bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 457: Depletion of glioma infiltrating myeloid derived suppressor cells promotes anti-tumor T cell responses
Authors: Kamran Neha , Li Youping , Moreno-Ayala Mariela , Assi Hikmat , Candolfi Marianela , Dzaman Marta , Lowenstein Pedro , Castro Maria 
Published: August 2015

Abstract
MDSCs represent a population of immature myeloid cells at various stages of differentiation that have the potential to inhibit anti-tumor T cell immunity. We demonstrate the accumulation of MDSCs in GL26 and M7-induced glioma (GBM) bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSC numbers were significantly elevated in the blood of GL26 and M7 intracranial tumor bearing mice at 28 days. While both Gr-1high and Gr-1low MDSCs isolated from the TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Gr-1low MDSC were found to be more efficient. Gr-1high or Gr-1low MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. In vivo, depletion of Gr-1+ cells enhanced the median survival of GBM bearing mice. Furthermore, when combined with Ad-TK + Ad-FLT3L immune-gene therapy, Gr-1+ depletion significantly enhanced the frequency of tumor-specific T cells within the TME and spleen and increased IFN-γ production by splenic T cells. Our data therefore indicates that inhibiting the accumulation of MDSCs with in the GBM TME promotes the generation of robust anti-tumor immunity. Preliminary experiments to determine the mechanism of MDSC trafficking to the TME point towards the receptor CXCR2 and its ligand CXCL1. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA. Additionally a culture of primary mixed glial cells also produced CXCL1 when stimulated with GBM cell lysates. SB225002, a CXCR2 inhibitor suppressed the migration of MDSCs towards GBM cells in an in vitro migration assay. Overall, our data suggests that strategies that inhibit MDSC recruitment to the GBM TME and/or block their activity could enhance the T cell mediated tumor clearance and provide survival benefit.
Work supported by grants from NIH-NINDS
Citation Format: Neha Kamran, Youping Li, Mariela Moreno-Ayala, Hikmat Assi, Marianela Candolfi, Marta Dzaman, Pedro Lowenstein, Maria Castro. Depletion of glioma infiltrating myeloid derived suppressor cells promotes anti-tumor T cell responses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 457. doi:10.1158/1538-7445.AM2015-457
Abstract 4573: 6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1
Authors: Li Haitao , Zhu Feng , Chen Hanyong , Cheng Ka Wing , Zykova Tatyana , Oi Naomi , Lubet Ronald A. , Bode Ann M. , Wang Mingfu , Dong Zigang 
Published: August 2015

Abstract
Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and cyclooxygenase-1 (COX-1) is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of preneoplastic cells. We also successfully applied a ligand-docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer.
Citation Format: Haitao Li, Feng Zhu, Hanyong Chen, Ka Wing Cheng, Tatyana Zykova, Naomi Oi, Ronald A. Lubet, Ann M. Bode, Mingfu Wang, Zigang Dong. 6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4573. doi:10.1158/1538-7445.AM2015-4573
Abstract 4577: Mitagation of potassium dichromate micronuclei induction and kidney damage by ethanol extract of Moringa oleifera in Swiss albino rats
Authors: Akinwum Kazeem A. , Adedoja Ayobami W. , Osifeso Osifeso O. , Adegboyega Adenike M. , Aralamo Deborah O. , David Olaitan O. , Akinwumi Kazeem A. 
Published: August 2015

Abstract
Chromate (VI) compounds are human carcinogen. Exposure by inhalation or ingestion causes lung and intestinal cancers. Current therapy has side effects, necessitating the search for antidote from medicinal plant such as Moringa oleifera (M.oleifera). This study was undertaken to evaluate the effect of ethanol extract of M. oleifera on potassium dichromate (K2Cr2O7) induced clastogenicity and kidney damage. Leaves of M.oleifera were air dried, powdered, extracted with ethanol and phytochemical analysis carried out. Thirty male rats were grouped into 6 of 5 animals each. Negative and positive control rats had water and 12mg/kg K2Cr2O7 once per week respectively. Test rats were exposed to 3.5 and 7.0 body weight M.oleifera alone for 35 days and / or 12 mg/kg body wt K2Cr2O7 once a week before they were sacrificed. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was monitored in the bone marrow while creatinine and urea levels were assessed in the serum. Kidney superoxide dismutase (SOD), glutathione S-transferase (GST) and malondialdehyde (MDA) levels were also determined. K2Cr2O7 significantly (p &lt;0.05) increased mPCEs and urea while creatinine was decreased when compared with control. MDA was also markedly increased, while SOD and GST were significantly reduced. Severe kidney damage was observed in the same sets of animals. However, M.oleifera mitigated the toxicity by reversing the markers towards that of control. M.oleifera is rich in flavonoids and phenolics which may account for the observed .protection. The results suggest that extract of M.oleifera has valuable potentials in the treatment/management of chromate (VI) toxicity
Note: This abstract was not presented at the meeting.
Citation Format: Kazeem A. Akinwum, Ayobami W. Adedoja, Osifeso O. Osifeso, Adenike M. Adegboyega, Deborah O. Aralamo, Olaitan O. David, Kazeem A. Akinwumi. Mitagation of potassium dichromate micronuclei induction and kidney damage by ethanol extract of Moringa oleifera in Swiss albino rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4577. doi:10.1158/1538-7445.AM2015-4577
Abstract 4580A: Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4)
Authors: Murray Jessica R. , Huang Meng , Zang Tianzhu , Arlt Volker M. , Schmeiser Heinz H. , Penning Trevor M. 
Published: August 2015

Abstract
In 2012, the International Agency for Research on Cancer (IARC) classified diesel exhaust as a Group 1 carcinogen due to sufficient evidence that exposure is associated with increased risk for lung cancer in humans. However, only a subset of individuals exposed to diesel exhaust develops cancer, indicating the need to identify the genes involved in metabolic activation of these compounds and their genetic variants. Nitro-polycyclic aromatic hydrocarbons (NO2-PAH) are a major component of diesel exhaust and require metabolic activation to exert their carcinogenic activity. A representative NO2-PAH, 3-nitrobenzanthrone (3-NBA), is metabolically activated to 3-aminobenzanthrone (3-ABA) via a 6-electron nitroreduction catalyzed by NQO1 and POR. The reaction leads to the formation of 3-aminobenzanthrone (3-ABA) derived DNA adducts which promote G to T transversions. Building upon previous data that shows human aldo-keto reductase 1C3 (AKR1C3) contains nitroreductase activity towards chemotherapeutic agents (Guise, C.P., Abbattista, M.R., et al., Cancer Res, 70(4), 2010), we chose to examine the nitroreductase activity of AKR1C1-AKR1C4 towards NO2-PAH. We have demonstrated here for the first time that AKR1C enzymes catalyze the nitroreduction of 3-NBA to 3-ABA. We monitored reactions with reverse phase HPLC coupled to in-line photo-diode-array detection (PDA) and fluorescence detection (FLD) to quantify 3-NBA and 3-ABA levels. Fluorescence and UV spectroscopy were used to validate the identity of the compounds. This method was adapted for discontinuous enzymatic assays to measure steady state kinetic parameters for the nitoreductase activity of AKR1C1-AKR1C4 and NQO1. Results indicate that the NQO1 catalyzed reduction of 3-NBA has a higher specific activity, but the combined specific activities of AKR1C catalyzed reduction may play a more significant role in the overall production of 3-ABA. These results suggest that the relative expression of NQO1 and AKR1C enzymes will determine their respective contribution to 3-NBA reduction, especially since all the aforementioned enzymes are inducible by the Nrf2-Keap1 system. This work is supported by P30E513508 and RO1 CA39504 to TMP.
Citation Format: Jessica R. Murray, Meng Huang, Tianzhu Zang, Volker M. Arlt, Heinz H. Schmeiser, Trevor M. Penning. Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4580A. doi:10.1158/1538-7445.AM2015-4580A
Abstract 4583: Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer
Authors: Koseki Jun , Colvin Hugh , Fukusumi Takahito , Nishida Naohiro , Konno Masamitsu , Kawamoto Koichi , Tsunekuni Kenta , Doki Yuichiro , Mori Masaki , Ishii Hideshi 
Published: August 2015

Abstract
Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer, and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in colorectal cancer patients. This effect was further accentuated by reduced expression of the beta-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of colorectal cancer development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the beta-oxidization pathway is diminished. Additional validation analysis with other gene expression dataset has resulted in that IDH1/2 imbalanced expression had a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of colorectal cancer.
Citation Format: Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4583. doi:10.1158/1538-7445.AM2015-4583
Abstract 459: Targeting TIGIT and PD-1 to increase the expansion and function of tumor antigen-specific CD8+ T cells in melanoma patients
Authors: Chauvin Joe-Marc , Pagliano Ornella , Fourcade Julien , Sun Zhaojun , Sanders Cindy , Kirkwood John M. , Chen Tseng-hui T. , Maurer Mark , Korman Alan , Zarour Hassane 
Published: August 2015

Abstract
T-cell Immunoglobulin and ITIM Domain (TIGIT) is an inhibitory receptor expressed by activated T cells, regulatory T cells and NK cells. Here, we show that tumor antigen (TA)-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) upregulate TIGIT and most often co-express TIGIT and PD-1 in melanoma patients. CD8+ TILs downregulate CD226, supporting an imbalance of TIGIT/CD226 expression in metastatic melanoma. TIGIT is a marker of early T cell activation, which is further upregulated by T cells upon PD-1 blockade and by dysfunctional PD-1+Tim-3+ TA-specific CD8+ T cells. PD-1+TIGIT+, PD-1−TIGIT+ and PD-1+ TIGIT− CD8+ TILs exhibit similar functional capacities ex vivo, suggesting that TIGIT upregulation alone or together with PD-1 is not a marker of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT blockade adds to PD-1 blockade to increase the proliferation, cytokine production and degranulation of TA-specific CD8+ T cells and CD8+ TILs. Collectively, our findings show that TIGIT together with PD-1 regulate the expansion and function of TA-specific CD8+ T cells and CD8+TILs in melanoma patients. They also support the use of dual TIGIT and PD-1 blockade to stimulate potent antitumor CD8+ T cells responses in patients with advanced melanoma.
Citation Format: Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Cindy Sanders, John M. Kirkwood, Tseng-hui T. Chen, Mark Maurer, Alan Korman, Hassane Zarour. Targeting TIGIT and PD-1 to increase the expansion and function of tumor antigen-specific CD8+ T cells in melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 459. doi:10.1158/1538-7445.AM2015-459
Abstract 4594: Serum microRNA signatures predict recurrence and survival in Caucasian patients with early stage non-small cell lung cancer
Authors: Zhang Liren , Roth Jack A. , Lian Jie , Ye Yuanqing , Gu Jian , Wu Xifeng 
Published: August 2015

Abstract
Early stage non-small cell lung cancer (NSCLC) patients can be curatively treated by surgery alone or with adjuvant chemotherapy. However, about half of patients develop recurrence and eventually die of this disease. The purpose of this study is to identify circulating microRNAs (miRNA) as minimally invasive biomarkers for the prognosis of early stage NSCLC that may allow personalized clinical management of early stage NSCLC patients. Using a large series of 171 stage I and II NSCLC Caucasian patients, we screened and validated serum miRNA signatures predictive of recurrence and survival in these patients. We identified six miRNA expression ratios that were associated with recurrence and three miRNA expression ratios that were associated with overall survival. In Receiver Operating Characteristic (ROC) curve analysis, the area under the curve (AUC) for clinical variable-only model was 0.714 for recurrence and 0.678 for survival; however, the AUC increased to 0.878 for recurrence and 0.796 for survival when the miRNA ratio signatures were added to the recurrence and survival models respectively. The patients in the high risk group as defined by the 6 miRNA ratio signature exhibited an approximately 5-fold increased risk of develop recurrence compared with low risk patients. In survival analysis, the death rate increased over 4-fold in the high risk group compared with the low risk group. Our results suggest that the miRNA ratio signatures could serve as prognostic biomarkers for early stage NSCLC.
Citation Format: Liren Zhang, Jack A. Roth, Jie Lian, Yuanqing Ye, Jian Gu, Xifeng Wu. Serum microRNA signatures predict recurrence and survival in Caucasian patients with early stage non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4594. doi:10.1158/1538-7445.AM2015-4594
Abstract 4596: Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia
Authors: Machiela Mitchell J. , Hsiung Chao A. , Shu Xiao-Ou , Seow Wei J. , Wang Zhaoming , Matsuo Keitaro , Hong Yun-Chul , Seow Adeline , Wu Chen , Hosgood H Dean , Chen Kexin , Wang Jiu-Cun , Wen Wanqing , Wu Tangchun , Wong Maria P. , Wu Yi-Long , Yang Pan-Chyr , Zhou Baosen , Shin Min-Ho , Fraumeni Joseph F. , Zheng Wei , Lin Dongxin , Chanock Stephen J. , Rothman Nathaniel , Lan Qing 
Published: August 2015

Abstract
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, P-value = 4.54×10−14) even after removing rs2736100 (P-value = 4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
Citation Format: Mitchell J. Machiela, Chao A. Hsiung, Xiao-Ou Shu, Wei J. Seow, Zhaoming Wang, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Chen Wu, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Wanqing Wen, Tangchun Wu, Maria P. Wong, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F. Fraumeni, Wei Zheng, Dongxin Lin, Stephen J. Chanock, Nathaniel Rothman, Qing Lan. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: A report from the Female Lung Cancer Consortium in Asia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4596. doi:10.1158/1538-7445.AM2015-4596
Abstract 4597: A novel variant in DNA repair gene GTF2H4 is associated with lung cancer risk: A reanalysis of GWAS datasets from the TRICL consortium
Authors: Wei Qingyi , Liu Hongliang , Liu Zhensheng , Amos Christopher I. , Doherty Jennifer A. , Bickeboller Heike , Hung Rayjean J. , Brennan Paul , Houlston Richard , Landi Maria Teresa , Caporaso Neil E. , Christiani David 
Published: August 2015

Abstract
DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair is involved in cancer. We hypothesize that genetic variants in DNA repair genes are associated with risk of lung cancer. To test this hypothesis, we performed a large-scale meta-analysis of 123,371 SNPs in 169 DNA repair genes obtained from six datasets of previously published genome-wide association studies (GWASs), consisting of 12,160 lung cancer cases and 16,838 controls. We evaluated functional relevance of the identified, previously unpublished important and significant SNPs. Across the six GWASs, 14 SNPs were found to be significantly associated with lung cancer risk with a false discovery rate (FDR) of P &lt; 0.05, of which rs114596632 in GTF2H4 at 6q31.33 was the most statistically significant SNP (OR = 1.19, 95% CI = 1.12-1.25, Pcombined = 5.40 × 10−10). The SNP rs114596632 was not strongly correlated with the previously reported GWAS hit MSH5 rs3131379 in that region (r2 = 0.383). Further mapping of the human leukocyte antigen (HLA) region identified that rs114596632 was partially tagged by HLA-B*0801 (r2 = 0.592) and HLA-C*0701 (r2 = 0.675). Importantly, the rs114596632 T allele was significantly associated with decreased DNA repair capacity (DRC) measured in peripheral T lymphocytes and decreased mRNA expression levels of GTF2H4 in lymphoblastoid cell lines. We also validated two previously known SNPs in DNA repair genes MSH5 and XRCC4 associated with lung cancer risk. Subsequent pathway analysis with gene relationships across implicated loci (GRAIL) revealed multiple significant connections for GTF2H4, ERCC2, and MMS19. Our results provide evidence that genetic variants of GTF2H4 confer susceptibility to lung cancer and suggest the involvement of GTF2H4 in the etiology of lung cancer. (Supported by U19CA148127, R01CA CA074386, R01CA092824 and the start-up funds from Duke Cancer Institute, Duke University Medical Center)
Citation Format: Qingyi Wei, Hongliang Liu, Zhensheng Liu, Christopher I. Amos, Jennifer A. Doherty, Heike Bickeboller, Rayjean J. Hung, Paul Brennan, Richard Houlston, Maria Teresa Landi, Neil E. Caporaso, David Christiani. A novel variant in DNA repair gene GTF2H4 is associated with lung cancer risk: A reanalysis of GWAS datasets from the TRICL consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4597. doi:10.1158/1538-7445.AM2015-4597