bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3597: Xenobiotic detoxification enzymes and cancer risk: A multiplex immunofluorescence detection of AE1/AE3, GSTA1 and GSTA3 in the tissue microarrays of gastrointestinal tract
Authors: Ma Victor Wan-San , Cheung Goretti Hoi-Yan , Lau Eunice Yuen-Ting , Cho William Chi-Shing 
Published: August 2018

Abstract
Background: Glutathione S-transferases (GSTs) are an enzyme family responsible for the metabolism of toxins and carcinogens in the phase II detoxification pathway. Among the 5 alpha class isoforms, GSTA1 and GSTA3 are involved in metabolizing several active carcinogenic substrates generated from benzo-[a]-pyrene mainly found in grilled meats and burnt coal. The expression of GSTA1 and GSTA3 in gastrointestinal (GI) tract may be implicated with cancer development associated with the intake of xenobiotic substances.
Methods: Formalin-fixed and paraffin-embedded tissue cores of esophagus (190), stomach (180), small intestine (372), colon (120) and rectum (142) were stained with a multiplex tyramide-immunofluorescence (T-IMF) technique for the simultaneous demonstration of cytokeratin AE1/AE3, GSTA1 and GSTA3. The tissue types range from normal to cancer progression spectrum. All tissue cores were screened for AE1/AE3 expression to confirm the epithelial cell lineage before scoring for GSTA1 and GSTA3 positivity. A p-value &lt;0.05 by Chi-squared test is considered significant.
Results: T-IMF is useful in studying the interaction of multi-markers in a single slide. This technique is superior to chromogenic immunohistochemical application in multi-color presentation. This highly sensitive and handy technique will save multiple sectionings and precious tissues. We found a significant down-regulation of two alpha class GSTs in the malignancies of GI tract (Table 1).
Table 1. Positive percentages of glutathione S-transferases markersMarkerEsophagusStomachSmall intestineColonRectumNMNMNMNMNMGSTA141%24%99%40%90%15%22%3%43%21%p-value0.0603&lt;0.0001&lt;0.00010.0010.0194GSTA378%35%99%54%96%64%100%39%88%40%p-value&lt;0.0001&lt;0.0001&lt;0.0001&lt;0.0001&lt;0.0001Abbreviation: N= normal; M= malignant
Conclusion: The differential expression of these detoxification enzymes in normal epithelium vs GI cancer may shed some light on their role in protecting normal tissue from cancer development. This finding may provide a potential target for the development of intervention strategies against GI cancer. Further investigations will be conducted to decipher the mechanism underlying this observation.
Citation Format: Victor Wan-San Ma, Goretti Hoi-Yan Cheung, Eunice Yuen-Ting Lau, William Chi-Shing Cho. Xenobiotic detoxification enzymes and cancer risk: A multiplex immunofluorescence detection of AE1/AE3, GSTA1 and GSTA3 in the tissue microarrays of gastrointestinal tract [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3597.
Abstract 361: Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in uveal melanoma
Authors: Rago Florencia , Xiang Xiaoqin , Desplat Aurore , Niemezyk Emilie , Ruddy David , Kerr Grainne , Robles Eusebio Manchado , Castelletti Deborah , Jagani Zainab 
Published: August 2018

Abstract
Uveal melanoma is a rare and aggressive cancer that originates in the pigmented tissues of the eye, which include the iris, the choroid and the ciliary body. To date, no targeted therapies have been approved for this cancer, and much remains to be described about the underlying biology of the disease. The most common driver mutation is an activating mutation in either the GNAQ or GNA11 GTPase, which in turns leads to hyperactivation of the MAPK pathway, but the precise downstream effectors driving tumorigenesis are poorly understood. Using pooled shRNA screening, we discovered that the SWI/SNF complex represents a novel genetic vulnerability in uveal melanoma, and further interrogated this dependency by a more targeted analysis across various uveal melanoma cell lines. While we observed the dropout of multiple SWI/SNF complex subunits in the screens, we defined the ATPase activity of SWI/SNF as central to the observed phenotype, implicating the chromatin remodeling function of the SWI/SNF complex in this phenotype. The regulation of gene expression by transcription factors can involve coordinated activity of SWI/SNF directed chromatin remodeling activity, so we began to investigate mechanistic links between SWI/SNF and other transcription factors such as MITF, which is known to play important roles in the differentiation of melanocytes. We observed that depletion of SWI/SNF affected transcription of certain MITF target genes, and are further investigating the precise pathways that are altered with SWI/SNF modulation. Taken together, these data suggest that the SWI/SNF complex plays an important role in maintaining tumor cell survival in uveal melanoma, and may represent a novel therapeutic target.
Citation Format: Florencia Rago, Xiaoqin Xiang, Aurore Desplat, Emilie Niemezyk, David Ruddy, Grainne Kerr, Eusebio Manchado Robles, Deborah Castelletti, Zainab Jagani. Identification of a novel dependence on the SWI/SNF chromatin remodeling complex in uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 361.
Abstract 3626: A genome scale screen to identify regulators of PD-L1 in HNSCC
Authors: Mann Jacqueline , Ludwig Megan , Kulkarni Aditi , Kafelghazal Judy , Eisenberg Julia , Hoesli Rebecca , Nesvizhskii Alexey , Brenner Chad 
Published: August 2018

Abstract
The immune checkpoint inhibitor Pembrolizumab was recently approved for the treatment of metastatic and recurrent HNSCC, but only 18% of patients in the initial trial responded to therapy, and it remains difficult to predict patients likely to experience benefit. We expect a broader understanding of checkpoint regulation in HNSCC to lead to improved response rates and identification of potential responders. To this end, we sought to identify targetable genetic factors modulating PD-L1, a molecule that serves to dampen the anti-tumor immune response. We developed a high throughput screen employing a Genome-scale CRISPR Knock-Out (GeCKO) library in HNSCC cell lines to identify targetable genes and pathways that may regulate PD-L1 expression. In UM-SCC-49, stable knockout pools with representation of approximately 300 gRNAs for each of over 20,000 target genes were expanded and serially sorted to create stable sub-populations with enhanced or diminished PD-L1 expression. These sub-populations were sequenced to identify gRNAs that increased or reduced PD-L1 expression, indicating that their genetic targets may function to regulate PD-L1. We observed 70% library coverage (44,900 gRNAs) in the initial population and 15% and 11% coverage in the sub-populations selected for high and low PD-L1 expression, respectively. We prioritized for validation 61 gRNAs that were enriched at least 2 fold in High or Low PDL1 pool over the control pool. Future experiments focus on validation of these targets in UM-SCC-49 and other cell lines. As we expand this screen and validate hits across multiple genetic backgrounds, we expect to reveal signaling networks promoting immune evasion and potential targets for combination immunotherapeutic protocols.
Citation Format: Jacqueline Mann, Megan Ludwig, Aditi Kulkarni, Judy Kafelghazal, Julia Eisenberg, Rebecca Hoesli, Alexey Nesvizhskii, Chad Brenner. A genome scale screen to identify regulators of PD-L1 in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3626.
Abstract 3647: Prior DNA repair improves the read quality in next-generation sequencing of cell-free tumor DNA
Authors: Yin Hong , Greer Adam H. , Mills Glenn 
Published: August 2018

Abstract
The cell-free tumor DNA (ctDNA) in patient's plasma is a noninvasive tumor biomarker. The detection of ctDNA is helpful to evaluate tumor progression, tumor response to the therapy, and subtyping of tumor cells. Targeting next-generation sequencing (NGS) technology provides a sensitive and specific technique for ctDNA detection. It can detect multiple tumor-related gene mutations. However, collection of high quality of cell-free DNA (cfDNA) may not be available in some cases. The quality of cfDNA in plasma is impacted by multiple factors, such as plasma collection and storage conditions, DNase activity in the blood, and the apoptotic and necrotic status of the tumor. These factors affect the integrity of cfDNA, leading to full or partial degradation of cfDNA, including double-strand DNA breaks and single strand DNA nicking. Lesions on cfDNA decrease the usability of ctDNA by digital PCR and targeted NGS. Due to amount limitation of cfDNA in some cases, the repair of damaged cfDNA could be a necessary rescue step in producing viable libraries for NGS.
CfDNA was extracted from the plasma with Zymo Research's Quick-cfDNA Serum and Plasma kit and was quantified by realtime PCR with Alu primer sets. The size of cfDNA was about 160 base pairs, as estimated by Agilent Tapestation 2200 with the High Sensitivity DNA kit. The DNA repair of cfDNA was conducted with PreCR Repair Mix of New England BioLabs. The sequencing library was prepared with Accel-Amplicon 56G Oncology Panel of Swift Biosciences and sequenced in Illumina's MiSeq. The quality of sequencing data was determined with FastQC. Compared to PreCR Repair Mix treated cfDNA samples, fastQ data from some of untreated cfDNA samples showed failed per base sequencing quality, about 50% of sequencing cycles with the mean quality score below 30. The per sequencing quality score of these cfDNA samples failed also to pass the quality filter. The read size distribution analysis indicated that about 60 to 70% of read sized between 30 to 45 bases and about 75 to 80% of read was smaller than 75 bases. However, sequencing data from same cfDNA samples treated with PreCR Repair Mix show a greatly improved sequencing quality. Both per base sequencing quality and per sequencing quality score passed quality filter. The above 97% of reads sized over 92 bases, complying with the requirement of 56G Oncology Panel.
In conclusion, the DNA repair process before library preparation is necessary to rescue damaged cfDNA for amplicon-based NGS.
Citation Format: Hong Yin, Adam H. Greer, Glenn Mills. Prior DNA repair improves the read quality in next-generation sequencing of cell-free tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3647.
Abstract 3683: Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas
Authors: Matsubara Daisuke , Soda Manabu , Yoshimoto Taichiro , Amano Yusuke , Kihara Atsushi , Sakuma Yuji , Endo Shunsuke , Hagiwara Koichi , Fukayama Masashi , Mano Hiroyuki , Niki Toshiro 
Published: August 2018

Abstract
The molecular targeted therapies against EGFR, ALK etc. have improved progression-free survival of patients with lung adenocarcinomas. However, targetable driver mutations have mainly been found in TTF-1-positive terminal respiratory unit (TRU)-type, but have yet been undiscovered in non-TRU type despite the advances in genomics technologies. In order to find the molecular candidate characterizing major subtype of non-TRU type adenocarcinomas, we compared TTF-1-positive/CDH1-positive adenocarcinoma cell lines (“TRU-type” cell lines) (n=11) and TTF-1-negative/CDH1-positive adenocarcinoma cell lines (“non-TRU-type” cell lines) (n=8), and found that TFF-1 (trefoil factor family-1), a gastric mucosal protective factor, was characteristically highly expressed in “non-TRU-type” cell lines. Immunohistochemical analysis of primary lung adenocarcinomas (n=70) revealed that TFF-1 expression was inversely correlated with TTF-1 expression (p=0.0116) and was very rare in primary lung adenocarcinoma cases (5.7%:4/70). So we focused on the non-TRU type adenocarcinomas on the basis of histologic pattern (acinar, solid or mucinous morphology predominant tumors without non-mucinous lepidic growth components) (n=43). Among them, TFF-1 was frequently expressed (62%:27/43), and significantly correlated with the expressions of MUC5AC, HNF4A and CK20 (p&lt;0.0001, p=0.0001, and p=0.0007, respectively), and inversely correlated with TTF-1 expression (p=00039). Next generation sequencing analysis of the 43 cases revealed that KRAS gene mutations and Inactivating mutations and hypermethylation of the TTF-1 gene were frequent in TFF-1 positive cases. The analysis of publicly available data of 442 lung adenocarcinoma cases revealed that high expression of TFF-1 correlated with low expression of TTF-1 and worse prognosis. We confirmed that shRNA against TFF-1 inhibited the cell proliferation and the colony formation, and induced the apoptosis, in the TFF-1 positive “non-TRU-type” cell lines. These results indicate that TFF-1 is not only the marker but also can possibly be the molecular target of a subset of non-TRU-type lung adenocarcinomas.
Citation Format: Daisuke Matsubara, Manabu Soda, Taichiro Yoshimoto, Yusuke Amano, Atsushi Kihara, Yuji Sakuma, Shunsuke Endo, Koichi Hagiwara, Masashi Fukayama, Hiroyuki Mano, Toshiro Niki. Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3683.
Abstract 3706: Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test
Authors: Shimomura Osamu , Oda Tatsuya , Tateno Hiroaki , Ozawa Yusuke , Kimura Sota , Hirabayashi Jun , Ohkohchi Nobuhiro 
Published: August 2018

Abstract
Background: We recently developed lectin-drug conjugate (LDC) for targeting pancreatic cancer specific glycan and showed potent anti-cancer effect both in vitro and in vivo (Osamu Shimomura et al., Molecular Cancer Therapeutics 2017). The additional evaluation of anti-cancer effects and the toxicity studies of LDC need to be clarified.
Methods: LDC, rBC2LC-N lectin fused with 38 kDa of pseudomonas exotoxin (PE) A, was used in this study. We confirmed of the anti-cancer effect of LDC in orthotopic mouse models and developed dissemination mouse models to make sure of the survival benefits in LDC by both intra-peritoneally and intra-venously injection by log-rank test. We checked the damage of all organs pathologically after injection of the minimal or maximal tolerance doses and performed the blood sample analyses.
Results: We have already validated the cytotoxic effect of LDC for PDAC cell lines in vitro i.e., IC50= 1.04 pico g/ml. Intraperitoneal and intravenous injection of LDC reduced tumor weight from 390 mg in normal saline group to 130.8 mg and 203 mg, respectively in the orthotopic models (P=0.001 and P=0.007, respectively), and improved median survival duration from 62 days to 105 and 90 days in the peritoneal dissemination models, respectively (P&lt;0.0001 and P&lt;0.0001, respectively). Intravenous injection of LDC conferred comparable therapeutic effects to intraperitoneal injection. Inconsistent with the apprehension that all lectins mediate harmful hemagglutination, the rBC2LC-N never caused hemagglutination with human erythrocytes in every blood types. The laboratory test after injection of therapeutic dose (1µg/mouse) of LDC showed no obvious abnormality except slightly elevation of aspartate and alanine aminotransferase. Surprisingly, no adverse event were observed after administration of rBC2LC-N lectins without PE up to 15 µg/mouse in wild type mice. Although some epithelial desquamations were revealed in the mucosa of the gut after fatal dose of LDC injection, we could not figure out the organ damage after the therapeutic dose of LDC injection pathologically.
Conclusions: We show the successful in vivo application of a lectin for cancer treatment. Lectin itself did not cause severe adverse events and could be a potential candidate of a drug carrier, providing a new insight into anti-cancer drug development.
Citation Format: Osamu Shimomura, Tatsuya Oda, Hiroaki Tateno, Yusuke Ozawa, Sota Kimura, Jun Hirabayashi, Nobuhiro Ohkohchi. Novel therapeutic strategy for pancreatic cancer with lectin drug conjugate (LDC): The efficacy and pilot safety test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3706.
Abstract 371: Utilizing metabolic pathways to improve diagnosis and risk stratification of prostate cancer
Authors: Alqazzaz Aymen , Fu Dexue , Karimi Arman , Ferreira Gustavo , McKenna Mary , Siddiqui Mohummad M. 
Published: August 2018

Abstract
Prostate cancer has well-characterized changes that take place metabolically in the citric acid cycle (CAC) such as increased lactate formation, reversal of physiologic buildup of citrate and breakdown into downstream CAC products. Metabolic MR spectroscopy utilizing 13C-labeled pyruvate now allows for clinical characterization of metabolic pathways in tissue. However, the traditionally utilized substrate of [1-13C]pyruvate has limitations because as the pyruvate is broken down, the labeled carbon does not enter the CAC and instead is lost as CO2. We propose that [2-13C]pyruvate, is better to characterize changes in the CAC. Specifically, [2-13]C-pyruvate can be converted to 13C-labeled acetyl CoA and subsequently metabolized in the CAC as 13C-labeled intermediate compounds (such as glutamate which rapidly pools alpha-ketogluterate). Alternatively in altered bioenergetic states, [2-13C]pyruvate is reduced to 13C-labeled lactate (Warburg effect) or transaminated to 13C-labeled alanine. By exposing prostate cancer cells to [2-13C]pyruvate and determining the relative labeling of lactate, glutamate, and alanine, we can elucidate which metabolic pathways (CAC, Warburg, transamination) are utilized in prostate cancer metabolism. The aim of this study was to determine how the metabolism of [2-13C]pyruvate via the CAC, reduction to lactate, and transamination differed in high and low malignancy prostate cancer cells.Methods: Tumorigenic prostate cells LNCaP and PC3 were exposed a medium containing [2-13C]pyruvate for 4 hours. PCA extraction was then performed to obtain the metabolites. 13C labeled compounds formed intracellularly and those released into the medium were analyzed using NMR chemical shifts with focus on peaks associated with pyruvate, lactate, alanine, glutamate, and other compounds related to the CAC. Dioxane was used as an internal standard for NMR characterization. Results: The labeled carbon from the [2-13C]pyruvate can be identified in the downstream metabolites of the citric acid cycle, after reduction to lactate, and/or transamination by determining labeled metabolites by 13C-NMR analysis. This allows for the ability to calculate the relative metabolism of pyruvate via the three pathways; transamination (74%), lactate formation (16%), and CAC (10%).
Conclusions: [2-13C]pyruvate can be successfully utilized as a tool to explore the alterations in pathways of metabolism, including the citric acid cycle, in prostate cancer cells.
Citation Format: Aymen Alqazzaz, Dexue Fu, Arman Karimi, Gustavo Ferreira, Mary McKenna, Mohummad M. Siddiqui. Utilizing metabolic pathways to improve diagnosis and risk stratification of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 371.
Abstract 3712: Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model
Authors: Bilgicer Basar , Kiziltepe Tanyel , Omstead David , Deak Peter 
Published: August 2018

Abstract
Ligand-targeted liposomes have garnered interest as drug delivery vehicles for cancer therapy, however they have not consistently produced successful outcomes. These inconsistencies likely arise from differences in disease models and target receptors, as well as from nanoparticle design parameters which can significantly influence therapeutic efficacy. We systematically evaluated the role that peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size play on tumor targeting using a multifaceted synthetic strategy to prepare highly controlled and consistent peptide-targeted liposomes. We analyzed these parameters in a VLA-4-expressing multiple myeloma model system where liposomes were functionalized with a VLA-4-antagonist peptide to evaluate in vitro targeting efficiency and in vivo biodistribution and tumor cell uptake. Our studies demonstrated that by increasing the hydrophilicity of the targeting peptide sequence via addition of an oligolysine chain and simultaneously optimizing the EG peptide-linker length, cellular uptake of targeted liposomes was significantly enhanced in vitro. Specifically, the cellular uptake was greatly enhanced for 50-100 nm size liposomes with shorter peptide-linker lengths of EG6 when compared to the industry standard EG45 linker. For in vivo applications, although targeted formulations did not enhance tumor accumulation directly relative to non-targeted formulations, liposomes designed with EG6 linker and an oligolysine chain provided a significant advantage by demonstrating significantly enhanced tumor cell uptake relative to non-targeted liposomes. These results highlighted the importance of creating a comprehensive understanding of the effect of each liposome design parameter on multifactorial biological endpoints in determining the therapeutic potential of peptide-targeted liposomes.
Citation Format: Basar Bilgicer, Tanyel Kiziltepe, David Omstead, Peter Deak. Optimizing design parameters of a VLA-4-targeted liposomal nanoparticle in a multiple myeloma disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3712.