bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4277: Development and validation of a novel IDH1-mutant astrocyte cell line as a model for high-grade gliomas
Authors: Robinson Nathaniel D. , Purshouse Karin R. , Fons Nathan R. , Breuer Gregory A. , Pusch Stefan , von Deimling Andreas , Sundaram Ranjini K. , Bindra Ranjit S. 
Published: July 2016

Abstract
High-grade gliomas (HGGs) are devastating malignancies of the central nervous system, and few treatment options are available for these tumors. In the most malignant form of the disease, glioblastoma multiforme (GBM), over 90% of patients will succumb to their tumor within 5 years after standard of care treatment, consisting of surgery, radiation therapy, and temozolomide chemotherapy. It is now clear that gliomas are molecularly heterogeneous entities, with mutations in tumor suppressors and oncogenes defining many distinct sub-types with important therapy implications. However, almost all HGGs are treated with a limited array of initial therapies, regardless of these molecular differences. Isocitrate dehydrogenase-1 (IDH1), a gene recently found to be mutated in many gliomas, is involved in the conversion of isocitrate to 2-oxoglutarate in cells. The IDH1 R132H mutant enzyme converts 2-oxoglutarate to the oncometabolite (R)-2-hydroxyglutarate (D2HG), which leads to profound metabolic alterations in tumor cells. In addition, recent studies indicate that mutations in IDH1 may also induce altered DSB repair, differential sensitivities to chemo-radiotherapy, and substantial changes in chromatin modifications. Here, we present the creation of a novel astrocyte cell line harboring an engineered heterozygous IDH1 R132H mutation at the endogenous gene locus using CRISPR/Cas9 gene editing. We confirmed expression of the engineered mutation at the protein level, and we have characterized this cell line in a comprehensive panel of functional assays. In particular, we demonstrated that our mutant cell clones secrete high levels of D2HG, and we confirmed that the levels of this oncometabolite can be suppressed with small molecule inhibitors of mutant IDH1. We also characterized the DNA damage response network in IDH1-mutant cells using high-content DNA damage foci assays recently developed by our group, and also in clonogenic survival assays. To our knowledge, this is the first report of an astrocyte cell line harboring an engineered, heterozygous R132H mutation at the endogenous locus. This novel cell line represents a new model system for studying gliomas and has tremendous applications for further cell characterization, mechanistic studies, and drug screening.
Citation Format: Nathaniel D. Robinson, Karin R. Purshouse, Nathan R. Fons, Gregory A. Breuer, Stefan Pusch, Andreas von Deimling, Ranjini K. Sundaram, Ranjit S. Bindra. Development and validation of a novel IDH1-mutant astrocyte cell line as a model for high-grade gliomas. [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 4277.
Abstract 4291: Vitamin B6 biomarkers and colorectal cancer: Modifications by time
Authors: Gylling Björn , Myte Robin , Schneede Jörn , Hallmans Göran , Häggström Jenny , Johansson Ingegerd , Ulvik Arve , Midttun Øivind , Ueland Per Magne , van Guelpen Bethany , Palmqvist Richard 
Published: July 2016

Abstract
Background: Pyridoxal 5’-phospate (PLP) is the most commonly used marker of circulating vitamin B6 status. In prospective case-control studies, individuals with higher plasma concentrations of PLP had a 30-50% decreased risk of colorectal cancer (CRC). This may partly be explained by decreased PLP due to inflammatory activity in persons at an increased risk of CRC. We aimed to investigate different markers of vitamin B6 in relation to CRC risk in a population with a very long follow-up time between screening and diagnosis.
Methods: This was a prospective case-control study of 613 incident CRC cases and 1190 matched controls nested within the population-based Northern Sweden Health and Disease Study. PLP, pyridoxal (PL), pyridoxic acid (PA), 3-hydoxykynurenine (HK) and xanthurenic acid (XA) were measured in plasma by LC-MS/MS. Besides PLP, we investigated the recently introduced metabolite ratios PAr (PA/(PLP+PL)) and HK:XA as markers of vitamin B6 status in relation to CRC risk.
Results: PAr, a marker of vitamin B6 catabolism during inflammation, was linearly associated with CRC risk, with a 50% higher risk in the highest vs. lowest quartile. In the group with a follow up time between screening and diagnosis over 10.5 years no association was observed, while in the groups with a follow up time between 5.8-10.5 years and below 5.8 years risk was approximately twofold in most quartiles vs the lowest quartile. A 50% risk decrease was observed in the in the third vs the lowest quartile of plasma PLP and a similar risk increase was observed in the highest vs the lowest quartile of the functional vitamin B6 marker HK:XA.
Conclusions: PAr may influence later stages of tumor development, but possibly not early tumorigenesis. Poor functional vitamin B6 status and inflammatory activity might influence both the risk of CRC and plasma concentrations of PLP. Our results underscore the need to use several biomarkers for vitamin B6 status together with the already well established plasma PLP. This may be generalizable not only to CRC but also other diseases with an inflammatory aspect.
Citation Format: Björn Gylling, Robin Myte, Jörn Schneede, Göran Hallmans, Jenny Häggström, Ingegerd Johansson, Arve Ulvik, Øivind Midttun, Per Magne Ueland, Bethany van Guelpen, Richard Palmqvist. Vitamin B6 biomarkers and colorectal cancer: Modifications by time. [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 4291.
Abstract 4314: Using antioxidant to enhance liver cancer preventive effect of n-3 PUFAs
Authors: Fu Ying , Bai Angela Y. , Dyba Marcin , Kang Jing X. , Chung Fung-Lung 
Published: July 2016

Abstract
In various animal models, n-3 polyunsaturated fatty acids (PUFAs) have demonstrated cancer preventive effects. This protective effect is associated with reduced levels of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2). On the other hand, an endogenous DNA adduct formed from the peroxidation of ω-3 PUFAs, γ-hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG), is known to be mutagenic. In light of these observations, we hypothesized that the combination of n-3 PUFAs with an antioxidant to inhibit lipid peroxidation (e.g. α-lipoic acid) will result in an enhanced cancer preventive effect than n-3 PUFAs alone. The chemical carcinogen diethylnitrosamine (DEN) induced HCC model is employed in this study. The DEN-induced HCC model has a histology and genetic signature similar to that of human HCCs, such that it has poor prognosis and recapitulates a dependence on inflammatory signaling. It also reflects the same gender disparity seen in human HCCs. Fat-1 transgenic mice were used because they express a Caenorhabditis elegans desaturase converting n-6 to n-3 PUFAs endogenously without using dietary supplementation. This model underlies the importance of dietary control of PUFAs intake and ratios due to the inability of mammalian cells to generate anti-inflammatory n-3 PUFAs from pro-inflammatory n-6 PUFAs, which are a major component of the standard Western diets. The results showed that antioxidant can efficiently suppress the elevated level of γ-OHPdG in fat-1 mice. The tumor incidence, multiplicity, and size are monitored continuously. This work was supported by the NCI grant: RO1-CA-134892. Y.F. thanks the Prevent Cancer Foundation for his fellowship (Marcia and Frank Carlucci Charitable Foundation Award in Cancer Prevention and Early Detection)
Citation Format: Ying Fu, Angela Y. Bai, Marcin Dyba, Jing X. Kang, Fung-Lung Chung. Using antioxidant to enhance liver cancer preventive effect of n-3 PUFAs. [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 4314.
Abstract 4325: High-fat diet enhances and monocyte chemoattractant protein-1 deficiency reduces bone loss in mice with pulmonary metastases of Lewis lung carcinoma
Authors: Sundaram Sneha , Yan Lin 
Published: July 2016

Abstract
Bone is adversely affected by metastasis and metastasis-associated complications. Obesity is a risk factor for both bone and cancer. Adipose tissue is an endocrine organ that produces pro-inflammatory adipokines, such as monocyte chemotactic protein-1 (MCP-1), that contribute to obesity and obesity-related diseases. This study (2×2 factorial design) investigated the effects of a high-fat diet (45% of energy from corn oil) and MCP-1 deficiency on bone micro-structural changes, analyzed by micro-computed tomography, in male C57BL/6 mice bearing lung metastases of Lewis lung carcinoma (LLC). Subcutaneous injection of LLC cells resulted in lung metastasis which was significantly enhanced by the high-fat diet and attenuated by MCP-1 deficiency. Micro-computed tomographic measurement showed significant reductions in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in right femurs and vertebrae of LLC-bearing mice compared to non-tumor-bearing controls. In LLC-bearing mice, compared to the low-fat diet (16% of energy from corn oil), the high-fat diet significantly reduced BV/TV, Tb.N and BMD in femurs but not in vertebrae. Furthermore, compared to wild-type mice, MCP-1 deficiency significantly increased BV/TV and Tb.N in both femurs and vertebrae and BMD in vertebrae in LLC-bearing mice. These results demonstrate that metastasis causes bone loss which is enhanced by the high-fat diet and attenuated by MCP-1 deficiency. Overall, it indicates that the high-fat diet and MCP-1 contribute positively to metastasis-associated bone deterioration.
Citation Format: Sneha Sundaram, Lin Yan. High-fat diet enhances and monocyte chemoattractant protein-1 deficiency reduces bone loss in mice with pulmonary metastases of Lewis lung carcinoma. [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 4325.
Abstract 4334: A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates
Authors: Kolakowski Robert V. , Haelsig Karl , Jeffrey Scott , Senter Peter 
Published: July 2016

Abstract
Antibody-drug conjugates (ADCs) have emerged as important therapeutics for treating cancer as evidenced by the recent FDA approval of brentuximab vedotin Adcetris™ and trastuzumab emtansineKadcyla™, and the large number of ADCs (&gt;35) currently in clinical trials. ADCs are composed of two core units: the targeting antibody and the drug-linker. The drug-linker typically consists of a cytotoxic payload, a moiety for covalent attachment to the antibody, and a conditionally cleavable linker that is stable in circulation but releases the cytotoxic payload upon internalization into a target cell. The released payload will possess a residual chemical functional group that is used for attachment of the drug to the cleavable linker. Functional groups that have been exploited within the ADC field for this purpose include amines (primary and secondary), thiols, and carboxylic acids. Unfortunately, many potential ADC payloads do not possess any of these functional group ‘handles’ that allow for stable conjugation and release of the drug in an unmodified form. Use of these payloads often requires modification of the drug structure to introduce a handle for conjugation. To avoid this, we have developed new linker chemistry, the methylene-alkoxy-carbamate (MAC), which enables direct conjugation of drugs through alcohol functional groups. Such groups are present on a diverse array of synthetic drugs and cytotoxic natural products, thus, expanding the potential chemical space available for payload selection. As proof-of-concept, we have linked Auristatin E through the secondary alcohol of the norephedrine residue and characterized the stability and in vivo activity of the resulting ADCs. To further define the potential applicability of the MAC unit, we have examined its stability and release properties with a series of model systems including primary, secondary, and tertiary alcohols as well as a phenol. We have also explored the effect of substitution of the MAC nitrogen on these properties. This novel linker chemistry is currently being applied to new payloads that were inaccessible with previous technology.
Citation Format: Robert V. Kolakowski, Karl Haelsig, Scott Jeffrey, Peter Senter. A novel linker to enable alcohol-containing payloads for the preparation of antibody-drug conjugates. [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 4334.
Abstract 4338: Advanced neoplasia detection in colorectal cancer screening using multiple stool DNA markers and haemoglobin
Authors: Bosch Linda J.W. , Melotte Veerle , Mongera Sandra , Daenen Kathleen L.J. , Coupe Veerle H.M. , van Turenhout Sietze T. , Stoop Esther M. , de Wijkerslooth Thomas R. , Mulder Chris J.J. , Kuipers Ernst J. , Dekker Evelien , Domanico Michael , Lidgard Graham P. , Berger Barry M. , Carvalho Beatriz , van Engeland Manon , Meijer Gerrit A. 
Published: July 2016

Abstract
Purpose of the study: Molecular tests have the potential to improve current non-invasive faecal immunochemical test (FIT) screening for colorectal cancer (CRC) and advanced precancerous lesions. We examined the performance of a panel of faecal DNA (sDNA) markers and FIT in archival samples from an invitational CRC screening population.
Methods: Whole stool samples were prospectively collected from individuals participating an invitational primary colonoscopy-screening program (COCOS trial). Only participants that provided stool, performed FIT (OC-Sensor) and underwent colonoscopy were selected. The sDNA panel included quantitative molecular assays for KRAS mutations and for aberrant NDRG4 and BMP3 methylation. The performance of the sDNA plus FIT panel was compared to the FIT results alone, by Receiver Operator Characteristic (ROC) analyses.
Results: A total of 1047 individuals (51% male) with a median age of 60 years (range 50-75) were included, of which 7 (0.7%) had colorectal cancer and 104 (9.9%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps ≥ 1 cm).
The combination of sDNA and FIT was more sensitive than FIT alone for detecting advanced precancerous lesions (49% (50/102) and 25% (26/102), respectively). Specificities among individuals with non-advanced or negative findings (controls) were 89% and 96% for sDNA and FIT testing, respectively.
ROC analysis of CRC and advanced precancerous lesions compared to controls revealed an Area Under the Curve (AUC) of 0.75 for the sDNA plus FIT test, compared to 0.68 for FIT alone. At an equal specificity of 95%, advanced precancerous lesions were detected with a higher sensitivity by the sDNA plus FIT test compared to FIT alone (36% vs 28%, p = 0.08).
Conclusions: In an invitational colorectal cancer screening cohort, combining stool DNA markers with FIT detected more advanced neoplasia than FIT alone, primarily due to detecting more advanced adenomas.
Citation Format: Linda J.W. Bosch, Veerle Melotte, Sandra Mongera, Kathleen L.J. Daenen, Veerle H.M. Coupe, Sietze T. van Turenhout, Esther M. Stoop, Thomas R. de Wijkerslooth, Chris J.J. Mulder, Ernst J. Kuipers, Evelien Dekker, Michael Domanico, Graham P. Lidgard, Barry M. Berger, Beatriz Carvalho, Manon van Engeland, Gerrit A. Meijer. Advanced neoplasia detection in colorectal cancer screening using multiple stool DNA markers and haemoglobin. [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 4338.
Abstract 4348: A prospective study of smoking habit and risk of synchronous colorectal cancers
Authors: Drew David A. , Nishihara Reiko , Lochhead Paul , Kuchiba Aya , Rong Qian Zhi , Mima Kosuke , Nosho Katsuhiko , Wu Kana , Wang Molin , Spiegelman Donna , Giovannucci Edward L. , Fuchs Charles S. , Ogino Shuji , Chan Andrew T. 
Published: July 2016

Abstract
Background: Synchronous colorectal cancers (CRC) (2 or more distinct primary carcinomas simultaneously identified in one patient) may arise as a result of a “field effect” or shared etiologic factors. Synchronous CRC has been associated with somatic epigenetic changes; cigarette smoking has been associated with DNA methylation in CRC. Thus, we examined the association between cigarette smoking and risk of synchronous CRC.
Methods: Among men and women enrolled in the Health Professionals Follow-up Study and Nurses’ Health Study over 24 and 32 years, respectively, we examined the association of smoking with CRC. We examined the differential risk of developing synchronous CRC compared with solitary CRC, classified based on review of pathology reports, through duplication-method Cox proportional hazards regression.
Results: During 3,477,211 person-years of follow-up of 45,691 men and 88,614 women, we documented 1,960 individuals with solitary CRC and 45 individuals with synchronous CRC. The association of smoking with CRC differed significantly according to the presence of synchronous compared with solitary tumors (Pheterogeneity = 0.0008). Compared with never smokers, current smokers experienced a higher risk of synchronous CRC (multivariable HR = 5.26; 95% CI, 2.08-13.32). In contrast, current smokers did not experience an elevated risk of solitary cancer (multivariable HR = 0.97; 95% CI, 0.83-1.13). Similar differences in the association of cumulative pack-years smoked with CRC according to tumor synchronicity status were also observed (Pheterogeneity = 0.006). Smoking cessation for ≥10 years was significantly associated with reduced risk of synchronous tumors (multivariable HR = 0.44; 95% CI, 0.20-1.00), but not solitary tumors (multivariable HR = 1.07; 95% CI, 0.91-1.25) (Pheterogeneity = 0.003).
Conclusion: Current cigarette smoking is associated with an increased risk of synchronous but not solitary CRC. These data support a model in which smoking contributes to an etiologic field effect predisposing individuals to the development of synchronous CRC.
Citation Format: David A. Drew, Reiko Nishihara, Paul Lochhead, Aya Kuchiba, Zhi Rong Qian, Kosuke Mima, Katsuhiko Nosho, Kana Wu, Molin Wang, Donna Spiegelman, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino, Andrew T. Chan. A prospective study of smoking habit and risk of synchronous colorectal cancers. [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 4348.
Abstract 4354: CRISPR/Cas9 genome-wide gRNA library for target identification
Authors: Tedesco Donato , Diehl Paul , Makhanov Mikhail , Baron Sylvain , Suchkov Dmitry , Frangou Costa , Chenchik Alex 
Published: July 2016

Abstract
Genome-wide loss-of-function screening is a fundamental method to identify genes responsible for driving biological responses, and complex pooled lentiviral-based libraries expressing large numbers of genetic disruptors, such as shRNAs, make large-scale cell screening practical. While RNAi-based approaches have proven to be an effective strategy for these screens, recent work suggests CRISPR technology offers an effective alternative. Although shRNA and sgRNA pooled library screens are similar in concept, the gene interruption with the two techniques occurs by a very different mechanism so some divergence may be expected when comparing results obtained using one method versus the other.
To investigate the potential difference in the two methodologies, we performed parallel dropout viability screens to identify essential genes in a pair of primary isogenic CML cell lines using a CRISPR/Cas9 knockout library and an RNA interference (RNAi) library targeting the same set of 6,300 genes with the same number of targeted effectors (sgRNA or shRNA) for each gene. The results showed significant, but not complete, overlap in the essential genes identified by each assay in each cell line indicating that both approaches are effective to identify the majority of essential genes in a cell system. However, analysis did indicate that a small number of essential targets were only identified with CRISPR and certain unique targets seemed to show up only in the RNAi screen results. By combining data from the two screening methodologies, a consistent number of viability genes and pathways could be identified and subsequently validated by independent cell based assays at a very high confirmation rate.
Citation Format: Donato Tedesco, Paul Diehl, Mikhail Makhanov, Sylvain Baron, Dmitry Suchkov, Costa Frangou, Alex Chenchik. CRISPR/Cas9 genome-wide gRNA library for target identification. [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 4354.