bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3899: PCB153-induced angiogenesis depends on redoxsensitive Pyk2 signaling.
Authors: Das Jayanta K. , Felty Quentin H. 
Published: August 2014

Abstract
Estrogenic chemicals have been shown to increase the expression of the growth factor VEGF in breast cancer cells. Hence, there is some concern that environmental exposure to estrogenic chemicals such as polychlorinated biphenyls (PCBs) may excacerbate the growth of breast cancer via angiogenesis. Highly metastatic breast cancer cells exposed to PCB153 have been reported to produce a significantly greater amount of ROS compared to non-metastatic breast cancer cells. A number of paracrine effects have been reported in tumors exposed to estrogen, however, the role of estrogen-induced ROS in signaling tumor angiogenesis remains to be defined. We previously reported that PCB-induced angiogenesis can be blocked by
Pyk2 siRNA. Therefore, the goal of this study was to determine whether Pyk2 small molecule inhibitors block PCB-induced vascularization in a 3-D breast tumor model. Human umbilical vein endothelial cells (HUVEC) or brain microvascular endothelial cells (hCMEC/D3) were used to study the effect of small molecule inhibitors. The effect of Pyk2 inhibition on breast tumor spheroid angiogenesis was tested in a 3-D co-culture of MDA-MB-231 breast cancer cells. MDA-MB-231 cells exposed to PCB153 produced ROS most likely H2O2; therefore we determined whether external H2O2 exposure increased DNA synthesis of vascular endothelial cells. Our results showed a significant increase in DNA synthesis from exposure to H2O2 for
18hrs. Breast tumor spheroids treated with PF431396 or Pyk2 siRNA showed a significant reduction in microvessel sprouting and length when compared to control. Confocal microscopy of endothelial cells co-cultured with smooth muscle cells and fibroblasts further showed a significant increase in endothelial cell branching when exposed to PCB153. The effects of PCB153 on endothelial cells in co-culture were inhibited by treatments with the ROS scavenger
N-acetylcysteine. We have provided evidence for the role of Pyk2 redox signaling in the aggressive angiogenic phenotype of endothelial cells. Our results suggest that metastatic breast cancer cells exposed to PCBs release ROS that may directly activate the redox sensitive kinase Pyk2 in neighboring endothelial cells. Consequently, Pyk2 redox signaling in neighboring endothelial cells may promote the aggressive spread of breast cancer.
Citation Format: Jayanta K. Das, Quentin H. Felty. PCB153-induced angiogenesis depends on redoxsensitive Pyk2 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3899. doi:10.1158/1538-7445.AM2013-3899
Abstract 3906: Magnolol suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting Ras-dependent mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways.
Authors: Kim Ki Mo , Kim No Soo , Kim Jinhee , Park Jong-Shik , Yi Jin Mu , Lee Jun , Bang Ok-Sun 
Published: August 2014

Abstract
Magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, has been reported to possess anti-cancer activity. Recent studies have also demonstrated that magnolol inhibits cell growth and induces the apoptosis of cancer cells. However, the effects of magnolol on vascular endothelial growth factor (VEGF)-induced angiogenesis in endothelial cells have not been studied. In the present study, we have used human umbilical vein endothelial cells (HUVECs) to investigate the anti-angiogenic effect and molecular mechanism of magnolol. Magnolol inhibited the VEGF-induced proliferation, chemotactic motility and tube formation of HUVECs in vitro as well as the vessel sprouting of the aorta ex vivo. Furthermore, magnolol inhibited VEGF-induced Ras activation and subsequently suppressed extracellular signal-regulated kinase (ERK), phosphatidylinositol-3-kinase (PI3K)/Akt and p38, but not Src and focal adhesion kinase (FAK). Interestingly, the knockdown of Ras by short interfering RNA produced inhibitory effects that were similar to the effects of magnolol on VEGF-induced angiogenic signaling events, such as ERK and Akt/eNOS activation, and resulted in the inhibition of proliferation, migration, and vessel sprouting in HUVECs. In combination, these results demonstrate that magnolol is an inhibitor of angiogenesis and suggest that this compound could be a potential candidate in the treatment of angiogenesis-related diseases.
Citation Format: Ki Mo Kim, No Soo Kim, Jinhee Kim, Jong-Shik Park, Jin Mu Yi, Jun Lee, Ok-Sun Bang. Magnolol suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting Ras-dependent mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3906. doi:10.1158/1538-7445.AM2013-3906
Abstract 3907: Expression of vascular endothelial growth factor a (VEGF-A) in advanced gallbladder cancer.
Authors: Letelier Pablo , Buchegger Kurt , Ili Carmen , Garcia Patricia , Brevi Priscilla , Sandoval Alejandra , Leal Pamela , Riquelme Ismael , Roa Juan Carlos 
Published: August 2014

Abstract
Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. Molecular mechanisms involved in GBC pathogenesis remain poorly understood. The Vascular Endothelial Growth Factor A (VEGF) is a potent proangiogenic agent involved in the carcinogenesis of many human tumors and it is an attractive target for cancer therapy. The aim of this study was characterize VEGF expression in advanced gallbladder cancer and determine it's relationships with clinicopathologic features and utility as a prognostic factor. VEGF expression was examined by immunohistochemistry (IHC) in tissue microarrays containing 224 advanced gallbladder carcinomas and 39 cases of chronic cholecystitis (CC). The advanced GBC were classified as low or high expression to evaluate the association of VEGF expression level with clinical variables. Statistical analysis was performed using univariate analyses with a significance level of P&lt;0.05; survival analysis was performed by the Kaplan- Meier method with the log-rank test. High expression of VEGF was observed in 183 of 224 (81%) tumors and 2 of 39 (5.1%) of chronic cholecystitis (P&lt;0.0001). The VEGF expression had a significant relationship with clinical or pathological features included histological grade and TNM stage (P&lt;0.05). Moreover, 5-year survival analysis indicated that high expression of VEGF is associated with a poor prognosis in patients with advanced gallbladder cancer (P = 0.0116). Our results indicate that VEGF is highly expressed in gallbladder cancer and correlates with poor prognostic, suggesting that VEGF expression could be used as a biomarker for predicting malignant behavior and to identify a subset of patients who may benefit from anti-VEGF therapies.
Citation Format: Pablo Letelier, Kurt Buchegger, Carmen Ili, Patricia Garcia, Priscilla Brevi, Alejandra Sandoval, Pamela Leal, Ismael Riquelme, Juan Carlos Roa. Expression of vascular endothelial growth factor a (VEGF-A) in advanced gallbladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2013-3907
Abstract 3926: Molecular imaging of VEGFR expression modulation by antiangiogenic therapy in mouse model of human breast cancer.
Authors: Zhu Wenlian , Kato Yoshinori , Mease Ronnie C. , Sarkar Susanta , Backer Marina V. , Backer Joseph M. , Artemov Dmitri 
Published: August 2014

Abstract
Antiangiogenic therapy targeting VEGF/VEGFR signaling is an important strategy for cancer treatment, which is currently used in mono-therapy or combination therapy settings. However, the emerging resistance to antiangiogenic therapy as well as varied clinical response calls for the development of early, preferably noninvasive, markers of treatment response. In this study we used a recently developed molecular imaging tracer, site-specifically 99mTc-labeled engineered single-chain VEGF derivative, to monitor the VEGF receptor expression during the course of sunitinib antiangiogenic therapy in orthotopic human breast cancer model MDA-MB-231. The treatment protocol included two cycles of therapy delivered daily for 5 days (80mg/kg, orally) with a 5-day vacation between the cycles. Micro SPECT/CT imaging was performed longitudinally up to day 16. Animals in the control group received vehicle solution only. Tumors were excised and stained for the expression of CD31 endothelial cell marker. Experimental results suggest a highly heterogeneous vascular regression response to the first round of treatment, with significantly decreased tracer uptake and CD31 prevalence in some but not all tumors. As judged by the increase in tracer uptake and CD31 prevalence, a significant vascular rebound took place in all tumors after the vacation period. Judging by the same criteria, the second round of treatment was significantly less effective than the first round. Taken together, these results suggests that noninvasive molecular imaging of VEGF receptors reflects vascular regression and rebound in individual tumors and can provide clinically relevant information for monitoring and scheduling antiangiogenic therapy.
Citation Format: Wenlian Zhu, Yoshinori Kato, Ronnie C. Mease, Susanta Sarkar, Marina V. Backer, Joseph M. Backer, Dmitri Artemov. Molecular imaging of VEGFR expression modulation by antiangiogenic therapy in mouse model of human breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2013-3926
Abstract 3973: Effects of anti-PD-1 and anti-4-1BB antibody treatment on melanoma-specific T cells in a murine model of melanoma.
Authors: Robinson John L. , Kodumudi Krithika , Weber Amy , Sarnaik Amod , Pilon-Thomas Shari 
Published: August 2014

Abstract
Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) is a promising immunotherapeutic approach and has resulted in durable response rates of 20-30% in patients with metastatic melanoma. However, several limitations exist to prevent the widespread implementation of adoptive cell therapy, including inadequate infiltration of tumor-specific T cells into tumors and anemic expansion of tumor-specific T cells in vitro. One such factor is PD-1 expression on T cells that plays an important role in T cell exhaustion. Agonistic co-stimulatory molecules such as 4-1BB which is transiently expressed on activated T cells can reverse T cell exhaustion and enhance anti-tumor immune response. In this study, we have examined two approaches to improve the frequency of tumor-specific T cells in tumors and TIL cultures. First, we examined whether blocking PD-L1/PD-1 signaling increased the infiltration of tumor-specific T cells in the murine B16 melanoma model. Mice bearing B16 tumors were treated with NrIgG or anti-PD-1 antibodies. T cells were isolated from B16 tumors on day 18 after tumor injection. Increased IFN-γ production following B16 restimulation was observed in TIL isolated from mice treated with anti-PD-1 antibody (1445 ± 48 pg/ml) compared to TIL isolated from mice treated with control antibody (748 ± 25 pg/ml, p&lt;0.001). In addition, we examined whether the expansion of T cells during TIL culture in vitro could be augmented by targeting the co-stimulatory molecule, 4-1BB. T cells were isolated from B16 tumors and cultured in vitro with 10 mcg/mL anti-4-1BB antibody. After 5 days, increased B16-specific IFN-γ was measured in TIL cultured with anti-4-1BB antibody (1865 ± 64 pg/ml, p&lt;0.001 compared to TIL cultured with control antibody). Combination treatment with anti-PD-1 antibody therapy in vivo and anti-4-1BB antibody in vitro demonstrated synergistic effects, with increased levels of IFN-γ (4440 ± 486 pg/ml) produced by B16-specific TIL. These findings suggest that anti-PD-1 antibody treatment in combination with in vitro 4-1BB antibody treatment can enhance the frequency of tumor-specific T cells isolated from B16 melanoma. This may represent a potential strategy to increase the effectiveness of TIL therapy in patients with melanoma.
Citation Format: John L. Robinson, Krithika Kodumudi, Amy Weber, Amod Sarnaik, Shari Pilon-Thomas. Effects of anti-PD-1 and anti-4-1BB antibody treatment on melanoma-specific T cells in a murine model of melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3973. doi:10.1158/1538-7445.AM2013-3973
Abstract 3976: PD-1 blockade combined with TEGVAX (TLR agonists-enhanced GVAX) can induce regression of established palpable tumors.
Authors: Malm Ian-James , Fu Juan , Pardoll Drew , Kim Young J. 
Published: August 2014

Abstract
Background: Cell-based vaccines have been developed for several types of tumors, but these vaccines have two critical shortcomings that weaken their clinical efficacy. The first of which is a limited capability to activate antigen presenting cells. Second, they fail to address critical immune checkpoint molecules that dampen the subsequent T-cell response against the established tumor. In order to optimize the activation of antigen presenting cells capable of marshaling both an innate and adaptive immune response against the tumor, we formulated a GM-CSF secreting tumor cell vaccine with multiple TLR agonists. To address the immune checkpoint signaling pathway, we combined our formulated vaccine with a blocking αPD-1 antibody in two mouse models of established tumor - one with melanoma and the other with tongue cancer.
Methods: To optimize in vivo efficacy of anti-tumor T-cell response, we engineered TEGVAX, a GM-CSF secreting cell-based tumor vaccine formulated with GLA (TLR4 agonist) and R848 (TLR7/8 agonists), molecules that are amenable for clinical translation. We then combined TEGVAX with αPD-1 blocking antibody (G4 clone) in the murine B16 melanoma and SCCFVII tongue cancer model. Furthermore, we studied immunological parameters that correlated with in vivo anti-tumor response.
Results: In both B16 and SCCFVII treatment models, TEGVAX demonstrated statistically significantly (p&lt;0.01) enhanced anti-tumor responses in comparison to the parental cell vaccine in vivo. For tumor bearing mice treated with TEGVAX, these potent anti-tumor responses were correlated with a statistically significant increase in CD4+ and CD8+ T-cells that secrete IFNγ in the tumor microenvironment. TEGVAX treated mice also had significantly higher levels of tumor antigen p15E-specific cell mediated killing in vivo. Blockade of the PD-1 immune checkpoint pathway further augmented the therapeutic potential of TEGVAX and induced the regression of established B16 and SCCFVII tumors.
Conclusion: When combined with αPD-1 antibody, TEGVAX was able to induce regression of established B16 and SCCFVII tumors. Our results with these combinatorial immunotherapeutic strategies provide preclinical evidence to support the translation of these reagents for HNSCC or melanoma patients that are refractory to standard treatment modalities.
Citation Format: Ian-James Malm, Juan Fu, Drew Pardoll, Young J. Kim. PD-1 blockade combined with TEGVAX (TLR agonists-enhanced GVAX) can induce regression of established palpable tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2013-3976
Abstract 3977: Mark cancer cells for CTL attack through coating with viral antigenic peptides.
Authors: Hung Chien-Fu 
Published: August 2014

Abstract
Selectively coating tumor cells with foreign antigenic peptide may render coated tumor susceptible to immune recognition and elimination, thereby bypassing immune tolerance. Here we create a therapeutic chimeric protein comprised of a tumor-homing module fused to a functional cargo domain containing foreign antigenic peptide. The tumor-homing module is comprised of mesothelin-specific single chain variable fragment that specifically binds to mesothelin, commonly overexpressed in ovarian tumors. The functional cargo domain is comprised of Fc (IgG2a) protein and MHC class I-restricted foreign CD8+ T cell epitope flanked by furin cleavage sites, which can be recognized by furin highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto MHC class I of bound tumor cells, rendering them susceptible to antigen-specific CD8+ T cell-mediated killing for potent antitumor effects in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.Selectively coating tumor cells with foreign antigenic peptide may render coated tumor susceptible to immune recognition and elimination, thereby bypassing immune tolerance. Here we create a therapeutic chimeric protein comprised of a tumor-homing module fused to a functional cargo domain containing foreign antigenic peptide. The tumor-homing module is comprised of mesothelin-specific single chain variable fragment that specifically binds to mesothelin, commonly overexpressed in ovarian tumors. The functional cargo domain is comprised of Fc (IgG2a) protein and MHC class I-restricted foreign CD8+ T cell epitope flanked by furin cleavage sites, which can be recognized by furin highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto MHC class I of bound tumor cells, rendering them susceptible to antigen-specific CD8+ T cell-mediated killing for potent antitumor effects in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.
Citation Format: Chien-Fu Hung. Mark cancer cells for CTL attack through coating with viral antigenic peptides. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3977. doi:10.1158/1538-7445.AM2013-3977
Abstract 3997: Nanoproteomic analysis of extracellular receptor kinase-1/2 post-translational activation in microdissected human hyperplastic aberrant crypt foci.
Authors: Drew David A. , Devers Thomas , Horelik Nicole , Yang Shi , O'Brien Michael , Wu Rong , Rosenberg Daniel W. 
Published: August 2014

Abstract
Oncogenic activation resulting in hyperproliferative lesions within the colonic mucosa has been identified in putative precancerous lesions, aberrant crypt foci (ACF). KRAS (codons 12 and 13) and BRAFV600E mutation status was determined in 172 ACF identified in colorectum of screening subjects by in situ high-definition, magnifying chromoendoscopy. Lesions were stratified according to histology: serrated hyperplastic versus distended (non-serrated) hyperplastic. Due to their limiting size, however, it was not technically feasible to examine downstream signaling consequences of these oncogenic mutations. We have combined ultraviolet-infrared (UV/IR) micro-dissection with an ultra-sensitive nanofluidic proteomic immunoassay (NIA) to enable accurate quantification of post-translational modifications to mitogen-activated protein kinase (MAPK) in total protein lysates isolated from hyperproliferative crypts and adjacent normal mucosa. Using this approach, levels of singly and dually (activated) phosphorylated isoforms of extracellular receptor kinase(ERK)-1 and -2 were quantified in samples containing as little as 16-ng of total protein recovered from &lt;200 colon epithelial cells. ERK activation is responsible for the observed hyperplasia found in these early lesions, but its activation state is not directly dependent on KRAS and/or BRAF mutation status. This study describes the novel use of a sensitive nanofluidic platform to measure oncogene-driven proteomic changes in diminutive lesions procured at the time of endoscopy and highlights the advantage of this approach over classical immunohistochemistry-based analyses.
Citation Format: David A. Drew, Thomas Devers, Nicole Horelik, Shi Yang, Michael O'Brien, Rong Wu, Daniel W. Rosenberg. Nanoproteomic analysis of extracellular receptor kinase-1/2 post-translational activation in microdissected human hyperplastic aberrant crypt foci. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3997. doi:10.1158/1538-7445.AM2013-3997