bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 398: Genome-wide comparison of matched canine osteosarcoma primary tumours and metastases by array comparative genomic hybridization.
Authors: Liu Jonathan H W , Shao Yang Washington , Molyneux Sam D. , Khokha Rama , Wood Geoffrey A. 
Published: August 2014

Abstract
Canine osteosarcoma is a common and highly aggressive cancer that shares many characteristics with human osteosarcoma and can serve as a model of this disease. We collected snap frozen normal muscle, primary appendicular skeleton tumour, and matched terminal lung metastases from 8 canine osteosarcoma patients. DNA was isolated from these samples and gene copy number aberrations were assessed using high-resolution oligonucleotide array comparative genomic hybridization (Agilent G3 Canine 180k array). Data analysis was performed using Agilent Genomic Workbench 5.0 analysis software and the Aberration Detection Method 2 and Circular Binary Segmentation algorithms were applied to identify aberrant chromosomal intervals with the log2 ratio threshold set to 0.5. As expected, many cases had copy number aberrations that contain genes commonly altered in canine and human osteosarcoma, including MYC, CDKN2A/CDKN2B, PTEN, p53, and RB. To assess the degree of genomic similarity of the 8 primary tumours to their corresponding metastasis, we used these same samples to generate 8 random pairings of unmatched primaries and metastases, as well as 8 random pairs of primary tumours and 8 random pairs of metastases. A set of 11,000 random 10 base pair segments spanning the entire genome was generated and a correlation analysis was conducted between pairs of samples using the log2 ratios for each segment. Matched samples showed significant correlation with the square of the correlation coefficient (R2) being 0.44 (p&lt;0.05), whereas unmatched primaries and metastases, random pairs of primaries, and random pairs of metastases did not show any significant correlation (R2= 0.08, 0.08, and 0.06 respectively, p&gt;0.05 for each). Thus, as a group, primary tumours are genomically more similar to their corresponding metastasis than to unmatched metastases, and are also more similar than primary tumours or metastases are to each other. However, the range of similarity between matched primaries and metastases was relatively wide, with half the cases showing very high similarity and half showing moderate similarity that was close to the upper range of unmatched samples. These results have implications for therapies that rely on analysis of primary tumours to derive strategies that target metastases.
Citation Format: Jonathan H W Liu, Yang Washington Shao, Sam D. Molyneux, Rama Khokha, Geoffrey A. Wood. Genome-wide comparison of matched canine osteosarcoma primary tumours and metastases by array comparative genomic hybridization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 398. doi:10.1158/1538-7445.AM2013-398
Abstract 3985: Sorafenib modulates macrophages to promote T helper type 1 immunity.
Authors: Sunay Melek M. , Leatherman James M. , Chen Gang , Emens Leisha A. 
Published: August 2014

Abstract
Multiple regulatory processes within the tumor microenvironment work in concert to limit local anti-tumor immunity, and it is likely that integrative cancer therapies that target multiple cellular components in the tumor will be required to optimize antitumor immunity. Sorafenib is a promiscuous small molecule tyrosine kinase inhibitor developed as an anti-angiogenesis agent. We have previously shown that Sorafenib treatment can shift bone-marrow derived macrophages activated with lipopolysaccharide (LPS) and prostaglandin E2 (PGE2) from the pro-tumorigenic IL-10 secreting phenotype to the anti-tumor IL-12 secreting phenotype. Here, we extend these studies to explore the effect of Sorafenib on tumor-associated macrophages (TAMs) in a murine model of HER2+ breast cancer. Sorafenib treatment effectively delays the outgrowth of HER-2-overexpressing tumors in FVB/N mice relative to vehicle-treated controls. Immunohistochemical analysis revealed increased infiltration of F480+ macrophages in Sorafenib-treated tumors. F480+ TAMs isolated from Sorafenib-treated tumors had greater levels of IL-12 gene expression, and secreted higher levels of monocyte chemotactic protein-1 (MCP-1); there was no difference in IL-10 gene expression. Furthermore, F480+ TAMs isolated from Sorafenib-treated tumors demonstrated a superior ability to stimulate CD4+ T cell proliferation, and intracellular cytokine staining of tumor infiltrating lymphocytes isolated from Sorafenib-treated tumors showed an increase in CD4+ IFNγ-secreting T cells. Taken together, these data suggest that Sorafenib may alter the activation state of TAMs to increase pro-immunogenic signals and promote T helper type 1 immunity in the tumor microenvironment.
Citation Format: Melek M. Sunay, James M. Leatherman, Gang Chen, Leisha A. Emens. Sorafenib modulates macrophages to promote T helper type 1 immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3985. doi:10.1158/1538-7445.AM2013-3985
Abstract 3986: Protein-bound polysaccharide induces IL-1β via NLRP3 inflammasome activation.
Authors: Yang Yi , Inatsuka Carol , Disis Mary L. , Lu Hailing 
Published: August 2014

Abstract
Protein-bound polysaccharide-K (PSK) is a hot water extract from Trametes Versicolor mushroom. It is widely used in Asian countries for its immune enhancing and anti-cancer potential. We have recently reported that PSK activates TLR2 and has CD8 T cell- and NK cell- dependent anti-tumor activity. PSK stimulates the production of multiple pro-inflammatory cytokines, including IL-1β, the production of which requires both TLR and inflammasome activation. The current study was undertaken to investigate the mechanism by which PSK activates inflammasome and induces IL-1β. RT-PCR and Western blot analyses showed that PSK induces pro-IL-1β in a dose- and time- dependent manner. PSK activates caspase-1 and pre-incubation with z-VAD-FMK, a caspase inhibitor, abolishes PSK-induced IL-1β. Comparison of THP-1 cells and THP-1 cells deficient for NLRP3 demonstrated that PSK-induced IL-1β production requires NLRP3 inflammasome. PSK also up-regulates the expression of NLRP3 mRNA. Further experiments were performed to investigate whether potassium efflux, reactive oxygen species (ROS) generation, or lysosomal perturbation was involved in PSK-induced NLRP3 inflammasome activation. Results showed that CA-074-Me, a cathepsin B inhibitor, significantly decreased PSK-induced IL-1β, while the production of TNF-α was not affected. Phagocytosis or ROS generation was not required for PSK-induced NLRP3 inflammasome activation. Altogether, our results suggest that PSK-induced IL-1β production is a two step process. Step 1 requires TLR2-dependent induction of pro-IL-1β and upregulation of NLRP3 expression; Step 2 involves NLRP3 inflammasome activation in a cathepsin B-dependent manner. These results provide novel insights into the mechanisms of the immune stimulatory and anti-tumor effects of PSK.
Citation Format: Yi Yang, Carol Inatsuka, Mary L. Disis, Hailing Lu. Protein-bound polysaccharide induces IL-1β via NLRP3 inflammasome activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3986. doi:10.1158/1538-7445.AM2013-3986
Abstract 3987: Functional implication of TGFBR3 dysregulation and its clinical application in oral cancer.
Authors: Fang Wei-Yu , Hsiao Jen-Ren , Chang Jang-Yang , Tsai Sen-Tien , Hsu Li-Jin , Wu Li-Wha 
Published: August 2014

Abstract
TGF-β type III receptor (TGFBR3), a co-receptor for TGF-β family members, is required for the high-affinity binding of ligands to their receptors to begin their cellular function. More and more studies showed contrasting roles of TGFBR3, tumor suppressor or oncogene, depending on the cancer type. However, the exact role of TGFBR3 and the responsible mechanism in oral cancer remains to be characterized. By using immunohisotochemical staining and real-time PCR, we found a down-regulation of TGFBR3 in oral cancer tissues. In the same line of this observation, we also detected a significant decrease of soluble TGFBR3 (sTGFBR3) in the oral cancer patient sera when compared with normal sera. Using Kaplan Meyer survival curve analysis and log rank test, we found that low TGFBR3 expression patients tend to have poor clinical outcome than those with high expression. Genetic manipulation of TGFBR3 was used to examine the role of TGFBR3 in oral cancer cells. Although the alteration resulted in differential effects on cell proliferation, TGFBR3 knockdown significantly increased migration and Matrigel invasion. TGFBR3 overexpression had the opposite effect on cell migration and invasion. Xenograft tumorigenesis and metastasis will be used to confirm the effect observed in vitro. Since TGFB is frequently overxpressed in oral cancer cells, we will evaluate the therapeutic potential of using sTGFBR3 in treating oral cancer in mice. Our study should facilitate studying the role of TGFBR3 in oral cancer progression and metastasis, and evaluating the possibility of using TGFBR3 as a therapeutic target for oral cancer treatment.
Citation Format: Wei-Yu Fang, Jen-Ren Hsiao, Jang-Yang Chang, Sen-Tien Tsai, Li-Jin Hsu, Li-Wha Wu. Functional implication of TGFBR3 dysregulation and its clinical application in oral cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3987. doi:10.1158/1538-7445.AM2013-3987
Abstract 3996: ErbB4 is critical for tumor suppressive HPP1/STAT signaling in colon cancer.
Authors: Elahi Abul , Clark Whalen , Hernandez Jonathan , Humphries Leigh Ann , Wang Jian , Ajidahun Abidemi , Shibata David 
Published: August 2014

Abstract
Background: HPP1 (also known as TMEFF2) encodes a cleavable transmembrane protein that is thought to be a tumor suppressive EGF-like ligand that activates STAT1 and 2-associated pathways. From phylogenetic analyses, it is postulated that HPP1 exerts its effects via erbB4. We sought to characterize the role of erbB4 in the context of the HPP1/STAT tumor suppressive signaling axis.
Methods: Transient knockdown of erbB4 was achieved using siRNA in stable HPP1-overexpressing HCT116 transfectants. The impact of erbB4 manipulation on STAT signaling was assessed by expression and activation analyses using RT-PCR and Western blotting. Subsequent alterations in cell proliferation and anchorage-independent growth were evaluated by MTT and soft agar assays, respectively.
Results: We have previously demonstrated that HPP1’s tumor suppressive effects are associated with activation of suppressive STAT1 and 2 and downregulation of oncogenic STAT3 and 5. Abrogation of erbB4 expression resulted in a reversal of this profile with a reduction in activated STAT1 and 2 and increased phosphorylation of STAT3 and 5. Moreover, inhibition of ErbB4 receptor in HPP1 over-expressing transfectants resulted in an attenuation of tumor suppressive behavior with increased cell proliferation (Optical Density: 0.12±0.11 vs. 0.35 ±0.040; p≤0.001) and colony formation in soft agar (385±25 vs. 66±30 colonies; p≤0.001) as compared to scrambled siRNA control transfectants.
Conclusion: The EGF-like domain of HPP1 via erbB4 receptor signaling is essential for its tumor suppressive effects. Knockdown of erbB4 elicits a reversal of HPP1-mediated effects on cell behavior and STAT-family activation status. Therapeutic targeting of the erbB family of receptors is of great interest and our findings may lead to a greater understanding of the complex nature of their associated signaling pathways.
Citation Format: Abul Elahi, Whalen Clark, Jonathan Hernandez, Leigh Ann Humphries, Jian Wang, Abidemi Ajidahun, David Shibata. ErbB4 is critical for tumor suppressive HPP1/STAT signaling in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3996. doi:10.1158/1538-7445.AM2013-3996
Abstract 4007: Different patterns of Akt and ERK feedback activation in response to allosteric and active-site mTOR inhibitors in comparison to metformin in pancreatic cancer cells.
Authors: Soares Heloisa P. , Yang Ni , Sinnett-Smith James , Kui Robert , Rozengurt Enrique 
Published: August 2014

Abstract
The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feedback loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with allosteric mTOR inhibitors (rapamycin and everolimus) or active-site mTOR inhibitors (KU63794 and PP242) suppressed p70S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin and everolimus caused a striking increase in Akt phosphorylation at Ser473 while the active-site inhibitors of mTOR completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin and everolimus did not have any stimulatory effect on ERK activation. Exposure to the compound A66, a selective inhibitor of the 110α catalytic subunit of PI3K, did not prevent enhancement of ERK activation in response to exposure to either KU63794 or PP242, implying that KU63794 and PP242 enhance ERK via a novel PI3K-independent pathway. These results suggest that active-site inhibitors, in contrast to mTORC1 allosteric inhibitors, enhanced ERK through a PI3K-independent pathway. In contrast, metformin which potently inhibited the mTORC1/S6K axis did not cause over-stimulation of Akt phosphorylation on Ser473 and inhibited mitogen-stimulated ERK activation in PDAC cells. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited mTORC1/S6K. Metformin is emerging as a potential novel agent in cancer chemoprevention. We propose that the favorable effects of metformin on preventing over-activation of pro-oncogenic pathways, such as Akt and ERK, may contribute to its beneficial anticancer effects.
Citation Format: Heloisa P. Soares, Ni Yang, James Sinnett-Smith, Robert Kui, Enrique Rozengurt. Different patterns of Akt and ERK feedback activation in response to allosteric and active-site mTOR inhibitors in comparison to metformin in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4007. doi:10.1158/1538-7445.AM2013-4007
Abstract 4015: Amplification of GEP at chromosome 17q21 and its overexpression in human liver cancer.
Authors: Yung Man Kuen , Yip Chi Wai , Cheung Phyllis Fung Yi , Cheung Siu Tim 
Published: August 2014

Abstract
Amplification of GEP at chromosome 17q21 and its overexpression in human liver cancer
Hermann M.K. Yung, Wallace C.W. Yip, Phyllis F.Y. Cheung and Siu Tim Cheung
Department of Surgery, The University of Hong Kong.
Introduction:
Hepatocellular carcinoma (HCC) is the 3rd most lethal cancer worldwide. Curative treatments, such as surgical resection, are limited to only a small group of patients. Granulin-epithelin precursor (GEP), which is a secretory growth factor, has been shown to enhance the growth, invasion, metastasis and chemo-resistance of HCC. GEP was found to overexpress in tumors compared to the non-tumor counterpart, and the overexpression correlates to poor prognosis in HCC patients. Antibody targeting GEP inhibited tumor growth in vivo. However, the overexpression mechanisms in HCC are not clear.
Hypothesis:
Gene amplification may be one of the mechanisms for GEP overexpression as its locus, 17q21, is frequently amplified.
Method:
Quantitative Microsatellite Analysis (QuMA) was used to determine the copy number alteration of the GEP gene locus. In this method, quantitative PCR was used to quantify the GEP and microsatellite loci. The genomic stable microsatellite loci were used as reference. Copy number variations were determined by normalization of HCC data to the copy numbers of blood samples from healthy donors, which were defined as diploid 2N. GEP mRNA level was quantified by real-time RT-PCR. Correlations between GEP copy number and its mRNA expression level were analyzed.
Results:
GEP DNA copy numbers were quantified in a panel of clinical HCC (n=60). Amplification of GEP locus was observed in 30% (20/60) HCC, and the amplification frequency was comparable to published reports on chromosome 17q. Overall, GEP copy number correlated to the mRNA overexpression levels (n=60, r=0.267, P=0.039). For HCC with GEP gene locus amplification (n=20), tight correlation with GEP expression levels were observed (r=0.646, P=0.002).
Summary:
We showed that GEP gene was frequently amplified in HCC, and this amplification correlates to the expression level of GEP. Fluorescent in situ hybridization (FISH) will be performed to further investigate the amplification status.
Citation Format: Man Kuen Yung, Chi Wai Yip, Phyllis Fung Yi Cheung, Siu Tim Cheung. Amplification of GEP at chromosome 17q21 and its overexpression in human liver cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4015. doi:10.1158/1538-7445.AM2013-4015
Abstract 4018: Whole exome sequencing analysis of familial Medulloblastoma.
Authors: Sasaki Mark M. , Skol Andrew D. , Pugh Trevor J. , Meyerson Matthew , Onel Kenan 
Published: August 2014

Abstract
Medulloblastoma (MB) is the most common malignant brain cancer in children. Although MB can be categorized into four distinct subtypes, the underlying genetic changes required to promote MB remain unclear. We performed whole exome sequencing was performed on germ-line DNA from two affected cousins who were diagnosed at similar ages with classic WNT subtype MB, and their unaffected mothers, who are full sisters. We found cousins to be homozygous for a variant in a gene regulating WNT-signaling (variant 1), while their mothers were heterozygous. In a mouse model of WNT-type MB, incomplete penetrance and the requirement for inactivation of TP53 were observed. We, therefore, hypothesized that a deleterious mutation in the TP53 pathway may be present. Indeed, we found a single copy of a novel mutation in a regulator of TP53 shared between the affected cousins (variant 2). This allele segregated through the cousins’ maternal line as evidenced by both mothers being heterozygous for this allele. Finally, we identified a common homozygous variant in a gene involved in promoting RAS-mediated cell proliferation (variant 3). We found that mutations in the genes of variants 1 and 3 have been previously reported to be involved in sporadic MB, suggesting that what we observe in this family translates to sporadic disease. Thus, our model for MB development is that of a threshold effect in which combinations of both familial and common variants interact to increase susceptibility. We hypothesize that this model with incomplete penetrance may underlie cancer susceptibility in many families with apparent cancer predisposition syndromes but in whom no causative mutation has been identified. We also hypothesize that this multi-gene model with incomplete penetrance may also explain a proportion of apparently sporadic cases of cancer. This work underscores the advantages of analyzing sequence data from multiple well-chosen affected and unaffected individuals in well-chosen families for gene discovery in cancer and other complex diseases. It also puts forth a new model for analysis, incorporating both agnostic and hypothesis driven models using data from the literature and complementary datasets.
Citation Format: Mark M. Sasaki, Andrew D. Skol, Trevor J. Pugh, Matthew Meyerson, Kenan Onel. Whole exome sequencing analysis of familial Medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4018. doi:10.1158/1538-7445.AM2013-4018
Abstract 4031: Distinct gene expression profile of recurrent stage II colorectal cancers in African American and Caucasian American patients.
Authors: Jadhav Trafina , Chen Dongquan , Putcha Balananda-Dhurjati Kumar , Samuel Temesgen , Posey James , Heslin Martin , Manne Upender 
Published: August 2014

Abstract
Objective: To determine gene expression profile of Stage II colorectal cancers (CRCs) based on disease recurrence and patient race/ethnicity.
Background: About 25-35% of Stage II CRCs recur after potentially curative surgery. Furthermore, the incidence, recurrence, and mortality rates for CRC are higher in African Americans (AAs) relative to Caucasian Americans (CAs), even when they are diagnosed with early stage disease. Differences in tumor biology may contribute to this race-based disparity. Thus, identification of these ‘high-risk’ patients is an unmet medical need.
Methods: Using GeneChip microarray technology, we obtained gene expression profiles for Stage II CRCs from 16 AA and 30 CA patients. Samples from recurrent disease, within 5 years post-surgery (n=5 in AA, n= 9 in CA) were compared against non-recurrent, within 10 years post-surgery, (n=11 in AA, and n=21 in CA) samples. The data were analyzed for expression differences at the gene level comparing AA with CA patients and further analyzed for functions and pathways.
Results: In the samples of recurrent CRCs, a significant number of genes (n=561) were differentially expressed, with a false-discovery rate of ≤5%. Further analyses showed 253 genes differentially expressed within the AA recurrent subgroup and 317 genes in CA recurrent subgroup. In recurrent CRCs, there were 9 genes common to AA and CA patients, suggesting a common gene signature specific for Stage II disease. Canonical pathway analyses and interaction network analyses for these differentially expressed genes revealed that ERK/MAPK, protein kinase A, and CDK5 signaling were the top three affected signaling pathways in recurrent samples from AAs. In contrast, RhoA, integrin, and cell cycle control signaling were the top three affected pathways in Stage II CRCs of CAs. This suggests, for samples from CAs and AAs, a distinct race-based gene expression and downstream effects on pathways.
Conclusion: A common gene expression signature, specific for stage II, together with a race-specific expression profile may have therapeutic implications for AA and CA patients.
Citation Format: Trafina Jadhav, Dongquan Chen, Balananda-Dhurjati Kumar Putcha, Temesgen Samuel, James Posey, Martin Heslin, Upender Manne. Distinct gene expression profile of recurrent stage II colorectal cancers in African American and Caucasian American patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4031. doi:10.1158/1538-7445.AM2013-4031