bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-129: CD8+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model
Authors: Yang Yajun , Li Xiaozhu , Wang Yaohe , Wang Shengdian 
Published: August 2012

Abstract
The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tumor model in immunocompetent mice. Here, we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of adenovirus. We found that CD8+ T cells were critical mediator for antitumor efficacy by oncolytic adenovirus. Intratumoral viral therapy induced intensive infiltration of CD8+ T cells in tumor, increased tumor-specific IFN-γ (interferon-γ) production and CTL (cytotoxic T lymphocyte) activity of lymphocytes, and generated a long-term tumor-specific immune memory. Boosting CD8+ T cell responses by agonistic anti-4-1BB (cluster differentiation 137, CD137) antibody showed synergistic anticancer effects with oncolytic viro-therapy. Our results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.
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-129. doi:1538-7445.AM2012-LB-129
Abstract LB-140: Targeting brain tumour initiating cells using a dual-pronged approach of oncolytic virotherapy and chemotherapeutics
Authors: McKenzie Brienne , Zemp Franz J. , Lun Xueqing , Narendran Aru , McFadden Grant , Kurz Ebba , Forsyth Peter 
Published: August 2012

Abstract
BACKGROUND: Brain tumour initiating cells (BTICs) are stem-like cells hypothesized to mediate tumorigenesis and recurrence in glioblastoma multiforme (GBM). Patient-derived BTICs represent highly relevant preclinical GBM models, forming aggressive, infiltrative tumours in nude mice that closely recapitulate the phenotypic heterogeneity of patient GBMs. BTICs have also been shown to possess mechanisms mediating both chemo- and radio-resistance. Recently, success has been demonstrated in treating BTICs with oncolytic virotherapy (OV), which uses replication-competent viruses to specifically target and kill malignant cells. Myxoma virus (MyxV) is a promising oncolytic candidate, which our lab has shown to be highly efficacious in preclinical GBM models, effectively curing GBM xenografts with a single intra-cranial injection. By contrast, long-term survival is not obtained in MyxV-treated, BTIC-tumour-bearing mice, though survival is prolonged. HYPOTHESIS: We hypothesize that MyxV treatment of BTICs can be improved by utilizing clinically relevant chemotherapeutics identified via high-throughput pharmacoviral screens. RESULTS: We utilized a diverse, comprehensive panel of 80 small molecule inhibitors with preclinical and clinical anti-cancer efficacy to screen for synergy with MyxV treatment in vitro. Multiple candidates have been identified and are currently being validated for synergy (Chou-Talalay method) using a panel of genetically distinct, patient-derived BTICs. Our results implicate multiple potential targets for OV combination therapy, including topoisomerase I and the PI-3K/Akt/mTOR pathway. Target validation is currently underway using shRNA knockdowns and additional targeted inhibitors of these pathways. Further, the mechanism of synergistic cell death during these combination treatments is being explored. In vivo experiments utilizing the dual-pronged pharmacoviral approach are also underway. SIGNIFICANCE: We describe the nature and identity of compounds that carry the potential to sensitize BTICs to MyxV infection. Our findings offer an effective avenue to elucidate resistance mechanisms and develop efficacious combination therapies for targeting disease reservoirs within highly refractory GBMs.
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-140. doi:1538-7445.AM2012-LB-140
Abstract LB-144: A p53-dependent G2/M checkpoint governed by the cell-fate factor dachshund in non-small cell lung cancer
Authors: Chen Ke , Wu Kongming , Zhang Wei , Zhou Jie , Stanek Timothy , Li Zhiping , Wang Chenguang , Shirley L. Andrew , Rui Hallgeir , Mcmahon Steven , Pestell Richard G. 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer mortality worldwide with more than 170,000 cases diagnosed each year in the United States. Genetic studies have identified several oncogenes activated in lung cancer including K-Ras and EGFR. Tumor suppressor inactivation occurs including p53 in which LOH is observed in - 60% and mutations arise in 50%. Initially cloned as a dominant inhibitor of the hyperactive EGFR, Ellipse in Drosophila, the mammalian DACH1 gene regulates gene expression of target genes in part through interacting with DNA-binding transcription factors and in part through intrinsic DNA-sequence specific binding properties. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer. Given the importance of the EGFR in human lung cancer, we examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response. Herein, endogenous DACH1 was reduced in human non-small cell lung cancer (NSCLS). Expression levels of DACH1 correlated inversely with clinical stage and pathological grade. Re-expression of DACH1 reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated G2/M block by ectopic expression of DACH1 occurs synergistically with p53. DACH1 band p53, requiring p53 R248 and R273, residues commonly mutated in lung cancer. Fluorescent microscopy demonstrated co-localization of DACH1 with p53. Immunoprecipitation and western blot assay showed DACH1 association with p53 required the C-terminus of DACH1. DACH1 enhanced p53 transcriptional induction of p21 promoter, p53 and DACH1 repressed Rad51 expression. DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLS. Together, our studies demonstrate that p53 is DACH1 binding partner that inhibits NSCLS cellular proliferation.
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-144. doi:1538-7445.AM2012-LB-144
Abstract LB-200: IL-1beta promotes the development of intestinal epithelial stem cells
Authors: Shi Jishu , Wang Lei , Liu Ziyan , Li Yijing , Pappan Loretta 
Published: August 2012

Abstract
Although iflammation has been linked to stem cell-mediated tumorigenesis, the inflammatory factors responsible for the induction of abnormal proliferation of stem cells remain to be identified. Up-regulation of IL-1β has been associated with colon tumor initiation and progression. The objective of this study is to determine whether IL-1β alone may contribute to intestinal stem cells (ISC)-mediated tumorigenesis by promoting the development of ISCs. In a preliminary study, it was shown that rat normal intestinal epithelia cell line IEC-18 cells proliferated as a monolayer culture under serum-free conditions, demonstrating that either IEC-18-ISCs are not active in these conditions or ISCs are absent in IEC-18 cell line. However, we have found that addition of IL-1β to the cell culture medium caused monolayer IEC-18 cells to form spheres with up-regulated expression of stem cell markers including Bmi-1, β-catenin, Lgr5, c-Myc, and Nanog. This shows that IL-1β can induce the development and/or self-renewal of ISCs to form spheres. IL-1β-mediated ISC self-renewal is further demonstrated by a colony-forming assay when IEC-18 cells were cultured in soft agar under serum-free conditions. Interestingly, IL-1β promoted only a relatively small population (about 0.03%) of IEC-18 cells to form colonies, suggesting that the majority of IEC-18 cells are terminally differentiated cells. Furthermore, we have found that, when cultured in collagen-coated plates in serum-free medium, IL-1β-treated IEC-18 cells demonstrated a loss of cell-cell contact inhibition, growth to relatively high cell densities as evidenced by the presence of foci, and up-regulated expression of stem cell markers. Overall, results from our studies provide the first evidence that IL-1β alone can promote the development and self-renewal of ISCs. IL-1β-activated ISCs possess typical characteristics of malignant cells including colony formation in soft agar and loss of cell-cell contact inhibition of growth. Thus, aberrant production of IL-1β in intestinal inflammation may contribute to the initiation and progression of colon cancer by inducing the abnormal development of intestinal epithelial stem cells.
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-200. doi:1538-7445.AM2012-LB-200
Abstract LB-202: The significance of stress-responsive molecules in cancer stem cells derived from ovarian and endometrial cancer
Authors: Yasuda Kazuyo 
Published: August 2012

Abstract
Cancer stem cells (CSC) are characterized by their high tumor-initiating capacity, self-renewal and differentiation. Recent studies have been reported that higher aldehyde dehydrogenase1 (ALDH1) activity represent the characters of CSCs. By using ALDEFLUOR assay, we could successfully isolate stem-like cells from endometrial and ovarian cancer cell lines. ALDH1-high cells expressed stem cell markers, such as SOX-2, Oct-3/4 and Nanog. They showed significantly higher tumorigenicity than ALDH1-low cells in the transplantation test using NOD/SCID mice. Comparative gene expression analysis revealed several characteristic molecules that were expressed preferentially in ALDH1-high cells, including stress-responsive molecules, oxidoreductase and heat shock proteins. It is suggested that high levels of stress-responsive genes may explain at least in part highly stress resistance properties of CSCs. In addition, stress-responsive pathway might become a therapeutic molecular target of CSCs.
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-202. doi:1538-7445.AM2012-LB-202
Abstract LB-207: Tissue transglutaminase (TG2) - the key driver in inflammation-induced progression of cancer*
Authors: Mehta Kapil , Kumar Santosh , Kumar Anupam 
Published: August 2012

Abstract
It is becoming evident that chronic inflammation plays important roles during carcinogenesis, tumor invasion and metastasis. However, molecular mechanisms linking inflammation to cancer progression remains elusive. Here we report that aberrant expression of tissue transglutaminase (TG2), a stress-responsive gene whose expression is modulated by multiple inflammatory signals, plays a key role in reprogramming epithelial cancer cells to dedifferentiation pathway. TG2 expression initiated the developmental program of epithelial to mesenchymal transition (EMT) and conferred stem cell traits in non-transformed and transformed epithelial cells. At molecular level, TG2 expression resulted in constitutive activation of nuclear transcription factor, NF-κB via a non-canonical pathways. Thus, TG2 associates in complex with the inhibitory protein IκBα, resulting in its rapid degradation via non-proteasomal pathway. Hypoxia-induced factor (HIF-1α) was identified as one of the direct downstream targets for TG2-induced NF-κB. TG2/ NF-κB-induced increase in HIF-1α resulted in regulation of transcription repressors like Snail, Zeb-1, and Twist, the known inducers of EMT/CSC. Importantly, our studies suggested that TG2 in closed or compact conformation could promote the oncogenic functions while open or extended conformation is completely inactive in this regard. TG2-induced programming rendered epithelial cells resistant to stress-induced death (including chemo- and radiation-therapies) and increased their propensity to metastasize. Indeed, previous studies support this contention and suggested that inhibition of TG2 could increase the sensitivity of cancer cells to chemotherapy and inhibit their metastasis, both in vitro and in animal models. Moreover, high basal expression of TG2 in breast, ovarian and pancreatic tumor samples is associated with poor disease outcome. These data warrants further studies to develop selective inhibitors/modulators of TG2 to increase the sensitivity of cancer cells to chemotherapy and to prevent their progression to metastatic disease. *Supported by a grant from Susan G. Komen Foundation for Cure.
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-207. doi:1538-7445.AM2012-LB-207
Abstract LB-212: Ionizing radiation selectively promotes invasion of ErbB2-expressing breast cancer cells via regulation of FoxM1
Authors: Kambach Diane M. , Sodi Valerie , Lelkes Peter I. , Reginato Mauricio , Azizkhan-Clifford Jane 
Published: August 2012

Abstract
ErbB2 is frequently amplified in premalignant breast cancers including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it modulates in the progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here we show that clinically relevant doses of ionizing radiation (IR) induce cellular invasion of ErbB2-expressing breast cancer cells, such as SKBR3 and BT-474, as well as MCF10A cells transduced to express ErbB2. This effect is specific to ErbB2 expression, as ErbB2-negative breast cancer cells, such as MCF7 and T47D, do not invade following treatment with IR, nor do parental MCF10A cells or MCF10A cells overexpressing EGF receptor alone. Exposure of cells to X-rays leads to ErbB2 phosphorylation at Y877 in a dose- and time-dependent manner, and activates signaling pathways, including Src and PI3K/Akt. Inhibition of these pathways, as well as inactivation of IR-induced reactive oxygen species with the antioxidant N-acetylcysteine, prevented invasion. Activation of ErbB2-dependent signaling resulted in the upregulation of the transcription factor, FoxM1, a member of the forkhead family which has previously been shown to have a role in invasion, in part through transcriptional regulation of MMP2. Indeed, we have seen upregulation of MMP2 in irradiated ErbB2-expressing breast cancer cells, which is abolished when Src or ErbB2 is inhibited. Inhibition of FoxM1 by shRNA abrogated the increase in MMP2 level and prevented induction of invasion by IR, and overexpression of FoxM1 alone in MCF10A cells was sufficient to promote IR-induced invasion. Our data show that low level IR stimulates invasion of ErbB2-expressing breast cancer cells in a FoxM1-dependent manner.
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-212. doi:1538-7445.AM2012-LB-212
Abstract LB-22: Gemcitabine resistance is associated with EMT phenotype along with expression of cancer stem cell markers and a specific miRNA profile in the human pancreatic cancer cell line BxPC3
Authors: Bera Alakesh , Freeman James W. , VenkataSubbaRao Kolaparthi , Zhao Shujie 
Published: August 2012

Abstract
Despite new therapeutic strategies, human pancreatic ductal adenocarcinomas (PDAC) remain one of the greatest oncological challenges, as the rate of incidence almost equals the rate of mortality with a 5-year survival of less than 5%. Gemcitabine is the standard therapy for PDAC and is mostly used alone or in combination with an EGFR inhibitor. While tumors respond to Gemcitabine treatment initially, they generally develop chemoresistance. A thorough understanding of molecular events that promote resistance against Gemcitabine may identify pathways that can be efficiently targeted to reverse chemoresistance. A cell line model resistant to Gemcitabine was generated by transiently exposing BxPC3 cells to increasing concentrations of Gemcitabine. This Gemcitabine resistant cell line, BxPC3-GzR, was compared with untreated BxPC3 control cells. BxPC3-GzR cells showed properties of undergoing epithelial to mesenchymal transition (EMT) and these included a spindle shaped morphology, an increase in expression of vimentin and a decrease in expression of E-cadherin. BxPC3-GzR cells also showed an increase of expression of CD44 and in expression of phosphorylated STAT3TY705, which are characteristic of cancer stem cells. BxPC3 and BxPC3-GzR where further compared by microarray analyses for expression of micro-RNAs (miRNAs). BxPC3-GzR cells showed a specific miRNA expression profile (9 positively and 8 negatively regulated). Thus far seven of eight miRNAs identified as altered in BxPC3-GzR cells were validated by real-time RT-PCR (miR-15b, miR-21, miR-100, miRNA -125b, miRNA-155, miRNA-205 and miRNA-455-3p). These studies suggest that Gemcitabine treatment of PDAC selects for a resistant population of tumor cells that have a mesenchymal/stem cell-like phenotype and that express a distinct miRNA profile. Targeting these miRNAs may provide novel targets for restoring or enhancing anti-tumor response of Gemcitabine.
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-22. doi:1538-7445.AM2012-LB-22
Abstract LB-223: An open-label, exploratory phase II study of oral itraconazole for the treatment of basal cell carcinoma
Authors: Kim Daniel , Kim James , Spaunhurst Katrina , Montoya Javier , Chandra Kalyani , Khodosh Rita , Fu Teresa , Epstein Ervin H. , Molgo Montserrat , Beachy Philip , Tang Jean Y. 
Published: August 2012

Abstract
Purpose: Itraconazole is an FDA-approved antifungal drug that has been recently shown to antagonize the Hedgehog (Hh) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis. As oral itraconazole reduced BCC growth in mice, we assessed itraconazole's efficacy in treating human BCC tumors in an open-label, exploratory phase II study. Patients and Methods: Patients with at least one BCC tumor greater than 4 mm in diameter and with no co-morbidities were eligible to enroll. Patients were enrolled in 2 cohorts to receive oral itraconazole 200 mg twice-daily for one month (Cohort A) or 100 mg twice-daily for a longer duration (Cohort B). The primary endpoint was to determine changes in tumor size, proliferation (Ki67 levels), and a target gene of the Hh pathway (GLI1 mRNA). Results: Of the 29 patients that enrolled in the clinical trial, 19 patients were treated with itraconazole. Itraconazole caused 2 treatment-related adverse events (grade 2 fatigue and grade 4 CHF). Tumors treated with itraconazole showed a 23% reduction in clinical tumor area (95% CI: 17.2% to 28.1%), a 45% reduction in cell proliferation (P=0.04), and a 65% reduction in Hedgehog activity (P=0.03). Eight subjects with multiple tumors were assessed for clinical size changes: 4 subjects had partial response and 4 had stable disease. Tumors from control patients and patients previously treated with other Hedgehog inhibitors saw no significant changes in cell proliferation or Hedgehog activity. Conclusion: Itraconazole reduced BCC tumor size, tumor proliferation, and Hedgehog pathway activity in this exploratory study. Additional studies with larger numbers of patients are needed to validate these findings, however this proof-of-concept study demonstrates the possibility of repurposing FDA approved drugs for the treatment of cancers driven by the Hedgehog signaling pathway.
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-223. doi:1538-7445.AM2012-LB-223
Abstract LB-228: Association of XRCC1 SNPs with clinical response in AML patients
Authors: Mitra Amit K. , Crews Kristine , Pounds Stanley , Cao Xueyuan , Rubnitz Jeffrey , Ribeiro Raul , Lamba Jatinder K. 
Published: August 2012

Abstract
DNA repair system is critical in maintaining genome stability and integrity in response to various exogenous and endogenous stress factors. It is a multistep processes involving several enzymes including XRCC1 (X-ray repair cross-complementing group1) protein which plays a vital role in DNA repair activities and therefore is important for maintenance of genetic stability. The current study involves investigation of single nucleotide polymorphisms (SNPs) in the XRCC1 gene and their association with clinical response in pediatric acute myeloid leukemia (AML) patients treated with cytarabine (ara-C) based anti-leukemic chemotherapy in the St. Jude AML02 clinical trial. The St. Jude AML02 trial enrolled 232 AML patients less than 22 years of age, randomized to receive induction I therapy containing high-dose cytarabine or low-dose cytarabine plus daunorubicin and etoposide. A total of eighteen XRCC1 SNPs were genotyped using MALDI-TOF based Sequenom assay and screened for association with 3 endpoints, namely: in vitro ara-C LC50 determined in leukemic cells obtained at diagnosis (which was measured by treating leukemic cells in vitro with varying concentrations of ara-C), event free survival (EFS) and overall survival (OS). Jung statistic was used to determine association of the number of minor alleles with EFS and OS. Association of genotypes with EFS and OS was measured using Cox regression models while considering previously identified prognostically important variables. Our results showed significant association of 4 XRCC1 SNPs with survival and ara-C LC50 in pediatric AML patients. Three of these were present in the coding region, while one was a regulatory SNP located in the promoter region of the XRCC1 gene. XRCC1 SNPs have also been shown to be associated with cancer susceptibility and survival in previous studies. Our results now demonstrate clinical significance of XRCC1 SNPs in pediatric AML and suggest a role of these SNPs as prognostic factors in AML chemotherapy. These results might open up opportunities for tailored chemotherapy based on genomic markers to improve therapeutic outcome.
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-228. doi:1538-7445.AM2012-LB-228