bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1177: Pharmacological stimulation of DLL1-Notch signaling as an effective cancer immunotherapy
Authors: Biktasova Asel K. , Dudimah Fred D. , Uzhachenko Roman , Arasada Rajeswara Rao , Tchekneva Elena E. , Carbone David P. , Shanker Anil , Dikov Mikhail M. 
Published: May 2015

Abstract
Our data demonstrated that in cancer, expression of Notch ligands is selectively altered and Notch signaling in the hematopoietic compartment is attenuated and associated with impaired anti-tumor immunity caused by the aberrant T cell differentiation and function. Our important and therapeutically relevant finding is that stimulation of DLL1-mediated Notch signaling by systemic administration of soluble multivalent (clustered) DLL1 efficiently restores Notch signaling in the hematopoietic compartment. Such therapy strongly activates Notch downstream signaling and variably modulates expression of Notch receptors and ligands. Clustered DLL1 treatment results in significant enhancement of tumor antigen-specific T cell immune responses and memory, decreased proportion of regulatory T cells, remarkably increased tumor infiltration by T cells, attenuated tumor vascularization, and suppression of tumor growth. In an inducible model of lung tumor expressing L858R mutant EGFR in lung epithelium, clustered DLL1 elicited robust anti-tumor immune responses in concert with EGFR inhibition by erlotinib and produced remarkably improved progression-free survival. It is also likely that more efficient tumor killing and induction of T cell memory would significantly delay tumor progression/recurrence. Activation of Notch signaling by multivalent DLL1 in a panel of lung cancer cells in vitro did not stimulate cells proliferative of colony-forming potential, but rather demonstrated inhibitory effect in several cases. Pharmacological stimulation of Notch by multivalent DLL1 might represent an efficient strategy for enhancement of anti-tumor immunity and targeting multiple mechanisms of tumor growth. Reagents based on the multivalent forms of Notch ligands can be efficiently utilized for the therapeutic modulation of Notch signaling.
Citation Format: Asel K. Biktasova, Fred D. Dudimah, Roman Uzhachenko, Rajeswara Rao Arasada, Elena E. Tchekneva, David P. Carbone, Anil Shanker, Mikhail M. Dikov. Pharmacological stimulation of DLL1-Notch signaling as an effective cancer immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1177. doi:10.1158/1538-7445.AM2014-1177
Abstract 1179: Macrophage conditioned media increases the expression of a metastasis-associated oncogene, RhoC, and the migration of inflammatory breast cancer cells
Authors: Fournier Chelsea L. , Allen Steven G. , Chen Yu-Chih , Yoon Euisik , Merajver Sofia D. 
Published: May 2015

Abstract
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer because it progresses rapidly and often presents with distant metastases at diagnosis. RhoC GTPases, known to play an important role in the movement of cells, are overexpressed in IBC tumor cells. The mechanism that causes this increase in RhoC expression is unknown. Tumor associated macrophages (TAMs) have been found to facilitate the movement and invasion of breast cancer. Therefore, as a component of the immune system attracted to sites of inflammation, we hypothesized that TAMs play a role in increasing RhoC expression in IBC cells, which consequently leads to IBC's severe migratory and metastatic capabilities.
The expression of RhoC increased in two different IBC cell lines, SUM149 and SUM190, in the presence of conditioned media (CM) from macrophage-differentiated U937 cells. This increase was not observed in either the normal-like MCF-10A cell line or the non-IBC MDA-MB-231 breast cancer cell line. From this observation, a novel microfluidic device allowed the study of the migratory phenotype of individual cells of the two IBC cell lines in response to standard chemoattractants as well as the macrophage CM. As expected, the presence of a serum gradient promoted the chemotaxis of IBC cells versus serum-free control. A CM gradient also increased the migration of IBC cells to a moderate degree. However, in the overlapping presence of CM without a gradient and serum with a gradient, the cells exhibiting an extreme migratory phenotype migrated roughly twice the distance of the serum gradient control. We believe the CM acts to “prime” the IBC cells in order to manifest an ultra-response to the serum chemoattractant. In both IBC cell lines stably-transfected with shRNA targeted to RhoC, we observed decreased migration when exposed to the CM migration conditions. Therefore, RhoC expression is necessary for this increase in migration.
Studies involving RhoC inhibitors are ongoing, but could yield promising therapies for the prevention of metastasis of IBC. Future studies will aim to identify which cytokines in the CM and which specific pathways are responsible for the increased RhoC expression and migration of IBC cells. By understanding the specific mechanism of TAMs' effects on IBC cells we hope to learn better how to control the lethal metastatic nature of inflammatory breast cancer.
Citation Format: Chelsea L. Fournier, Steven G. Allen, Yu-Chih Chen, Euisik Yoon, Sofia D. Merajver. Macrophage conditioned media increases the expression of a metastasis-associated oncogene, RhoC, and the migration of inflammatory breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1179. doi:10.1158/1538-7445.AM2014-1179
Abstract 1188: Primary human breast tumor explant platform for integrated profiling and target validation
Authors: Nevalaita Liina , Ala-Hongisto Hanna , Lehtivaara Maria , Heikkilä Päivi , Leidenius Marjut , Kovanen Panu , Monni Outi , Klefström Juha 
Published: May 2015

Abstract
Primary explant culture preserves three-dimensional architecture of tumor tissue, intra-tumoral heterogeneity and aspects of tumor microenvironment, including interactions between tumor cells and the adjacent tissue cells. For these reasons, it is believed that the explant cultures capture tumor-specific pathways and their complexities better than possibly any other in vitro or ex vivo tumor model. We are developing a primary human breast tumor explant platform allowing integration of rapid, small-scale genome profiling with validation of tumor specific targets. We show that the explants, processed to 100 uM fragments and cultured on a 3D matrix, contain both epithelial and stromal cells and maintain the viability for up to 12 days. To characterize the explant phenotype and similarity to the original tumor, we have examined explants and the original tumors side-by-side by immunohistochemistry (IHC), immunocytochemistry (ICC) and genome profiling. The biomarkers analyzed by IHC and/or ICC include hormone receptors, cytokines, epithelial and stromal cell markers as well as proliferation and apoptosis markers. A small-scale genome profiling analysis was performed with TruSeq Amplicon Cancer panel. Cancer-related missense mutations were identical in 60% of original tumor/ explant pairs and had minor differences in 40% of original tumor/ explant pairs. Compared to original tumors, proliferation was increased in explants but clear correlation in the level of proliferation between original tumor/ explant was observed. In conclusion, our preliminary findings suggest surprisingly similar genetic landscapes between breast tumor explants and the cognate primary tumors. Therefore, breast tumor explant platforms could predict well the efficacy of molecular targeted and personalized therapies.
Citation Format: Liina Nevalaita, Hanna Ala-Hongisto, Maria Lehtivaara, Päivi Heikkilä, Marjut Leidenius, Panu Kovanen, Outi Monni, Juha Klefström. Primary human breast tumor explant platform for integrated profiling and target validation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1188. doi:10.1158/1538-7445.AM2014-1188
Abstract 1211: Application of PDX models in mimic clinical trials for anticancer drug development
Authors: Chen Taiping , Hu Yan , Zhang Hui , Sun Xiaoqin 
Published: May 2015

Abstract
The utilization of patient derived xenograft (PDX) models has recently gained huge recognition in anticancer drug research and development. Based on molecular profiling the resemblance between patient tumor and PDX is significantly closer than that between patient tumor and traditional cell lines. Therefore, new initiatives are proposed to apply PDX models in in vivo target validation, clinical relevant MOA study, tumor addiction and heterogeneity characterization, sensitivity and resistance to chemotherapeutics and targeted therapeutics, and even mimic clinical trials for cancer type indication. In order to evaluate the efficacious and pharmacodynamic responses in PDX models and support the rationale for mimic clinical trials, we freshly established PDX models from the patients with colorectal (CRC), lung, pancreatic, gastric, liver cancers. The tumor take rate was very high for CRC and lung cancer patient, 90% and 70% respectively. Irinotecan and Cetuximab for colorectal PDX model, Docetaxel and Tarceva for lung PDX model were organized as mimic clinical trials. The high tumor take-rate (9 of 10 colorectal; 7 of 10 lung cancer) will ascertain pharmacologic significance when tested in mimic clinical trials. To illustrate the usefulness of this platform, we first evaluate the responders and non-responders based on efficacious trials. Then we will further continue with single dose for pharmacodynamic (PD) biomarker evaluation from selected drug targets or related pathway regulators. Efficacy results and corresponding PD biomarkers confirmed in this approach have potential to be used for cancer indication and patient stratification in later phase II clinical trials.
Citation Format: Taiping Chen, Yan Hu, Hui Zhang, Xiaoqin Sun. Application of PDX models in mimic clinical trials for anticancer drug development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1211. doi:10.1158/1538-7445.AM2014-1211
Abstract 1218: Telomerase-specific GFP-expressing adenovirus enables fluorescence-guided surgery (FGS) for patient-derived orthotopic xenograft (PDOX) in nude mice
Authors: Yano Shuya , Hiroshima Yukihiko , Maawy Ali , Katz Matthew H.G. , Fleming Jason B. , Kishimoto Hiroyuki , Suetsugu Atsushi , Uehara Fuminari , Miwa Shinji , Tazawa Hiroshi , Bouvet Michael , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: May 2015

Abstract
We have previously developed the genetically-engineered GFP-expressing telomerase-specific oncolytic adenovirus (OBP-401) which selectively targets tumors. Our laboratory pioneered the patient-derived orthotopic xenografts (PDOX) model (Proc. Natl. Acad. Sci. USA 88, 9345-9349, 1991). In order to develop fluorescent-guided surgery (FGS) in the clinical setting, we used OBP-401 to label PDOX of pancreatic cancer in nude mice. OBP-401 (ip) effectively labeled pancreatic cancer PDOX in nude mouse models. GFP-expressing PDOX pancreatic tumors were readily resected using fluorescence-guided surgery (FGS). Our results suggest that OBP-401 therefore has clinical potential for labeling pancreatic cancer for FGS. This is particularly important in pancreatic cancer where positive margins result in most cases of standard surgery, leading to extremely low survival rates.
Citation Format: Shuya Yano, Yukihiko Hiroshima, Ali Maawy, Matthew H.G. Katz, Jason B. Fleming, Hiroyuki Kishimoto, Atsushi Suetsugu, Fuminari Uehara, Shinji Miwa, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman. Telomerase-specific GFP-expressing adenovirus enables fluorescence-guided surgery (FGS) for patient-derived orthotopic xenograft (PDOX) in nude mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1218. doi:10.1158/1538-7445.AM2014-1218
Abstract 1230: Efficacy of Salmonella typhimurium A1-R and anti-VEGF therapy on a patient-derived orthotopic xenograft (PDOX) pancreatic cancer model
Authors: Hiroshima Yukihiko , Zhao Ming , Katz Matthew H.G. , Fleming Jason B. , Sato Sho , Murakami Takashi , Yamamoto Mako , Uehara Fuminari , Miwa Shinji , Yano Shuya , Momiyama Masashi , Zhang Yong , Maawy Ali , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: May 2015

Abstract
We have previously developed the genetically-modified Salmonella typhimurium A1-R (A1-R) strain that selectively targets tumors and demonstrated that A1-R was able to eradicate primary and metastatic tumors in monotherapy in nude mouse models of various cancers including pancreatic cancer. The aim of this study was to examine the efficacy of A1-R treatment on VEGF-positive human pancreatic cancer in a patient derived orthotopic xenograft (PDOX) model in combination with anti-VEGF therapy. A VEGF-positive human pancreatic cancer cell line (MiaPaCa-2-GFP) and VEGF-positive pancreatic cancer PDOX were orthotopically implanted in nude mice. The nude mice were treated in the following groups: (1) gemcitabine (GEM) (80 mg/kg, ip, weekly, 4 weeks); (2) GEM (80 mg/kg, ip, weekly, 4 weeks) + Bevacizumab (Bev) (5 mg/kg, ip, twice a week, 4 weeks); (3) GEM (80 mg/kg, ip, weekly, 2 weeks) + Bev (5 mg/kg, ip, twice a week, 2 weeks) → A1-R (1.5x108 CFU/body, ip, weekly, 2 weeks); and (4) saline (vehicle/control, ip, weekly, 4 weeks). The mean tumor weight of each group in the MiaPaCa-2-GFP model was as follows: (1) GEM; 775.9 ± 273.8 mg; (2) GEM/Bev; 413.5 ± 108.3 mg; (3) GEM/Bev→A1-R; 257.5 ± 57.1 mg; and (4) Control; 2655.4 ± 583.9 mg. GEM/Bev→A1-R significantly reduced tumor weight compared to GEM/Bev treatment in the MiaPaCa-2-GFP model (p=0.022). The tumor weight of each group in the PDOX model was as follows: (1) GEM; 263.1 ± 129.1 mg, (2) GEM/Bev; 65.9 ± 41.9 mg, (3) GEM/Bev→A1-R; 21.9 ± 6.2 mg and (4) Control; 998.8 ± 377.7 mg. GEM/Bev→A1-R significantly reduced tumor weight compared to GEM/Bev treatment in the PDOX model (p=0.029). These results demonstrate that A1-R is effective on pancreatic cancer in combination with anti-VEGF, including the PDOX model indicating the clinical potential of this combination.
Citation Format: Yukihiko Hiroshima, Ming Zhao, Matthew H.G. Katz, Jason B. Fleming, Sho Sato, Takashi Murakami, Mako Yamamoto, Fuminari Uehara, Shinji Miwa, Shuya Yano, Masashi Momiyama, Yong Zhang, Ali Maawy, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Efficacy of Salmonella typhimurium A1-R and anti-VEGF therapy on a patient-derived orthotopic xenograft (PDOX) pancreatic cancer model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2014-1230
Abstract 1247: Assessment of the roles of prostaglandin E2 receptors in a rodent model of chemically induced esophageal carcinogenesis
Authors: Shi Ni , Chen Tong 
Published: May 2015

Abstract
Esophageal carcinogenesis is a multistage process characterized by morphological changes from normal esophagus to basal cell hyperplasia, dysplasia, carcinoma in situ and squamous cell carcinoma (SCC). Our laboratory has used a rodent model of N-nitrosomethylbenzylamine (NMBA)-induced esophageal SCC to investigate molecular carcinogenesis and identify putative chemopreventive agents. In our previous studies, we found that the expression of cyclooxygenase-2 and the production of prostaglandin E2 (PGE2) in rat esophageal epithelium were elevated in papillomatous lesions relative to precancerous and normal tissues. PGE2 exerts its cellular effect by binding to its cognate receptors. There are four subtypes of PGE2 receptors, EP1, EP2, EP3 and EP4, which are involved in carcinogenesis depending on the cell or tissue types. The overall objective of the current study was to assess the roles of PGE2 receptors in NMBA-induced rat esophageal tumorigenesis. F344 rats were injected subcutaneously with NMBA (0.30 mg/kg b.w.) three times per week for five weeks. One week after NMBA treatment, animals were randomized into five experimental groups and fed 300 ppm celcecoxib plus 50 ppm S,S'-1,4-phenylenebis(1,2-ethanediyl)bisisothiourea (PBIT) starting from week 6, 9, 12 , or 15, respectively, or 5% freeze-dried black raspberries (BRB) starting from week 6. Esophagi were collected at 29 weeks. Results of real-time PCR, western blot analysis and immunohistochemistry demonstrated a correlation between the upregulation of EP1, EP2, EP3 and EP4 and neoplastic progression in the rat esophagus. The expression of the PGE2 receptors in preneoplastic tissues and papillomas was significantly elevated when compared to normal tissues. Moreover, we observed that celecoxib + PBIT and 5% BRB significantly reduced EP2 expression. Our data suggest, therefore, that the production of PGE2 receptors by the esophageal epithelium is associated with the development of NMBA-induced esophageal tumorigenesis in rats, and EP2 antagonist may have chemopreventive potential in esophageal cancer. Research efforts are needed to elucidate the function of PGE2 receptors and related oncogenic pathways in esophageal SCC. (Supported by NIH/NCI R01 CA131073-01A1).
Citation Format: Ni Shi, Tong Chen. Assessment of the roles of prostaglandin E2 receptors in a rodent model of chemically induced esophageal carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1247. doi:10.1158/1538-7445.AM2014-1247
Abstract 1263: Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality
Authors: Yang Meng , Kenfield Stacey A. , Blarigan Erin L. Van , Kasperzyk Julie L. , Sesso Howard D. , Ma Jing , Stampfer Meir , Chavarro Jorge E. 
Published: May 2015

Abstract
Objective: We investigated the relation of post-diagnostic dietary patterns with prostate cancer-specific and all-cause mortality.
Methods: 926 men participating in the Physicians' Healthy Study diagnosed with non-metastatic prostate cancer completed a food frequency questionnaire (FFQ) a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years. Two dietary patterns, a Prudent and a Western pattern, were identified using principal component analysis. Multivariate Cox proportional hazards regression was used to estimate the relative hazard of prostate cancer-specific and all-cause mortality in relation to post-diagnostic dietary pattern scores. Models were adjusted for age at diagnosis, time between diagnosis and FFQ completion, energy intake, vigorous exercise, BMI, smoking status, and a modified D'Amico risk score.
Results: We identified 333 deaths, 56 due to prostate cancer, during 8,093 person-years of follow-up. The Prudent pattern was characterized by higher intake of vegetables, fruits, fish, legumes and whole grains, while the Western pattern was characterized by higher intake of processed and red meats, potatoes, high-fat dairy and refined grains. Men in the highest quartile (Q4) of the Western pattern had a higher risk of prostate cancer-specific death than men in the lowest quartile (Q1) (Hazard ratio [HR]: 2.39; 95% Confidence Interval [CI]: 0.95, 6.00; P for linear trend=0.03). The association between the Western pattern and prostate cancer-specific mortality appeared to be driven by intake of potatoes (HR[Q4 vs Q1]: 2.85; 95% CI: 1.06, 7.62; P for linear trend=0.01). In addition, the Western pattern was associated with higher all-cause mortality (HR[Q4 vs Q1]: 1.73; 95% CI: 1.20, 2.49; P for linear trend=0.005). A Prudent pattern after diagnosis was unrelated to prostate cancer-specific mortality but was associated with lower all-cause mortality (HR[Q4 vs Q1]: 0.60; 95% CI: 0.42, 0.88; P for linear trend=0.007).
Conclusions: A Western dietary pattern may increase risk of prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern may decrease the risk of all-cause mortality, all among men diagnosed with localized prostate cancer.
Citation Format: Meng Yang, Stacey A. Kenfield, Erin L. Van Blarigan, Julie L. Kasperzyk, Howard D. Sesso, Jing Ma, Meir Stampfer, Jorge E. Chavarro. Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1263. doi:10.1158/1538-7445.AM2014-1263
Abstract 1305: Basal level of FANCD2 monoubiquitination is required for the maintenance of a sufficient number of licensed-replication origins to fire at a normal rate
Authors: Jayabal Panneerselvam , Pickering Anna , Bing Han , Peiwen Fei 
Published: May 2015

Abstract
Normal DNA replication starts following the stepwise recruitment of replication initiators to assemble Mini-chromosome Maintenance (MCM) 2-7 protein complexes at an adequate amount of DNA replication origins. Under normal conditions, the monoubiquitination of Fanconi Anemia (FA) group D2 protein (FANCD2) occurs in each S-phase of cell cycle, which is the basal level of FANCD2 monoubiquitination. However, little is known regarding the roles of this basal level of monoubiquitinated FANCD2. Here, we report that monoubiquitnated FANCD2 in each S-phase of a given cell cycle can interact with replication origins and MCM3. In normally growing cells, the presence of non-monoubiquitinated FANCD2 or mutant MCM3 lacking AA 477-480 responsible for interacting with FANCD2 can lead to an insufficient amount of licensed origins ready for firing and, thereby, enlarged intervals between the fired origins. These results demonstrate that in normally cycling cells, the monoubiquitinated FANCD2 is required to maintain an enough number of licensed origins to initiate a normal DNA replication. This finding is the first to provide insights into how FANCD2 functions under normal conditions of cell cycle to maintain genome stability, as well as its resulting implications in the strategic improvement for the fight against human cancer. This study is funded by NIH RO1CA136532.
Citation Format: Panneerselvam Jayabal, Anna Pickering, Han Bing, Fei Peiwen. Basal level of FANCD2 monoubiquitination is required for the maintenance of a sufficient number of licensed-replication origins to fire at a normal rate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1305. doi:10.1158/1538-7445.AM2014-1305