bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1184: The circadian factor Period2 modulates p53 function in unstressed cells
Authors: Finkielstein Carla V. , Gotoh Tetsuya , Vila-Caballer Marian , Santos Carlo , Liu Jingjing , Yang Jianhua 
Published: August 2012

Abstract
Circadian rhythms are mechanisms that measure time on a scale of about 24 h and that adjusts our body to external environmental signals. Core circadian clock genes are defined as genes whose protein products are necessary components for the generation and regulation of circadian rhythms. Circadian proteins also regulate genes involved in either cell division or death; and a perturbation of the balance among these processes leads to cancer development and progression. A key aspect of cancer research is identifying new regulatory pathways involved in proliferation and differentiation of cell. Disruption of circadian rhythm has recently emerged as a new potential risk factor in the development of cancer, pointing to the core gene period 2 (per2) as a tumor suppressor. However, it remains unclear how the circadian network regulates tumor suppression, nor which, if any, of its components is either the ultimate effector that influences the fate of the cell. Initial experiments were devoted to identify new interacting partners for Per2 using a two-hybrid system. Interestingly, among the positive clones analyzed was the tumor suppressor protein p53. This result was validated by immunoprecipitation of recombinant and endogenous Per2/p53 complexes from unstressed cells. Pull-down assays using tagged-expressed proteins fragments and labeled proteins were later used to map the interacting regions between Per2 and p53. Our results show Per2 binds to the C-terminus of p53 in a region that includes the DNA binding and tetramerization domains and that includes the ubiquitination sites. Thus, we hypothesized that binding of Per2 to p53 might act by blocking Mdm2-mediated ubiquitination of p53 target residues in the C-terminus and therefore altering its stability. We next examined the formation of the Mdm2/p53/Per2 complex by immunoprecipitation. Our data show anti-p53 antibody is able to co-immunoprecipitate Per2 and Mdm2. Moreover, in vitro and in vivo ubiquitination assays show that binding of Per2 to p53 prevented ubiquitination of p53 by Mdm2 without altering their binding. Immunofluorescence studies using H1299 cells (p53-) confirmed Per2 role in p53 stabilization and for localization. Overall our results suggest that Per2 modulates the stability of p53 in unstressed cells, and might be responsible for the oscillatory levels of p53 observed in a 24 h cycle.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1184. doi:1538-7445.AM2012-1184
Abstract 1186: Differences in the levels, localization and DNA binding of p53 in breast cancer cell lines
Authors: Ray Debolina , Murphy Keith R. , Gal Susannah 
Published: August 2012

Abstract
Mutations in the p53 tumor suppressor affect protein accumulation, localization and DNA binding. We undertook to determine these properties of p53 in breast cancer cells and to see how those attributes change following oxidative stress. We analyzed the p53 in 8 different breast cancer cell lines, with either wild-type or mutant p53 protein. By ELISA and western blots, we found that the levels of the p53 protein were generally low for cells carrying wild-type protein and high in cells having a mutation in the TP53 gene. This was contrasted to the case in the HCC2157 cell line which has wild-type p53 but accumulates the protein to high levels. Using biotinylated DNA and streptavidin magnetic beads, we found that wild-type p53 protein from MCF-7 and ZR-75-1 cells binds with different affinity to 12 gene sequences covering several pathways regulated by p53. Treatment of MCF-7 cells with H2O2 caused an increase in this binding affinity. The p53 from the HCC2157 cells and all of the mutant p53 proteins had minimal to weak binding to these sequences even after treatment with H2O2. We also analyzed the phosphorylation of serine 15 on p53 in 4 of the cell lines. The p53 protein from the HCC2157 cells and two other cell lines showed phosphorylated protein at this site, but we found no correlation between that modification and the levels, localization, or binding affinity of the protein. From this and other work, it appears that the mutation status of the TP53 gene alone can not predict the activity of this tumor suppressor since cell lines with the same genetic information do not show the same properties of this protein. We argue that the analysis of DNA binding or transcription activity must be done in order to correlate the functionality of p53 with clinical outcome in tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1186. doi:1538-7445.AM2012-1186
Abstract 1308: Achaete-scute homolog 1 (Ascl1) lineage in the lung gives rise to multiple cell types
Authors: Li Yan , Linnoila Ilona 
Published: August 2012

Abstract
Lung contains many highly specialized cells. Type I pneumocytes are responsible for gas exchange, while type II pneumocytes secrete surfactant which prevents alveoli from collapsing. Airways are lined by non-ciliated secretory (Clara) and ciliated cells that eliminate excess mucus and harmful particles, and rare pulmonary neuroendocrine cells (PNECs) which regulate breathing and contribute to carcinogenesis. PNECs have unknown histogenesis but differentiate prior to the other cells. The neural transcription factor achaete-scute homolog 1 (Ascl1) is critical for PNEC development and is associated with stem cell marker expression in normal and neoplastic lung. Hence, we used in vivo lineage and fate tracing strategy to investigate Ascl1-defined cells (ASDCs) during lung development and injury repair. R26R-stop-lacZ (Rosa) reporter mice were crossed with Ascl1-Cre and Ascl1-CreERTM mice, in which the Ascl1 promoter drives the expression of Cre or inducible Cre recombinase, respectively (Battiste et al., Development (2007) 134:285-93). Following recombination, ASDCs and their descendants will be permanently labeled and were further characterized by immunohistochemistry using cellular differentiation markers. Labeled cells in Ascl1-Cre/Rosa mice gave rise not only to PNECs but also to neural, Clara, ciliated, alveolar type I and type II cells. Interestingly, tamoxifen (TM) administration to Ascl1-CreERTM/Rosa dams at embryonic day E9.5 labeled both airway and alveolar cells, while TM injected at E11.5 only labeled airway cells. Moreover, adult Ascl1-CreERTM/Rosa mice were administered TM followed by naphthalene (Nap), which kills Clara cells. It is notable that in addition to PNECs which are resistant to Nap, regenerating Clara cells were now labeled during the injury repair. We conclude that ASDCs are not limited to giving rise to neural cells or PNECs during pulmonary development, but they also contribute to a range of non-neuroendocrine cells such as Clara and ciliated cells as well as alveolar pneumocytes. Further, the lineage participates in injury repair of the airway lining in mature lung. The current Ascl1 lineage study provides a basis for recent studies on mouse small cell lung cancer (Sutherland et al., Cancer Cell (2011) 19:754-64) which suggested that both PNECs and non-neuroendocrine cells such as alveolar type II pneumocytes may serve as progenitors for this very virulent lung cancer type.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1308. doi:1538-7445.AM2012-1308
Abstract 1313: Mutually exclusive somatic mutations in WNT pathway medulloblastomas reveal a critical interaction between DDX3X and SMARCA4
Authors: Weeraratne Shyamal D. , Archer Tenley , Pugh Trevor J. , Hargreaves Diana , Yu Furong , Kautzman Amanda , Jones David T.W. , Jaeger Natalie , Tamayo Pablo , Mesirov Jill P. , Pfister Stefan M. , Lichter Peter , Crabtree Gerald , Meyerson Matthew , Pomeroy Scott L. , Cho Yoon-Jae 
Published: August 2012

Abstract
DDX3X is an ATP-dependent RNA helicase that belongs to an extended family of D-E-A-D motif (DEAD-box) containing proteins whose functions have been implicated in key biological processes ranging from RNA transcription and splicing to the regulation of translation initiation. Through whole exome sequencing of 94 primary medulloblasotmas, we have identified DDX3X as one of the most common recurrently mutated genes in medulloblastoma. These mutations predominantly occur in WNT pathway medulloblastomas which concurrently harbor stabilized forms of mutant beta-catenin. Interestingly, we have also identified SMARCA4 mutations in WNT pathway tumors that are mutually exclusive of DDX3X mutations. In addition, two WNT pathway tumors that have neither DDX3X nor SMARCA4 gene mutations have mutations in genes known to encode for direct binding partners of DDX3X and SMARCA4 (EIF3E and ACTL6A, respectively). This mutual exclusivity of DDX3X and SMARCA4 mutations suggests either a direct interaction between the DDX3X and SMARCA4 gene products or an overlap of the biological processes regulated by each. Here we reveal the direct interaction between DDX3X and SMARCA4 in normal physiological conditions and further investigate the impact of somatic mutations in DDX3X and SMARCA4 on this interaction in WNT pathway associated medulloblastomas. Our results point to a critical link between RNA helicases and the SWI/SNF chromatin remodeling complex in WNT/beta-catenin signaling and disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1313. doi:1538-7445.AM2012-1313
Abstract 1315: An in vivo platform for drug screening in colorectal cancer
Authors: Cho Yong Beom , Hong Hye Kyung , Seo Sun Ae , Choi Yoon-La , Jin Juyoun , Nam Do-Hyun , Ko YoungHyeh , Kim Hee Cheol , Yun Seong Hyeon , Chun Ho-Kyung , Lee Woo Yong 
Published: August 2012

Abstract
We aimed at generating a clinically meaningful in vivo platform for preclinical drug screening in colorectal cancer. Surgical specimens were collected from 143 patients, and 97 carcinomas were engrafted in immunodeficient mouse (tumor take rate 67%). To develop in vivo platform suitable for drug screening, 39 of xenografted carcinomas were selected and expanded satisfactorily in mice with a mean time to reach a size of 1000-1500 mm3 of 90 ± 20 days. In order to validate the similarity of molecular characters between the patient tumor and carcinomas obtained from xenografts, we conducted the mutation status, an expression array, arrayCGH, and other molecular profiling in colon cancer to look at the molecular progression and transition along with primary tumor, metastatic tumor and xenograft model. Histological analysis and the molecular profiles of tumors revealed a high degree of similarity between the patient tumor and xenografted carcinomas. The xenografted tumors maintain their genotypic features of original tumors, suggest that the in vivo platform can be useful for the personalized drug development in colorectal cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1315. doi:1538-7445.AM2012-1315
Abstract 1318: Establishment of patient primary colorectal tumor xenograft models for test of anticancer agents
Authors: Liu Changnian , Alsanabani Hani , Zhou Wen , Liu Rong , He Fang , Li Wenwei , Xu Chunpin 
Published: August 2012

Abstract
BACKGROUND Human xenograft tumor models established by transplantation of human tumor cell lines into immunodifficient mice have been routinely used for preclinical test of anticancer agents. But tumor cell lines have a relatively low transplantability, which resulted a limited number of tumor models available for test of novel anticancer agents. Recently, we have developed a large number of patients’ primary colorectal tumor xenograft models by transplanting human fresh colorectal tumor tissues into nude mice, which have been employed for preclinical test of standard clinically used drugs and novel anticancer agents for their chemosensitivity screening. METHODS The fresh colorectal tumor samples were collected from local hospitals. The tumor fragments of 2-3 mm were subcutaneously implanted in the flanks of nude mice by trocar needle. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue (passage 1). The clinically used drugs included 5-FU, irinotecan, oxaliplatin, and avastin. The histology and gene sequensing of the established primary tumor models were analyzed and compared with patients’ original tumors. RESULTS A total of 120 patients’ colorectal tumor samples were implanted into nude mice; and 65 primary tumor models have been established with a tumor taking rates of 54% for the first passage. The tumor taking rates were higher in the later passages ranged from approximately 80-100%. The test anticancer drugs’ therapeutic efficacy was consistent with their clinical findings. The patients’ primary colorectal tumor xenografts from 5 passages retained a similarity in architecture, histopathological morphology, and genomic mutation status to their patients’ original tumors. CONCLUSIONS The patient primary tumor model system can provide a larger number of models for selection of right models for preclinically testing novel agents based on their anticancer mechanism. The primary tumor models retain a similarity in histology and genomic mutation status to their patients’ original tumors. They may predict more relevant clinical response rate and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Especially, they have advantages for test of target-oriented therapeutics in new drugs development programs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1318. doi:1538-7445.AM2012-1318
Abstract 1320: Over expression of HGF accelerates hepatitis B virus-induced liver carcinogenesis and hastens the malignancy of hepatocellular carcinoma
Authors: Xie Qian , Su Yanli , Dykema Karl , Koaman Julie , Essenburg Curt , Bradley Robert , Iwava Keiichi , Seki Shuhji , Khoo SokKean , Furge Kyle , VandeWoude George F. , Nariyoshi Shinomiya 
Published: August 2012

Abstract
Genetically modified mouse models play important roles in improving our understanding of HGF/MET signaling in liver development, regeneration and in tumor formation. To evaluate the role of HGF/MET in HBV induced HCC, we generated 1) alb-Cre-Metflox/flox mice which lack of MET expression in the liver; 2) a mouse strain over-expressing human HGF (C3HHGF) to determine if MET is required for HCC development and how HGF accelerates HCC malignancy. We show here that overexpression of human HGF in a C3HHGF mouse model induced spontaneous hepatocellular carcinoma (HCC). Such overexpression also accelerated hepatitis B virus (HBV) surface antigen expression in the liver, which in turn selectively promoted the growth of Met-positive hepatocytes and ultimately led to hepatocellular carcinogenesis. We also demonstrate here that HCC in C3HHGF mice presented gene expression patterns highly associated with malignant human HCC. Molecularly, the HCCs of C3HHGF mice had up-regulated VEGF/HGF signal pathways that can be effectively inhibited by pathway inhibitors. We conclude that C3HHGF mouse model can serve as a good tool for studying human HCC, and we suggest that anti-angiogenic therapeutics can be applied for the treatment of HGF-driven HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1320. doi:1538-7445.AM2012-1320
Abstract 1329: Personalizing gastrointestinal cancer treatment by the utilization of TumorGraft™ technology
Authors: James Meredith , Bruckheimer Elizabeth , Morris Ronnie , Rowinsky Eric , Sidransky David , Paz Keren 
Published: August 2012

Abstract
Malignancies of the lower gastrointestinal (GI) tract share similarities in their symptoms, histology, genetic composition and sites of metastasis, but differ in their incidence rates. While colorectal cancer is common with over 130,000 new cases annually in the US alone, small intestinal adenocarcinoma is relatively rare with only 2500 new cases annually. Nevertheless, the overall clinical benefit of “standard of care” therapeutics is negligible, thereby underlining the need for novel therapeutics, especially personalized approaches. Champions Oncology focuses on personalizing cancer treatment via generating Tumorgraft models from each patient's individual whole tumor. The current study describes the attempt to identify a personalized solution for two patients with metastatic colorectal and duodenal cancers. Using Champions revolutionary Tumorgraft™ technology, personalized ‘trials’ were performed in vivo. Tumor fragments, obtained from the patient's liver metastases, were implanted into immunodeficient mice in a manner that preserves the biological properties of the original tumor and supporting stroma. Once the Tumorgrafts models were established, individual therapeutics and combinations were evaluated to identify treatment regimens likely to be maximally effective in the clinic. Each drug study encompassed 16 different treatment groups, including FDA-approved, as well as investigational agents. Of the different treatment arms in the colorectal model, two demonstrated partial response with tumor growth inhibition values of 152 and 149% for irinotecan/cetuximab/sunitinib and bevacizumab/cetuximab/irinotecan, respectively. While the combination of cetuximab/irinotecan resulted in stable disease in the duodenal model as well, complete responses were observed in all mice treated with eribulin as a single agent. Mutation status analysis of the tumors revealed wild type KRAS. Additional molecular characterization is ongoing to determine other potential signatures of response. The results from the Tumorgraft study were recommended to the patients and their medical oncologists and new lines of treatment were commenced subsequently. The results from these Tumorgraft studies, the molecular profile of the tumors, and correlation with clinical outcome will be presented. Results demonstrate the application of Personalized Tumorgraft models to personalized oncology and their impact on the future of cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1329. doi:1538-7445.AM2012-1329
Abstract 1332: Cisd2 haploinsufficiency leads to non-alcoholic fatty liver disease (NAFLD) and accelerates hepatocarcinogenesis in mice
Authors: Kao Cheng-Heng , Shen Zhao-Qing , Chen Yi-Fan , Tsai Ting-Fen 
Published: August 2012

Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic steatosis (fatty liver) is a vulnerable factor that could lead to liver damage, inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). However, despite the high prevalence of NAFLD, the genetic factor determining the disease progression remains poorly understood. CISD2 is a previously uncharacterized novel gene located within the overlapping region of HCC critical region and human longevity region on chromosome 4q. We have recently demonstrated for the first time that Cisd2 is a mitochondrial outer membrane protein which mediates mitochondrial integrity and lifespan in mammals. Surprisingly, we have observed phenotype similar to NAFLD in the liver of Cisd2 heterozygous (+/−) knockout mice. Cisd2 haplo-insufficiency led to abnormal lipid metabolism accompanying with fatty liver, cell death, severe inflammation and fibrosis in the liver. Moreover, there was a low incidence (1/18; 5.6%) of HCC developed at 16-18 months of age in the Cisd2+/− mice. Interestingly, our results revealed a significant increase of the Srebp1c which is the master regulator of lipogenesis; the increase in Srebp1-c seems to further up-regulate the expression of its target gene, fatty acid synthase (Fas), in the Cisd2+/− livers. In addition, we found that liver fibrosis was associated with activation of hepatic stellate cells, as revealed by increased expression of α-ΣMA, in the Cisd2+/− livers. Furthermore, we provide evidence that Cisd2 haplo-insufficiency promoted hepatocarcinogenesis and accelerated HCC development by 4-6 months in the transgenic mice expressing HBV X protein. In summary, our results suggested that Cisd2 is likely to be a haplo-insufficient tumor suppressor gene for HCC. Heterozygous deficiency of Cisd2 led to NAFLD, and accelerated the progression of HBV-associated HCC. Our data suggest that Cisd2 is a molecular target for the development of chemoprevention and therapeutic strategy for NAFLD.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1332. doi:1538-7445.AM2012-1332
Abstract 1335: Involvement of canonical Wnt/β-catenin signaling pathway in pancreatic ductal adenocarcinoma
Authors: Sano Makoto , Driscoll David , Klimstra David S. , DeJesus-Monge Wilfredo , Lewis Brian C. 
Published: August 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, develops through the progression of premalignant lesions called pancreatic intraductal neoplasms (PanINs). Acinar-to-ductal metaplasia (ADM) is postulated to contribute to PanIN development, and the canonical Wnt/β-catenin pathway has been implicated in this process. To ascertain the impact of postnatal activation of the Wnt/β-catenin pathway in PanIN-PDAC progression, we combined the elasatse-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37A, but not RCAS-GFP, stimulated a shift to higher-grade PanIN lesions in young adult mice. Moreover, mice injected with RCAS-β-cateninS37A had reduced survival relative to RCAS-GFP controls (log-rank test; p &lt;0.05). In addition, overexpression of active β-catenin or its DNA-binding partner TCF4 in PDAC cell lines enhanced cell proliferation, soft-agar colony formation, as well as migration and invasion activity. In contrast, these phenotypes were significantly blocked by the introduction of Icat, an inhibitor of the β-catenin/TCF4 interaction. Together, these data suggest that activation of the Wnt/β-catenin signaling pathway is closely related to pancreatic tumorigenesis and progression of this malignancy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1335. doi:1538-7445.AM2012-1335