bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 264: Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy
Authors: Hidalgo Greta Garrido , Schrand Brett , Rabasa Ailem , Levay Agata , Berezhnoy Alexey , Modi Shrey , Bhuwan Giri Bhuwan , Dudeja Vikas , Doorduijn Elien , Hall Thorbald van , Gilboa Eli 
Published: August 2018

Abstract
Development of therapeutic strategies to prevent recurrence in cancer patients, or tumor progression in at risk individuals has been challenging given the long and often unpredictable time to the emergence of the malignant tumors. Neoantigens represent the most potent antigens to induce antitumor immunity, yet the ability to predict which neoantigens will be expressed in future tumors is at present not an option. We have developed a simple and broadly applicable approach to induce neoantigens in tumor cells in situ by reducing the expression of antigen processing mediators like TAP, ERAAP, or invariant chain (Ii), using siRNAs that were targeted to tumor cells by conjugation to a nucleolin-binding aptamer. Exploiting the ability to induce neoantigens in situ, we describe a novel vaccination strategy targeting potent neoantigens to control the growth of the future tumors whereby patients in remission or individuals at risk are first vaccinated against the antigen processing downregulation-induced neoantigens and when or if tumor develops the same antigens are induced in the tumor, termed prorapeutic vaccination (prophylactic + therapeutic). Mice were vaccinated against the TAP downregulation-induced neoantigens by targeting the corresponding siRNAs to dendritic cells (DC) in situ via conjugation to a short CpG oligonucleotide (ODN); the CpG ODN also activated the targeted DC to avoid induction of tolerance against the neoantigens. Vaccination with CpG ODN-TAP siRNA conjugates inhibited subsequently implanted or autochthonous tumors in several tumor models, provided the said neoantigens were also induced in the tumor by nucleolin aptamer-targeted siRNA inhibition of TAP. The CpG-siRNA and nucleolin aptamer-siRNA conjugates are simple, chemically- synthesized, off-the-shelf, and broadly applicable reagents to vaccinate against neoantigens and control the growth of future tumors irrespective of their origin.
Citation Format: Greta Garrido Hidalgo, Brett Schrand, Ailem Rabasa, Agata Levay, Alexey Berezhnoy, Shrey Modi, Giri Bhuwan Bhuwan, Vikas Dudeja, Elien Doorduijn, Thorbald van Hall, Eli Gilboa. Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy [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 264.
Abstract 2643: Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy
Authors: Koudelakova Vladimira , Trojanec Radek , Potockova Jana , Drabek Jiri , Stranska Jana , Smickova Petra , Kourilova Pavla , Grygarkova Ivona , Kolek Vitezslav , Skarda Jozef , Hajduch Marian 
Published: August 2018

Abstract
Background: Lung cancers are the leading cause of cancer-related deaths worldwide. Surgical resection alone remains preferred treatment for early stage patients with non-small cell lung cancer (NSCLC), whereas surgery plus platinum-based adjuvant chemotherapy is recommended for stages II - IIIa. Despite wide spectrum of known genetic alterations, there is a lack of biomarkers predicting response to adjuvant therapy. The aim of our study was to determine the predictive role of selected gene alterations. Methods and patients: Formalin-fixed paraffin embedded tumor samples were obtained from 209 NSCLC patients with stage I to IIIa. Of these, 59 patients were treated by surgical resection only, the follow-up adjuvant chemotherapy was indicated in remaining 150 cases. There were 146 males and 63 females (mean age 66; range 29-82 years), tumor histology revealed 79 adenocarcinomas, 105 squamous cell carcinomas, 21 large cell carcinomas, two adenosquamous carcinomas and two sarcomatoid carcinomas. Fluorescent in situ hybridization (FISH) was used for evaluation of EGFR, CMYC, MET and FGFR1 gene copy numbers and ALK and ROS1 copy numbers and rearrangements, respectively. EGFR, KRAS and BRAF mutations were screened using Cobas EGFR Mutation Test (Roche), TheraScreen: KRAS Mutation kit (Qiagen) and BRAF p.Val600Glu kit (IntellMed). Results: In the group of 150 resectable NSCLC patients treated with platinum-based adjuvant therapy, increased copy number of EGFR gene predicted poor overall survival (OS) (p = 0.00001, hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.32-2.10) as well as disease-free survival (DFS) (p = 0.0001, HR 1.54, 95% CI 1.23-1.91) in univariate analysis. In multivariate analysis adjusted to age and stage, the EGFR copy number was independent predictor of OS (p = 0.001) as well as DFS (p = 0.0004). In the group of 59 patients treated by surgical therapy only, no correlation of tested markers with clinical-pathological data was identified. Conclusions: Increased copy number of EGFR gene was found to be an independent predictor of outcome in NSCLC patients treated by adjuvant platinum-based therapy. Acknowledgment: This work was financially supported by NPU LO1304, TE02000058 and EATRIS-CZ.
Citation Format: Vladimira Koudelakova, Radek Trojanec, Jana Potockova, Jiri Drabek, Jana Stranska, Petra Smickova, Pavla Kourilova, Ivona Grygarkova, Vitezslav Kolek, Jozef Skarda, Marian Hajduch. Increased copy number of EGFR gene is an independent outcome predictor in resected non-small cell lung cancer patients treated by adjuvant chemotherapy [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 2643.
Abstract 2652: Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women
Authors: Audet-Delage Yannick , Villeneuve Lyne , Grégoire Jean , Plante Marie , Guillemette Chantal 
Published: August 2018

Abstract
Endometrial cancer (EC) is the most frequent cancer of the female genital tract in developed countries. Most EC occurs after menopause and are diagnosed as endometrioid type I carcinomas that exhibit a favorable prognosis especially for grades 1 and 2. In contrast, type II non-endometrioid carcinomas such as serous tumors have a poor prognosis. The use of small molecule biomarkers may facilitate accurate diagnosis and prognostic predictions. Our goal was to identify novel blood-based markers associated with EC subtypes and recurrence after surgery in postmenopausal women. Using mass spectrometry (MS)-based metabolomics, we examined preoperative serum metabolites of healthy women (n=18), non-recurrent and recurrent cases with type I endometrioid (n=24) and type II serous (n=12) carcinomas, matched for pathological characteristics, body mass index and age. Biochemicals including complex lipids were analyzed by gas chromatography-MS and ultrahigh performance liquid chromatography-tandem MS. A total of 1592 compounds of known identity and 14 different lipid classes were assessed. When comparing EC cases to healthy women, 137 metabolites were significantly different, with spermine as the most altered biochemical, identifying this metabolite as a potential biomarker of EC. Furthermore, recurrent cases of both histological types had higher levels of the monoacylglycerol 1-oleoylglycerol than non-recurrent cases. Type I recurrent cases were also characterized by much lower levels of bile acids and elevated concentrations of phosphorylated fibrinogen cleavage peptide, whereas type II recurrent cases displayed higher levels of ceramides and their derivatives. Our findings provide a first detailed metabolomics study in EC and identify potential non-invasive biomarkers to define clinically relevant risk groups.
Citation Format: Yannick Audet-Delage, Lyne Villeneuve, Jean Grégoire, Marie Plante, Chantal Guillemette. Metabolomics biomarkers for endometrial cancer and its recurrence after surgery in postmenopausal women [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 2652.
Abstract 2658: Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature
Authors: Lokeshwar Soum D. , Jordan Andre R. , Lahorewala Sarrah S. , Lokeshwar Vinata B. 
Published: August 2018

Abstract
Introduction and Objective: With 10% survival at 5-years, metastatic disease presents poor prognosis for renal cell carcinoma (RCC) patients. Prognosis can be improved if biomarkers that predict disease outcome are identified and validated. Aberrantly expressed microRNAs (miRs) promote (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, consensus of a clinically significant miRNA signature has not been established. The objective of this study was to identify a miRNA signature for predicting clinical outcome in RCC patients using a four-pronged interconnected discovery and validation approach.
Methods: Differentially expressed miRs were identified and analyzed in 113 specimens (Normal kidney: 59; tumor: 54). In the discovery phase, miRNA-profiling was initially performed in matched normal and tumor specimens from 8 patients, followed by validation in 16 additional specimens. Seven miRs that were significantly aberrantly expressed in miRs in both discovery phases were analyzed by qPCR and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in a TCGA dataset of 241 RCC specimens.
Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150 and miR-155 as significantly upregulated (2-4-fold) and miR-192, miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (&lt; 4 cm) from benign oncocytomas. miR-142-5p levels were significantly up-regulated in patients with lymph node positive disease and metastasis (P=0.0002). A 3-miR combination, miR-21+142-5p+194 significantly but negatively correlated with metastasis (P=0.0017; OR: 0.53) and disease-specific mortality (P=0.018; OR: 0.37). The signature had high sensitivity (86.7 - 93.3%) and specificity (82 - 87%) to predict metastasis and disease-specific mortality. In the TCGA dataset, the 3-miR signature significantly and negatively associated with metastasis (P=0.019; OR: 0.54) and overall survival (P=0.0919; OR: 0.37).
Conclusion: The interconnected discovery-validation approach identified a novel signature of 3 aberrantly expressed miRs as a potential prognostic indicator for disease outcome among RCC patients. Early detection of metastasis using the validated qPCR assay for the 3-miR signature may allow early intervention for improving patient prognosis.
Citation Format: Soum D. Lokeshwar, Andre R. Jordan, Sarrah S. Lahorewala, Vinata B. Lokeshwar. Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature [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 2658.
Abstract 2659: GLUT1 variants and the prognosis of patients with NSCLC after surgery
Authors: Lee Shin Yup , Do Sook Kyung , Choi Jin Eun , Neugent Michael , Goodwin Justin , Kim Jung-whan , Park Jae Yong 
Published: August 2018

Abstract
Background This study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection.
Methods Five single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) was analyzed.
Results Among the five SNPs investigated, two SNPs (GLUT1 rs3820589T&gt;A and rs4658G&gt;C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T&gt;A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34-0.94, P = 0.03, under dominant model), and rs4658G&gt;C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09-3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma, but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10-3).
Conclusion This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.
Citation Format: Shin Yup Lee, Sook Kyung Do, Jin Eun Choi, Michael Neugent, Justin Goodwin, Jung-whan Kim, Jae Yong Park. GLUT1 variants and the prognosis of patients with NSCLC after surgery [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 2659.
Abstract 2665: Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from Tephrosia apollinea and its anticancer property
Authors: Hassan Loiy E. Ahmed , Iqbal Muhammad Adnan , Majid Aman Shah Abdul , Majid Amin M. Abdul , Zainudeen Zarina Thasneem 
Published: August 2018

Abstract
Cancer is characterized by uncontrolled cell division caused by dysregulation of cell proliferation. Therefore, agents that impair cancer cell proliferation could have potential therapeutic value. Higher plants are considered to be a good source of anticancer agents, and several clinically tested chemotherapeutic agents have been isolated from plants or derived from constituents of plant origin. In the present study, a prenylated flavone (isoglabratephrin) was isolated from aerial parts of Tephrosia apollinea using a bioassay-guided technique. Chemical structure of the isolated compound was elucidated using spectroscopic techniques (NMR, IR, and LC-MC) and confirmed using single crystal X-ray analysis. The antiproliferative effect of isoglabratephrin was tested using three human cancer cell lines (prostate (PC3), pancreatic (PANC-1), and colon (HCT-116) and one normal cell line (human fibroblast). Isoglabratephrin displayed selective inhibitory activity against proliferation of PC3 and PANC-1 cells with median inhibitory concentration values of 20.4 and 26.6μg/ml, respectively. Isoglabratephrin demonstrated pro-apoptotic features, as it induced chromatin dissolution, nuclear condensation, and fragmentation. It also disrupted the mitochondrial membrane potential in the treated cancer cells. Thus, isoglabratephrin could be a new lead for development of cancer chemotherapies to treat human prostate and pancreatic malignancies.
Citation Format: Loiy E. Ahmed Hassan, Muhammad Adnan Iqbal, Aman Shah Abdul Majid, Amin M. Abdul Majid, Zarina Thasneem Zainudeen. Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from Tephrosia apollinea and its anticancer property [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 2665.
Abstract 2667: Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma
Authors: Moll Garrick M. , Yuzbasiyan-Gurkan Vilma 
Published: August 2018

Abstract
Treatment success in lymphoma, the most common hematopoietic cancer seen in dogs and cats, continues to be elusive. The clinical arsenal is limited to a few conventional chemotherapeutic drug protocols that result in short-term responses. In this study, dog and cat patient-derived tumor cells were tested via high-throughput screening (HTS) against a pool of over 100 FDA-approved compounds for human cancer treatment as a means to identify potential treatment strategies that can be relatively easily adapted to the dog and cat, as well as over 500 protein kinase inhibitors as a means to identify potential oncogenic driver pathways. Cells from lymph node fine needle aspirates, pleural effusions, or peripheral blood mononuclear cells from over 20 lymphoma patients were placed in cell culture media with and without growth factors. Cells from two cases, ZS15 from a Boxer dog and MT16 from a domestic shorthair cat, have continued to expand for over 12 and 6 months, respectively. Characterization by flow cytometry for detection of CD3 and CD21 identified these patient-derived cells to be T-cell lymphocytes. HTS and follow-up dose response curve (DRC) assays were performed, identifying multiple drugs effective in inhibiting growth of MT16 and ZS15 cells at nanomolar concentrations in vitro; these included anthracenedione/anthracycline-class and actinomycin-class drugs, as well as mRNA synthesis, microtubule/spindle formation, proteasome, histone deacetylase, or insulin growth factor-1 receptor inhibitors, many of which are currently not used in veterinary species. Notably, ZS15 cell growth was inhibited by mammalian target of rapamycin (mTOR) inhibitors, corroborating previous exome sequencing data of Boxer T-cell lymphomas that identified recurrent driver mutations in the PTEN-mTOR pathway. In addition, many of these drugs showed much higher IC50s in HTS and DRC assays on primary canine and feline fibroblasts, used as surrogates for normal tissue, revealing the specificity of their action on the cancer cells. These results advocate use of HTS and DRC assays as a means for identification of oncogenic driving mechanisms and for identification of drugs novel to veterinary medicine that warrant further investigation as alternative treatments for lymphoma in companion animals, which in turn can serve as valuable and accessible models for human lymphomas.
Citation Format: Garrick M. Moll, Vilma Yuzbasiyan-Gurkan. Patient-derived lymphoma cell lines and high-throughput screening enable identification of potential cytotoxic therapeutic agents for dogs and cats with lymphoma [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 2667.
Abstract 2668: Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads
Authors: Ding Ye , Li Dengfeng , Ding Chunyong , Liu Zhiqing , Wold Eric A. , Ye Na , Chen Haiying , White Mark A. , Shen Qiang , Zhou Jia 
Published: August 2018

Abstract
The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin.
Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads [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 2668.
Abstract 2669: Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients
Authors: Park Chun-Ho , Hur Sun-Chul , Kim Joseph , Lee Dae Hee , Park Yoon Sun , Shin Jae-Sik , Hong Seung-Woo , Moon Jai-Hee , Kim Hyojin , Lee So Hee , Park Hyebin , Jung Joonyee , Kim Mi Jin , Park Sang Soo , Hong Jun Ki , Gong Ji Hee , Kim Jieun , Ku Il-Whea , Lee Hyun Ho , Jin Dong-Hoon 
Published: August 2018

Abstract
As the representative targeted anticancer drug for colon cancer patients, Erbitux is the EGFR targeted therapeutic antibody and used for treatment of KRAS wild-type colon cancer patients. Even some patients with KRas wt gene did not respond to Erbitux. However, there is no treatment available for Erbitux-resistant patient group with KRAS WT gene, which is almost 50% of KRAS WT gene holders. Recently, our team identified Erbitux primary resistant related proteins named as CRG (Cetuximab-Resistant Gene) by array analysis based Erbitux responder or nonresponder colon cancer patients derived tissues and confirmed by in vitro and in vivo assay system. Based on these results, we synthesized a novel series of CRG targeted inhibitor. CRG inhibitor (CRG i;WM compound) is a lead compound for treating colon cancer patients who do not respond to Erbitux and have KRAS wild-type gene. CRG i has potent in vitro enzyme activity and high anticancer activity against various colon cancer cell lines with good selectivity in in vitro and in vivo system. Furthermore, the compound has good potent ADME/Tox. profiles for optimized lead. CRG i also displays strong anticancer effect in in vivo xenograft models and patient-derived xenograft (PDX) models. In addition, CRG i shows promising signs of overcoming Erbitux resistance in CRG knockout cells-derived xenograft model. We continue to discover improved preclinical candidates with better selectivity and ADME/Tox. profiles and validate predictive biomarker in colon cancer patients. In these efforts, we found some compounds with better profiles than CRG i. We are also trying to develop small molecules having highly potent activity against mutant CRG. In conclusion, active CRG is a promising biomarker and target for Erbitux-resistant KRAS wt colon cancer patients. Our compounds can be promising therapeutic agents for Erbitux-resistant KRAS wt colon cancer patients.
Citation Format: Chun-Ho Park, Sun-Chul Hur, Joseph Kim, Dae Hee Lee, Yoon Sun Park, Jae-Sik Shin, Seung-Woo Hong, Jai-Hee Moon, Hyojin Kim, So Hee Lee, Hyebin Park, Joonyee Jung, Mi Jin Kim, Sang Soo Park, Jun Ki Hong, Ji Hee Gong, Jieun Kim, Il-Whea Ku, Hyun Ho Lee, Dong-Hoon Jin. Identification of a novel small-molecule inhibitor for treatment of human colon cancer patients [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 2669.