bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3482: Hypoxia induces translational regulation of lymphangiogenic growth factors
Authors: Garmy-Susini Barbara H. , Pujol Francoise , Van den Berghe Loic , Prats Anne-Catherine 
Published: June 2012

Abstract
Hypoxia is a major condition for induction of angiogenesis during tumor development, nevertheless its role in lymphangiogenesis remain unclear. In this study, we investigate the role of hypoxia in the translational regulation of lymphangiogenic growth factors. The majority of cellular stresses such as hypoxia leads to an inhibition of mRNA translation in cell by the classical cap-dependent mechanism. However, several mRNAs are translated by an alternative mechanism mediated by internal ribosome entry sites (IRESs) located in their 5’ untranslated regions.
We found IRES elements in mRNAs of lymphangiogenic growth factors such as VEGFA and FGF2, and demonstrated that hypoxia is able to activate IRES-mediated mRNA translation both in vitro and in vivo. Interestingly, our recent data demonstrated a strong induction of VEGFA and FGF2 IRES activities in vivo in pancreas adenocarcinoma CAPAN-1, that correlates with development of hypoxia area and lymphangiogenesis in primary tumors. Such an activation is not observed with the viral EMCV IRES used as a control, indicating a translational activation in response to tumoral hypoxia could be specific of angiogenic/lymphangiogenic factors IRESs.
We are interested in the translational control of more specific of lymphangiogenic growth factors, VEGFC and VEGFD. We've shown, in CAPAN-1 model, that VEGFC and VEGFD translation correlates with hypoxia area development in vivo. To determine the presence of IRESs in VEGFC and -D mRNAs, we cloned the 5’ untranslated regions of murine and human VEGF-C and -D mRNAs in bicistronic lentivectors. First data suggest the presence of an IRES VEGFC and -D mRNAs.
In further investigations, our purpose is to demonstrate that the process of IRES-dependent translation plays a pivotal role in the hypoxic response, and should lead to induction of lymphangiogenic factors, including VEGFC and VEGFD. Thus, cell proteins able to activate IRESs, called IRES trans-acting factors (ITAFs), would be crucial protagonists in the lymphangiogenesis process and potential taget for anti-angiogenic therapy.
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 3482. doi:10.1158/1538-7445.AM2011-3482
Abstract 3490: Identification and characterization of novel galectin-9 splice variants in endothelial cells
Authors: Heusschen Roy , de Bree Martijn , Griffioen Arjan W. , Thijssen Victor Ljl 
Published: June 2012

Abstract
Evidence is accumulating that endothelial galectins play an important role in tumor angiogenesis. Recently, we reported altered galectin-9 expression during endothelial cell activation. Here, we further assessed the expression and function of galectin-9 in endothelial cells. Using cDNA flanking PCR and subsequent cloning we identified 5 different galectin-9 splice variants in endothelial cells, 2 of which result in truncation of the C-terminal carbohydrate recognition domain and one of which has not been described previously i.e. galectin-9Δ5/6/10. By real-time PCR analysis we confirmed the expression of these 5 splice variants in endothelial cells and found that galectin-9Δ5 is the dominant splice variant in endothelial cells, as has been described for most other cell types. Endothelial cell activation resulted in a decreased expression of total galectin-9 levels which was mainly due to a decrease in galectin-9Δ5 expression. The expression of 2 other splice variants, galectin-9Δ5/6 and galectin-9Δ5/6/10 was retained after cell activation. To study the functional consequences of alternative splicing patterns on endothelial cell function, we cloned the 5 endothelial galectin-9 splice variants into expression constructs. We were able to demonstrate efficient transcription/translation of galectin-9 splice variants by real time PCR and Western blot respectively, following transfection of cell lines from non-endothelial (HEK293T) and endothelial (HMEC) origin. These data confirmed that exclusion of exon 10 causes a frameshift and premature stopcodon, resulting in the generation of protein that lacks the C-terminal CRD. Next, we assessed the function of gal-9 splice variants in endothelial cells by determining the effects on endothelial cell proliferation, migration and sprouting. Finally, we explored whether these splice variants have diverging roles in regulating the interaction between endothelial cells and immune cells. In conclusion, we report that endothelial cells express 5 splice variants of gal-9, one of which has not been described previously, and we show that these splice variants have diverging roles in endothelial cell biology. We hypothesize that interfering with the function of endothelial gal-9 splice variants might be an interesting approach for novel anti-cancer therapies.
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 3490. doi:10.1158/1538-7445.AM2011-3490
Abstract 3497: Benzyl isothiocyanate potentiates the in vivo anti-tumor effects of gemcitabine against pancreatic cancer by targeting NF-kB and STAT3
Authors: Boreddy Srinivas Reddy , Srivastava Sanjay K. 
Published: June 2012

Abstract
The persistent activation of nuclear factor kB (NF-kB) and signal transducer and activator of transcription 3 (STAT3) contributes to gemcitabine resistance in pancreatic ductal adenocarcinoma. We have previously shown that benzyl isothiocyanate (BITC) down-regulates the activation of both NF-kB and STAT3 in pancreatic cancer in vivo and in vitro. In the present study we investigated whether the inhibition of these molecules by BITC could enhance gemcitabine-induced apoptosis in culture and antitumor activity of gemcitabine in vivo. Our results show that pretreatment of cells with BITC (2.5 µM) for 24 hours followed by gemcitabine (5 nM) for 72 h resulted in enhanced apoptosis in BxPC-3 and PanC-1 pancreatic cancer cells as compared with either agent alone. The IC50 of BITC and gemcitabine is 10 µM and 25 nM, respectively. Furthermore, phosphorylation (activation) of STAT3 at Tyr-705 & Ser-727 and NF-KB (Ser-536), which were increased by gemcitabine treatment, were significantly reduced in the combination treatment in BxPC-3 and PanC-1 cells. Interestingly, gemcitabine resistant BxPC-3 (BxPC-3-GR, IC50: 11µM) cells were equally sensitive (p&lt;0.05) to BITC induced apoptosis as compared to BxPC-3 wild type cells (IC50: 10 µM). In addition, gemcitabine-induced DNA binding activity of NF-kB and STAT3 was significantly reduced in BxPC-3, BxPC-3-GR and PanC-1 cells as measured by EMSA and transcriptional activity. Furthermore, our in vivo results show that BITC (10 µmol; daily, oral) in combination with gemcitabine (40 mg/kg; i.p, every third day) was much more effective in suppressing tumor growth as compared with either agent alone in a BxPC-3 tumor xenograft model. Tumor volume (341 ± 20 vs 155 ± 9 mm3) and tumor weight (0.53 ± 0.01 vs 0.195 ± 0.006 g) were significantly reduced (54 % and 63 %, respectively) in BITC and gemcitabine combination treated mice as compared to control mice. Most importantly, our western blot and immunohistochemistry data shows that gemcitabine-induced activation of NF-KB (Ser-536) and STAT3 (Tyr-705) was completely inhibited in the tumors of mice treated with BITC and gemcitabine combination. These results provide strong evidence that inactivation of NF-KB and STAT3 signaling pathways by BITC could potentiate anti-tumor activity of gemcitabine in pancreatic cancer. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].
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 3497. doi:10.1158/1538-7445.AM2011-3497
Abstract 3502: Activity of combinations of anticancer agents in pancreatic carcinoma cell lines
Authors: Schwarting Christina , Belgardt Julia , Warnecke Andre , Kratz Felix , Graeser Ralph 
Published: June 2012

Abstract
Long term and successful treatment of pancreatic cancer remains a considerable challenge, and there is an urgent need to develop new therapeutic strategies that improve the response rate and overall survival of this disease that responds poorly to monotherapy with anticancer agents such as gemcitabine or 5-fluorouracil. Instead of combining drugs at their respective maximum tolerated doses, a number of recent studies have shown that the “more is better” paradigm may not be the optimal strategy for maximizing the clinical outcome for combination therapy and rather synergistic effects can be achieved if the drugs are dosed at a defined ratio. Such an approach is currently being investigated clinically with liposomal formulations which contain irinotecan and floxuridine at a 1:1 ratio or cytarabine and daunorubicin at a 5:1 ratio. We therefore tested a number of combinations of chemotherapeutic agents using defined ratios ranging from 10:1 to 1:10 for their efficacy against a luciferase transduced pancreatic cell line, MIAPaCa2 ELN, using a 72 h Luciferase proliferation assay. Using this assay, a combination of camptothecin with gemcitabine showed synergy at a ratio of 1:5 over a cell survival range of 10-80% with combination indexes (CIs) between 0.36 and 0.71.
In addition, a synergy was found at a 1:10 ratio for methotrexate with doxorubicin with CI values from 0.36 to 0.32 over a 20-90% cell survival range. A third synergistic combination was observed between cytarabine and gemcitabine at a 1:5 ratio with CIs from 0.16 to 0.21 over a 20-90% cell survival range. None of the other combinations tested, including campthotecin with methotrexate, camptotecin with doxorubicin, or cytarabine with daunorubicin showed synergistic effects at ratios from 5:1 to 1:5.
These in vitro results show that the ratio of the respective drug combination is a decisive factor for inducing additive, synergistic or even antagonistic effects.
We are currently testing the most promising combinations in additional pancreatic carcinoma cell lines in order to elucidate whether the synergistic effects of these combinations and specific ratios apply to pancreatic cancer cells in general.
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 3502. doi:10.1158/1538-7445.AM2011-3502
Abstract 3504: Targeting the Akt pathway and HDAC signaling in prostate cancer
Authors: Paesante Silvia , Miles Marie Kiersten , Nguyen Holly , Vessella Robert , Pili Roberto 
Published: June 2012

Abstract
Loss of the tumor suppressor phosphatase and tensin homolog protein (PTEN), a negative regulator of the survival Akt pathway, and elevated levels of histone deacetylase (HDAC) enzymes which regulate DNA transcription, correlated positively with the prostate cancer progression, recurrence and metastasis. MK-2206 is an allosteric Akt inhibitor with a broad antitumor activity; clinical studies have recently been completed in patients with solid tumors, showing MK-2206 good tolerability and evidences of clinical activity. vorinostat, an HDAC inhibitor, is involved in more than 100 clinical trials in solid tumors and it showed antitumor activity in different prostate cell lines. In this study we hypothesized that combination of MK-2206 and vorinostat may provide a greater antitumor efficacy, targeting different survival pathways activated in prostate cancer.
Different prostate cell lines were tested in both in vitro and in vivo xenograft models. LuCaP23.1. hormone-sensitive tumors were placed subcutaneously into male SCID mice. Tumor growth was assessed twice weekly by using serial caliper measurements. Luciferase-transfected PC3 hormone-independent tumor cells were injected in the right tibiae of male SCID mice and tumor progression was monitored weekly by bioluminescence assay using the Xenogen IVIS Living Imaging System. At the end of the experiment, Faxitron radiographs of the tibiae were taken. Mice were treated with MK-2206 at 120 mg/kg/d by oral gavage and i.p. injection of vorinostat at 100 mg/kg/d, 5 days per week. In vitro treatment of PC3 cells showed that both MK-2206 and vorinostat affected cell proliferation in a dose and time dependent manner, with a greater effect in combination. Western blot experiments validated p-Akt protein level inhibition due to MK-2206 treatment. Preliminary PC3 and LuCaP23.1. xenograft in vivo experiments confirmed the therapeutic activity of MK-2206 and vorinostat as single agents. The combination therapy showed a modest but greater inhibition of tumor growth in the PC3 xenograft bone metastatic model though not statistically significant. The antiproliferative effect of this combination was more evident in the subcutaneously LuCaP 23.1. xenograft model. This study showed for the first time the therapeutic association of MK-2206 and vorinostat in prostate cancer. We expect to further investigate the MK-2206 +/- vorinostat therapy and to provide new insight into the role of HDACs signaling and Akt pathway in prostate cancer.
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 3504. doi:10.1158/1538-7445.AM2011-3504
Abstract 3533: DNA binding molecules as a new tool to regulate cancer cell fate
Authors: Nagase Hiroki , Kimura Makoto T. , Wang Xiaofei , Watanabe Takayoshi , Fujiwara Kyoko , Mishra Rajeev , Sugiyama Hiroshi , Fukuda Noboru , Terui Tadashi 
Published: June 2012

Abstract
Pyrrole-Imidazole (PI) polyamide molecule was originally designed from structures of natural DNA binding molecule, such as Distamicine and Diocarbamicine and has been discovered as a synthetic molecule which recognizes the minor groove of Watson-Click base pair of double-stranded DNA in a sequence-dependent manner. We have recently developed a semi-automatic synthesis system for PI polyamide, which are able to regulate specific target gene-expression under specific transcription factor binding inhibition for biological functional studies and perhaps patients’ therapy. PI polyamide immediately penetrated the nucleus in vitro and in vivo without any vehicle. After intra venous injection It rapidly reduce the serum concentration, delivered to most of tissue cells, excreted to urine or bile juice and did not metabolize in animals. The PI polyamides, designed for anti-Tgfb1 and anti-MMP9 activity, were well tolerated, reduced target gene expression and showed therapeutic effects in animal models of human diseases. For instance, when performed two studies using I.V. treatment by either of two independent anti-MMP9 polyamides, tumor metastasis was significantly suppressed in both studies using the same mouse model of human liver metastasis of colon cancer. This new auto-synthetic chemicals can be designed for many transcriptional regulation of transcripts and applied to prove many biological hypothesis of transcriptional regulation for cancer research, and may be used for cancer therapy in the future.
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 3533. doi:10.1158/1538-7445.AM2011-3533
Abstract 3616: Highly potent antibody-amanitin conjugates cause tumor-selective apoptosis
Authors: Anderl Jan , Müller Christoph , Heckl-Östreicher Brigitte , Wehr Roland 
Published: June 2012

Abstract
Alpha-amanitin blocks RNA polymerase II activity and is the most specific and most potent inhibitor of eukaryotic transcription. While widely used as a tool in molecular biology, only a few attempts have been made to employ alpha-amanitin as a therapeutic agent in oncology. The reason for this may be the high liver toxicity caused by the transport of amanitin into hepatocytes by the organic-anion transporter 1B3 (OATP1B3) present on hepatocytes, but not on other cell types. In this study we show that a direct impact on the transcription machinery can provide a novel approach in tumor therapy, provided that the amanitin can be targeted to tumor cells. This was achieved by using tumor-specific antibodies of high affinity armed with amanitin via suitable linker moieties.
Using the HER2 specific monoclonal antibody Herceptin (Her) as a carrier, the antibody-drug conjugate (ADC) Her-DSC-30.0134 exhibits antiproliferative activity in HER2-expressing human tumor cell lines like SK-OV-3, SK-BR-3 and NCI-N87 in picomolar concentrations, indicating an up to 100.000-fold higher toxicity of the conjugate over non-conjugated alpha-amanitin. On cells lacking the HER2 receptor, e.g. HEK293 cells, toxicity of Her-DSC-30.0134 was not detected up to micromolar concentrations. This is also observed in HEK293 cells transfected with OATP1B3 (which incorporate amanitin similar as hepatocytes) indicating that amanitin-antibody-conjugates are no longer substrates for OATP1B3. These data suggest that a low hepatotoxicity of amanitin conjugates is expected.
Subsequently, antitumoral activity of Her-DSC-30.0134 was evaluated in vivo in a s.c. xenograft mouse model using Herceptin-sensitive SK-OV-3 and Herceptin-resistant JIMT-1 cells. The ADC is well tolerated in nude mice and shows complete tumor remission in 7 out of 7 animals after a single i.v. injection in the SK-OV-3 and JIMT-1 models. By contrast, Herceptin shows only moderate antitumoral activity in the SK-OV-3 and no activity in the resistant JIMT-1 model, even after multiple injections. These data encourages further examination of amanitin-based antibody conjugates as highly potent and selective compounds for the treatment of various maligancies.
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 3616. doi:10.1158/1538-7445.AM2011-3616
Abstract 3666: Inhibition of the tumor growth and prevention of metastases with MORAb-004, a human monoclonal IgG targeting endosialin/TEM-1
Authors: Tomkowicz Brian E. , Skidan Igor , Rybinski Katherine , Lin JianMin , Grasso Luigi , Nicolaides Nicholas , Sass Philip , Zhou Yuhong 
Published: June 2012

Abstract
Endosialin/Tumor Endothelial Marker-1 (TEM-1) is a cell surface glycoprotein that is expressed on cells involved in the development of tumor vasculature, primarily pericytes, smooth muscle, and stromal fibroblasts. Studies have found endosialin to play a key role in tumor growth and neovessel formation in numerous cancer types including (but not limited to) renal, breast, colon, pancreatic, lung, endometrial, ovarian, melanoma, sarcoma, and neuroectodermal tumors. We are currently evaluating the therapeutic efficacy of MORAb-004, a human monoclonal IgG1 targeting TEM-1, in a Phase I clinical trial. Because MORAb-004 only recognizes human/monkey TEM-1 and has no cross-reactivity with rodent TEM-1, we generated a human TEM-1 knock-in mouse line in order to assess its activity in in vivo tumor models. In a B16-F10 subcutaneous melanoma model we found that MORAb-004 significantly inhibited tumor progression by ∼70%. Moreover, using the Lewis Lung Carcinoma model of metastatic disease our results showed that MORAb-004 had a significant inhibitory effect on the number of lung metastases. Taken together our results demonstrated the ability of MORAb-004 in inhibiting the growth of solid tumors and preventing the emergence of distant metastases. The potential MOA is currently under evaluation and will be discussed.
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 3666. doi:10.1158/1538-7445.AM2011-3666
Abstract 3682: Response of biomarkers of inflammation (IL-8,TNF-α, sTNFRI & II) to cruciferous vegetable feeding in a controlled diet study in humans: Effects of GSTM1 and GSTT1 genotypes
Authors: Navarro Sandi L. , Schwarz Yvonne , Song Xiaoling , Wang Ching-Yun , Chen Chu , Lampe Johanna W. 
Published: June 2012

Abstract
Isothiocyanates (ITC) in cruciferous vegetables modulate several signaling pathways involved in carcinogenesis, including nuclear factor kappa-B (NF-κB), a transcription factor and central mediator in the generation of inflammation. Glutathione S-transferase (GST)M1 & GSTT1 metabolize ITC; genotypic differences in biologic response to cruciferous vegetable intake, and variation in ITC pharmacokinetics have been reported. Previously, we found reduced serum IL-6 and CRP concentrations in response to cruciferous (broccoli family) and apiaceous (carrot family) vegetable feeding compared to a basal diet in a randomized, crossover trial. Reductions were most marked among individuals with a GSTM1-null genotype. Here, we extend our panel of biomarkers in this intervention to include serum interleukin (IL)-8, tumor necrosis factor-alpha (TNF-α), and soluble TNF receptors I & II (sTNFRI & II). We tested whether supplementation of cruciferous or apiaceous vegetables alters serum concentrations of these markers, and whether this response is GSTM1/GSTT1 genotype-dependent. Men (n=26) and women (n=30), 20-40 y, ate four 14-day controlled diets – basal (fruit &vegetable-free), basal + two doses of crucifers (single & double “dose”), and single-dose cruciferous + apiaceous vegetables – fed per kg body weight. Fasting bloods from days 0 & 14 of each period were analyzed for serum inflammatory markers (IL-8 & TNF-a using the High Sensitivity Human Cytokine Panel, sTNFRs using the Human Soluble Cytokine Receptor Panel, Millipore). In this healthy population, we observed no overall reduction in any of the current biomarkers in response to vegetable supplementation. However, similarly to what we observed with IL-6 and CRP, both sTNFRI & II were lower at day 14 on the double-dose cruciferous vegetable diet among GSTM1-null individuals (P=0.006 & 0.007, respectively). NF-kB is one regulator of these inflammatory markers; but overlap with other pro-inflammatory pathways that may be differently regulated by diet, e.g., STAT3, may preclude observation of an effect. Such diet interventions may be more effective in populations with higher circulating inflammation biomarkers.
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 3682. doi:10.1158/1538-7445.AM2011-3682