bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-344: Emergence of carcinoma resistance to EGFR blockade via an integrin avb3/RalB/NFkB signaling axis
Authors: Seguin Laetitia J. , Mielgo Ainhoa , Huang Miller , Camargo Fernanda Camargo , Lesperance Jacqueline , Weis Sara M. , Desgrosellier Jay S. , Cheresh David A. 
Published: August 2012

Abstract
EGFR inhibitors have been used to treat several cancers including pancreatic, breast, lung and colorectal cancers. However, resistance to EGFR inhibitors has emerged as a significant clinical problem. KRAS activation in cancer has been associated with tumor cell resistance to EGFR inhibition. Here we identify integrin αvβ3 as a marker for tumors that are resistant to EGFR blockade. In addition, we find that tumor cells initially lacking or expressing low levels of integrin αvβ3 specifically upregulate this integrin upon treatment with EGFR inhibitors. Surprisingly, αvβ3, even in the unligated state, interacts with and promotes a specific KRAS ependent function leading to the EGFR independent growth of various tumors. Specifically, αvβ3 promotes KRAS dependent activation of RalB and its downstream effectors TBK1/NFkB and Src leading to tumor growth in the presence of EGFR inhibitors. Accordingly, knockdown of RalB sensitizes αvβ3-expressing tumors to EGFR blockade while expression of an active RalB mutant promotes resistance of αvβ3 negative tumor cells to EGFR blockade. These findings reveal a new role for integrin αvβ3 in mediating tumor cell resistance to EGFR inhibition through activation of a specific KRAS dependent function. Our findings suggest a new way to circumvent EGFR resistance of a wide range of cancers by targeting the αvβ3/KRAS signaling pathway and its downstream effectors.
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 LB-344. doi:1538-7445.AM2012-LB-344
Abstract LB-346: EGF receptor, Jaks and Stat3 crosstalk promote enhanced colony-forming, motility, migration, and invasive phenotype of cisplatin-resistant ovarian cancer cells
Authors: Yue Peibin , Zhang Xiaolei , Paladino David , Sengupta Bhaswati , Ahmad Sarfraz , Holloway Robert W. , Ingersoll Susan B. , Turkson James 
Published: August 2012

Abstract
Majority of the ovarian cancer patients who initially respond to cisplatin therapy develop recurrent and resistant disease that is mechanistically not well understood. To define the biological presentations and the molecular phenotype of cisplatin resistant ovarian cancer, we subjected the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments, followed by recovery and derived the lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3), and A2780S/CP5 (S/CP5), which are resistant to 1, 3, and 5 μM cisplatin, respectively. In vitro studies show the three resistant lines have increased colony-forming ability and altered morphology consistent with enhanced motility, migration, and invasiveness. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase 1/2 and Janus kinases (Jaks), and aberrant Signal Transducer and Activator of Transcription (Stat) 3 activation. Elevated expression of survivin and vascular endothelial growth factor (VEGF), and enhanced matrix metalloproteinase activities are evident in the resistant cells, together with increased vimentin and snail expression, and E-cadherin downregulation, indicative of epithelial-mesenchymal transition (EMT). The inhibition of EGFR or Stat3 activity in the resistant cells repressed the enhanced colony-forming, motility, and migratory phenotype, downregulated survivin, VEGF and vimentin expression, and sensitized the resistant cells to cisplatin. In vivo studies using intra-peritoneal xenograft models in nude mice revealed the resistant lines have a high tumor incidence and formed small, cisplatin-resistant tumor nodules at several locations on the small-intestine and colon, compared to the sensitive A2780S line that exhibited low tumor incidence and formed exclusively ovarian tumors. Treatment with EGFR or Stat3 inhibitor sensitized the resistant tumor nodules to cisplatin. Studies together indicate hyperactive EGFR and Jak signaling predominantly through the induction of aberrantly-active Stat3 promote EMT during cisplatin resistance development. Collectively, these events serve as critical mediators of the invasive phenotype associated with cisplatin resistant ovarian cancer and hence, are targets for preventing the development of resistance and the recurrent disease during cisplatin therapy in ovarian cancer.
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 LB-346. doi:1538-7445.AM2012-LB-346
Abstract LB-349: ZO1 gene represents a chemosensitivity gene in multiple myeloma
Authors: Yang Lin , Orlowski Robert , Zhang Xingding , Meng Huimin , An Gangli , Wang Hua 
Published: August 2012

Abstract
Chemotherapy agents are extremely important in the treatment of liquid malignancies, such as multiple myeloma (MM). Unfortunately, chemotherapy resistance in MM therapy is the most significant cause of treatment failure. The ability to predict, treat, or circumvent resistance is extremely likely to improve clinical outcomes. Thus, identification of novel genes that play a crucial role in MM progression and chemosensitivity is necessary to understand this disease better at the molecular level. Moreover, these genes and their products may serve as new therapeutic targets for MM, whose expression could improve patient outcomes or served as a predictor for chemotherapy outcome. To identify potential chemosensitivity genes, establishing a high-throughput method for validation of targets becomes urgently needed. Toward this purpose, we have successfully developed a high-throughput siRNA based functional target validation approach and identified a group of potential chemosensitivity genes. Our preliminary studies focusing on one of the candidate gene, ZO1 (zonula occludens 1), suggested that targeting ZO1 led to tumor cell resistant to several chemotherapy agents, including doxorubicin (Dox), cisplatin (Cis), methotrexate (MTX), and bortezomib. Further analysis with 264 bortezomib treated MM patients indicated that expression level of ZO1 correlated with patient response to bortezomib treatment. Two clones and pooled RPMI 8226 MM cell line, which were developed against bortezomib treatment in our lab, showed loss of ZO1 expression, suggesting a role of ZO1 may play in bortezomib resistance development. More importantly, ZO1 targeting in myeloma cells resulted in cell resistance to bortezomib treatment. Taken together, our studies reveal a novel chemosensitivity gene, which may lay the foundation for further clinical studies. Moreover, in the clinical arena, it may form a basis for algorithms to help predict chemosensitivity based on baseline gene expression profiles in the future, and may provide the strategies aimed at enhancing chemosensitivity by increasing expression of target genes of interest.[[Unsupported Character - &#8194;]]
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 LB-349. doi:1538-7445.AM2012-LB-349
Abstract LB-363: Intravesical delivery of lipid nanoparticle formulated p21(Waf1/Cip1) activating dsRNA induces tumor regression and enhances animal survival in a orthotopic bladder cancer model
Authors: Kang MooRim , Yang Glen , Charisse Klaus , Epstein-Barash Hila , Manoharan Muthiah , Li Long-Cheng 
Published: August 2012

Abstract
Small RNA molecules are a promising new class of drugs by offering expanded targets not druggable by conventional therapies with high target specificity and low toxicity. However, their clinical use is significantly hindered by the lack of vehicles that deliver the molecules efficiently to target tissues and cells. The bladder is an easily accessible hollow organ and is ideal for local delivery of drugs or molecules such as small RNA. RNA activation (RNAa) is a newly discovered mechanism of gene induction triggered by promoter targeted double-stranded RNA, also known as small activating RNA (saRNA). In this study, we investigate, in an orthotopic bladder cancer model, antitumor effects of a saRNA (dsP21) targeting the promoter of the p21WAF1/CIP1 (p21) gene, a key negative regulator of the cell cycle rarely mutated or deleted in bladder cancer. Introducing dsP21 into bladder cancer cells activated p21 expression with subsequent inhibition of cell proliferation, arrest of the cell cycle and induction of apoptosis accompanied by the activation of caspase 3 and PARP. Chemical modification (2′-Fluoro) and subsequent formulation of dsP21 in lipid nanoparticles (LNPs) retained its RNAa activity with minimal immunostimulatory effect and extended its stability in urine, and when delivered intravesically it could well diffuse into the bladder wall. Delivery of LNP-formulated dsP21 (LNP-dsP21) into mouse bladder with established human bladder cancer significantly inhibited tumor growth and extended animal survival with demonstrated p21 activation in vivo. Of particular significance, LNP-dsP21 treatment caused the regression or disappearance of established tumors in 30% of the treated mice. Our results provide proof-of-principle that targeted activation of p21 can be applied to the treatment of bladder cancer and LNP-formulated small RNA can be successfully delivered to the bladder by intravesical instillation. Further clinical development of RNAa-based intravesical therapy is warranted for the treatment of residual and recurring bladder cancer in humans. Acknowledgement: financial support from the AACR Henry Shepard Bladder Cancer Research Grants (09-60-30-LI).
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 LB-363. doi:1538-7445.AM2012-LB-363
Abstract LB-369: Coxsackievirus B3 is an immunostimulatory oncolytic virus active against lung adenocarcinoma
Authors: Miyamoto Shohei , Inoue Hiroyuki , Wang Beibei , Yasunari Keisuke , Nakamura Takafumi , Yamada Meiko , Urata Yasuo , Marumoto Tomotoshi , Takahashi Atsushi , Takayama Koichi , Nakanishi Yoichi , Shimizu Hiroyuki , Tani Kenzaburo 
Published: August 2012

Abstract
Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacies are hampered by low tumor selectivity. To identify a potent and selective oncolytic virus, we performed large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of viral receptors, CAR and DAF, on NSCLC cells, and attenuated by loss of CAR expression by siRNA transfection on NSCLC cells. In vitro assays revealed that CVB3 induced apoptosis and PI3K/Akt and MEK/ERK survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of pre-established tumors in vivo. Furthermore, administration of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well-tolerated without treatment-related deaths. In addition, intratumoral CVB3 administration markedly recruited NK cells and granulocytes, both of which expressed cytolytic degranulation marker CD107a and contributed to the antitumor effects as demonstrated by depletion assays, macrophages, and mature dendritic cells (DCs) into tumor tissues. Furthermore, we found that CVB3 infection induced abundant calreticulin (CRT) exposure, known as a major checkpoint of immunogenic cell death, on the cell surface of NSCLC cells, as well as extranuclear high mobility group box 1 (HMGB1) translocation from the nuclei to the cytosol in NSCLC cells. Altogether, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC and may yield a unique and more effective antitumor activity.
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 LB-369. doi:1538-7445.AM2012-LB-369
Abstract LB-397: Deep sequencing of Xenografts and case-matched blood and primary tumors reveals a 20 folds enrichment of loss of heterozygosity versus somatic mutations suggesting LOH plays an ever important role in tumorigenesis
Authors: Xu Qiang , Wang Guan , Fang Douglas D. , Gao Yibo , Chen Yundi , Sun lele , Yan Xuelan , Li Ou , Yang Quanyu , Qian Maoxiang , Zhang Bin , Chen Zhaoli , Chan Chi-Chung , Sun Hongye , He Jie 
Published: August 2012

Abstract
The double hits theory suggests a major mechanism of tumorigenesis. However, compared to the somatic mutations, the loss of heterozygosity (LOH) was not frequently identified in many sequencing projects. Unlike the somatic mutations that were detected by the evidence of novel alleles in tumor tissue, the alleles involving in the LOH are present in normal tissues as well. Given the high level of tissue heterogeneity of primary tumors, including both tumorous cells and normal stroma cells, at whole tissue or million cells level LOH can only be detected as a quantitative change between tumor and normal samples, which are not easily distinguished from potential sequencing errors or other artifacts especially with low depth sequencing. By applying whole exome capture deep sequencing on case-matched primary tumor, blood and xenograft samples, we found that xenografts represent a much purer human tumor cell population than primary tumor tissues. These tumor cells growing in mice not only contain the majority of somatic mutations in the primary tumors (&gt;95%), but also reveal a &gt;20 folds enrichment of somatic LOH events, which were not categorized as LOH in primary tumors, versus somatic mutations. All these findings were detected after removing mouse sequence contaminations, which if included will induce about half of the total variations observed in the xenograft samples. We found that these LOH events affect both tumor suppressor genes and oncogenes. Given that driver mutations or other variations that are implicated in oncogenesis are most likely preserved in xenografted tumor cells in immunedeficient mice, we hypothesize that the bigger range of somatic LOH events that we observed in xenograft samples play a potential ever important role in tumorigenesis than what we thought previously. Our finding also sheds a new light on a novel approach for the discovery of potential drug targets by sequencing xenograft samples.
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 LB-397. doi:1538-7445.AM2012-LB-397
Abstract LB-408: An integrative genomic approach uncovers oncogenic roles of YY1-signaling in hepatocellular carcinoma with stem cell-like traits
Authors: Zhao Xuelian , Roessler Stephanie , Budhu Anuradha , Yu Zhipeng , Jia Huliang , Ye Qinghai , Qin Lunxiu , Tang Zhaoyou , Wang Xin Wei 
Published: August 2012

Abstract
Hepatocellular carcinoma (HCC) is an aggressive solid tumor with vast heterogeneity in its clinical presentation and tumor biology. Genomic and transcriptomic analyses have revealed numerous HCC subtypes that are associated with patient outcome. Recently, we have identified a subset of aggressive HCC with stem cell-like traits and elevated levels of EpCAM and AFP (EpCAMhigh/AFPhigh). To identify key pathways contributing to this subset of HCCs, we used an integrated genomic strategy by comparing gene expression profiles of a well-defined HCC cohort consisting of 38 EpCAMhigh/AFPhigh and 40 EpCAM−/AFP− HCC cases using Affymetrix U133A array analyses. We identified a robust gene expression signature that can classify these two subgroups and is predictive of HCC prognosis. We validated this signature as an independent predictor of patient survival in two additional independent cohorts of HCC samples with mixed etiologies and ethnicity. Gene Set Enrichment Analysis revealed that genes containing YY1 transcriptional factor binding sites are most significantly enriched in the signature, suggesting that the YY1 signaling pathway may be functionally critical in regulating stem cell-like HCC. Genomic analysis using the Agilent 105A human arrayCGH platform revealed that the YY1 co-activator gene YY1AP1, but not YY1, is highly amplified in a majority of EpCAMhigh/AFPhigh HCCs (85%). YY1AP1 expression in HCC was significantly correlated with its genomic amplification and was also associated with patient prognosis. Using a lentiviral construct expressing YY1AP1 shRNA either constitutively or inducibly via tetracycline, we found that silencing of YY1AP1 completely blocked the growth of EpCAMhigh/AFPhigh HCC cell lines that contain YY1AP1 gene amplification. Furthermore, we found that YY1 transcriptionally activated YY1AP1-dependent EpCAM expression. In parallel, silencing of EpCAM via RNA interference also inhibited HCC cell growth. Our results suggest that YY1-YY1AP1 signaling is an oncogenic driver critical to the development of stem cell-like HCC through activation of EpCAM. Our results also demonstrate the feasibility and power of our strategy to utilize well-defined patient samples to uncover critical pathways linked to HCC subtypes.
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 LB-408. doi:1538-7445.AM2012-LB-408
Abstract LB-419: Multi-scalar approaches to interrogate the IκBα:NF-κB negative feedback loop: Quantitative dynamics in single cells, cell populations, and live animals in vivo
Authors: Moss Britney , Elhammali Adnan , Fowlkes Tiffanie , Gross Shimon , Vinjamoori Anant , Contag Christopher H. , Piwnica-Worms David 
Published: August 2012

Abstract
Cells have evolved complex molecular networks to sense environmental signals, transmit this information through the cell, and elicit appropriate biological responses. In particular, negative feedback loops represent a widely-utilized network motif capable of eliciting transient responses. To truly understand the biological significance of negative feedback processes, it is critical to study them at multiple scales: in single cells, in cell populations, and in animals. The IκBα:NF-κB negative feedback loop, a pivotal regulatory node of innate immunity and inflammation active in both immune cells and non-immune tissues, represents a model system for the use of multi-scalar reporter systems. To this end, we have utilized the κB5→IκBα-FLuc bioluminescent reporter to study dynamics of this transcriptionally-coupled negative feedback loop in response to diverse modes of stimulation which may be particularly relevant during cellular responses to inflammatory cytokines, such as TNFα. The κB5→IκBα-FLuc reporter enabled rigorous evaluation of the stimulus-specific dynamics of βκγα degradation and the downstream consequences of NF-κΔ nuclear translocation (i.e., NF-κΔ transcriptional activity) in single cells, cell populations and live animals in vivo. In response to modulation of TNFα concentration and pulse duration, complex, differential patterns in βκγα degradation and re-synthesis were discovered in both cell populations and single cells. Furthermore, IκBα dynamics observed in live animals in vivo upon modulation of TNFα dose strongly resembled those observed in single cells and cell populations upon modulating TNFα pulse duration, suggesting that increased doses of circulating TNFα were perceived by hepatocytes in vivo as pulses of increasing duration. Thus, a single bioluminescent reporter strategy enabled correlative quantitation of dynamic NF-κα:βκβα negative feedback loop responses in live single cells, cell populations, and tissues in vivo with a variety of rapid, low-cost, high-throughput approaches.
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 LB-419. doi:1538-7445.AM2012-LB-419
Abstract LB-42: Susan G. Komen for the Cure- Puerto Rico- fighting breast cAncer through awareness, alliances and community grants
Authors: Segarra-Vasquez Barbara 
Published: August 2012

Abstract
Puerto Rico (PR) is a Caribbean island with a population of 3.7 million. Currently, PR has 16% unemployment rate, which affects the health care of approximately 42% of the population and their access to quality health services. Cancer represents the second cause of death among Puerto Ricans. Breast cancer is the most diagnosed cancer among women representing 33% of the yearly cancer cases. Susan G. Komen for the Cure (SGK) is the global leader of breast cancer awareness. The SGK Puerto Rico affiliate was established in 2003 and currently has a Board of Directors of 11 members, three full-time employees and a group of passionate volunteers. With awareness ans service initiatives, SKG Puerto Rico has positively impacted 1.8 million people 15 years and older during 2011. The affiliate's 2011 community profile defined three major objectives: continue educational efforts for breast cancer awareness provide access to early detection programs and create a breast cancer patient profile. Grants are giver to community outreach organizations through a structured process. The affiliate's signature program is Banders through which alliances with companies, organizations, hospitals, schools and other entities are formed. With Banderas, large amount of individuals are educated, volunteers are recruits, sponsors are engaged and the network of breast cancer advocates increases.
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 LB-42. doi:1538-7445.AM2012-LB-42