bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2730: Novel animal models of pancreatic cancer induced by smoking and chronic pancreatitis.
Authors: Xu Shiping , Grippo Paul J. , Khayrutdinova Oxana M. , French Samuel W. , Pandol Stephen J. , Gukovskaya Anna S. , Edderkaoui Mouad 
Published: August 2014

Abstract
Background and Aims: Smoking and pancreatitis are two major risk factors for pancreatic cancer. We developed novel mouse models of pancreatic cancer induced by smoking and chronic pancreatitis. We used two pancreatic cancer mouse models induced by overexpression of Kras with two different degrees of disease complexity. Methods: Wild type (WT), EL-Kras and Pdx1-Cre;LSL-Kras transgenic mice were subjected to a major cigarette smoke compound nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at doses close to those accumulated with smoking (100mg/kg) or exposed to tobacco smoke (80mg/m3) in tobacco smoke chambers for five days a week during 6 weeks. Standard model of chronic pancreatitis induced by cerulein injections (50μg/kg) for 3 weeks was applied to WT and Pdx1-Cre;LSL-Kras mice. Mice were then sacrificed and pancreatic tissue analyzed. Apoptosis was assessed by TUNEL. Autophagy was assessed by measuring autophagic markers LC3-II and p62. Pancreatic lesions, proliferation, fibrosis and inflammation were analyzed by immunohistochemistry. Epithelial to mesenchymal transition (EMT) and expression of stem cell markers were analyzed by Western. Results: NNK and exposure to tobacco smoke significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions in Kras transgenic mice. Smoking stimulated fibrosis and stellate cells activation but had no significant effect on inflammation. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by NNK and tobacco smoke exposure in both WT and transgenic mice. NNK decreased apoptosis and LC3-II level in Kras mice. In addition, smoking stimulated expression of stem cell markers sox2 and CD133. Cerulein stimulated fibrosis, stellate cells activation, inflammation, and slightly stimulated EMT in WT and transgenic mice. Combination of smoking and cerulein had additive effect on stimulation of PanIN lesion formation, fibrosis, EMT and stem cell markers induction. Conclusion: The results indicate that both tobacco smoke and chronic cerulein pancreatitis promote pancreatic cancer progression in both EL-Kras and Pdx1-Cre;LSL-Kras mice models. Smoking acts through enhancing fibrosis and EMT; whereas pancreatitis stimulates mainly inflammation and fibrosis. Smoking and pancreatitis have additive effect on fibrosis, EMT and acquiring of stem cell characteristics.
Citation Format: Shiping Xu, Paul J. Grippo, Oxana M. Khayrutdinova, Samuel W. French, Stephen J. Pandol, Anna S. Gukovskaya, Mouad Edderkaoui. Novel animal models of pancreatic cancer induced by smoking and chronic pancreatitis. [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 2730. doi:10.1158/1538-7445.AM2013-2730
Abstract 2733: K14-GFP-miR-31 transgenic mice confer high susceptibility to squamous cell tumorigenesis on oral tongue and esophagus.
Authors: Tseng Ssu-Hsueh , Lee Yong-Syu , Chang Kuo-Wei , Lin Shu-Chun 
Published: August 2014

Abstract
Squamous cell carcinoma (SCC) occurring on head and neck region and esophagus causes tremendous cancer mortality around the world. Effects from tobacco and/or alcoholic carcinogens and other factors are highly associated with the prevalence of these malignancies. MiRNAs are small non-coding RNAs mediating the RNA interference on targeted mRNAs. They play important roles in the pathogenesis of malignancies. miR-31 is among the most eminently up-regulated miRNAs in SCC occurring in head and neck region and esophagus. To elucidate the molecular pathogenesis of SCC, we established miR-31 transgenic mouse lines, in which miR-31 is under the control of K14 promoter and co-expressed with GFP. GFP and miR-31 were detected in basal and suprabasal squamous cells of skin, oral cavity and esophagus in these transgenic mice. The transgenic mice exhibited higher potential for tumor induction than wild type mice on oral tongue and esophagus by 4-nitroquinoline 1-oxide (4NQO) treatment. The precancerous lesions on oral tongues and esophagus in transgenic mice were also in more advanced stages in contrast to counterparts of wild type mice. Homozygous transgenic mice had the worst prognosis than the others. 4NQO induction also up-regulated miR-31 expression in tumors of wild type mice. The tumors induced in transgenic mice expressed more abundant miR-31 and VEGF, and less abundance of factor inhibiting HIF (FIH) than tumors in wild type mice. Base excision repair genes were validated as targets of miR-31 in human SCC cell lines, and the expression of these target genes were also decreased in the squamous epithelium of transgenic mice. This study identifies the high sensitivity of K14-GFP-miR-31 transgenic mice for chemical carcinogen-induced squamous cell tumorigenesis, and this could be associated with the down-regulation of tumor suppressor genes and the impairment of repair activity to counteract carcinogenic stimuli in squamous cells.
Citation Format: Ssu-Hsueh Tseng, Yong-Syu Lee, Kuo-Wei Chang, Shu-Chun Lin. K14-GFP-miR-31 transgenic mice confer high susceptibility to squamous cell tumorigenesis on oral tongue and esophagus. [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 2733. doi:10.1158/1538-7445.AM2013-2733
Abstract 2734: Residual embryonic cells as precursors of a Barrett's-like metaplasia.
Authors: Wang Xia 
Published: August 2014

Abstract
Barrett's esophagus is an intestine-like metaplasia and precursor of esophageal adenocarcinoma. Trig- gered by gastroesophageal reflux disease, the origin of this metaplasia remains unknown. p63-deficient mice, which lack squamous epithelia, may model acid-reflux damage. We show here that p63 null embryos rapidly develop intestine-like metaplasia with gene expression profiles similar to Barrett's metaplasia. We track its source to a unique embry- onic epithelium that is normally undermined and re- placed by p63-expressing cells. Significantly, we show that a discrete population of these embryonic cells persists in adult mice and humans at the squa- mocolumnar junction, the source of Barrett's meta- plasia. We show that upon programmed damage to the squamous epithelium, these embryonic cells migrate toward adjacent, specialized squamous cells in a process that may recapitulate early Barrett's. Our findings suggest that certain precancerous lesions, such as Barrett's, initiate not from genetic alterations but from competitive interactions between cell lineages driven by opportunity.
Citation Format: Xia Wang. Residual embryonic cells as precursors of a Barrett's-like metaplasia. [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 2734. doi:10.1158/1538-7445.AM2013-2734
Abstract 2750: Targeted therapy of childhood ALL and Ewing's sarcoma using antiCD19 (antiCD99)-Hybrid Polymerized Liposomal Nanoparticles (HPLN).
Authors: Kang HyungGyoo , Shahbazian Violette , Nagy Jon , Triche Timothy 
Published: August 2014

Abstract
Current success in childhood cancer therapy improves the survival rate of patients but unfortunately not all childhood cancers have shown successful survival rates and still many types of childhood cancer continue to have a poor prognosis. Furthermore due to the poor specificity of cancer therapies almost two-third of childhood cancer survivals experience side effects such as secondary cancers, heart or lung damage, infertility or chronic hepatitis. Therefore a reliable, non-toxic high therapeutic window targeted therapy is urgently needed to treat childhood cancer patients. In our study a novel nanoparticle (HPLN) was used for the treatment of childhood ALL and Ewing's sarcoma. The tumor specific monoclonal antibody was conjugated to the PLN into which Doxorubicin was uptaken using active loading method. AntiCD19 and antiCD99 antibodies were used for targeting of ALL and Ewing tumor, respectively. These tumor specific HPLNs effectively inhibit tumor growth in a murine model of ALL and Ewing's sarcoma. Removal of targeting antibody or drug eliminates the antitumor effects, which proves this anticancer effect of HPLN is very specific to the target cancer cells and dependent upon drug. Additionally, no abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted HPLN delivery system of anticancer drugs to childhood cancer.
Citation Format: HyungGyoo Kang, Violette Shahbazian, Jon Nagy, Timothy Triche. Targeted therapy of childhood ALL and Ewing's sarcoma using antiCD19 (antiCD99)-Hybrid Polymerized Liposomal Nanoparticles (HPLN). [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 2750. doi:10.1158/1538-7445.AM2013-2750
Abstract 2756: Targeted inhibition of Chromosomal Maintenance Region Protein (CRM1) potently suppresses growth of human neuroblastoma cell line models.
Authors: Attiyeh Edward F. , McKeon-Fish Aaron , Landesman Yosef , Senapedis William , McCauley Dilara , Kashyap Trinayan , Shacham Sharon , Kauffman Michael , Maris John M. 
Published: August 2014

Abstract
Background: Neuroblastoma is a childhood malignancy of the peripheral nervous system, and most patients with high-risk disease are not cured. New therapies are needed, but recurrent somatic mutations indicative of a tractable therapeutic target are rare. Translocation of p53, FOXO, IκB and other critical tumor suppressor proteins (TSPs) from the nucleus to the cytosol is mediated by exportin 1 (CRM1, XPO1), suggesting that inhibition of CRM1 is a rational anti-cancer strategy. KPT-330 is a Selective Inhibitor of Nuclear Export (SINE) that irreversibly binds CRM1 and is currently in Phase 1 clinical trials. SINE inhibits CRM1-mediated nuclear export across multiple tumor types leading to activation of TSPs and cancer cell death.
Methods: A panel of 14 well-characterized neuroblastoma cell lines was treated with KPT-330 across a 5-log range. Growth inhibition was measured using CellTiter-Glo (Promega) viability assays and a real time growth monitoring system (xCELLigence, Roche). NOD/SCID mice with neuroblastoma xenografts were treated orally with KPT-330 and tumor size was monitored.
Results: KPT-330 showed cytotoxicity against 14 neuroblastoma cell lines with a median IC50 of 289±47.5 nM. Sensitivity to KPT-330 was independent of MYCN amplification status. Combination of KPT-330 with commonly used cytotoxic agents (irinotecan, topotecan, cisplatin, doxorubicin) showed additive effects. In xenograft models using the neuroblastoma cell lines IMR-32 and SH-SY5Y, oral administration of KPT-330 (10 or 20 mg/kg, twice or thrice weekly) was well tolerated and showed significant tumor growth inhibition (p&lt;0.001). KPT-330 treatment resulted in decreased Myc family protein levels as well as activation of apoptotic pathways.
Conclusions: Neuroblastomas show sensitivity to CRM1 inhibition both in vitro and in vivo. Ongoing work is focused on discovering the cellular and genomic factors responsible for increased sensitivity to nuclear export inhibition. With the expected completion of the first in human phase I trials by mid 2013, treatment with KPT-330 has the potential to be rapidly translated into a clinical trial for children with neuroblastoma.
Citation Format: Edward F. Attiyeh, Aaron McKeon-Fish, Yosef Landesman, William Senapedis, Dilara McCauley, Trinayan Kashyap, Sharon Shacham, Michael Kauffman, John M. Maris. Targeted inhibition of Chromosomal Maintenance Region Protein (CRM1) potently suppresses growth of human neuroblastoma cell line models. [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 2756. doi:10.1158/1538-7445.AM2013-2756
Abstract 2766: YM155 inhibits survivin-mediated survival, migration, and tumor growth in neuroblastoma.
Authors: McClung Heather M. , Zhao Ping , Smith Lauren , Eckardt Alexandra , Sholler Giselle L. 
Published: August 2014

Abstract
Background: Neuroblastoma is the most common extracranial solid tumor in children, with poor prognosis in children diagnosed after 12-15 months of age. Even with current multimodal therapies, the 5-year event-free survival is below 50%, necessitating the development of new, targeted therapies. Survivin is a developmentally regulated gene that is highly up-regulated in many cancers. In neuroblastoma, survivin is up-regulated by PI3Kinase-AKT signaling and its expression correlates with poor prognosis. Survivin is a member of the Inhibitor of Apoptosis family of proteins and is involved in cell survival through caspase dependent and independent pathways. Knockdown of survivin in melanoma cells reduces cell migration in vitro and its expression correlates with metastasis in Ewing's Sarcoma and Schwann cell tumors. YM155 is a transcriptional suppressor of survivin and has shown efficacy in several cancer model systems both in vivo and in vitro and is currently under clinical investigation for adult cancers. In this study, we investigate the effects of YM155 on neuroblastoma cell apoptosis and migration in vitro and on tumor growth in vivo.
Methods: Four neuroblastoma cell lines were treated with YM155 and subject to cell viability and migration assays. Gene expression was investigated by microarray and signaling by Western Blotting. In vivo, effects on tumor volume were determined by xenograft implant of neuroblastoma cell lines followed by YM155 treatment and measurement by calipers.
Results: Treatment with YM155 caused a dose-dependent decrease in survivin expression and reduced cell viability in neuroblastoma cell lines; however IC50 values vary by cell line. Cells treated with YM155 near the respective IC50 showed increased cleavage of Caspase 3 and PARP indicating apoptosis. Gene and protein expression changes include reduced CXCR4 and Mcl-1. Low levels of YM155 reduced cell migration by 30-50%; cytotoxicity was not observed at the lower concentrations. Treatment with YM155 reduced tumor growth in vivo by 25-70% and depended on cell line.
Conclusions: YM155 inhibits survivin expression, reduces cell viability, induces apoptosis, and migration in vitro, and reduces tumor volume in vivo. Further investigation is warranted in characterization of YM155 as a possible therapeutic agent for neuroblastoma.
Citation Format: Heather M. McClung, Ping Zhao, Lauren Smith, Alexandra Eckardt, Giselle L. Sholler. YM155 inhibits survivin-mediated survival, migration, and tumor growth in neuroblastoma. [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 2766. doi:10.1158/1538-7445.AM2013-2766
Abstract 2768: Molecular properties and antiproliferative activity against tumor cells of a new poly-alkylamino-bis-maltolic synthetic molecule (maltonis).
Authors: Manara Maria Cristina , Fanelli Mirco , Amatori Stefano , Guerzoni Clara , Landuzzi Lorena , Lollini Pier-Luigi , Giorgi Luca , Fusi Vieri , Scotlandi Katia 
Published: August 2014

Abstract
Introduction Hydroxypyrones are highly versatile molecules and several members of this family, both alone and in combination with metals, were found to exert anti-proliferative activities against a wide range of tumor cells. In this study, we show the anti-tumor potential of the prototype of new molecules belonging to the family of hydroxypyrones, named maltonis [4(N),10(N)-bis[(3- hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane], in different tumor cell lines (derived from both hematopoietic and solid human tumors).
Methods and Results We examined the potential of maltonis to induce, in cell-free assays, covalent modifications of DNA structure, together with anticancer activities (cell growth inhibition, cell cycle perturbations, effects on programmed cell death). The cellular response to maltonis treatment was assessed also at the molecular level by evaluation of the transcript level of genes involved in cell cycle and programmed cell death regulation. The possible induction of a maltonis-mediated DNA damage response was investigated monitoring the histone H2AX phosphorylation (γH2AX). Sarcoma cell lines appeared to be particularly sensitive to maltonis in in vitro assays. Consistently, preliminary in vivo experiments reported a cytostatic effect of maltonis, monitoring a consistent reduction of the neoplastic lesions, when intra-tumor injected at doses of 20/40 mg/kg (for two weeks) in a xenograft model of Ewing Sarcoma. However, a range of different levels of sensitivity was observed in the different histotypes (osteosarcoma, Ewing sarcoma and rhabdomyosarcoma) and among cell lines, indicating the need of further studies to identify markers of efficacy.
Conclusions Taken together, these results show that maltonis appears to be a good candidate for sarcoma treatment. It induces complex DNA structural modifications, which need to be further analysed in order to clarify mechanisms of action and efficacy of this new drug.
Grants from: AIRC 10452 and Ministry of Health_RF2008 to KS; A.S.S.O., PRIN 2008 and PRIN 2009 to MF and VF.
Citation Format: Maria Cristina Manara, Mirco Fanelli, Stefano Amatori, Clara Guerzoni, Lorena Landuzzi, Pier-Luigi Lollini, Luca Giorgi, Vieri Fusi, Katia Scotlandi. Molecular properties and antiproliferative activity against tumor cells of a new poly-alkylamino-bis-maltolic synthetic molecule (maltonis). [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 2768. doi:10.1158/1538-7445.AM2013-2768
Abstract 2769: DSRCT: Establishing xenograft and tissue culture cell lines and assessing chemosensitivity.
Authors: Markides Constantine SA , Vardeman Dana M. , Luong Linh , Coil Douglas R. , Kozielski Anthony , Mendoza John , Giovanella Beppino C. 
Published: August 2014

Abstract
Desmoplastic small round cell tumor (DSRCT) is an extremely rare and aggressive neoplasm which mainly affects young males and generally presents as a widely disseminated tumor within the peritoneal cavity. Due to the rarity of the tumor, a younger and overall healthier patient population, and because it lacks definitive histologic and immunohistologic features, it is possible that DSRCT is frequently delayed in diagnosis or is entirely misdiagnosed as a different kind of abdominal sarcoma. This study seeks to rectify the dearth of models that exist for this rare neoplasm through the development of several DSRCT tissue culture and xenograft lines. Samples were received from surgeries and biopsies from patients around the world and were immediately processed for xenograft development in nude mice. Tumor tissues were minced and fragments were injected onto the dorsal flank of nude mice. Of the 15 samples received, 9 were established into xenograft lines and 6 of those into tissue culture lines. Xenografts displayed the microscopic histology of their parent tumors and two different growth rates among established xenograft lines. Chemosensitivity of tumors was assessed against a variety of chemotherapeutic agents and IC50 values established for each drug and cell line. Interestingly, the cell lines were split into two distinct groups in terms of morphology, growth rate and chemosensitivity. Overall, the establishment of these xenograft and tissue culture lines gives researchers tools to evaluate DSRCT response to chemotherapy and investigate DSRCT-specific signaling pathways or mechanisms.
Citation Format: Constantine SA Markides, Dana M. Vardeman, Linh Luong, Douglas R. Coil, Anthony Kozielski, John Mendoza, Beppino C. Giovanella. DSRCT: Establishing xenograft and tissue culture cell lines and assessing chemosensitivity. [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 2769. doi:10.1158/1538-7445.AM2013-2769
Abstract 277: Investigation of the signaling factors involved in Ras/MAPK-promoted metastasis in the PTEN−/−TP53−/− mouse model.
Authors: Tillman Heather S. , Yin Juan Juan , Liu Yen Nien , Awan Musaddiq , Martin Philip , Kelly Kathleen 
Published: August 2014

Abstract
The most significant challenges for advanced prostate cancer patients are resistance to androgen-deprivation therapy and the dissemination of metastatic cancer cells. Our study begins to address how enhanced Ras signaling cooperates with combined TP53 and PTEN loss for enhanced metastatic capability. Because neither PTEN nor TP53 deletion alone is not sufficient for metastasis, we asked what other signaling pathways are required. Ras pathway activation is implicated in prostate cancer metastatic progression in comprehensive genetic analyses of human prostate tumors. We introduced a lentiviral vector expressing K-rasG12V into a non-metastatic PTEN−/−/TP53−/- adenocarcinoma cell line (clone 2). Orthotopic prostate injection of clone2/Ras expressing cells resulted in 100% pulmonary metastasis. The metastatic phenotype was paralleled by an inhibition of sarcomatoid carcinoma transformation. We hypothesized that Ras signaling modified TGFβ-mediated EMT signaling, which we have previously demonstrated leads to sarcomatoid carcinoma formation in this model. Multiple pathways downstream of TGFβ initiate signaling including SMAD4 dependent transcription and other non-SMAD mediated pathways like TAK1 induced NF-κB activation. Pathologic analysis of nuclear p65 labeling, a canonical NF-κB marker, showed enhanced labeling in clone2/Ras developed tumors and lung metastases and undetectable levels in clone 2 developed tumors. These in vivo findings suggest enhanced canonical NF-κB signaling may enable Ras transformed prostate cancer cells with metastatic capability.
Citation Format: Heather S. Tillman, Juan Juan Yin, Yen Nien Liu, Musaddiq Awan, Philip Martin, Kathleen Kelly. Investigation of the signaling factors involved in Ras/MAPK-promoted metastasis in the PTEN−/−TP53−/− mouse model. [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 277. doi:10.1158/1538-7445.AM2013-277