bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6465: Clinicopathological features of TROP-2 and pTROP-2 in gastric cancer
Authors: Kushiyama Syuhei , Yashiro Masakazu , Nishimura Sadaaki , Togano Shingo , Kuroda Kanji , Sugimoto Atsushi , Sera Tomohiro , Yamamoto Yurie , Okuno Tomohisa , Miki Yuichiro , Nakada Hiroshi , Ohira Masaichi 
Published: September 2020

Abstract
Introduction: The human trophoblast cell-surface antigen TROP-2 is a cell surface glycoprotein receptor involved in tight junctions at the epithelial barrier. Although TROP-2 is reportedly overexpressed in various epithelial tumors and its expression correlates with aggressive tumor behavior, there is no report of the clinicopathological features of gastric cancer (GC) with TROP-2 and phosphorylated TROP-2 (pTROP-2) expression. We evaluated the clinicopathologic significance of TROP-2 and pTROP-2 expression in GC patients.
Materials and methods: We retrospectively analyzed the cases of 720 GC patients who underwent resection for GC. The expressions of TROP-2 and pTROP-2 in each tumor were evaluated by immunohistochemistry. We then divided the patients into the TROP-2 high group, TROP-2 low group, pTROP-2 high group, and pTROP-2 low group. The association between TROP-2 or pTROP-2 expression and clinicopathological variables were assessed by the chi-square test. Overall survival was analyzed by Kaplan-Meier method, and compared by log-rank test. The Cox proportional hazards model was used for multivariate analysis.
Results: TROP-2 high group was found to be overexpressed in 330 (46.7%) tumor samples. Significantly higher expression of TROP-2 was significantly correlated with intestinal type, tumor invasion depth, lymph node metastasis, lymphatic invasion, and venous invasion. pTROP-2 high group was found to be overexpressed in 306 (43.4%) tumor samples. Significantly higher expression of pTROP-2 was correlated with intestinal type, low tumor invasion depth, no lymph node metastasis, and no lymphatic invasion. TROP2 overexpression was predictive for poor overall survival of patients with GC (p = 0.0002, log rank test), while multivariate analysis to overall survival revealed that TROP-2 overexpression was not an independent prognostic marker (p=0.06). In contrast, pTROP-2 overexpression was predictive for good overall survival of patients with GC (p = 0.004, log rank test).
Conclusion: TROP-2 might be associated with metastatic ability of gastric cancer cells, resulting poor prognosis of patients with GC.
Citation Format: Syuhei Kushiyama, Masakazu Yashiro, Sadaaki Nishimura, Shingo Togano, Kanji Kuroda, Atsushi Sugimoto, Tomohiro Sera, Yurie Yamamoto, Tomohisa Okuno, Yuichiro Miki, Hiroshi Nakada, Masaichi Ohira. Clinicopathological features of TROP-2 and pTROP-2 in gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6465.
Abstract 6487: Circulating tumor cells, tumor- and endothelium- derived extracellular vesicles, but not circulating endothelial cells associate with poor prognosis in colorectal cancer
Authors: Nanou Afroditi , Mol Linda , Koopman Miriam , Punt Cornelis J. , Terstappen Leon W. 
Published: September 2020

Abstract
Elevated tumor-derived EV (tdEV) and Circulating Tumor Cell (CTC) load in patients with metastatic cancer is associated with poor clinical outcome. In this study, we investigated whether endothelium-derived extracellular vesicles (edEVs) can be detected in the blood of metastatic colorectal cancer (mCRC) patients and whether there is an association with prognosis.
The open-source ACCEPT software was used to enumerate edEVs, tdEVs and other objects from digitally stored CellSearch® images obtained after Circulating Endothelial Cell (CEC) and CTC enrichment from blood of 395 mCRC patients, before the initiation of a new therapy. Patients had participated in the prospective phase III CAIRO2 study. ACCEPT classified objects, CTC and CEC counts and patient information were used in univariable and multivariable analysis to determine their relation with Progression-Free Survival (PFS) and Overall Survival (OS).
edEVs are present in blood of mCRC patients at 5-10 fold higher frequencies than CECs. A significantly shorter PFS and OS was observed for patients with ≥ 3 CTCs/ 7.5 mL, ≥ 40 tdEVs/ 7.5 mL and ≥ 287 edEVs/ 4.0 mL. The Hazard Ratio HR (95% CI) of PFS for increased CTCs, tdEVs and edEVs was 1.4 (1.1-1.9), 2.0 (1.5-2.6) and 1.7 (1.2-2.5), respectively. Similarly, the HR of OS for increased CTCs, tdEVs and edEVs was 2.2 (1.7-3.0), 2.7 (2.0-3.5) and 2.1 (1.5-2.8), respectively. There was no cut-off value for CECs leading to a dichotomization of patients with a significant HR. Both tdEVs and edEVs remained significant predictors of OS in multivariable analysis.
edEVs and tdEVs are independent prognostic factors for OS in mCRC patients.
Funded by the NWO Applied and Engineering Sciences Cancer-ID project #14190.
Citation Format: Afroditi Nanou, Linda Mol, Miriam Koopman, Cornelis J. Punt, Leon W. Terstappen. Circulating tumor cells, tumor- and endothelium- derived extracellular vesicles, but not circulating endothelial cells associate with poor prognosis in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6487.
Abstract 6530: Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T
Authors: Jung Jin G , Kim Min-Seok , Jung Hwa-Chul , Choi Hoil , Moon Kyung-Duk 
Published: September 2020

Abstract
Purpose: The characteristics of aberrant overexpression and distinct features of cancer-associated (CA)-MUC1 has been often considered as a promising target in most of the solid cancers. MUC1 is composed of α and β subunits to form a full length of MUC1, and α subunit is released and circulated into the blood in cancer, which is used as biomarkers such as CA 15-3 and CA 27-29. As those α subunit-targeting strategies were failed in the numerous clinical trials due to, at least in part, the diminished α subunit of MUC1 in cancer, we have developed a humanized Ab, PAb001 targeting the residual β subunit of MUC1, called as an onco-tethered (OT)-MUC1. To prove the concept of this strategy, an antibody-drug conjugate (ADC) and chimeric antigen receptor (CAR) T cells were applied to assess its efficacies.
Methods: We produced a monoclonal antibody (mAb) against OT-MUC1 from mouse and sequentially generated its derivative humanized antibody, PAb001. Then, the target product profiles (TPP) were determined by SPR, ELISA, FACS, immunohistochemical analysis, pilot tissue cross-reactivity, and pharmacokinetics (PK) analysis. Then, to evaluate anti-cancer efficacies, we either conjugated PAb001 with Monomethyl auristatin E (MMAE) or generated the second-generation CAR T cells and then sequentially tested in vitro and in vivo cancer models.
Results: Based on the TPP criteria, PAb001 antibody was chosen over a hundred of candidate antibodies tested. Next, it was conjugated with MMAE, treated and measured its cytotoxicity in ovarian and breast cancer cell lines, including triple-negative breast cancers (TNBC). As a result, PAb001-ADC selectively inhibited the growth of cancer cell lines, depending on the expression level of MUC1. Also, it showed 80-100 % tumor growth inhibition rates (TGI) in the cell lines- and patient-derived xenograft models. Lastly, OT-MUC1 Car-T cells showed significant and selective growth inhibition of cancer cells.
Conclusion: Taken together, the preclinical studies of PAb001-ADC and Car-T indicate the high therapeutic potentials targeting OT-MUC1 in cancer, which further provided the rationale for clinical development.
Citation Format: Jin G Jung, Min-Seok Kim, Hwa-Chul Jung, Hoil Choi, Kyung-Duk Moon. Old target, but new approach: Targeting cancer-associated MUC1 with ADC and Car-T [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6530.
Abstract 6550: WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells
Authors: Wu Wei , Ding Huaiwei , Zhang Huiyong 
Published: September 2020

Abstract
Androgen receptor (AR) is a primary target for treatment of prostate cancer (PCa). AR signaling plays a critical function in all stages of PCa. Our previous research demonstrated that decursin and its isomer decursinol angelate, a pair of natural compounds from Angelica gigas Nakai, inhibit AR signaling and suppressed the growth of prostate cancer cells in vitro and in vivo. In this study, we have designed a series of pro-drug conjugates of decursin, based on acid-esterified modification, in order to achieve higher water solubility, stronger cytocidal effect and better AR suppression activity. Twelve novel esterified derivatives of decursin were synthesized from decursinol and characterized by 1H-, 13C-NMR and HR-MS techniques. Among them, WD105 displayed the best solubility. Initial structure-activity relationship (SAR) studies were carried out with a cell growth (CCK8) assay and identifıed WD105 and WD106 as lead compounds with more potency at suppressing LNCaP cell growth than decursin judged by IC50 value. In addition, both WD105 and WD106 induced caspase-mediated cell apoptosis (48h), evidenced by cleavage of PARP, in a concentration-dependent manner. Furthermore, WD105 decreased the transcriptional activity of AR and androgen-induced expression of PSA better than WD106 and decursin when assessed by Western Blot and ELISA. Taken together, these data suggest that WD105 has greater in vitro activity than decursin as an AR targeting lead compound. Future studies will characterize the PK metrics and, if warranted, determine the in vivo antitumor effect of WD105 on the growth of LNCaP-AR xenografts.
Citation Format: Wei Wu, Huaiwei Ding, Huiyong Zhang. WD105, a novel decursin derivative, showed greater growth inhibition and androgen receptor suppression in LNCaP human prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6550.
Abstract 6562: Design, synthesis and anticancer properties of trans-cinnamaldehyde and curcumin based scaffolds compounds
Authors: Omar Abdel-Sattar M. , Al-Abd Ahmed M. 
Published: September 2020

Abstract
Cinnamaldehyde and curcumin scaffolds are known for their anticancer potential via reactive oxygen species (ROS) generation and cellular damage. Herein, we synthesized a set of heterocyclic compounds build on the naturally-occurring trans-cinnamaldehyde and curcumin scaffolds and assessed their antiproliferative/cytotoxic properties against hepatocellular carcinoma (HepG2), breast adenocarcinoma (MCF-7) and colorectal cancer cells (HCT-116). The general structure of the synthesized compounds comprised 2-(4-fluorophenyl)-4-imidazolone nucleus attached to a 2-phenylpropylidene moiety. The imidazolone's N1 diversity point was attached to a variety of groups that are different in steric as well as electronic properties. Compounds FC01, FC09, FC11, FC12, FC14, FC30 and FC37 (groups attached to N1 diversity point are phenyl, methyl, 4-methylpiperazinyl, n-propyl, 4-hydroxyphenyl, 2-furylmethyl, and 4-methoxyphenyl, respectively) showed considerable cytotoxicity with IC50 ranging from 0.1 to 11.9 µM against MCF-7, HepG2, and HCT-116 cells. Within one hour of exposure to the IC50's of compounds FC09, FC12 and FC31, total ROS was significantly increased to 143.3±1.2%, 158.2±8.6% and 138±9.3% of control. After 2 hours of exposure, compounds FC09, FC12, FC14, FC30 and FC31 significantly raised the total ROS by 148.3±2.1%, 144.2±5.9%, 112±3.1%, 134.8±10.3% and 140.7±5.7%, respectively. Interestingly, all compounds under investigation significantly raised the intracellular ROS within 1.5 h of exposure. After 24 h of exposure, only compounds FC01, FC07, FC30, and FC31 kept the intracellular level of ROS significantly higher than control cells (111.1±3.6, 113.8±4.3%, 110.4±2.2%, and 117.7±7.5%, respectively). On the other hand, the ROS level within cells treated with the IC50 of compounds FC09 and FC12 for 24 h was significantly lower than control cells (85.7±1.3 and 68.4±4.7, respectively). Apoptosis/necrosis differential assessment using annexin-V/FITC with PI as a counterstain coupled with flow cytometric analysis, showed that compounds FC01, FC09, and FC12 induced significant apoptosis as well as necrosis by 2-5 folds compared to control cells. Compound FC14 failed to induce any significant apoptosis or necrosis. In conclusion, trans-cinnamaldehyde and curcumin scaffold-based compounds under investigation, particularly FC01, FC09 and FC12 might represent promising candidates in anticancer molecules for further optimization.
Citation Format: Abdel-Sattar M. Omar, Ahmed M. Al-Abd. Design, synthesis and anticancer properties of trans-cinnamaldehyde and curcumin based scaffolds compounds [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6562.
Abstract 6565: Impact of TIM-3 modulation on the sensitivity of anti-PD-1
Authors: Zhu Jian , Zhu Rebecca L. 
Published: September 2020

Abstract
Concurrent inhibition of TIM-3 and PD-1 may have enhanced anti-tumor effects. In this study, computational models were established to identify factors involved in the interactions between these two immunotherapeutic targets. Abstracts published on TIM-3, PD-1, PD-L1, anti-PD-1/PD-L1 were downloaded from PubMed, and analyzed by natural language processing and text mining. Interactions among genes, compound/therapies, cell/animal models, pathway/disease, and clinical studies were retrieved from the text. Networks were constructed to simulate effects of TIM-3 inhibition on anti-PD-1. The TIM-3/anti-PD-1 network consists of 57 nodes, 175 interactions with 11,626 possible regulatory paths from TIM-3 to anti-PD-1. Overall, 6142 paths are associated with the agonistic interactions between TIM-3 inhibition and anti-PD-1, while 5484 are antagonistic. Factors associated with the enhancement of anti-PD-1 by TIM-3 inhibition include up-regulation of IL-2, IFN-gamma, Th1 cells/cytokines, CD8+ T cells or NK cells, and down-regulation of IL-10, NFkB-p65, COX2 or EMT. Treatments with either EGFR inhibitors (e.g. gefitinib), anti-CTLA-4, IL-2 agonist or radiation therapy may enhance the combination efficacy of TIM-3 and PD-1 inhibitors. On the other hand, CTLA-4, galectin-9, Wnt/beta-catenin or Tregs combined with TIM-3 over-expression may confer resistance to anti-PD-1. PD-L1 is a validated biomarker for anti-PD-1 response and its expression can be correlated with TIM-3. Similar text-mining approach was adopted to construct the TIM-3/PD-L1 network which consists of 65 nodes, 165 interactions and 1372 paths from TIM-3 to PD-L1. Up-regulation of either galectin-9, WNT/beta-catenin or Tregs by TIM-3 results in the induction of PD-L1. As the network analyses revealed, interactions between TIM-3 and PD-L1 are context dependent, and assessment of the effect of TIM-3 inhibition on anti-PD-1 requires profiling of multiple factors along the regulatory and signaling pathways. The TIM-3/PD-L1 and TIM-3/anti-PD-1 networks prove to be useful tools to facilitate the therapeutic development of TIM-3 and PD-1 inhibitors, especially for selecting patients with potential agonistic effects of this promising drug combination.
Citation Format: Jian Zhu, Rebecca L. Zhu. Impact of TIM-3 modulation on the sensitivity of anti-PD-1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6565.
Abstract 6588: Omics integration provides insight into esophageal cancer inhibitory mechanisms of a cranberry extract
Authors: Weh Katherine M. , Howard Connor L. , Tripp Bridget A. , Clarke Jennifer L. , Howell Amy B. , Kresty Laura A. 
Published: September 2020

Abstract
Our laboratory studies chemoprevention of esophageal adenocarcinoma (EAC) through utilization of the rat esophagogastroduodenal anastomosis (EGDA) surgical model of reflux-induced EAC. Specifically, we evaluated mechanisms by which cranberry proanthocyanidins (C-PAC) inhibit reflux-induced EAC by utilizing multi-omics integrative approaches employing multiple program platforms. Herein, we investigated whether pathway-based integration could be used to examine cross-talk between genes, metabolites and the microbial profiles. For this analysis, we utilized transcriptomic and untargeted metabolomic data from rat esophagi of animals that received water or C-PAC in the drinking water alone or combined with reflux inducing EGDA surgery. Additionally, we isolated DNA from fecal pellets and performed 16S rRNA sequencing to assess gut microbiome composition and functionality. Each omics dataset was analyzed for significant pathway enrichment and network generation using Metacore, DAVID and Metabolync. PICRUSt was utilized to predict microbiota functionality. Analysis of transcriptomic and metabolomic data suggest that EGDA upregulates inflammatory, NF-kB, DNA damage, cell cycle and immune function pathways as well as metabolic pathways related to eicosanoids, amino acids and primary and secondary bile acids, while C-PAC mitigates these alterations. Preliminary microbiome data analysis also suggests that bacteria related to inflammation, metabolite transport and DNA damage are increased in abundance in EGDA, with a decrease in abundance following C-PAC treatment. Analysis of omics datasets can provide insightful relationships into the cross-talk between different processes regulated by transcription, metabolism and the microbiome. Single dataset and integrative analysis showed similarities in altered pathways for vehicle and C-PAC treated animals in the context of reflux. Integration is limited by the infancy of multi-omics analysis programs, as well as the limited amount of research involving prediction of bacterial function and integration of microbiome data with other omics datasets. Further research and development of these omics programs is needed to determine accuracy of predicted results as well as continued investigation of identified pathways.
Citation Format: Katherine M. Weh, Connor L. Howard, Bridget A. Tripp, Jennifer L. Clarke, Amy B. Howell, Laura A. Kresty. Omics integration provides insight into esophageal cancer inhibitory mechanisms of a cranberry extract [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6588.
Abstract 6611: Functional characterization of a novel gene in the antigen presentation pathway allows specific immunotherapeutic targeting of glioblastoma cancer stem cells
Authors: Kidwell Reilly L. , Li Xiqing , Rich Jeremy N. 
Published: September 2020

Abstract
Glioblastoma is the most prevalent and aggressive primary brain tumor in adults, and conventional treatment strategies have made minimal progress in prolonging overall survival. Cancer stem cells are critical for tumor initiation, growth, and maintenance, and are able to co-opt complex host mechanisms to evade immune recognition. Immune checkpoint inhibition has proven revolutionary for the treatment of several types of solid tumors, but has largely failed in attempts to improve outcomes in glioblastoma. Developing a deeper understanding of the functional immunomodulatory role of genes unique to glioma stem cells (GSCs) may help to elucidate this enigma, and inform more specific immunotherapeutic targeting. To better understand the ability of GSCs to promote immunosuppression and self-tolerance in the tumor niche, we interrogated RNA-seq data from GSCs and differentiated glioma cells (DGCs) and identified a novel gene in the antigen presentation pathway (APP). In vitro targeting of this gene increased sensitivity to CD8+ T cell killing and reduced expression of other T-cell inhibitory ligands in GSCs alone, decreasing tumor-mediated immunosuppression. Compared to DGCs, GSCs were found to be key promoters of immune self-tolerance and evasion, with unaltered GSCs exhibiting minimal peptide binding to MHC Class I and, therefore, decreased antigen presentation. Specific targeting of the identified APP gene led to a reversal of this interaction, with increased binding capacity and, correspondingly, tumor antigen recognition. In vivo administration of a specific APP gene targeting agent in human GSC xenograft mice displayed decreased tumor burden and a striking prolongation of overall survival compared to both controls and mice treated with known immune checkpoint inhibitors. High expression of the APP gene is associated with poor clinical prognosis, supporting the clinical relevance of this discovery. Thus, novel targeting of the antigen-presenting pathway may provide a therapeutic vulnerability unique to glioblastoma cancer stem cells.
Citation Format: Reilly L. Kidwell, Xiqing Li, Jeremy N. Rich. Functional characterization of a novel gene in the antigen presentation pathway allows specific immunotherapeutic targeting of glioblastoma cancer stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6611.