bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2386: High-throughput assessment of the VEGFR2 kinase activity profile in pediatric brain tumor tissue
Authors: Sikkema Arend H. , de Bont Eveline S. , Molema Grietje , Dimberg Anna , Zwiers Peter J. , Diks Sander H. , Hoving Eelco W. , Kamps Willem A. , Peppelenbosch Maikel P. , den Dunnen Wilfred F. 
Published: February 2011

Abstract
For enhanced tumor cell survival and progression, tumors depend on angiogenesis. Vascular endothelial growth factor receptor (VEGFR) signaling plays a major part in this process. Previously we generated a comprehensive description of the biological tyrosine kinase activity present in pediatric brain tumor tissue lysates by the application of a peptide microarray containing 144 different tyrosine kinase peptide substrates (Sikkema et al., Cancer Res 2009). The results suggested the presence of activated VEGF receptors in pediatric pilocytic astrocytoma tissue. We hypothesized that this detected VEGFR activity reflects the angiogenic status of the tumor endothelium.
In this study we demonstrated that VEGFR2 expression is not present in a pilocytic astrocytoma cell line. Moreover, proximity ligation assays on tumor cryosections showed VEGFR2 phosphorylation, primarily localized on endothelial cells. qRT-PCR analysis of endothelial markers and VEGFRs showed a 10 to 30-fold enrichment of VEGFR2 expression on laser microdissected endothelium compared to whole tumor. Hence, we conclude that the endothelial cells are the high producers of VEGFR2 kinase activity in these tumors and therefore responsible for the VEGFR2 kinase activity that we observed in our kinase activity screens.
In conclusion, potential VEGFR kinase substrates present on the peptide microarray are adequately sensitive to pick up enzymatic activity which is present in only a subset of the total cell population within solid tumors such as pilocytic astrocytoma. In the near future, high throughput measurement of enzymatic activity of key players in angiogenesis could make a rapid assessment of the angiogenic profile of a tumor possible. This could serve as an indicator of anti-angiogenic treatment response and result in more personalized anti-angiogenic cancer treatment strategies.
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 2386.
Abstract 2406: Increased efficacy of combination of IL-13 receptor-targeted cytotoxin and DNA vaccine in murine tumor models
Authors: Nakashima Hideyuki , Husain Syed R. , Puri Raj K. 
Published: February 2011

Abstract
Recent studies show that interleukin-13 receptor α2 chain (IL-13Rα2) is a tumor-associated antigen that is a promising potential target for immunotherapy. High levels of IL-13Rα2 are expressed on a variety of human tumors, but its precise role in tumor immunology is not known. IL13-PE, a targeted cytotoxin composed of IL-13 fused to mutated form of Pseudomonas exotoxin, induces specific killing of tumor cells expressing abundant levels of IL-13Rα2. In this study, we sought to determine the effect of IL13-PE in combination with DNA vaccination in murine MCA304 sarcoma and 4T1 breast carcinoma, which naturally over-express IL-13Rα2 antigen.
Three intramuscular prophylactic IL-13Rα2 DNA immunizations in syngeneic mice (n=6) on −8, −4, and −2 weeks resulted in partial protection (382 mm3) against subcutaneous MCA304 tumor challenge compared to mock vector vaccine (1498 mm3) on day 21. Three additional intratumoral (i.t.) treatments of IL13-PE on day 4, 6 and 8 post-tumor challenge further decreased tumor burden (85 mm3) by 78%, measured on the same day (day 21) compared to DNA vaccination alone. In an established MCA304 tumor model, mice receiving three i.t. injections of IL13-PE (on day 7, 9, and 11) and four subsequent DNA vaccinations (on day 13, 18, 23 and 28) reduced tumor size to 44 mm3 (94% less) compared to DNA vaccination alone (693 mm3) on day 24. For comparison, the untreated control tumors had a size of 1579 mm3 on day 24. Interestingly, the combination therapy with IL13-PE and DNA vaccination produced 50% complete responders; however, tumors in remaining 50% partial responders grew slowly. Combination therapy prolonged the mean survival to 60 days compared to control (24 days) and DNA only vaccinated groups (36 days). Similar results were also observed in the 4T1 murine breast carcinoma model. Combination therapy group showed higher CTL activity and IFN-γ release from splenocytes compared to the single therapy groups in both tumor models. Immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and expression of IFN-γ-induced chemokines (CXCL9 and CXCL10) in tumor tissues of immunized mice. These results suggest that combination therapy with IL13-PE and IL-13Rα2 DNA vaccination inhibited tumor growth in a T cell dependent manner. In addition to the combination therapy strategy, elimination of immunosuppressive elements such as regulatory T cells and myeloid-derived suppressor cells may further enhance tumor immunity.
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 2406.
Abstract 2432: Fully human anti-interleukin-6 (IL-6) monoclonal antibody suppresses the growth of human tumor xenograft in vivo
Authors: Zhong Haihong 
Published: February 2011

Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the response to injury or infection and is involved in the immune response, inflammation, and hematopoiesis. Aberrant expression of IL-6 has been implicated in many human diseases. In cancer, high levels of circulating IL-6 are observed in many tumor types and associated with poor outcome. We hypothesized that a monoclonal antibody that neutralizes IL-6 activity may be effective in inhibiting the progression of cancer. A fully humanized monoclonal antibody against human IL-6 (CAT-6001) was isolated by screening phage-display libraries. CAT-6001 completely neutralizes IL-6 activities via binding to the IL-6 receptor and signal transducer gp130 binding sites of human IL-6. We demonstrate that several cancer cell lines secrete high levels of IL-6 and soluble IL-6 receptor, and express gp130. High constitutive pStat3 activation is seen in several of these cell lines suggesting an IL-6 autocrine loop. Treatment of these cell lines with CAT-6001 effectively blocked phosphorylation of Stat3 and in some cell lines, functionally inhibited IL-6 induced cell proliferation. In vivo, CAT-6001 inhibited the growth of DU145, a human prostate cancer xenograft model, and significantly blocked the release of human IL-6 and inhibited Stat3 phosphorylation. Taken together, our data suggest that IL-6 signaling contributes to tumor growth, and provide support for the further development of CAT-6001 for the treatment of solid tumors.
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 2432.
Abstract 2474: Increased PKC expression in diacylglycerol-induced mammary carcinogenesis in the human c-Ha-ras proto-oncogene transgenic rat
Authors: Suzui Masumi , Yoshida Ichiro , Ishihara Masashi , Nakashima Makoto , Matsunaga Toshiyuki , Hara Akira , Fukamachi Katsumi , Tusda Hiroyuki 
Published: February 2011

Abstract
Protein kinase C (PKC) is implicated in cell proliferation and tumor promotion. PKC is activated by 1, 2-diacylglycerol (1, 2-DAG). An edible oil that includes 70% 1,3-DAG and 30% 1,2-DAG is commercially available in Japan, USA, and European countries. To examine whether the DAG oil enhances mammary carcinogenesis and to measure whether DAG affects the levels of PKC expression, we carried out this study with human c-Ha-ras proto-oncogene transgenic (Hras128) rats that are highly susceptible to mammary carcinogenesis. Hras128 rats (6-week-old) were randomly assigned into four experimental groups. DAG oil was administered to the rat as oral drops. Group 1 (G1): 0.5 mL triacylglyceraol (TAG) x2/week, Group 2 (G2): 0.5 mL DAG x2/week, Group 3 (G3): 0.5 mL TAG x1/week plus 0.5 mL DAG x1/week, Group 4 (G4): 0.5 mL DAG x1/2 weeks + 0.5 mL TAG x3/2 weeks. Experiment was terminated after 15 weeks. Mammary tumors were histologically identified as adenocarcinoma. Tumor incidence of G2 (77%) and G3 (77%) was significantly higher than G1 (22%). Tumor multiplicity of G2 (1.3 ± 1.1) was significantly higher than the other 3 groups (G1, 0.4 ± 1.0; G3, 0.9 ± 0.6; G4, 0.7 ± 1.0). In tumor samples, the mRNA expression levels of 6 PKC isoforms (α, δ, ε, η, λ, ν) increased compared to the adjacent normal tissues. In a parallel study, we also examined the levels of PKC expression in normal mammary tissues of Hras128 rats treated with either TAG or DAG oils alone for 4 weeks. The mRNA expression levels of 5 PKC isoforms (δ, ε, η, λ, θ) significantly increased in the DAG-treated normal tissues compared to the TAG-treated normal tissues. These findings provide evidence that treatment of Hras128 rats with DAG oil may promote mammary carcinogenesis by inducing expression of several PKC isoforms.
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 2474.
Abstract 2491: Biphasic effect of psoralidin on cell cycle regulatory markers in hormone refractory prostate cancer
Authors: Koduru Srinivas , Rohr Jurgen , Damodaran Chendil 
Published: February 2011

Abstract
Cell cycle deregulation has been strongly associated with the pathogenesis of prostate cancer (PCa). Overexpression of cell cycle regulatory proteins (cyclin D1-25%, cyclin A-35% and cyclin B-75%) have been reported in clinical PCa samples when compared to normal prostate tissue. Based on this, we rationalized that downregulation of cell cycle regulatory molecules may play an important role in chemoprevention/therapy of PCa. We previously published that psoralidin; a natural compound effectively suppresses PCa growth both in vitro and in vivo. Hence, in this study we determined whether psoralidin alters cell cycle regulatory proteins in PCa cells. To determine this we performed cell cycle analysis using PI staining and also studied the expression patterns and activity of various cell cycle regulatory markers using Western blot analysis and kinase assays respectively in two hormone refractory prostate cancer (HRPC) cells (PC-3 and DU-145) following treatment with or without psoralidin in dose dependent manner. Psoralidin has biphasic effect on PCa cells where at a lower concentration (40µM) caused a G0/G1 cell cycle arrest whereas at a higher concentration (60µM) caused a G2/M cell cycle arrest. Psoralidin at lower concentration induced expression of cyclin dependent kinase inhibitors (p27, p57, p21, p16) in PC-3 and DU-145 cells whereas at higher concentration upregulation of p18 was observed in both HRPC cells. Additionally, we found that at lower concentration cyclins (E & E2 and H) and cdks (6 and 9) are downregulated whereas at higher concentration psoralidin downregulated expression of cyclins (D1, A, E & E2, B1, D3 and H) and cdks (6, 7, 2 and 9) in both HRPC cells. At lower concentration psoralidin inhibits expression of cdc-2 and cdc-25B whereas at higher concentration cdc-2, −25A and −25B are downregulated in both PC-3 and DU-145 cells. Also, psoralidin inhibited phosphorylation of Rb at both lower and higher concentration in HRPC cells causing irreversible cell cycle arrest resulting in the induction of apoptosis. These results clearly highlight the potential of psoralidin as a therapeutic agent for PCa. Currently, we are investigating the effect of psoralidin on cell cycle markers using both xenograft and TRAMP models. The outcome of our study may enable bringing psoralidin to the mainstream of medicine for prevention and/or therapy for PCa.
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 2491.
Abstract 2563: Upregulation of miR-155 is associated with cisplatin resistance in the head and neck cancer UMSCC-10B/15S cells
Authors: Gupta Ashim , Zhu Shoumin , Sachdeva Mohit , Rao Krishna , Robbins Thomas , Mo Yin Yuan 
Published: February 2011

Abstract
Introduction: Cisplatin combination chemotherapy is the cornerstone of treatment for many cancers including head and neck cancer. These complexes bind to the DNA and form adducts such that they ultimately trigger apoptosis. Although initial platinum responsiveness is usually high, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Thus, chemotherapy resistance is a major clinical obstacle in the successful treatment of head and neck cancer. This study aims to investigate the role of microRNAs (miRNAs) in cisplatin resistance and to better understand the underlying mechanism of cisplatin resistance in the head and neck cancer UMSCC-10B/15S cells.
Methods: To determine whether aberrant miRNA expression is associated with cisplatin resistance in human head and neck cancer cells, we profiled miRNA expression in the cisplatin resistant UMSCC-10b/15S and the parental line UMSCC-10B cells by real-time PCR. Luciferase reporter assays and western blot were used to confirm targets for miR-155. We also suppressed miR-155 by anti-sense locked nucleic acid (LNA) oligo to further determine the role of miR-155 in cisplatin resistance.
Results: We showed that several miRNAs were altered in UMSCC-10B/15S and among them, miR-155 was the most significantly upregulated miRNA. This was also confirmed by in situ hybridization. Furthermore, ectopic expression of miR-155 was able to increase the resistance of UMSCC-10B cells to cisplatin, which is likely in part through targeting DMTF1, a tumor suppressor that directly binds to the Arf promoter to activate its expression, thereby inducing p53-dependent cell cycle arrest and apoptosis. To determine whether miR-155 directly targets DMTF1, we cloned 1.2 kb 3′-untranslated region (UTR) of DMTF1 into a luciferase reporter and demonstrated that miR-155 was able to suppress luciferase activity by over 70%. We also showed that the endogenous DMFT1 protein was reduced by over 50% in the miR-155 highly expressed resistant cells compared to the parental sensitive cells. Experiments are under way to determine whether ectopic expression of DMTF1 or its suppression by RNAi impacts cisplatin resistance in these cells.
Conclusion: These findings suggest that deregulation of miRNAs is in resistant head and neck cancer cells and miR-155 may play a causal role in cisplatin resistance through targeting the DMTF1 gene. As a result, suppression of miR-155 may provide a strategy to overcome the resistance in head and neck 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 2563.
Abstract 2567: Expression of BRAF splice variants lacking the catalytic domain predicts dacarbazine response in advanced melanoma
Authors: Busch Christian , Geisler Jürgen , Lillehaug Johan Richard , Lønning Per Eystein 
Published: February 2011

Abstract
BACKGROUND: Metastatic melanomas respond poorly to chemotherapy. The aim of this single institution study was to correlate BRAF and NRAS mutation status to dacarbazine (DTIC) response and outcome in metastatic melanomas.
METHODS: Snap-frozen tissue samples were obtained from 85 malignant melanoma deposits. Seventy-five of these were from patients evaluable for response to dacarbazine treatment, and BRAF and NRAS status was correlated to treatment outcome. In addition, cell culture studies were performed, evaluating the effect of BRAF/NRAS status on dacarbazine sensitivity.
RESULTS: We identified two BRAF splice variants lacking key parts of the catalytic domain (exon 12-15 and exon 14-15, respectively). Splice expression and BRAF V600E mutation status were mutually exclusive (p=0.006). All patients obtaining an objective response to chemotherapy expressed splice variants (p=0.014 and p=0.043 at 6 and 12 weeks, respectively). siRNA-mediated BRAF knockdown increased dacarbazine sensitivity in a melanoma cell line wt for BRAF (SBcl2) but not in SK-MEL 28, harbouring BRAF V600E. No correlation between BRAF or NRAS mutation status and treatment response was recorded.
CONCLUSION: Our findings suggest that BRAF plays a key role conferring resistance to dacarbazine treatment in metastatic melanomas and the del 12-15 or del 14-15 splice variants to have BRAF antagonizing effects.
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 2567.
Abstract 2573: Molecular mechanism of cisplatin-based chemoresistance with human head and neck cancer: A translational clinical study
Authors: Yamashita Taku , Miyamoto Shunsuke , Hwang Wei-Ting , O'Malley Bert W. , Li Daqing 
Published: February 2011

Abstract
(Background) Cisplatin is a commonly used chemotherapy agent for many kinds of cancers including head and neck cancer. Chemoresistance to cisplatin significantly contributes to treatment failure in clinical practice. The MRE11/RAD50/NBS1 (MRN) complex is well known a major DNA repair system. Our previous in vitro study shows that enhanced DNA repairing by MRN is a critical molecular mechanism for cisplatin-based chemoresistance. The present study further investigates if the finding of enhanced DNA repairing is responsible for cisplatin-based chemoresistance with human head and neck squamous cell carcinoma (HNSCC) in an animal model and, more important, if this finding correlates to the clinical study with patients who suffer from HNSCC.
(Methods) An animal model with human HNSCC was used for this study. Tumor volume changes were measured before and after cisplatin treatment. Immunohistochemistry studies were carried out for detecting the expression levels of MRN and apoptosis. The chemoresistant profile of the tumor model was established depending on these studies. The patients with HNSCC who initially received cisplatin monotherapy along with the patients without having cisplatin treatment were investigated. Immunohistochemistry studies were carried out for detecting the expression levels of MRN and apoptosis. These results were carefully analyzed by using a linear regression model with random effects to compare with established animal tumor model and in vitro findings.
(Results) Our animal model with human HNSCC demonstrated that chemoresistance to cisplatin is associated with increased expression levels of MRN after cisplatin treatment (p&lt;0.0001(MRE11), p&lt;0.0001(RAD50), p&lt;0.0001(NBS1)). In addition, the resistant tumors showed decreased levels of apoptosis after cisplatin treatment (p&lt;0.0001). Our clinical study confirms these findings as shown that patients with HNSCC had increased expression of MRN when developing cisplatin chemoresistnace.
(Conclusion) It is strongly suggested that increased expression levels of MRN proteins after cisplatin treatment are associated with a resistant phenotype in the human HNSCC. Our study presents important findings that will facilitate a better understanding of the molecular mechanisms underlying tumor cell resistance to chemotherapy.
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 2573.
Abstract 2594: Reovirus replication in ovarian and peritoneal tumors after intravenous administration
Authors: Phelps Mitch A. , Cohn David E. , O'Malley David M. , Wei Lai , Wilkins Deidre , Campbell Angela , Schaaf Larry J. , Coffey Matthew C. , Villalona-Calero Miguel A. , Grever Michael R. , Nuovo Gerard J. , Zwiebel James A. 
Published: February 2011

Abstract
Background: Reovirus Serotype 3 - Dearing Strain is an oncolytic virus under clinical evaluation for treatment of solid tumor malignancies. We initiated a phase 1/2 study with reovirus in patients with ovarian, primary peritoneal and fallopian tube carcinoma. The objectives of the correlative studies in this trial include the verification of reovirus penetration and replication in ovarian and peritoneal tumors after IV and IP reovirus administration and to evaluate tumor RAS pathway activation status as a marker for reovirus activity in this patient population.
Methods: Percutaneous tumor biopsies and ascites fluid were collected at various times during therapy from patients receiving reovirus via both IV and IP routes. Biopsied tissue and cell preparations from ascites were evaluated for reovirus capsid particles via electron microscopy (EM) and viral protein via immunohistochemistry (IHC). The presence of viral RNA and transcribed DNA are evaluated via reverse-transcriptase in situ PCR (RTISPCR). IHC for phosphorylated ERK (pERK) is applied to determine RAS pathway activation status.
Results: To date, 5 patients have been accrued and treated on trial. Preliminary evaluation with IHC indicates the presence of viral protein in the biopsied ovarian and peritoneal tissue samples from a subset of these patients after IV administration of reovirus. Completion of EM, RTISPCR, and pERK IHC on biopsied tissues and ascites samples is in progress.
Conclusions: Results to date display evidence of viral replication in peritoneal and ovarian cancer cells after IV administration of reovirus. This data represents the first observation of reovirus penetration into the peritoneal space after systemic drug administration. Completion of correlative analyses will further characterize the ability of reovirus to penetrate and replicate within the IP space and ascites after IV and IP administration. Furthermore, the selective viral infection and replication within RAS-pathway-activated tumor cells will be assessed. Results of all correlatives will be presented at the meeting. This work is supported by the NCI, grant U01CA076576 and contract NO1CM62207.
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 2594.