bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 761: Specific inhibition of prostaglandin E2 production in medulloblastoma
Authors: Bergqvist Filip , Ljungblad Linda , Wickström Malin , Larsson Karin , Kock Anna , Korotkova Marina , Johnsen John Inge , Kogner Per , Jakobsson Per-Johan 
Published: July 2016

Abstract
Introduction: Prostaglandin E2 (PGE2) is a key lipid mediator of inflammation and carcinogenesis. Apart from promoting direct growth of cancer cells, PGE2 has been shown to be crucial in maintaining the immunosuppressive tumor microenvironment. Drugs targeting cyclooxygenase (COX)-1 and -2, enzymes upstream in the production of PGE2 and other prostanoids, have successfully reduced tumor growth in many cancer models but these drugs are all associated with adverse long-term effects. The aim of this study is to demonstrate an anti-tumor effect in medulloblastoma by selective inhibition of microsomal prostaglandin E1 (mPGES-1), the enzyme downstream of COX-1/2 specifically required for the synthesis of PGE2.
Experimental procedures: Human medulloblastoma cell lines (DAOY and D283) were treated with a selective small-molecule inhibitor against mPGES-1 or COX-2 in the presence or absence of pro-inflammatory interleukin (IL)-1â. Prostaglandins in supernatants were extracted and quantified with LC-MS/MS. Drug efficacy was determined and cell toxicity was measured with cell viability assay. Mice with human medulloblastoma xenograft will function as proof-of-concept for the anti-tumor activities associated with inhibition of PGE2 production. Key inflammatory enzymes were quantified with Western blot.
Results: Medulloblastoma cells express high levels of COX-2, mPGES-1, and produce PGE2. The increased production of PGE2 by IL-1â was completely blocked when cells were co-treated with inhibitor for mPGES-1 or COX-2. Both inhibitors showed cell toxicity. We did not observe any shunting towards other prostanoids.
Conclusion: We investigate the effect of selective inhibition of mPGES-1 or COX-2 on medulloblastoma growth. We aim to further characterize the mPGES-1 inhibitor and compare to selective COX-2 inhibitor in preclinical medulloblastoma models. Specific inhibition of PGE2 production, rather than general inhibition of prostanoid production, would potentially prove useful as a complement to current medulloblastoma treatments.
Citation Format: Filip Bergqvist, Linda Ljungblad, Malin Wickström, Karin Larsson, Anna Kock, Marina Korotkova, John Inge Johnsen, Per Kogner, Per-Johan Jakobsson. Specific inhibition of prostaglandin E2 production in medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 761.
Abstract 77: Establishment of lung cancer patient derived xenograft model from circulating tumor cells: Identification of somatic mutations associated with metastatic potentials
Authors: Lee Chansu , Kim Youngwook , Bae Eunkyung , Cho Sunghoon , Youn Sohyun , Ahn Kwang-Sung , Kim Bong-Seog 
Published: July 2016

Abstract
Carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, the existence and genetic alternations of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. The establishment of xenograft model using CTCs should help us to understand the biologic behaviors and genetic alternations of MICs associated the promotion of metastasis. Here, we demonstrate that xenograft model can be established by CTCs obtained from lung cancer patients and somatic mutations analyzed from xenograft model in which MICs develop metastatic tumor. After injecting mononuclear cells of lung cancer patients via tail vein, mouse was sacrificed at four weeks. After primary cultured cells were isolated from mouse lung tissues, the MICs were selected by using FASC sorting (EpCam+) and then re-injected via tail vein. And tumor formations in mouse were examined at 8 weeks. For identifying somatic mutations, target sequencing with NGS was performed in tumor DNA and cell free DNA (CF DNA) of lung cancer patients bloods. Our results indicated that nonsynonymous IDH, EGFR, KIT, ABL1, PTEN, ATM, P53, and SMAD4 were found in both tumor tissues and CF DNA of lung cancer patients’ bloods. IDH and EGFR was alternative homo. Others newly found in CF DNA. For further examination of the biologic behaviors of tumor cells which harvested from xenograft model using CTCs, we cultured primary cells from lung tissues and analyzed the anti-cancer drug resistance. Our results showed that primary cultured cells (BH-007) were resistant against cisplatin and erlotinib. In assay of migration and invasion, BH-007 cells possessed high metastatic potential when compared with A549 and H23 cell lines. These data suggested that several somatic mutations affect the anti-cancer drug resistance in lung cancer patients. Our future researches will include development of patient-derived xenograft models for preclinical testing of novel therapeutics. And we develop the possible integration of CF DNA analysis and PDX model from CTCs in the design of co-clinical studies for testing in individual lung cancer patients.
Citation Format: Chansu Lee, Youngwook Kim, Eunkyung Bae, Sunghoon Cho, Sohyun Youn, Kwang-Sung Ahn, Bong-Seog Kim. Establishment of lung cancer patient derived xenograft model from circulating tumor cells: Identification of somatic mutations associated with metastatic potentials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 77.
Abstract 773: Analysis of oncogene affected networks in tumorigenesis of lung cancer
Authors: Sathe Adwait , Chen Yong , Yoo Hyuntae , Zhang Michael Q. 
Published: July 2016

Abstract
Genetic abnormality is one of major causes of tumorigenesis by driving the progressive transformation of normal human cells into highly malignant derivatives. Tracing the downstream pathways through which and how the effects of the oncogenic-activating mutations are transmitted is an important and challenging problem in studying disease mechanisms, diagnoses and treatments. In this study, we designed a network-based computational method, called MAXMAP, to not only predict mutation downstream affected pathways, but also quantitatively measure the dynamics of the pathway genes.
We first constructed a heterogeneous network by integrating protein-protein interaction networks and signaling and regulatory networks from available up-to-date curated databases, as well as RNASeq expression data. The RNAseq dataset of these mutated cell lines has 18,096 genes whereas the Protein Protein Interaction and Signalling, regulation dataset has 14,864 genes. We then used the maximal information flow method to globally optimize the effects from the mutations to target downstream genes. The method was applied to analyze the biological network dynamics that is caused by single (TP53), double (TP53+KRAS) and triple (TP53+KRAS+STK11) mutations of HBEC30KT, an immortalized lung cell line, and revealed the core dynamical subnetworks of these mutations. Only the triple mutant is known to have tumor-like properties and as shown in earlier studies these sequential mutation accumulations lead to tumorigenesis in mouse xenograft models. The experimental validation of a small subnetwork was performed using transient knock down of the pathway genes and expression was verified using qPCR.
We showed the dynamical subnetworks through which a gene, SLC7A5 was affected by sequential single, double or triple mutations. We have experimentally validated the predicted small subnetwork for SLC7A5 which is an important transporter of neutral amino acids. It is associated with bladder and bile duct adeno carcinomas and overexpressed in lung cancers. We selected the subnetwork affected due to the single mutation (TP53) for validation, including THBS1, TNFRSF11B and MAPK1 and SLC7A5.
Hence, using the MAXMAP method we have successfully identified a dynamical subnetwork affected by changes in the known network of genes. These results suggest that this computational method may allow us to predict drug targets or biomarkers or to study interesting alternative paths and predict the most likely path leading to certain phenotypic outcomes.
Citation Format: Adwait Sathe, Yong Chen, Hyuntae Yoo, Michael Q. Zhang. Analysis of oncogene affected networks in tumorigenesis of lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 773.
Abstract 794: A genetic polymorphism of ALDH2 and breast cancer risk: an analysis of 6,624 cases and 5,750 controls from the Breast Cancer Association Consortium
Authors: Ugai Tomotaka , Milne Roger L. , Ito Hidemi , Matsuo Keitaro 
Published: July 2016

Abstract
Background.
Numerous epidemiological studies consistently indicate that consumption of alcoholic beverages is an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, it has been hypothesized that ethanol is mutagenic via its first metabolite, acetaldehyde. An impact of acetaldehyde on the carcinogenesis of several types of cancer has been shown in experimental models and in epidemiological studies in East Asian countries where a functional aldehyde dehydrogenase 2 (ALDH2) polymorphism Glu504Lys (rs671) is prevalent. However, its association with breast cancer risk has not been fully elucidated. We conducted an association analysis of original data from Asian studies participating in the Breast Cancer Association Consortium (BCAC).
Patients and Methods.
Nine studies were used for this analysis, including 6,624 cases and 5,750 controls. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with the ALDH2 polymorphism was estimated using logistic regression models. We estimated unadjusted ORs and adjusted ORs for potential confounders.
Results.
In the unadjusted (crude) analysis, no significant association between ALDH2 polymorphism and breast cancer was observed, with ORs relative to Glu/Glu, of 1.02 (95% CI = 0.95-1.11; P = 0.51) for Glu/Lys, 1.13 (0.96-1.32; 0.14) for Lys/Lys and 1.04 (0.97-1.12; 0.29) for carriers of any Lys allele. In addition, after adjustment for all potential confounding factors, this lack of significant association was consistently observed, with ORs relative to Glu/Glu, of 0.95 (95% CI = 0.86-1.04; P = 0.25) for Glu/Lys, 0.99 (0.82-1.20; 0.93) for Lys/Lys and 0.95 (0.87-1.04; 0.29) for carriers of any Lys allele. These findings were consistent across ER, PR and HER2 status.
Conclusions.
No significant association between ALDH2 polymorphism and breast cancer was observed in this study. Considering the established impact of ALDH2 504Lys on the carcinogenesis of several types of alcohol-induced cancer, our findings suggest that acetaldehyde is less influential to the breast carcinogenesis induced by alcohol, as is the case for upper-aerodigestive tract cancers.
Citation Format: Tomotaka Ugai, Roger L. Milne, Hidemi Ito, Keitaro Matsuo. A genetic polymorphism of ALDH2 and breast cancer risk: an analysis of 6,624 cases and 5,750 controls from the Breast Cancer Association Consortium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 794.
Abstract 811: Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk
Authors: Machiela Mitchell J. , Dagnall Casey L. , Pathak Anand , Loud Jennifer T. , Chanock Stephen J. , Greene Mark H. , McGlynn Katherine A. , Stewart Douglas R. 
Published: July 2016

Abstract
Background
Testicular germ cell tumors (TGCTs) affect approximately 6 in 100,000 men with peak incidence in men 15 to 40 years of age. Established risk factors include family history of disease, undescended testis, contralateral TGCT, impaired fertility, and 21 GWAS susceptibility loci. Recent evidence suggests a 1.6 Mb deletion in the AZFc region (“gr/gr” deletion) of chromosome Y previously associated with male infertility is also associated with two- and three-fold increased risks of sporadic and familial TGCT, respectively. Furthermore, population-based studies have suggested mosaic chromosome Y loss in blood-derived DNA may be associated with increased risk of various solid tumors. Our aim was to investigate if mosaic loss across the entire Y chromosome is a TGCT risk factor.
Methods
We obtained blood and buccal-derived DNA from two studies: the NCI Familial Testicular Cancer Study (FTC, Cases = 172, Controls = 163) and NCI's US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (STEED, Cases = 506, Controls = 611). We designed a quantitative polymerase chain reaction (qPCR) with 15 probes spanning the Y chromosome to assess Y loss. Samples were run in triplicate across three batches and normalized to a standard curve. We quantified probe signals as a target to reference (T/R) ratio, and averaged ratios across the 15 probes to yield an overall Y chromosome signal.
Results
On average, men with TGCT had slightly lower mean T/R ratios compared with control men lacking TGCT (1.02 vs. 1.03). Multivariate logistic regression models adjusted for study batch effects detected no significant relationship between mean Y chromosome T/R ratio and TGCT risk (OR = 0.34, 95% CI = 0.10-1.17, P = 0.09). A similar null relationship was observed when using a threshold of 1.5 standard deviations below the mean T/R ratio to dichotomize between mosaic Y loss and no mosaic Y loss (OR = 0.59, 95% CI = 0.21-1.63, P = 0.31).
Conclusion
Our study suggests that mosaic chromosome Y loss, as measured by 15 probes spanning the Y chromosome, is not associated with either sporadic or familial TGCT risk. Further studies aimed at investigating the AZFc region of the Y chromosome are needed to better assess whether this locus is directly associated with TGCT risk or is indirectly associated by means of a shared relationship with impaired fertility.
Citation Format: Mitchell J. Machiela, Casey L. Dagnall, Anand Pathak, Jennifer T. Loud, Stephen J. Chanock, Mark H. Greene, Katherine A. McGlynn, Douglas R. Stewart. Mosaic chromosome Y loss is not associated with testicular germ cell tumor risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 811.
Abstract 832: Preventing the progression of estrogen receptor-negative/HER2-overexpressing early stage breast disease by lapatinib
Authors: Acharya Sunil , Xu Jia , Wang Xiao , Jain Shalini , Wang Hai , Zhang Qingling , Bower Joseph , Richards-Kortum Rebecca , Yu Dihua 
Published: July 2016

Abstract
Tamoxifen and aromatase inhibitors (AIs) have shown efficacy to prevent estrogen receptor positive (ER+) breast cancer; however, there is no effective prevention strategy for ER- breast cancer. HER2 overexpression (HER2+) can be detected in up to 40% of ER- breast cancers and it has been reported to promote the progression of early stage breast cancer. Here, we tested the feasibility of lapatinib to prevent ER-/HER2+ early stage breast disease. Our data showed that lapatinib reduced the proliferation and increased the apoptosis in an in vitro ER-/HER2+ early breast disease model. Furthermore, lapatinib treatment in the HER2-driven MMTV-neu mouse model from early stage of disease development (atypia, at 10 weeks of age) significantly delayed tumor initiation and progression as detected by mammary gland biopsy and fiber optic micro-endoscope (FOME) imaging. Mechanistically, we found that lapatinib inhibited GLUT4 upregulation and increased glucose up-taking in HER2-overexpressing cells. These results suggested that lapatinib is a promising agent for the prevention/intervention of ER- and HER2+ breast cancers. Our study brings better understanding of the mechanism underlying ER-/HER2+ early stage breast disease progression to cancer and our strategy of cancer prevention with low-dose kinase inhibitor could be rapidly translated into the clinic for other cancer types in the near future.
Citation Format: Sunil Acharya, Jia Xu, Xiao Wang, Shalini Jain, Hai Wang, Qingling Zhang, Joseph Bower, Rebecca Richards-Kortum, Dihua Yu. Preventing the progression of estrogen receptor-negative/HER2-overexpressing early stage breast disease by lapatinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 832.
Abstract 836: Effect of voluntary running on metastasis in a mouse model of breast cancer
Authors: Mijwel Sara , Rundqvist Helene , Lindholm Carolin , Strell Carina , Roswall Pernilla , Pietras Kristian , Johnson Randall S. , Östman Arne 
Published: July 2016

Abstract
Introduction: Emerging evidence states that regular physical exercise provides a risk reduction for breast cancer by approximately 25%. In addition, recent studies suggest that physical activity may also have an effect on recurrence and mortality. Mouse models are suitable tools to study anti-neoplastic mechanisms.
Aim: to evaluate the effect of voluntary running on tumor initiation, growth and metastasis in the Polyoma Middle T (PyMT) model of breast cancer.
Methods: PyMT mice were housed with access either to wirelessly recording running wheels or locked control wheels. Running distances and tumor volumes were recorded. At 12 weeks, mice were sacrificed. Mammary glands were histologically staged and pulmonary metastases were quantified. In a follow up study, pre-trained mice were injected intravenously with tumor cells derived from the PyMT model and after an additional 10 weeks of voluntary running, pulmonary metastases were quantified.
Results: PyMT mice ran significantly more than wildtype mice (6.4 vs 3.4 km/day). No significant effects of voluntary running on tumor- initiation, volume or stage were found. However, a trend for reduced metastasis was observed. After intravenous injections of tumor cells, runners had a significantly lower pulmonary metastasis frequency than non-runners.
Conclusion: In this aggressive breast cancer model, an average of 6 km/day of voluntary running did not induce any effect on tumor formation or growth. However, the findings suggest that physical activity has impact on the metastatic process.
Citation Format: Sara Mijwel, Helene Rundqvist, Carolin Lindholm, Carina Strell, Pernilla Roswall, Kristian Pietras, Randall S. Johnson, Arne Östman. Effect of voluntary running on metastasis in a mouse model of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 836.
Abstract 86: Functional effects of MutL homolog 1 promoter polymorphism in prostate cancer
Authors: Fukuhara Shinichiro , Mitsui Yozo , Hashimoto Yutaka , Kato Taku , Wong Ryan K. , Shahryari Varahram , Yamamura Soichiro , Majid Shahana , Saini Sharanjot , Deng Guoren , Dahiya Rajvir , Tanaka Yuichiro 
Published: July 2016

Abstract
The mutL homolog (MLH1) gene protects the integrity of the genome by correcting erroneous insertions, deletions and mismatches that occur during DNA replication. Proper MLH1 expression is thus essential for the health of the cell and deficiency can result in mutation and genomic instability, which ultimately may lead to cancer. Polymorphisms in the promoter region can lead to altered gene expression and we tested the hypothesis that MLH1 promoter variants can affect levels as well as be a risk for prostatic cancer. Two polymorphic sites were analyzed, rs1800734 (A to G) and rs4647203 (G to A). A luciferase reporter construct containing the MLH1 promoter region was utilized and site-directed mutagenesis was performed to create rs1800734 and rs4647203 variants. Activity was tested using DU145, PC3 and LNCaP prostatic cells and interestingly, the rs1800734 G variant resulted in significantly decreased luciferase levels in all three cell lines compared to A (P&lt;0.01). No difference however, was seen for the rs4647203 variant. To determine whether rs1800734 can affect clinical expression levels, benign prostatic hyperplasia specimens were evaluated for MLH1 expression by immunohistochemistry. A significantly lower H score was observed for the GG genotype compared to AA (P&lt;0.01). To further explore the clinical relevance of rs1800734, a case-control study was performed using DNA extracted from normal healthy, BPH, and prostate cancer patients from a Japanese population by sequence-specific PCR and sequencing. Results of experiments showed a trend for the variant G allele to be associated with prostate cancer when compared to normal controls (P&lt;0.1). However, no differences were observed between BPH and controls as well as between stages or grades of prostate cancer. The MLH1 promoter polymorphism is thus capable of altering expression and associated with prostate cancer, and these results are important in understanding its role in this disease.
Citation Format: Shinichiro Fukuhara, Yozo Mitsui, Yutaka Hashimoto, Taku Kato, Ryan K. Wong, Varahram Shahryari, Soichiro Yamamura, Shahana Majid, Sharanjot Saini, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka. Functional effects of MutL homolog 1 promoter polymorphism in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 86.
Abstract 877: Evolution of resistance to EGFR inhibition from drug tolerant cancer cells
Authors: Hata Aaron N. , Drier Yotam , Gomez-Caraballo Maria , Siddiqui Faria , Sequist Lecia , Bernstein Bradley , Engelman Jeffrey 
Published: July 2016

Abstract
Acquired drug resistance to targeted cancer therapies remains a significant clinical problem. Although mechanisms of acquired resistance of EGFR mutant non-small cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. We demonstrate that acquired resistance caused by the T790M gatekeeper mutation can occur either by selection of pre-existing T790M clones or via evolution of T790M-negative drug tolerant cells that develop the mutation during drug treatment. Additionally, the path to resistance impacts the biology of the resistant clone, as those that evolved from drug tolerant cells have a diminished apoptotic response to third generation EGFR inhibitors that target T790M EGFR. To characterize drug tolerant cells in patients undergoing EGFR inhibitor therapy, we performed single-cell RNA-Seq on EGFR mutant NSCLC samples prior to and after initiation of EGFR inhibitor. These results offer novel insights into the evolution of acquired resistance to EGFR inhibitors and point to new therapeutic opportunities to prevent or overcome resistance in the clinic.
Citation Format: Aaron N. Hata, Yotam Drier, Maria Gomez-Caraballo, Faria Siddiqui, Lecia Sequist, Bradley Bernstein, Jeffrey Engelman. Evolution of resistance to EGFR inhibition from drug tolerant cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 877.