bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4269: Human monoclonal anti-angiopoietin-2 antibody, MEDI3617, inhibits angiogenesis in preclinical studies
Authors: Molnar Nikolett , Siemann Dietmar W. 
Published: July 2012

Abstract
Angiogenesis is two-step process that is critical in tumor angiogenesis. First, endothleial-endothelial and endothelial-smooth muscle cell interactions must be broken. Then, endothelial cells must be activated to proliferate, migrate, and form tubes. Presence of Angiopoietin-2 (Ang-2) leads to vessel destabilization while pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF) are key growth factors that activate new vessel formation. Both are upregulated in the tumor microenvironment. To date most anti-angiogenic therapies have focused on inhibiting the second step in angiogenesis, or activation of the endothelium, and anti-VEGF therapies have shown some success especially in combination with conventional cancer therapies. However, resistance to such therapies has emerged due to upregulation of other pro-angiogenic factors in the absence of VEGF. The present studies examine the impact of MEDI3617, a monoclonal antibody targeting Ang-2, on tumor cell induced angiogenesis by inhibiting the first step, or endothelial-endothelial and endothelial-smooth muscle cell interactions, in angiogenesis. An intradermal assay was used to evaluate the growth of vessels induced by the tumor. Nude mice injected intradermally with colorectal cancer cells, HT29, were treated with a range of MEDI3617 doses (2, 10, 20 mg/kg) and the effect on the number of vessel formation was determined. The results showed that at 2 mg/kg dose of MEDI3617 led to a 42% reduction in the number of vessels induced and 10 and 20 mg/kg induced even greater reduction in the number of vessels (48 and 61% respectively). Current studies are evaluating the mechanistic interaction of endothelial- endothelial cell and endothelial smooth-muscle cell interactions using a co-culture spheroid model. A core of smooth muscle cells are surrounded by a layer of endothelial cells mimicking the interaction of these cells in the vasculature. The effect of Ang-2 on destabilizing this co-culture spheroid and the ability of MEDI3671 on inhibiting this destabilization are being evaluated. Preliminary studies indicate the ability of MEDI3617 to inhibit sphere destabilization in the presence of Ang-2.
Human monoclonal anti-Ang-2 antibody, MEDI3617, was both developed and this study supported by MedImmune, LLC.
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 4269. doi:10.1158/1538-7445.AM2011-4269
Abstract 4271: Combination of VEGF Trap (Aflibercept) with docetaxel, but not with gemcitabine, is efficacious in tumors resistant to anti-VEGF therapy
Authors: Abrahams Cristina L. , Li Baosheng , Parveen Asma , Thurston Gavin 
Published: July 2012

Abstract
Increased anti-tumor efficacy is often observed when VEGF blockade is combined with certain chemotherapy agents. However, the mechanism by which combination treatment with certain agents, but not others, results in enhanced anti-tumor effects is poorly understood. In this study, we compared the anti-tumor effects of VEGF Trap in combination with either docetaxel or gemcitabine on HT1080, a human fibrosarcoma tumor line that is resistant to anti-VEGF treatment. Immunodeficient SCID mice bearing subcutaneous HT1080 tumors (size ∼150 mm3) were treated with either control protein plus vehicle, VEGF Trap, chemotherapy agent (docetaxel or gemcitabine), or the combination. Following three treatments administered every 3-4 days, tumors were harvested either one day after the final dose or allowed to grow and harvested when the average size of the treatment group reached ∼500mm3. We found that combination treatment with VEGF Trap plus docetaxel was significantly more effective compared to single agents, while there was no added benefit of combining VEGF Trap with gemcitabine. Although treatment with chemotherapy agents alone and in combination with VEGF Trap both initially regressed tumor size, only the combination with docetaxel was effective at delaying long-term tumor re-growth. Immunohistochemical analysis of tumors showed that both combination regimens produced a dramatic decrease in the number of proliferating tumor cells. However, only VEGF Trap and docetaxel combination treatment resulted in pruned tumor vessels with less branching, whereas VEGF Trap plus gemcitabine had minimal effect on tumor vessel morphology. Furthermore, VEGF trap plus docetaxel produced an increase in TUNEL-positive cells associated with the tumor vasculature and a marked decrease in tumor pericytes. These results suggest that in tumors resistant to VEGF blockade, taxanes (docetaxel) can sensitize the vasculature to anti-VEGF treatment (aflibercept), thus resulting in enhanced effects on the tumor vessels and improved anti-tumor efficacy. Further understanding of the mechanistic basis of different combination regimens may allow improvement of current strategies to treat tumors resistant to antiangiogenic 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 4271. doi:10.1158/1538-7445.AM2011-4271
Abstract 428: Positive correlation of beta1 integrin expression and prognosis in clinically localized prostate cancer
Authors: Jr Jose Pontes , Ribeiro-Filho Leopoldo Alves , dos Reis Sabrina T. , Timoszczuk Luciana , Bernardes Felipe S. , Antunes Alberto A. , Viana Nayara I. , Passerotti Carlo C. , Oliveira Luiz CN , Hagopian Ellen , Dall'Oglio Marcos F. , Leite Katia RM , Srougi Miguel 
Published: July 2012

Abstract
Introduction and objective: Integrins are transmembrane glycoprotein receptors that regulate cell-matrix interactions, functioning as sensors of the environment. They also act as cell adhesion molecules, being responsible for the maintenance of the epithelial phenotype. Some studies have reported correlation between alterations of integrins expression and carcinogenesis, specially β1 integrin, but their role in prostate cancer is unclear. Our aim is to study the expression of β1 integrin and evaluate its association with recurrence of prostate cancer after surgical treatment
Methods: For this case-control study, we selected 111 patients with localized tumor submitted to radical prostatectomy by the same surgeon. 60 of these patients have not presented recurrence after a median follow-up of 123 months. Recurrence was defined as a PSA level above 0.4ng/ml. Integrin expression was evaluated by immunohistochemistry in a Tissue Microarray containing two samples from each tumor. We employed a semiquantitative analysis and considered a case as positive when the expression was strong and diffusely present. We correlated expression with recurrence employing the χ2 test and p&lt;0.05 was considered significant.
Results: Positive expression of β1 integrin was found in 79 out of 100 evaluated cases, ten cases were lost in the tissue microarray. Correlating expression with recurrence we found in the univariate analysis that negative expression of β1 integrin was statistically associated with recurrence (p=0,042) and time to recurrence after radical prostatectomy, when expression of β1 is negative, the odds of recurrence was two times higher than that observed in positive cases (p=0.026 – IC 95% [1.09; 3.83]. In multivariate analysis, including PSA and Gleason, β1 integrin remained independently associated with recurrence p=0.01.
Conclusions: In the present study we have shown that a down regulation of β1integrin expression was significantly correlated with recurrence after radical prostatectomy for localized prostate cancer, making this integrin a potential candidate as a marker of prognosis. Larger series will be evaluated in order to confirm our initial findings
Figure Kaplan Meier curve for recurrence-free survival according to β1expression in 111primaryPCa submitted to RP
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 428. doi:10.1158/1538-7445.AM2011-428
Abstract 4286: Essential Roles of Jab1 in Cell Survival, Spontaneous DNA Damage, and DNA Repair
Authors: Claret Francois 
Published: July 2012

Abstract
Jun activation domain-binding protein 1 (JAB1) is a multifunctional protein that participates in the control cell proliferation and the stability of multiple proteins. JAB1 overexpression has been implicated in the pathogenesis of human cancer. JAB1 regulates several key proteins and thereby produces varied effects on cell cycle progression, genome stability, and cell survival. However, the biological significance of JAB1 activity in these cellular signaling pathways is unclear. Therefore, we developed mice that were deficient in Jab1 and analyzed the null embryos and heterozygous cells. This disruption of Jab1 in mice resulted in early embryonic lethality due to accelerated apoptosis. Loss of Jab1 expression sensitized both mouse primary embryonic fibroblasts and osteosarcoma cells to gamma radiation-induced apoptosis, with an increase in spontaneous DNA damage and homologous recombination (HR) defects, both of which correlated with reduced levels of the DNA repair protein Rad51 and elevated levels of p53. Furthermore, the accumulated p53 directly binds to Rad51 promoter, inhibited its activity, and represent a major mechanism underlying the HR repair defect in Jab1-deficient cells. These results indicate that Jab1 is essential for efficient DNA repair and mechanistically link Jab1 to the maintenance of genome integrity and to cell survival.
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 4286. doi:10.1158/1538-7445.AM2011-4286
Abstract 4289: Using the right tools: A catalog of ovarian cancer cell lines by subtype
Authors: Anglesio Michael S. , Sheppard Karen E. , Salamanca Clara M. , Chow Christine , Pearson Rick B. , Wang Yuzhuo , Kobel Martin , Gilks Blake , Kalloger Steve E. , Huntsman David G. 
Published: July 2012

Abstract
Ovarian cancer cell lines provide an important tool in exploring disease phenotypes and biology. Within the spectrum of ovarian epithelial cancers at least five histologically distinguishable unique diseases exist: high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous. While sharing a common site of presentation, these ovarian cancer types exhibit distinct genomic signatures, clinical characteristics and treatment responses. Thus, the critical interpretation of the results of cell based experiments performed in in-vitro and in-vivo model systems of ovarian cancer first requires characterization of the disease subtype each model represents. Our group has recently used a minimal panel of nine immunohistochemical (IHC) markers, termed “COSP” (Calculator for Ovarian carcinoma Subtype Prediction), to predict each ovarian cancer type. Application of COSP has suggested that as many as 19% of primary ovarian cancer samples may be misclassified prior to an expert review. Commonly used cell lines are rarely classified into ovarian cancer types, confounding interpretation of results and potentially delaying transition of basic research to clinically relevant application. We now apply COSP for typing commonly used ovarian cancer cell lines, as well as in-house derived xenografts, and primary culture models. The COSP immuno-predictive tool is combined with molecular and mutational data to support each cell line's subtype prediction while primary tumour types are compared to their derivative cell lines. We now present an extensive panel of accurately classified ovarian cancer cell lines to facilitate disease specific analysis of the biology of ovarian 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 4289. doi:10.1158/1538-7445.AM2011-4289
Abstract 43: Using matrix factorization to discover clinically-relevant molecular signatures across cancers
Authors: Szeto Christopher W. , Zhu Jingchun , Durbin James , Benz Stephen , Vaske Charles , Stuart Joshua , Haussler David 
Published: July 2012

Abstract
With increasing ubiquity of genome-wide assays it is now common to molecularly subtype cancers to predict patient therapy response. However identifying high-performing, robust molecular signatures for predictions remains difficult. Presented here is work towards a novel machine-learning algorithm that discovers intuitively understood and clinically relevant stratifying molecular signatures. This classification method, as well as many competing methods (SVM, random forests, Bayes nets, etc.), were applied by predicting drug-sensitivity to hundreds of compounds tested on the NCI60 cell lines. This new drug-sensitivity prediction method competes with and in many cases outperforms leading classifiers. The prediction results, as well as the molecular signatures that they are derived from, are publicly available for web-browsing through a new extension to the UCSC Cancer Genomics Browser, hgClassifications (http://genome-cancer.soe.ucsc.edu/hgClassifications).
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 43. doi:10.1158/1538-7445.AM2011-43
Abstract 4319: Effects of chemotherapeutics on organotypic corticostriatal slice cultures identified by a new panel of fluorescent and immunohistochemical markers
Authors: Jensen Stine S. , Nørregaard Annette , Kolenda Jesper , Aaberg-Jessen Charlotte , Garnier-Christensen Karina , Jensen Poul H. , Schrøder Henrik D. , Kristensen Bjarne W. 
Published: July 2012

Abstract
Effects of chemotherapeutics on glioma cell lines and spheroids are usually investigated without evaluating the effects of even very high concentrations of chemotherapeutics on normal brain tissue. To perform such investigations, the aim of the present study was to establish a panel of markers for detection of general cell death and more specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. Organotypic rat corticostriatal slice cultures were exposed to the alkylating agents temozolomide and nimustine, the tyrosine kinase inhibitor imatinib mesylate and the microtubule destabilizing agent vincristine. Densitometric measurements of uptake of the fluorescent dye propidium iodide were used for quantifying cellular degeneration. Moreover, paraffin sections were HE stained and immunohistochemically stained for the neuronal marker MAP2, the astroglial marker GFAP, and the oligodendrocyte marker p25α. The results showed that clinical drug concentrations were non-toxic. However, a time dependent increase in PI uptake was observed for supratherapeutic concentrations of the drugs, except for temozolomide, where no toxicity was observed at all. Corresponding immunostaining showed loss of MAP2 staining and increased expression of GFAP and p25α for cultures exposed to 1000 nM vincristine. Cultures exposed to supratherapeutic concentrations of nimustine and imatinib mesylate disintegrated, leaving no tissue for histology.
In conclusion, corticostriatal slice cultures and the established panel of markers represent an excellent tool for detecting toxicity by chemotherapeutics. Toxicity was not detected at clinical concentrations, but high concentrations with toxic effects were identified suggesting that some of the earlier identified anti-cancer effects in the literature are general cytotoxic effects and not specific anti-cancer effects.
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 4319. doi:10.1158/1538-7445.AM2011-4319
Abstract LB-162: Blockade of PD-L1 signaling, but not depletion of regulatory T cells, delays tumor growth in a murine pancreatic tumor model
Authors: Vohra Nasreen A. , Sarnaik Amod , Mackay Amy , Ghansah Tomar , Pilon-Thomas Shari 
Published: July 2012

Abstract
Pancreatic cancer is an aggressive disease with poor prognosis. Immunotherapy may be less effective in treating pancreatic tumors due to tumor-mediated suppression. Several mechanisms may contribute to immune suppression seen in mice bearing Panc02 pancreatic adenocarcinomas. We measured an increase in the percentage of CD4+CD25+foxp3+ regulatory T cells (Tregs) in the tumor and spleens of mice bearing Panc02 tumors (p&lt;0.001 compared to non-tumor bearing mice). These Tregs were capable of suppressing antigen-specific T cell proliferation in a dose-dependent manner. Treatment of mice bearing Panc02 tumors using combination therapy with dendritic cells (DC) and anti-CD25 antibody (PC-61) did not demonstrate a delay in tumor growth or survival. As depletion of Tregs had little effect on Panc02 tumor growth, we examined another mechanism of immune suppression. We measured the expression of programmed death ligand-1 (PD-L1) on the surface of Panc02. PD-L1 plays a crucial role in inhibiting T cell responses and maintaining peripheral tolerance. PD-L1 expression has been measured on most pancreatic adenocarcinomas and may lead to down-regulation of antigen-specific T cell responses. To examine PD-L1 signaling blockade, mice bearing Panc02 tumors were treated with anti-PD-L1 antibody at 3 day intervals. After 3 weeks, mice receiving anti-PD-L1 antibody displayed smaller tumors than mice receiving control antibody (134 mm2 vs 221mm2 respectively, p&lt;0.05). Splenocytes from PD-L1 treated mice secreted IFN-gamma in response to restimulation with Panc02 (p&lt;0.01 compared to control treated mice). Furthermore, treatment with anti-PD-L1 antibody in Panc02-bearing athymic nude mice had no effect on tumor growth, indicating that treatment is T cell dependent. Survival benefit was measured in tumor-bearing mice when anti-PD-L1 antibody treatment was combined with DC immunizations (35% survival on day 75 compared to 0% in all control groups, p&lt;0.05). To enhance this treatment, we examined combination therapy with DC, anti-PD-L1 and PC-61 antibodies. Depletion of Tregs did not enhance therapy with DC and anti-PD-L1 antibody. Together, these studies show that blockade of PD-L1 signaling inhibited tumor growth in mice with pancreatic cancer. Depletion of Tregs alone or in combination with PD-L1 blockade demonstrated no benefit in this model. Studies to optimize combination therapy using anti-PD-L1 antibody and DC-based vaccines are ongoing.
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 LB-162. doi:10.1158/1538-7445.AM2011-LB-162
Abstract LB-164: B lymphocytes inhibit anti-tumor response in a murine EMT6 tumor model by facilitating expansion of T regulatory cells
Authors: Zhang Yu , Tadmor Tamar , Eliav Yair , Schreiber Taylor H. , Podack Eckhard R. , Levy Robert , Shin Seung-uon , Rosenblatt Joseph D. 
Published: July 2012

Abstract
B lymphocytes play a central role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are still poorly understood. Murine EMT6 mammary tumors grow readily in immune competent mice (ICM) but poorly in B-cell deficient μ−/− BALB/c mice (BCDM). Both decreased T regulatory cell (Treg) expansion and impaired Treg function were observed in BCDM compared to ICM. In this study, we investigated how the presence or absence of B cells affects expansion of Tregs in response to tumor implantation. We compared tumor growth, and the number of Treg cells, T cell function, number and character of tumor infiltrating cells, immune effector molecule, chemokine and cytokine expression in tumor tissue in ICM, compared to BCDM and B cell reconstituted BCDM (BCDM+B).
Partial reconstitution of BCDM with adoptively transferred B cells restored tumor growth. Transfer of both normal and IL-10−/− B cells restored tumor growth in BCDM. Restored tumor growth correlated with an increase in CD4+FoxP3+ Treg cells in the spleen and draining lymph nodes and a decrease in interferon-γ secretion and cytotoxic T cell activity against EMT6 targets, in BCDM+B to BCDM. Tumor growth was completely inhibited in BCDM+B by depletion of Treg using PC61 antibody. Markedly increased levels of NK and CD8+ T cell infiltration into the tumor bed were seen in BCDM or BCDM+B treated with Treg depletion, compared to levels of infiltration seen in ICM or BCDM+B mice. PCR array analysis of mRNA expression in tumor tissue in BCDM, BCDM+B treated with PC61 antibody, or ICM following PC61 treatment, revealed down regulation of IL-17A, IL-17F, TGF-β and IL-23, CD73, VEGF-C, Rorγt and CCR4, when compared to either BCDM+B or BALB/c control mice. We observed similar changes in immune effector molecules/cytokines mRNA in all scenarios in which Treg levels were decreased.
In conclusion, our studies indicate that the T cell anti-tumor response is enhanced in the absence of B cells, in part due to effects on Treg cell expansion and changes in immune effector molecule and cytokine profile in the tumor micro-environment.
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 LB-164. doi:10.1158/1538-7445.AM2011-LB-164