bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 275: ER-886046, an antagonist of PGE2 receptor type-4, induces an effective antitumor immune response in mice by attenuating intratumoral MDSCs and TAMs
Authors: Albu Diana I. , Wang Zichun , Wu Jiayi , Huang Kuan-chun , Li Wei , Liu Diana , Kuznetsov Galina , Chen Qian , Bao Xingfeng , Woodall-Jappe Mary 
Published: August 2015

Abstract
One of the hallmarks of an immunosuppressive tumor microenvironment is the presence of myeloid-derived suppressor cells (MDSCs) and type 2 tumor-associated macrophages (TAMs). These myeloid cells derive from immature monocytes and their differentiation is highly regulated by the engagement of prostaglandin E2 (PGE2) receptor type 4 (EP4) with PGE2 in the tumor microenvironment. To understand the importance of EP4 for tumor support, we implanted mouse tumors in EP4 inducible knockout mice and found that these tumors grew significantly more slowly than in wild type mice, indicating an important role of host cell EP4 signaling for tumor progression. Here we report the development and evaluation of ER-886046, a novel and specific EP4 antagonist, for cancer treatment. Daily oral administration of ER-886046 inhibited the growth of multiple mouse syngeneic tumor models with an inhibitory activity up to 100%. The anti-tumor activity of ER-886046 was T cell-dependent since it was not observed in T cell deficient mice. Furthermore, we found in vitro and in vivo mechanistic evidence that ER-886046 interferes with tumor-induced monocyte differentiation into immunosuppressive type 2 macrophages and MDSCs, instead supporting monocyte differentiation into APCs and facilitating intratumoral T cell accumulation. Importantly, ER-886046 has a desirable pharmacokinetic and metabolism profile in mice, rats and dogs which qualifies it as a good candidate for clinical studies in humans. Thus, the preclinical data support further investigation of targeting EP4 signaling by ER-886046 as a novel immune therapy for cancer treatment in clinical setting.
Citation Format: Diana I. Albu, Zichun Wang, Jiayi Wu, Kuan-chun Huang, Wei Li, Diana Liu, Galina Kuznetsov, Qian Chen, Xingfeng Bao, Mary Woodall-Jappe. ER-886046, an antagonist of PGE2 receptor type-4, induces an effective antitumor immune response in mice by attenuating intratumoral MDSCs and TAMs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 275. doi:10.1158/1538-7445.AM2015-275
Abstract 2753: The germline TP53 p.R337H mutation: a putative selective advantage
Authors: Andrade Kelvin César , Leite Ana Carolina , Nobrega Amanda , Savage Sharon , Achatz Maria Isabel 
Published: August 2015

Abstract
Li-Fraumeni syndrome is a hereditary cancer predisposition disorder related to germline TP53 mutations. Although it is considered to be a rare condition worldwide, a high occurrence of a founder mutation, the p.R337H TP53, is present in 0.3% of Southern Brazilian population. In a subgroup of p.R337H carriers, specific characteristics associated with late aging were clinically observed, such as a lower frequency of metabolic alterations and diseases typical of aging. However, despite of these particular features no study has clinically characterized these individuals until the moment. Therefore, our aim was to evaluate clinical features of p.R337H carriers and compare them with a control group. We used a clinical form composed by information on physical characteristics, personal habits, clinical history of diseases and physical activity throughout life. After IRB approval, we applied it in 48 p.R337H carriers (mean age: 46,8; range: 16-100) and in 38 carrier's relatives who were mutation-negative, as controls, (mean age 52,7; range: 18-90). Fisher's exact test was performed for statistical analysis. Regarding personal characteristics and habits, no difference was found between groups neither among p.R337H asymptomatic and affected carriers. However, some diseases discrepancies were found: In individuals older than 55 years of age, prevalence of osteoporosis was significantly lower in the p.R337H group when compared to controls (12% vs 59%; p&lt;0,05). Anemia was also less frequent in p.R337H carriers (0% vs 13%; p&lt;0,05) when all ages are considered. Although non-statistically significant, lower frequencies of neurodegenerative disorders, gastritis and thyroid dysfunction were also observed in the p.R337H group. These findings provide further information about a better overall health in p.R337H carriers, suggesting a possible selective advantage. This could be a plausible explanation for why this deleterious mutation has persisted throughout successive generations. More detailed clinical characterization studies are under way as well as molecular approaches looking for interactions between the p.R337H mutation and cellular senescence mechanisms.
Citation Format: Kelvin César Andrade, Ana Carolina Leite, Amanda Nobrega, Sharon Savage, Maria Isabel Achatz. The germline TP53 p.R337H mutation: a putative selective advantage. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2753. doi:10.1158/1538-7445.AM2015-2753
Abstract 2798: Quercetin inhibits Cr(VI)-induced malignant transformation of human lung epithelial cells by targeting miR-21-Pdcd4 signaling pathway
Authors: Poyil Pratheeshkumar 
Published: August 2015

Abstract
Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Cancer prevention using natural products has become an integral part of cancer control. Quercetin is one of the most abundant dietary flavonoids widely present in many fruits and vegetables, possesses potent antioxidant activity capable of protecting normal cells from various stimuli-induced oxidative stress and cell death. MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, invasion and migration. Studies have shown that miR-21 exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (Pdcd4). The present study examined the effect of quercetin on the inhibition of Cr(VI) induced carcinogenesis and the role of miR-21-Pdcd4 signaling involved. Our results showed that quercetin decreased ROS generation induced by Cr(VI) exposure in Beas-2B cells. Chronic Cr(VI) exposure induced malignant cell transformation, increased miR-21 expression and caused inhibition of Pdcd4, which were significantly inhibited by the treatment of quercetin in a dose dependent manner. Stable knockdown of miR-21 or overexpression of pdcd4 in Beas-2B cells significantly reduced the Cr(VI) induced cell transformation. Furthermore, Quercetin also inhibited the Cr(VI) induced beta-catenin/TCF-dependent transcription. Taken together, these results demonstrate that quercetin is able to protect Beas-2B cells from Cr(VI)-induced carcinogenesis by targeting miR-21-Pdcd4 signaling.
Keywords: Hexavalent chromium, Quercetin, miR-21-Pdcd4 signaling
Citation Format: Pratheeshkumar Poyil. Quercetin inhibits Cr(VI)-induced malignant transformation of human lung epithelial cells by targeting miR-21-Pdcd4 signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2015-2798
Abstract 2808: Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450
Authors: Chen Ping , Hu Tao , Ma Yane , Chen Xiaoyu , Dai Liping , Lei Ningjing , Dong Ziming , Li Pei 
Published: August 2015

Abstract
Esophageal squamous carcinoma (ESCC) may be developed through a progressive sequence from mild to severe dysplasia, carcinoma in situ, and finally, invasive carcinoma. Chemoprevention can block or weaken the influence of development. Recent study has shown luteolin, a bioflavonoid, possesses anti-inflammatory, antioxidant, and anti-proliferative effects, and it might have a preventive effect in this progress. In this study, we focused on the effect of luteolin on cell cycle regulation in human Esophageal Squamous Carcinoma Cell Line EC1 and KYSE450 Cells in vitro and its potential mechanisms. Observations by flow cytometer showed that luteolin inhibited cell cycle progression at G2/M phase in a dose- and time-dependent manner. We also found that luteolin could induce cell apoptosis via decreasing activation of caspase-3 and down-regulation of mitochondrial membrane potential. Western blot results showed the protein expression of cycle related protein CyclinD1 and apoptosis related proteins caspase-3, caspase-9, and Bak were also significantly decreased in luteolin treated cells compared with the non-luteolin treated cells. Our results suggest that the proper use of luteolin might be a practical approach to the prevention of esophageal carcinoma via the inhibition of cell proliferation and other potential high risk regions for this disease.
Citation Format: Ping Chen, Tao Hu, Yane Ma, Xiaoyu Chen, Liping Dai, Ningjing Lei, Ziming Dong, Pei Li. Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2808. doi:10.1158/1538-7445.AM2015-2808
Abstract 2812: The chemo-prevention effect of statin on hepatocellular carcinoma cell lines
Authors: Ghalali Aram , Martin-Renedo Javier , Högberg Johan , Stenius Ulla 
Published: August 2015

Abstract
Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol lowering drugs. Recent epidemiology suggests that statins prevent aggressive HCC development (J Clin. Oncol. 2012; 30:623-630). In previous cell experiments we have shown that statins down-regulate nuclear Akt responses to insulin (J Biol Chem 2010; 285, 27900). We showed that atorvastatin decreases nuclear phosphorylated Akt (pAkt) levels in pancreatic and lung cancer cell lines within minutes. This rapid effect was apparently not mediated by HMG-CoA reductase inhibition; instead there were indications that it was mediated by the P2×7 receptor. Akt has oncogenic activity in HCC and many other cancer types, and we have now tested the possibility that the P2×7-Akt pathway is of importance for the anticipated anticancer effects of statins in HCC. We performed western blotting, immunocytochemistry and transfections assays and found that statins decrease insulin induced pAkt levels in the nucleus. Further, statin decrease the proliferation of liver cells significantly. Hepatocytes lacking P2×7 receptor was insensitive to these effects of statins. Overexpression of P2×7 restituted the statin effect on pAkt levels. Overexpression of Hepatit B X protein vector has been shown to increase pAkt levels (FEBS J 279, 1220) and we found that statin counteract the Hepatit B vector-induced pAkt. These data provide evidence for a signaling pathway by which statins decrease pAkt and its downstream effect on pGSK3β Ser9 in hepatocytes via the P2×7 receptor. As the Akt pathway is deregulated and may act as a driver in HCC development this signaling pathway may have a role in the indicated chemo-preventive effect of statins.
Citation Format: Aram Ghalali, Javier Martin-Renedo, Johan Högberg, Ulla Stenius. The chemo-prevention effect of statin on hepatocellular carcinoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2015-2812
Abstract 2826: Equimolar vs. pharmacokinetics-guided dosing in anti-cancer efficacy assessment of precursor-product pairs: Example with pyranocoumarins from Korean Angelica
Authors: Wu Wei , Puppala Manohar , Tang Suni , Zhang Jinhui , Xing Chengguo , Jiang Cheng , Lu Junxuan 
Published: August 2015

Abstract
Prostate cancer is a malignant disease quite unique to men and has the second highest mortality rate next to lung cancer in the United States, with an estimated 233,000 new cases to be diagnosed in 2014. Angelica gigas Nakai (AGN) is a traditional medicinal herb in Korea and China. Ethanol extract of dried AGN root has been shown by us and others to exert anti-cancer activity in several allograft and xenograft models. In recently completed studies in primary carcinogenesis model (TRAMP mice), our group has demonstrated that AGN ethanol extract can significantly suppress the growth of neuroendocrine (NE)-lineage cancers and inhibit prostate epithelial lineage lesions. These studies also found that major pyranocoumarin isomer compounds decursin (D) and decursinol angelate (DA) from AGN when provided at equimolar intake to that provided by AGN accounted for the epithelial lineage suppression efficacy, but was less active than AGN extract against NE-Ca growth. Because rodent models and humans convert D/DA rapidly and extensively (&gt;95%) into decusinol (DOH), we hypothesize that DOH (and/or its metabolites) may be the true “active” chemical for suppressing the epithelial cancer. To test this, we compared oral gavage of DOH at equimolar dose as D/DA in SCID mice carrying human LNCaP/AR-Luc cells inoculated subcutaneously. Whereas DOH treated mice showed greater suppression of tumor growth than D/DA, measurement of plasma DOH levels showed 1.7 fold higher in the former at 3 h post-dose. Our earlier work has shown in a rat model that gavage of DOH led to 2.4 fold area under curve (AUC) over that achieved by equimolar dosing of D/DA, suggesting differences for absorption, distribution, metabolism, and excretion (ADME) of DOH vs. D/DA in other species as well. We are currently conducting PK studies of DOH and D/DA in mice to establish their PK parameters in order to achieve bio-equivalent dosing to critically test DOH efficacy and our hypothesis. In summary, PK-evaluation of precursor-product pairs might be important to determine bio-equivalent dosing before costly anti-cancer efficacy tests are conducted to ensure valid efficacy comparison.
Citation Format: Wei Wu, Manohar Puppala, Suni Tang, Jinhui Zhang, Chengguo Xing, Cheng Jiang, Junxuan Lu. Equimolar vs. pharmacokinetics-guided dosing in anti-cancer efficacy assessment of precursor-product pairs: Example with pyranocoumarins from Korean Angelica. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2826. doi:10.1158/1538-7445.AM2015-2826
Abstract 2832: Targeting and depletion of circulating cancer cells by lipophilic antibody-modified erythrocytes
Authors: Simberg Dmitri 
Published: August 2015

Abstract
There is a great interest in targeting and selective ablation of populations of circulating cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers (natural life is 120 days) that are amenable to chemical modifications, drug loading and reinjection. Here we demonstrate that using our previously described lipophilic ligand painting strategy, red blood cells (RBCs) could be in one step converted into targeted entities that selectively seek and bind various cells in vitro and in vivo. In vitro, RBCs modified with lipophilic anti-EpCAM or anti-CD45 antibodies efficiently bound to cancer cells and leukocytes, forming characteristic rosettes. In vivo, intravenously injected RBCs painted with anti-CD45 antibody immediately associated with CD45 positive cells in blood, forming RBC-leukocyte rosettes. Moreover, anti-CD45-modified RBCs, but not the same amount of anti-CD45 antibody or anti-CD45-lipid conjugate (1-2 microgram per mouse), depleted over 50% of CD45+ leukocytes from circulation, with main clearance organs of leukocytes being liver and spleen with no visible deposition in kidneys and lungs. Anti-CD20 (rituximab)-painted RBCs efficiently (over 90%) depleted CD19+/CD20+/CD45+ human lymphoma cells in mantle cell lymphoma (MCL) JeKo-1 model, while the same amount of rituximab-lipid (2 microgram per mouse) was much less efficient in lymphoma cell depletion. Treatment of MCL mice with rituximab-modified RBCs carrying only 2 μg of the antibody resulted in a significant prolongation of survival as compared to the same amount of antibody control. Lipophilic ligand-painted RBCs is a novel tool that can be utilized for targeting blood borne cells for experimental immunology and cancer therapy applications.
Citation Format: Dmitri Simberg. Targeting and depletion of circulating cancer cells by lipophilic antibody-modified erythrocytes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2832. doi:10.1158/1538-7445.AM2015-2832
Abstract 2847: High complexity barcoding to study clonal dynamics in response to cancer therapy
Authors: Bhang Hyo-eun C. , Ruddy David A. , Krishnamurthy Radhakrishna Viveksagar , Zhao Rui , Kao Iris , Rakiec Daniel , Shaw Pamela , Balak Marissa , Caushi Justina X. , Ackley Elizabeth , Keen Nicholas , Schlabach Michael R. , Palmer Michael , Sellers William R. , Michor Franziska , Cooke Vesselina G. , Korn Joshua M. , Stegmeier Frank 
Published: August 2015

Abstract
Targeted therapies, such as erlotinib and imatinib, lead to dramatic clinical responses, but the emergence of resistance presents a significant challenge. Recent studies have revealed intratumoral heterogeneity as a potential source for the emergence of therapeutic resistance. However, it is still unclear if relapse/resistance is driven predominantly by pre-existing or de novo acquired alterations. To address this question, we developed a high-complexity barcode library, ClonTracer, which contains over 27 million unique DNA barcodes and thus enables the high resolution tracking of cancer cells under drug treatment. Using this library in two clinically relevant resistance models, we demonstrate that the majority of resistant clones pre-exist as rare subpopulations that become selected in response to therapeutic challenge. Furthermore, our data provide direct evidence that both genetic and non-genetic resistance mechanisms pre-exist in cancer cell populations. The ClonTracer barcoding strategy, together with mathematical modeling, enabled us to quantitatively dissect the frequency of drug-resistant subpopulations and evaluate the impact of combination treatments on the clonal complexity of these cancer models. Hence, monitoring of clonal diversity in drug-resistant cell populations by the ClonTracer barcoding strategy described here may provide a valuable tool to optimize therapeutic regimens towards the goal of curative cancer therapies.
Citation Format: Hyo-eun C. Bhang, David A. Ruddy, Viveksagar Krishnamurthy Radhakrishna, Rui Zhao, Iris Kao, Daniel Rakiec, Pamela Shaw, Marissa Balak, Justina X. Caushi, Elizabeth Ackley, Nicholas Keen, Michael R. Schlabach, Michael Palmer, William R. Sellers, Franziska Michor, Vesselina G. Cooke, Joshua M. Korn, Frank Stegmeier. High complexity barcoding to study clonal dynamics in response to cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2847. doi:10.1158/1538-7445.AM2015-2847
Abstract 2853: Investigating DNAPK as a biomarker and a novel therapeutic target in aggressive prostate cancer
Authors: Kothari Vishal , Goodwin Jonathan F. , Zhao Shuang , Davicioni Elai , Karnes Jeffrey R. , Den Robert B. , Mehra Rohit , Knudsen Karen E. , Feng Felix Y. 
Published: August 2015

Abstract
Background/purpose: Despite recent advances in the development of androgen deprivation therapies (ADT), prostate cancer (PCa) remains the second leading cause of cancer death in American men. Thus, there is a critical need to improve treatment outcomes for men with aggressive PCa. The purpose of this study was to identify and functionally characterize kinases that can serve as both prognostic biomarkers and therapeutic targets in PCa.
Methods: To identify kinases associated with metastatic progression of PCa, we utilized high-density oligonucleotide arrays to interrogate the expression of all kinases in 545 prostatectomy samples, obtained from high-risk patients with long-term clinical follow-up (&gt;10 years). We ranked all kinases by their fold change in expression between PCas that subsequently metastasized versus those that did not. We then characterized the top ranked kinase in preclinical PCa models with in vitro mechanistic experiments and in vivo therapeutic studies.
Results: We nominated DNA-dependent protein kinase (DNAPK) as the top kinase associated with metastatic PCa progression. Interrogation of pathways associated with DNAPK knockdown in PC3, DU145, VCaP and C4-2B, identified canonical Wnt signaling as the top DNAPK-activated pathway. In PCa cells (PC3, LNCaP C.S. {LNCaP grown under charcoal-stripped serum condition}, C4-2B and LNCaP-AR) DNAPK inhibition significantly abrogates Wnt signaling and abolishes cell proliferation, migration and invasion. Interestingly, we found that DNAPK directly modulates the Wnt signaling independent of the androgen receptor (AR), highlighting the therapeutic potential of DNAPK inhibition in cancers resistant to ADT. Indeed, in VCaP xenograft models, pharmacologic inhibition of DNAPK with NU7441 demonstrated 3.4 fold (p&lt;0.01) reduction of tumor growth at non-toxic doses. Using an independent prostate cancer tissue cohort, we validate DNAPK expression as a biomarker for metastatic disease progression (p = 6.4 e−06, hazard ratio = 2).
Conclusion: In summary, we nominate DNAPK as a potential biomarker of disease progression and as a novel therapeutic target in aggressive prostate cancer. Our data suggests that DNAPK mediates PCa progression by upregulating Wnt signaling, and demonstrates that DNAPK inhibition results in significant tumor responses in PCa xenografts.
Citation Format: Vishal Kothari, Jonathan F. Goodwin, Shuang Zhao, Elai Davicioni, Jeffrey R. Karnes, Robert B. Den, Rohit Mehra, Karen E. Knudsen, Felix Y. Feng. Investigating DNAPK as a biomarker and a novel therapeutic target in aggressive prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2853. doi:10.1158/1538-7445.AM2015-2853