bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2722: Characterization of human lung enzymes involved in the reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
Authors: Ashmore Joseph , Liu Ying , Peterson Amity , Fechtner Sabrina , Chen Gang , Lazarus Philip 
Published: August 2015

Abstract
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the primary tobacco-specific nitrosamine (TSNA) related to cancer. The major metabolic pathway for NNK is carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) which, like NNK, is a potent lung and pancreatic carcinogen in rodents, with it estimated that 39-100% of NNK is converted to NNAL in cigarette smokers. NNAL is formed as both (R)- and (S)-NNAL enantiomers; while (S)-NNAL is more readily formed from NNK, it is also more readily glucuronidated and detoxified by the phase II UGTs than is (R)-NNAL in monkeys and probably in humans. Therefore, both (S)- and (R)-NNAL are likely to be important metabolites in the NNK carcinogenic process. In the present study, we demonstrated that while (S)-NNAL is the major form (&gt;90%) produced using lung cytosolic fractions, lung microsomes formed primarily (R)-NNAL (&gt;95%). Consistent with previous studies using placenta-fractionated cytosolic enzymes, we demonstrated that several cytosolic enzymes including the aldo-keto reductases (AKRs) 1C1, 1C2, and 1C4, as well as carbonyl reductase I (CBR1) were active against NNK, with all of them forming primarily (&gt;90%) (S)-NNAL. This pattern is consistent with that observed for lung cytosolic fractions. Using HEK293 cells over-expressing microsomal enzymes HSD11β1, HSD11β2, HSD17β12, SDR5A1, SDR5A3, HSD17β1, HSD17β2 or HSD3β7, only HSD11β1 and HSD17β12, all of which were reported to be expressed in lung, exhibited activity against NNK. Most interestingly, both enzymes formed primarily (R)-NNAL (&gt;80%), which is consistent with that observed in lung microsomes. Real-time PCR showed that HSD17β12 was expressed at a level that, on average, was three-fold higher than that observed for HSD11β1 in a screening of normal lung tissue specimens from five individuals. These data suggest that both cytosolic and microsomal enzymes are active against NNK and that HSD11β1 and HSD17β12 are the active microsomal reductases in human lung microsomes, contributing to the exclusive formation of (R)-NNAL
Citation Format: Joseph Ashmore, Ying Liu, Amity Peterson, Sabrina Fechtner, Gang Chen, Philip Lazarus. Characterization of human lung enzymes involved in the reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). [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 2722. doi:10.1158/1538-7445.AM2015-2722
Abstract 2727: Molecular markers and pathway analysis of Middle Eastern colorectal carcinoma
Authors: Beg Shaham , Prabhakaran Sarita , Bu Rong , Al-Assiri Mohammed , Sairafi Rami , Al-Dayel Fouad , Al-Sanea Nasser , Siraj Abdul K. , Uddin Shahab , Al-Kuraya Khawla 
Published: August 2015

Abstract
Colorectal cancer (CRC) is one of the common cancers in the world. In Saudi Arabia CRC is the most common cancer in males and third most common in females. A newly proposed integrated pathways comprising traditional, alternate and serrated by genetic and epigenetic factors was defined recently and hypothesized to role in the pathogenesis of CRC; however there is a paucity of information about these proposed molecular pathways in different ethnic group. Hence we analyzed a large cohort of Saudi colorectal tumors to understand the role of these molecular pathways. 770 archival CRCs specimen were evaluated for Microsatellite Instability (MSI), BRAF, KRAS and 500 cases for CpG Island Methylator Phenotype (CIMP). Traditional pathway constituted 33.4% of CRC cases; the alternate pathway comprised 11.6% of cases. Strikingly, the serrated molecular pathway accounted for only 0.8% of Middle Eastern CRC that is extremely below compared to publish data. 54.2% CRC cases did not qualify to fit into any pathway and thus were designated an unassigned group. Molecular pathways were significantly associated with tumor site and grade. In our attempt to further classify unassigned group a subset of the uncategorized pathway showed a significant survival difference (p = 0.0079). The Unassigned group that accounted for the majority of our cases reflects the heterogeneity of colorectal cancers and warrants the need to unravel the molecular genetic basis of this disease to further subcategorize these CRC cases. It also identifies the need to do further studies on different populations for better understanding of their exact role and incidence.
Keywords: colorectal; molecular pathways; serrated
Citation Format: Shaham Beg, Sarita Prabhakaran, Rong Bu, Mohammed Al-Assiri, Rami Sairafi, Fouad Al-Dayel, Nasser Al-Sanea, Abdul K. Siraj, Shahab Uddin, Khawla Al-Kuraya. Molecular markers and pathway analysis of Middle Eastern colorectal carcinoma. [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 2727. doi:10.1158/1538-7445.AM2015-2727
Abstract 2733: Development of novel monoclonal antibodies for a cyclic DNA adduct derived from oxidation of ω-6 polyunsaturated fatty acids
Authors: Dyba Marcin , Da Silva Brandon , Pan Jishen , Chung Fung-Lung 
Published: August 2015

Abstract
Dietary polyunsaturated fatty acids (ω-3 and ω-6 PUFAs) play a role in certain human cancers. The oxidation of PUFAs produces reactive α,β-unsaturated aldehydes (enals) that can modify DNA producing mutagenic lesions. Of particular interest, 7-(1′,2′-dihydroxyheptyl)-1,N6- ethenodeoxyadenosine (DHHϵdA) is a novel DNA adduct in vitro and in vivo derived from lipid peroxidation of ω-6 PUFAs. Despite its recent identification in vivo, the role of DHHϵdA in tumorigenesis is not yet known. Previously, the endogenously formed DHHϵdA was detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Due to its low levels in vivo (1-30 adducts/109 DNA bases), a relatively high quantity of DNA is needed for its detection and quantification. In this study we developed a monoclonal antibody against DHHϵdA in order to detect and quantify this adduct in cells and tissues. Two antigens were synthesized by conjugating activated hapten: 5′-carboxy-7-(1′,2′-dihydroxyheptyl) adenosine (5′-carboxy DHHϵA) to BSA and KLH carrier proteins. KLH-conjugated hapten was used for mice immunization, whereas BSA-based hapten was used to test for an immune response. After immunization and several screenings, 6 monoclonal cell lines were chosen for further tests. Normal and competitive ELISA was performed to characterize the antibodies from all cell lines. Competitive ELISA revealed no cross-reactivity towards normal nucleosides and α- and γ-OHPdG, the cyclic 1,N2-propano adduct derived from acrolein, and 8-oxo-dG for all of the tested antibodies. However, we observed a weak (&lt; 1:100) specificity for HNE-dG, an adduct derived from (E)-4-hydroxy-2-nonenal produced from oxidized ω-6 PUFAs. Because of the relatively low level of endogenous HNE-dG compared to DHHϵdA, this weak cross-reactivity should not affect the specificity of the developed antibody to detect DHHϵdA. Two cell lines were discarded after antibodies from them showed moderate competitive effects against 1,N6-etheno-2′-deoxyadenosine (ϵdA). From the remaining 4 cell lines the best one was chosen to produce purified antibody. We believe that this antibody will be a useful tool in the studies of the role of DHHϵdA as an endogenous DNA lesion in cancer development associated with ω-6 PUFAs. This work was supported by the NCI grant CA134892.
Citation Format: Marcin Dyba, Brandon Da Silva, Jishen Pan, Fung-Lung Chung. Development of novel monoclonal antibodies for a cyclic DNA adduct derived from oxidation of ω-6 polyunsaturated fatty acids. [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 2733. doi:10.1158/1538-7445.AM2015-2733
Abstract 2735: Tributyltin alters the production and secretion of inflammatory cytokines from human and mouse immune cells
Authors: Lawrence Shanieek T. , Whalen Margaret , Pellom Samuel , Shanker Anil 
Published: August 2015

Abstract
Tributyltin (TBT) is an environmental contaminant that has been used for several industrial, agricultural and household purposes. Despite limited bans on the usage of Tributyltin, the stability and toxicity of the compound may prove to have negative effects on immune function in terrestrial mammals. Studies show that there is an increase in the incidences of tumors and decreased immune cell function in TBT-exposed mammals. TBT interferes with the ability of human natural killer (NK) cells to lyse target cells; it also alters the secretion of the pro-inflammatory cytokines Interferon gamma (IFNγ) and Tumor necrosis factor alpha (TNFα) from human immune cells ex vivo. Any dysregulation of the cytokine communication network may have detrimental effects on immune function, as cytokines play a key role in the regulation of immune responsiveness. There have been no in vivo studies on the effects of exposure to TBT on the cytokine communication network. The effects of 24 hour exposure to TBT on the production of IFNγ and TNFα from human immune cells were analyzed in an ex vivo system using western blotting. The serum of TBT-exposed mice was analyzed for changes in the levels of cytokine secretion and production using a Milliplex mouse cytokine/chemokine magnetic bead premixed 32 plex kit and western blotting; the effects of TBT-exposure was assessed using a time curve of 6h, 12h, 24h, 48h and control. TBT increased the levels of the cytokines IFNγ, TNFα, IL1β, IL5, IL7, IL12βp40, IL13, IL15, MIP1β, MIP2 and RANTES in the serum at a minimum of one time point. IFNγ and TNFα secretion and production from human cells also increased, showing striking agreement in the response to TBT between the human and mouse systems.
Supported by: NIH grant 5U54CA163066-03
Citation Format: Shanieek T. Lawrence, Margaret Whalen, Samuel Pellom, Anil Shanker. Tributyltin alters the production and secretion of inflammatory cytokines from human and mouse immune cells. [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 2735. doi:10.1158/1538-7445.AM2015-2735
Abstract 2756: Whole-exome sequencing reveals a novel germline variant in CEBPA-associated familial acute myeloid leukemia: 45-year follow-up of a large family
Authors: Pathak Anand , Seipel Katja , Pemov Alexander , Dewan Ramita , Brown Christina , Ravichandran Sarangan , Luke Brian T. , Yeager Meredith , Gatti Richard A. , Caporaso Neil , Mulvihill John J. , Goldin Lynn , Pabst Thomas Muller , McMaster Mary Lou , Stewart Douglas R. 
Published: August 2015

Abstract
Familial acute myeloid leukemia (AML) is rare and linked to germline mutations in RUNX1 or CCAAT/enhancer binding protein-α (CEBPA). We conducted whole-exome sequencing on a large family with AML originally evaluated at NIH in 1969 and uncovered a CEBPA Q311P mutation in all tested, affected members. The Q311P variant, located in the C-terminal bZip domain of CEBPA, was predicted to be highly deleterious by in silico algorithms; the Q311 position was highly conserved among CEBPA orthologs and paralogs. This variant has not been observed in the NHLBI's Exome Sequencing Project or the Broad Institute's Exome Aggregation Consortium. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mutant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation of a promoter with a tetramer of CEBP sites, consistent with a loss-of-function mutation. In addition, there was decreased colony survival in fibroblasts with CEBPA Q311P, associated with the clinical radiosensitivity postulated in one carrier. From 45 years of follow-up, we observed incomplete penetrance (46%) of CEBPA Q311P; we did not observe other cancers or leukemias segregating with the mutation. Thus, we present a comprehensive clinical and molecular characterization of a novel AML-associated variant in CEBPA in a NCI family with nearly half a century of follow-up. This study reveals that a germline mutation in the C-terminal bZip domain can alter the ability of CEBPA to bind DNA and reduces transactivation, leading to AML, though with lower penetrance than the canonical N-terminal frameshift germline mutations.
Citation Format: Anand Pathak, Katja Seipel, Alexander Pemov, Ramita Dewan, Christina Brown, Sarangan Ravichandran, Brian T. Luke, Meredith Yeager, Richard A. Gatti, Neil Caporaso, John J. Mulvihill, Lynn Goldin, Thomas Muller Pabst, Mary Lou McMaster, Douglas R. Stewart. Whole-exome sequencing reveals a novel germline variant in CEBPA-associated familial acute myeloid leukemia: 45-year follow-up of a large family. [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 2756. doi:10.1158/1538-7445.AM2015-2756
Abstract 276: Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate cancer
Authors: Wei Xiao X. , Chan Stephen , Lewis Jera , Kwek Serena , Dao Vinh , Fong Lawrence 
Published: August 2015

Abstract
Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) is a bone marrow growth factor that is often used as an adjuvant in cancer vaccine clinical trials and has the potential to enhance antitumor efficacy in combination with immune checkpoint blockade in preclinical studies and clinical trials. The effect of GM-CSF remains controversial, however. In this study, we sought to characterize the systemic and tissue-specific effects of GM-CSF in prostate cancer patients in the preoperative setting.
Methods: Patients with localized prostate cancer were treated on an open-label phase I/II study of neoadjuvant GM-CSF prior to planned radical prostatectomy (NCT00305669). Patients received GM-CSF 250mcg/m2 subcutaneously on days 1-14 (cohort 1), days1-21 (cohort 2), or days 1-28 (cohort 3), and underwent radical prostatectomy (RP) within 5 days after the last dose of GM-CSF. Blood collected at baseline, day 14, pre-RP, and 6 weeks post-RP were analyzed for immune cell subsets by flow cytometry. Immune infiltration in RP tissue were evaluated by immunohistochemistry and quantified by digital image analysis with comparison to RP tissue from untreated prostate cancer patients as controls.
Results: 18 patients were evaluated with 6 patients at each dose level. Treatment with GM-CSF was associated with an increase in the number of myeloid cells including myeloid dendritic cells. Treatment was also associated with increases in circulating conventional CD4 and CD8 T cells and NK cells. The number of FoxP3+ regulatory CD4+ T cells was also increased, but to a much lower magnitude. At the time of radical prostatectomy, treatment was associated with a recruitment of CD3+ T cells to the tumor rim, and with cohort 3, at the centers of tumor. These T cells were predominantly CD8+ T cells, although conventional CD4+ T cells were also increased. No increase in monocytes or dendritic cells was seen in the tissue.
Conclusion: Daily injection of systemic GM-CSF induces an increase in circulating antigen presenting cells as well as T and NK cells. While this treatment does not enhance the frequency of antigen presenting cells in the tumor microenvironment, this treatment recruits effector CD8+ T cells into the tumor rims.
Citation Format: Xiao X. Wei, Stephen Chan, Jera Lewis, Serena Kwek, Vinh Dao, Lawrence Fong. Recruitment of effector T cells into the tumor rim and center with neoadjuvant systemic GM-CSF in patients with localized prostate 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 276. doi:10.1158/1538-7445.AM2015-276
Abstract 2766: Advanced paternal age as a possible risk factor for retinoblastoma
Authors: Ayyasamy Vanniarajan , Gaikwad Namrata , Kannan Thirumalairaj , Abraham Aloysius A. , Muthukkaruppan Veerappan , Kim Usha 
Published: August 2015

Abstract
Retinoblastoma is a pediatric tumor arising in the retina with an incidence of 1 in 15000 to 18000 live births. Retinoblastoma is initiated by the inactivation of both the alleles of RB1 and it may be inherited or sporadic. There are several possible risk factors suggested for sporadic retinoblastoma including advanced paternal age.We evaluated the father's age in 42 children with retinoblastoma attending the Aravind Eye Hospital, Madurai, India from Mar 2013 to Feb 2014 retrospectively. Fathers with age 40 and above at the time of conception were included in the analysis. Patients with a positive family history were excluded from the analysis. Genetic analysis of RB1 was carried out in the tumor and blood samples of these patients of older father and their family.There were 5 patients (3 unilateral and 2 bilateral) having fathers with age 40 years and above. Genetic analysis identified RB1 mutations in the tumor samples of 4 patients and these mutations were not present in the blood samples of patient and family members. Since all these patients had somatic mutations, the involvement of paternal age impact was ruled out. In blood sample of one bilateral patient, we found de novo germline RB1 mutation possibly suggesting a role of advanced paternal age.In conclusion, the advanced paternal age seems to be a minor risk factor for retinoblastoma. Further study of large number of patients may provide a better understanding of the impact of advanced paternal age in retinoblastoma.
Citation Format: Vanniarajan Ayyasamy, Namrata Gaikwad, Thirumalairaj Kannan, Aloysius A. Abraham, Veerappan Muthukkaruppan, Usha Kim. Advanced paternal age as a possible risk factor for retinoblastoma. [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 2766. doi:10.1158/1538-7445.AM2015-2766
Abstract 2799: Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated cancer
Authors: Vendramini Costa Débora Barbosa , Francescone Ralph A. , Dmitrieva Oxana , Hou Vivi , Posocco David , Pilli Ronaldo A. , Grivennikov Sergei 
Published: August 2015

Abstract
Despite anticancer drug discovery advances, the worldwide cancer incidence is remarkable. Thus, there is continuous necessity on new therapies development and tumor microenvironment offers multiple targets for cancer therapy, including inflammation. Nature has been a source of new therapeutic and preventive agents and the styryl-lactone goniothalamin (GTN) has shown to be a promising anti-proliferative and anti-inflammatory agent. In previous studies we showed that GTN has pro-apoptotic activity, gastroprotective effects and inhibits tumor development and acute inflammation in mice. Thus, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on colitis and colitis-associate cancer (CAC) models, focusing on the elucidation of the relationship between the anti-proliferative and anti-inflammatory activities.
GTN was synthesized and evaluated in vitro in LPS-stimulated RAW 264.7 murine macrophages. Cells were pre-treated with GTN (20 μM) for 3 hours and then stimulated with LPS (1 μg/mL) for 4 hours. Gene expression was analyzed by real-time PCR and cytokines production by ELISA. Experimental colitis was induced by 3.5% dextran sulfate sodium (DSS) for 7 days and animals (mice, C57-BL/6) were treated with GTN daily by oral route (30 and 100 mg/kg). CAC was induced by Azoxymethane (AOM, 10 mg/kg) followed by 3 cycles of DSS (3.0%) and treatments with GTN (30 mg/kg) were conducted by oral route, twice week. Body weight was checked every week and in the end of experiments, colon tissues were collected and processed for microscopic, biochemical and gene expression evaluations.
GTN significantly reduced IL-1β, IL-6, TNF-α, IL-23, CXCL2 and iNOS expression on RAW cells, as well as levels of secreted IL-6 and TNF-α. Treatments with GTN also reduced inflammation severity on DSS-induced colitis model by reducing cytokines expression, thus suggesting a modulatory activity of the inflammatory environment. GTN treatment modulated tumor development in a mouse model of CAC. Together with previous data, these results highlight that goniothalamin can be used as a preventive and therapeutic agent to inhibit inflammation in colitis and cancer.
Citation Format: Débora Barbosa Vendramini Costa, Ralph A. Francescone, Oxana Dmitrieva, Vivi Hou, David Posocco, Ronaldo A. Pilli, Sergei Grivennikov. Goniothalamin, a natural product, modulates the inflammatory microenvironment on colitis and colitis-associated 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 2799. doi:10.1158/1538-7445.AM2015-2799
Abstract 280: Delta-24-RGDOX: making cancer more “visible” to the immune system
Authors: Jiang Hong , Fan Xuejun , Clise-Dwyer Karen , Bover Laura , Gumin Joy , Ruisaard Kathryn E. , Mukheef Farah J. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan 
Published: August 2015

Abstract
Emerging evidence indicates that host immunity is critical for successful cancer virotherapy. We found that oncolytic adenovirus Delta-24-RGD elicited antiglioma immunity in an immunocompetent murine model. Recent studies suggested that the therapeutic efficacy of immune checkpoint blockade in cancer patients could be enhanced by strategies inducing tumor inflammation. We hypothesized that highly immunogenic adenovirus combined with targeting immune co-stimulator would result in better anti-tumor efficiency. Thus, we used the backbone of Delta-24-RGD to express the mouse OX40 ligand to increase the recognition of tumor-associated antigens by immune cells. The resulting Delta-24-RGDOX adenovirus maintained the oncolytic potency of Delta-24-RGD and efficiently expressed OX40 ligand on infected cells. More importantly, compared to Delta-24-RGD, Delta-24-RGDOX induced higher antiglioma activity in immunocompetent glioma models but not in an immunodeficient model, and accordingly mediated greater lymphocyte infiltration at tumor sites and stronger lymphocyte antitumor activity. While blocking or stimulating immune checkpoints with antibodies currently dominates the clinical applications, our data demonstrate that intratumoral injection of oncolyticviruses carrying immune co-stimulatory ligands may constitute a powerful alternative to the use of antibodies and other strategies targeting immune checkpoints in cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Hong Jiang, Xuejun Fan, Karen Clise-Dwyer, Laura Bover, Joy Gumin, Kathryn E. Ruisaard, Farah J. Mukheef, Frederick F. Lang, Candelaria Gomez-Manzano, Juan Fueyo. Delta-24-RGDOX: making cancer more “visible” to the immune system. [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 280. doi:10.1158/1538-7445.AM2015-280