bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 467: Circulating DNA released from brain tumors in response to conditional cytotoxic/immune stimulatory gene therapy induces activation of TLR9 on pDCs, leading to antitumor immunity
Authors: CANDOLFI MARIANELA , Yagiz Kader , Balasubramanian Karthika , Puntel Mariana , King Gwendalyn D. , Mineharu Yohei , Muhammad AKM G. , Foulad David , Barnett Nicholas , Kroeger Kurt M. , Lowenstein Pedro R. , Castro Maria G. 
Published: June 2012

Abstract
Complexes of DNA and proinflammatory proteins are found in serum during autoimmune responses and activate antigen presenting cells, contributing to autoimmune pathogenesis. Although circulating DNA has been extensively evaluated as a biomarker for cancer progression, its role in the onset of anti-tumor immunity remains elusive. Here we aimed to evaluate the role of circulating DNA in the induction of anti-tumor immunity induced by the combination of immune-stimulant Flt3L and conditionally cytotoxic thymidine kinase (TK), which leads to long-term survival when delivered into intracranial brain tumor models using adenoviral vectors (Ad). Treatment of CNS-1 glioblastoma cells with Ad.TK+GCV led to substantial release of DNA in vitro. Similar results were observed in vivo; intratumoral treatment of established intracranial CNS-1 glioblastomas in rats with Ad-TK/GCV+Ad-Flt3L led to increased levels of circulating DNA in serum when compared to saline-treated tumor-bearing rats. Since our previous results suggest that tumor immunity was dependent on the function of activated pDCs, we aimed to evaluate the hypothesis that circulating tumor DNA induces pDC activation. Using specific inhibitors, such as DNAse, micrococcal DNAse, CpG2088 (an inhibitor of TLR9) and cloroquine (an inhibitor of endocytosis, required for intracellular TLR9 activation), we found that circulating DNA from treated rats induced TLR9-dependent activation of pDCs. Taken together, our results suggest that after treatment of brain tumors with Ad.TK+Ad.Flt3L dying tumor cells release DNA to the general circulation, which mediate antitumor immunity by acting as danger-associated molecular patterns, leading to TLR9 signaling and pDC activation.
Supported by NIH/NINDS grants
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 467. doi:10.1158/1538-7445.AM2011-467
Abstract 4672: Overexpression of NR5A2/LRH1 in pancreatic cancer and possible association with clinical outcome
Authors: Dong Xiaoqun , Li Yanan , Fisher William E. , Chang Ping , Abbruzzese James L. , Li Donghui 
Published: June 2012

Abstract
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States and it has the lowest 5-year survival rate in all tumors. Genome-wide association study (GWAS) has identified a significant association between NR5A2/LRH1 gene variants and risk for pancreatic cancer. LRH1, a direct target of PDX1, governs liver and pancreas differentiation in early embryonic development and controls cholesterol/bile-acid homeostasis and steroidogenesis in adulthood. LRH1 promotes cell proliferation by interacting with β-catenin/Tcf4 signaling and upregulating estrogen metabolic genes. We hypothesize that LRH1 acts as an oncogene in pancreatic cancer.
We measured LRH1 protein expression by immunohistochemistry (IHC) in 129 resected pancreatic tumors and LRH1 mRNA expression by RT-PCR in 15 frozen paired tumor and adjacent normal tissues. We examined the differences in expression levels between tumor and normal tissues using paired t-test. We evaluated the correlation of protein or mRNA expression levels with overall survival (OS) or tumor characteristics by Cox regression or χ2 test, respectively.
IHC showed both nuclear and cytoplasm staining for LRH1. Tumors had a higher level of LRH1 expression than normal tissue did (Mean ± SD of staining score: 5.46 ± 1.64 vs. 3.73 ± 1.77, respectively, p&lt;0.001). Patients with a higher level of nuclear LRH1 expression had worse survival (HR = 2.41, 95% CI=0.97-6.00, p=0.059) but patients with a higher level of cytoplasmic LRH1 expression had better survival (HR = 0.36, 95% CI = 0.09-1.46, p=0.15). Eight out of 8 tumors (100%) with lower nuclear LRH1 expression (staining score &lt;3) were well or moderately differentiated, while 44 out of 121 (36.4%) of tumors with higher nuclear LRH1 expression (staining score ≥ 3) were poorly differentiated (p=0.03). The LRH1 mRNA expression level was 8-fold higher in tumors than in normal tissues (p&lt;0.001).
The observed association between LRH1 overexpression and worse clinical outcome and more aggressive tumor type supports the hypothesis that LRH1 acts as an oncogene in pancreatic cancer. Whether LRH1 can be a putative therapeutic target for the treatment of pancreatic cancer needs further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4672. doi:10.1158/1538-7445.AM2011-4672
Abstract 4674: Associations between epidermal growth factor receptor polymorphism and survival in colorectal cancer patients treated with 5-FU based adjuvant chemotherapy
Authors: Lai Ching-Yu , Sung Fung-Chang , Hsieh Ling-Ling , Tang Reiping , Yeh Chih-Ching 
Published: June 2012

Abstract
Introduction: Colorectal cancer (CRC) is the second most common cancer and the third leading cause of cancer deaths in Taiwan. 5-Fluorouracil (5-FU) is one of the first line anti-cancer drugs used in the chemotherapy for CRC in older to raise survival rate. Epidermal growth factor receptor (EGFR) plays an important role to regulate gene expression causing cellular proliferation and apoptosis may induce malignant tumors. This retrospective study examined the association between EGFR polymorphism and overall survival of CRC patients treated with 5-FU-based chemotherapy.
Methods: A total of 499 patients diagnosed with CRC and received 5-FU-based chemotherapy after surgery between 1995 January and 2001 December was included in the present study. We genotyped the EGFR R497K (Arg 497 Lys) polymorphism using the polymerase chain reaction combined with the restriction fragment length polymorphism analysis (PCR-RFLP). Survival analyses on EGFR polymorphism were displayed with Kaplan-Meier curves and performed with log-rank test. The association between EGFR genotypes and survival was analyzed using Cox proportional hazard models.
Result: After 13 years follow-up, the median survival year was 4.56. The distribution of EGFR genotype was not significantly different by patients’ clinicopathologic characteristics. No significant EGFR genetic effects on overall survival were found in the present study, even the adjustment for age, gender, or tumor stage in the Cox proportional hazard models. However, in stage IV CRC patients, compared to the EGFR Arg/Arg genotype, the EGFR Arg/Lys and Lys/Lys genotypes were related to better overall survival with hazard ratio (HR) of 0.75 (95% CI = 0.49 – 1.15) and 0.61 (95% CI = 0.38 – 0.98), respectively. The Kaplan-Meier curves also showed that stage IV CRC patients carrying the EGFR Lys allele had a better survival (log-rank p = 0.07).
Conclusion: Our findings suggest that the EGFR R497K polymorphism may modify drugs activity to serve a prognostic predictor for stage IV CRC patients who receive 5-FU-based chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4674. doi:10.1158/1538-7445.AM2011-4674
Abstract 4680: Exploring the relationships between genetic variants within the UGT1A locus, cellular detoxification and risk of bladder cancer
Authors: Tang Wei , Fu Yi-Ping , Liu Luyang , Orduz Natalia , Kaushiva Alpana , Mumy Adam , Porter-Gill Patricia , Meyers Timothy , Garcia-Closas Montserrat , Malats Nuria , Chanock Stephen , Real Francisco X. , Kogevinas Manolis , Rothman Nathaniel , Silverman Debra , Prokunina-Olsson Ludmila 
Published: June 2012

Abstract
A recent genome-wide association study (GWAS) for urinary bladder cancer (UBC) has identified multiple novel genetic risk factors (Rothman et. al, Nat Gen, 2010). One of these factors was an intronic SNP rs11892031 (p=1.0×10-7) located within the UGT1A locus on chromosome 2q37. The human cellular detoxification uridine 5’ diphosphate (UDP)-glucuronosyltransferases (UGTs) belong to a superfamily of proteins that conjugate diverse endo and exotoxins, increase their solubility and facilitate their removal via bile and urine. The UGT1A locus includes nine protein-coding genes and four pseudogenes. Each first exon of these genes is regulated by its own promoter and is spliced to four constant exons producing nine UGT1A proteins.
Due to the complexity of the region and ∼90-95% similarity between the substrate-binding exon 1 sequences of UGT1A genes, this region is poorly represented in public databases (HapMap, 1000 Genomes, dbSNP). To ensure specificity of detection, we generated long-range amplicons and sequenced all UGT1A exons in HapMap individuals (CEU) and in 44 bladder cancer patients and identified 25 non-synonymous coding variations. All these variations have been genotyped in 1000 bladder cancer cases and 1000 controls from the Spanish Bladder Cancer Study (SBCS). We found one exonic SNP that showed association stronger than the original GWAS variant, and multiple variants that showed some evidence of gene and cigarette smoking interactions. Having ∼20 coding and potentially functional variants within the UGT1A region, we are exploring methods of simultaneous analysis of individual variants and their haplotypes. In conclusion, association of genetic variants within the UGT1A region confirms that altered cellular detoxification of environmental substrates is an important factor for development of bladder cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4680. doi:10.1158/1538-7445.AM2011-4680
Abstract 4686: Requirements of Gαi1 and Gαi3 for brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) induced PI3K/AKT and MAPK signaling as well as neuronal survival and migration
Authors: Cao Cong , Toorie Anika , Latorraca Emily , Zhitkovich Anatoly , Marshall John 
Published: June 2012

Abstract
After the discovery of the involvement of neurotrophin receptor Trk (tropomyosin receptor kinase) in the biology of cancer, it is appreciated that inhibition of Trk activity is beneficial in the clinical oncology setting. The key intracellular mediators of activated Trk's pro-survival and pro-metastatic signals are PI3K/AKT and MAPK (mitogen-activated protein kinases) signaling, which makes it extremely important to dissect the molecular mechanism and signaling components involved in Trk regulation of those signaling. Here we focus on the two inhibitory alpha subunits of heterotrimeric guanine nucleotide-binding proteins, Gαi1 and Gαi3, in Trk signaling. Gαi proteins are couple to cell surface receptors to convey extracellular messages to their effectors. Our previous study has indicated an unexpected and critical role of Gαi proteins in mediating receptor tyrosine kinase signaling (Cao et al., Science Signaling, 2009). Here we discovered a novel function of Gαi proteins in BDNF/NGF signaling. Gαi proteins are required for Brain-Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) to transduce signals from Trk receptor to stimulate MAPK (p38, JNK and ERK) and PI3K/AKT/mTORC1 signaling. Knockout of Gαi1 and Gαi3 completely blocked BDNF and NGF induced PI3K/AKT/mTORC1 and MAPK activation in MEFs (mouse embryonic fibroblasts). Both Gαi1 and Gαi3 associated with the Grb2-associated binding protein 1 (Gab1), and were required for the interaction of Gab1 with SHP2 as well as the interactions of Grb2 with SHP2, Shc, MEKK1 and MEKK2, in response to BDNF and NGF. Loss of Gαi1 and Gαi3 impaired the phosphorylation of Gab1, SHP2 and Shc in response to BDNF and NGF. Importantly, siRNA knockdown of both Gαi1 and Gαi3 inhibited BDNF and NGF induced AKT/mTORC1 and MAPK activation in cerebellar granule neuron, and BDNF induced neuronal survival, neuronal migration and neurite outgrowth were also largely impaired in cerebellar neurons with Gαi1 and Gαi3 deficiency. Notably, in mice brain tissues (both cortex and cerebellum); double knockout of Gαi1 and Gαi3 also totally abolished BDNF induced signaling. Overall, these results showed that Gαi1 and Gαi3 lie downstream of Trk receptor, but upstream of Gab1-Shc-Grb2-Shp2, mediating MAPK and PI3K/AKT/mTORC1 signaling as well neuronal survival and migration. We discovered for the first time that Gαi1 and Gαi3 proteins are novel players in Trk signaling, we support that therapeutic options can be developed by targeting these two new players as novel anti-tumor strategy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4686. doi:10.1158/1538-7445.AM2011-4686
Abstract 469: Mast cell inhibition by the BTK inhibitor PCI-32765 as a potential therapy in pancreatic cancer
Authors: Soucek Laura , Buggy Joseph , Kortlever Roderik , Swigart Lamorna Brown , Evan Gerard I. 
Published: June 2012

Abstract
A strong association between inflammation and cancer has long been recognized but the cause and effect relationship linking the two remains unclear. We previously showed that Myc, a pleiotropic transcription factor that is over-expressed in many human cancers, when expressed in a
β cell tumor model, triggers rapid recruitment of mast cells to the tumor site, a recruitment that is absolutely required for macroscopic tumor expansion. Indeed, such tumors did not grow in mast cell deficient mice. Furthermore, treatment of established
β cell tumors with cromolyn, a stabilizer that prevents mast cell degranulation, rapidly triggered hypoxia and cell death of tumor and endothelial cells. Our results suggested that inhibitors of mast cell function may prove therapeutically useful in restraining expansion and promoting regression of insulinomas and possibly other pancreatic cancers. However, such compounds have not yet been developed for systemic administration and applications in cancer therapy. In fact, there are no clinically effective systemic mast-cell blockers. Therefore, we tested PCI-32765 (Pharmacyclics, Inc.), a Bruton tyrosine kinase (BTK) inhibitor in clinical trials for treatment of B cell non-Hodgkin lymphoma, for its ability to inhibit mast cell function and tumorigenesis in our mouse model of β cell neoplasia and in a well characterized LSLKRasG12D model of pancreatic adenocarcinoma (PDAC). Here we compare and contrast the effects of long term treatment with PCI-32765 on mast cell degranulation, tumor growth and vasculature in both mouse models, establishing for the first time the therapeutic potential of mast cell inhibition by PCI-32765 in the treatment of insulinomas and other pancreatic cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 469. doi:10.1158/1538-7445.AM2011-469
Abstract 4690: Inhibition of PI3K-AKT signaling causes a FOXO-dependent induction of receptor tyrosine kinase expression and phosphorylation in cancer
Authors: Chandarlapaty Sarat , Sawai Ayana , Rodrik-Outmezguine Vanessa , Scaltriti Maurizio , Serra Violeta , Baselga Jose , Rosen Neal 
Published: June 2012

Abstract
Hyperactivation of the PI3K-AKT-mTOR pathway is a common mechanism for oncogenic signaling in tumors and multiple inhibitors of this pathway are now in clinical development. As the PI3K-AKT-mTOR pathway is known to be tightly regulated by negative feedback, we hypothesized that these drugs might relieve feedback inhibition, reactivate upstream signaling and limit their antitumor effects. We tested the effects of inhibitors of PI3K and AKT kinase on receptor tyrosine kinase signaling in a panel of cell lines derived from multiple tumor types. PI3K-AKT pathway inhibition resulted in increased expression and phosphorylation of a common set of receptor tyrosine kinases, including IGF-1R and insulin receptor and HER3. Induction of RTK expression was dependent on activation of members of the Forkhead transcription factor family in response to AKT inhibition. We found that depletion of FOXO proteins blocked the rise in HER3, IGF-1R, and insulin receptor protein and phosphorylation caused by AKT inhibition. Expression of a constitutively activated form of one of the FOXO proteins resulted in increased expression of these receptors. Moreover, immunoprecipitation of FOXO proteins revealed that they are preferentially associated with the promoters of these receptors upon AKT inhibition. To determine the consequences of induction of these RTKs, we utilized HER kinase inhibitors to block activation of the receptors. In multiple xenograft tumor models, PI3K-AKT inhibition resulted in potent RTK induction in vivo and combined inhibition of the HER kinases and AKT resulted in improved antitumor effects with tumor regressions observed in several cases. We conclude that the PI3K-AKT pathway feedback regulates RTK expression through a FOXO-dependent induction of RTK transcripts. This reactivation of upstream RTK signaling is likely to attenuate the effects of AKT inhibition. Blockade of feedback-upregulated RTKs may significantly improve the antitumor effects of PI3K-AKT inhibitors and is a potential combination strategy for PI3K-AKT driven cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4690. doi:10.1158/1538-7445.AM2011-4690
Abstract 4701: Integrated chemo-genomics approach for the identification of therapeutically amenable targets in small cell lung cancer
Authors: Sos Martin L. , Heynck Steffi , Peifer Martin , Thomas Roman K. 
Published: June 2012

Abstract
Small-cell lung cancer (SCLC) is the third most common lung cancer type and with a median overall survival of only 9.3 month for extended disease patients also one of the deadliest worldwide. While analyses of the genetic landscape of non-small cell lung cancers led to the identification of therapeutically amenable targets such as mutant EGFR or EML4-ALK fusions, the characterization of oncogenic pathways that drive tumorigenesis in SCLC lags behind this development, resulting in a lack of treatment options for SCLC patients. To address this therapeutic need systematically we performed high-resolution gene-copy number (6.0 SNP-arrays) in a cohort of 108 SCLC specimens (n=47 primary samples; n=61 cell lines). This analysis revealed novel recurrent amplifications and deletions that are specifically enriched in SCLC when compared to non-small cell lung cancer specimen. We next annotated the significant genetic lesions found in our SCLC set and linked these with the activity profiles of a library of 270 novel proprietary compounds as well as compounds currently in clinical develop, which were screened in 51 SCLC cell lines. Using an integrated genomics approach we detected genetic predictors for the activity and resistance to known PI3K/AKT-pathway inhibitors as well as novel inhibitors previously not associated with activity in SCLC. Using orthogonal functional assays we validated genetic alterations that predicted cytotoxicity of Pi3-kinase inhibition in SCLC cell lines and we validated compounds that exhibited exquisite cytotoxicity in MYC-amplified tumors. Overall, our data provides the first detailed genetic landscape of small-cell lung cancer with a functional annotation and implies that PI3K/AKT-pathway inhibitors represent therapeutics that warrant further clinical investigation in SCLC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2011-4701
Abstract 4705: MicroRNA-122 regulates liver metabolism and hepatocyte differentiation
Authors: Tsou Ann-Ping , Tsai Wei-Chih , Hsu Sheng-Da , Hsu Chu-Sui , Hsiao Ming-Shi , Chen Shu-Jen , Hsiao Michael , Huang Hsien-Da 
Published: June 2012

Abstract
MicroRNAs (miRNAs), inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. MicroRNA-122, a liver-specific miRNA, is known to regulate lipid metabolism and tumorgenesis and is down-regulated in the intrahepatic metastastic HCC. To obtain insights into the physiological function of miR-122, we successfully generated the mir-122-/- mutant mouse (122KO).
122KO mice are viable with reduced serum cholesterol, elevated alkaline phosphatase and portal infiltration. Collagen deposition suggested minor fibrosis in 122KO livers. 122KO mice have distinctly different lipid metabolism. The levels of cholesterol and triglyceride are low in serum but high in liver tissue. Lipoprotein analysis revealed that 122KO mice have defect in VLDL transport. These results indicate that mir-122 deletion generated pathological features reminiscent that of nonalcoholic fatty liver disease (NAFLD) in human. In addition, mir-122 deletion is also prone to hepatocarcinogenesis. Liver tumors developed at age of 11 months in 5/5 mice.
Expression of many genes was affected by mir-122 deletion. Pronounced changes are found in genes contributing to inflammation, cholestasis, fetal antigens, loss-of-imprinting and most importantly, expression of genes for metabolism of lipid and carbonhydrate are downregulated. The drastic change of transcriptome likely contributes to the pathological features presented in mir-122 knockout mice. We believe that 122KO mouse is a potential model for human HCC. This mouse model will provide a great opportunity to evaluate the physiological functions of mir-122 in hepatocyte differentiation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4705. doi:10.1158/1538-7445.AM2011-4705