine at early stage of rat bladder carcinogenesis. In experiment 1, rats were fed AIN-93G basal diet, 2% L-leucine or L-isoleucine in basal diet for 2 weeks. In experiment 2, rats were administered 0.05% BBN in drinking water for the first 2 weeks, and then fed basal diet, 2% L-leucine or L-isoleucine diet for 4 weeks. No treatment-related histopathologic changes in bladder were observed in both experiments. There were also no differences in proliferative activities and expressions of 12 genes that were previously found to be up-regulated in BBN-treated bladder urothelium from week 2 between basal diet group and L-leucine or L-isoleucine group regardless of BBN initiation. These findings indicated the possibility of lack of effects of L-isoleucine and L-leucine at early stage of rat bladder 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 2482.
Abstract 2485: Inhibitory effects of the water extract of Nelumbo Nucifera leaf on human breast carcinoma MCF-7 cells in vitro and in vivo
Authors: Chang Yun-Ching , Yang Mon-Yuan , Wang Chau-Jong 
Published: February 2011

Abstract
Over the passed decade, advances in understanding carcinogenesis have made possible the identification of the candidates of chemopreventive agents to be developed in targeting the key molecules. Lotus (Nelumbo nucifera Gaertn) is widely distributed in central and southern Taiwan. Its leaves are becoming popular as an ingredient of healthy beverages. Nelumbo nucifera Leaf extract (NLE) has been reported to exhibit different therapeutic effects, such as anti-oxidant and reduction of risks for cardiovascular disease. This study was aimed to investigate the antitumor effect of NLE on human MCF-7 cell line in vitro and in vivo. Qualitative analysis showed that the NLE contains several compounds using nine kinds of standard polyphenols by high-performance liquid chromatography (HPLC) method. The polyphenols present in identified compound of NLE were mainly gallic acid, rutin and quercetin. The MTT data showed no significant inhibition on growth of MCF-7 cells following NLE treatment, whereas flow cytometry revealed that the cell cycle was arrested at G0/G1 phase with a dose of 3 mg/ml in MCF-7 cells (approximately 86.54%). With western blotting, we found that treatment with NLE particularly induced p53 phosphorylation and p21 expression, and down-regulated expression of cyclins (cyclin D, cyclin E) and cyclin-dependent kinases (cdk2, cdk4) in a dose-dependent manner. The increased p21 also correlated with the decrease of cyclin D/cdk4 and cyclin E/cdk2 complexes, which was responsible for the high protein expression of Rb/E2F. Inactivation of fatty acid synthase (FAS) was shown in vitro and in vivo, implying that FAS was a potent regulator as well of NLE- mediated anti-carcinogenesis. The tumoricidal effect of NLE was further measured using a xenograft nude mice model. Treatment with NLE (0.5 and 1%) effectively reduced the tumor volume and tumor weight in the nude mice inoculated with MCF-7 cells when compared to the control tissue samples. These results confirmed that cell cycle arrest is sufficient to elicit tumor regression after NLE treatment. In conclusion, our studies indicate that NLE offers an anti-tumor activity and potentially can act as a chemotherapeutic agent.
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 2485.
Abstract 2486: A possible mechanism for plagiochiline A activity: Inhibition of cytokinesis
Authors: Stivers Nicole S. , Islam Ashraful , Casson Lavona K. , Aponte Jose C. , Hammond Gerald B. , Vaisberg Abraham J. , Bates Paula J. 
Published: February 2011

Abstract
We recently reported on the isolation of plagiochiline A, a 2,3-secoaromadendrane-type sesquiterpenoid, from the Peruvian medicinal plant Plagiochila distichia. This compound was found to have antiproliferative activity against a variety of solid tumor cell lines, including those derived from prostate, colon, breast, lung, and cervical cancers, as well as several leukemia cell lines. Other researchers have also noted the cytotoxicity of plagiochiline A (isolated from other plant species), but the mechanism for this activity was unknown. Here, we describe new research where we have investigated the mechanism of plagiochiline A using a variety of experimental techniques. First of all, we evaluated cell cycle parameters in DU145 prostate cancer cells treated for 24 h with 4 µg/mL (11.4 µM) plagiochiline A using flow cytometry based analysis of propidium iodide-stained cells. We found that plagiochiline A caused a statistically significant increase in the percentage of cells in the G2/M phase compared to vehicle-treated cells (41.7% compared to 24.8%, based on three independent experiments). We next examined similarly treated cells stained with DAPI (a DNA intercalator) and anti-tubulin antibodies (microtubule marker) using fluorescence microscopy to evaluate the mitotic status of the cells. These experiments revealed a large number of binucleate cells, many of which had intercellular bridges evident, specifically in the plagiochiline A-treated samples. Only a few cells were observed in earlier stages of mitosis, suggesting that the accumulation of cells in G2/M is due to a defect in cytokinesis. We are currently carrying out additional research in order to test this hypothesis. We also plan to determine the effects on cells following longer treatments with plagiochiline A and to investigate possible molecular target(s) of plagiochiline A. Although many anti-mitotic compounds are in current use as anticancer agents, there are apparently only a few agents in development that specifically target cytokinesis. Therefore, we anticipate that this research may ultimately lead to novel anticancer agents and new tools to study cytokinesis.
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 2486.