bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1981: Cell free DNA promotes malignant transformation in non-tumor cells
Authors: Souza Aline Gomes , Martins Mario Machado , Bastos Victor Alexandre , Resende Natassia Caroline , Santos Paula Sousa , Marangoni Karina , Goulart Luiz Ricardo , Goulart Vivian Alonso 
Published: September 2020

Abstract
Cell free DNA (cfDNA) are present at various biological fluids and when released by tumor cells it can contribute with the induction of pro-tumorigenic events, such as malignant transformations and metastasis. In this work we evaluated the effects of tumor derived cfDNA, isolated from blood of prostate cancer patients, in the non-tumoral prostate cellular linages RWPE-1 and PNT-2. We quantified, characterized and evaluated the function of the isolated cfDNA by qPCR of tumor progression related genes and MS-metabolomics. The results showed that the isolated cfDNA was able to induce the increase expression of MMP9 and CD44 in the normal prostate cellular linages, as well as to alter the consumption of tryptophan by the cells, these changes can indicate the sifting of the cells metabolism in favor of a tumoral profile. Those results demonstrate the potential of tumor derived cfDNA to alter receptor cells profiles, triggering malignant transformation events, making them a good target for new therapies and molecular targets for diagnosis.
Citation Format: Aline Gomes Souza, Mario Machado Martins, Victor Alexandre Bastos, Natassia Caroline Resende, Paula Sousa Santos, Karina Marangoni, Luiz Ricardo Goulart, Vivian Alonso Goulart. Cell free DNA promotes malignant transformation in non-tumor 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 1981.
Abstract 2099: Assessing cancer drug response prediction from gene expression
Authors: Talwar James , Carter Hannah 
Published: September 2020

Abstract
Customizing treatments targeted to a patient specific disease landscape remains an open challenge in precision medicine. Gene expression data, generated through next generation sequencing technologies, has shown significant power for supervised machine learning approaches. Here, we evaluated neural network performance at predicting cancer cell-line specific drug sensitivity. Gene expression data for 17,737 genes across 1014 human cancer cell-lines with IC50 concentrations for 251 anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in Cancer Project. Cell-lines were considered sensitive if IC50 concentration was below maximum drug concentration. For neural network input, gene expression values were scaled to a range of -0.5 to 0.5 through log transformation, z-scoring, subtracting the minimum and dividing by the range. A hyperparameter optimized neural network model consisting of two hidden layers of size 1024 and 512 respectively resulted in a test set accuracy ranging from 60.2% to 67.8% across drugs compared to an average baseline performance of 53.4%. Dimension reduction through clustering and Nearest Neighbor Networks did not result in improved performance. We found that classical machine learning classification methods including support vector machines showed comparable performance to our neural network approach. However, neural network cross-training on drugs sharing the same putative targets (e.g. AURKA) led to a 5.03% improvement in neural network prediction accuracy. Overall, our analysis shows that utilizing gene expression profiles independent of other -omics data for cancer drug response prediction through machine learning frameworks offers modest predictive capabilities. To increase performance, we suggest augmenting training size through shared pathway cross-training, optimizing feature encoding to maximize neural network predictive capabilities, and incorporating other -omics data.
Citation Format: James Talwar, Hannah Carter. Assessing cancer drug response prediction from gene expression [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 2099.
Abstract 2115: An atlas of transposable element derived alternative splicing in cancer
Authors: Clayton Evan A. , Rishishwar Lavanya , Huang Tzu-Chuan , Gulati Saurabh , Ban Dongjo , McDonald John F. , Jordan I. King 
Published: September 2020

Abstract
Transposable element (TE) derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially utilized in normal versus cancer tissues. We analyzed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumor tissue pairs across 13 cancer types, resulting in the discovery of 4,820 TE-generated alternative splice events distributed among 723 cancer-associated genes. SINEs (Alu) and LINEs (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes - including MYH11, WHSC1, and CANT1 - were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans-splicing mediated by dispersed TE repeats.
Citation Format: Evan A. Clayton, Lavanya Rishishwar, Tzu-Chuan Huang, Saurabh Gulati, Dongjo Ban, John F. McDonald, I. King Jordan. An atlas of transposable element derived alternative splicing in 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 2115.
Abstract 2118: Using electronic medical records to assemble a lung cancer cohort for prognosis study
Authors: Yuan Qianyu , Cai Tianrun , Hong Chuan , Cai Tianxi , Christiani David 
Published: September 2020

Abstract
Background: Electronic medical records (EMRs) provide a low-cost means of accessing longitudinal data on large populations with detailed information regarding diagnosis, clinical procedures, medications and tests. A lung cancer cohort assembled from EMR represents a powerful resource for studying prognosis.
Methods: EMRs are from the Massachusetts General Hospital and Brigham and Women's Hospital using Partners HealthCare System Research Patient Data Registry from 1988 to October 18, 2018. A previously validated phenotyping algorithm was developed to identify lung cancer patients based on a gold standard set of 200 patients. Demographics and clinical characteristics were extracted from both structured data and clinical notes utilizing natural language processing tools. The quality of EMR cohort was assessed by comparing to Boston Lung Cancer Study (BLCS) cohort using overlapped population. Specifically, we assessed: 1) absolute differences: the agreements of diagnosis dates, histological type and clinical stage; 2) relative differences: the effect sizes of variables on overall survival estimated from Cox regression models.
Results: The initial study population included 76,643 patients with a diagnostic code related to primary lung cancer. The phenotyping model identified 42,069 lung cancer patients with sensitivity of 75.2%, specificity of 90.0%, PPV of 94.4% and AUC of 0.927. A total of 5,053 patients overlapped in BLCS and EMR cohorts were used for quality assessment. The diagnosis dates from EMR agreed with diagnosis dates from BLCS cohort with median of 0 days. 10.9%, 7.5%, and 5.1% of the population had an absolute date discrepancy of more than 90 days, 180 days, and one year, respectively. The agreements of histological type and clinical stage were 90.1% and 82.8% respectively. Further analysis for overall survival showed high consistency in the two cohorts as Cox regression models controlled for age, sex, race, smoking status, histological type, stages and treatments yielded similar estimates.
Conclusion: We assembled a large lung cancer cohort from EMRs using phenotyping algorithm and extraction strategies combining structured and unstructured data. The quality of analytic data from EMRs were compared with the well curated epidemiology study to ensure their suitability for lung cancer prognosis research.
Citation Format: Qianyu Yuan, Tianrun Cai, Chuan Hong, Tianxi Cai, David Christiani. Using electronic medical records to assemble a lung cancer cohort for prognosis study [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 2118.
Abstract 2124: Hotspots of sequence variability in gut microbial metagenomic datasets and their association with colorectal cancer
Authors: Martinez-Ramirez Rachell M. , Girod-Hoffman Miguel M. , Roche-Lima Abiel , Carrasquillo-Carrión Kelvin , Pérez-Santiago Josué , Baerga-Ortiz Abel 
Published: September 2020

Abstract
The gut microbiome has been found to impact host predisposition to disease. Previous research shows that certain species of microbes, encoding pro-inflammatory factors, increase the probability of developing dysplasia and colorectal cancer (CRC). Recently, through the oligotyping approach, we found genetic variants for an amplified region of usp, a genotoxic protein made by E. coli in the gut. These different variants were present in healthy, adenoma and CRC clinical stool samples. To our surprise, the same positions of genetic variability found experimentally were confirmed by BLAST analyses of shotgun metagenomic data from a case-control study conducted in France and Washington D.C. In this work, using the same metagenomics data, we searched for hotspots of genetic variability in the sequences for five genes with known pro-inflammatory and toxicity profiles: usp, tcpC, gelE, clbB, and clbN. More importantly, we extended our analyses to cover the entire length of these genes using a command line approach to BLAST+. The sequence reads for both clbB and clbN lacked coverage, rendering their analysis unquantifiable. The output data for both tcpC and gelE showed high levels of homology between the sequences of the healthy and CRC patients. However, we found twenty-nine hotspots in the usp gene, thirteen of which cause a modification in the primary structure of the protein. Among these thirteen positions, nine were different in cases and controls suggesting that these hotspots of variation are associated with CRC. All these results provide insight into both the link between variability and pathogenicity, and the viability of shotgun sequencing for such types of analyses.
Citation Format: Rachell M. Martinez-Ramirez, Miguel M. Girod-Hoffman, Abiel Roche-Lima, Kelvin Carrasquillo-Carrión, Josué Pérez-Santiago, Abel Baerga-Ortiz. Hotspots of sequence variability in gut microbial metagenomic datasets and their association with 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 2124.
Abstract 2154: Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing
Authors: Song Tianyu Y. , Zhao Haixin , Fan Hongjie , Long Min , Geng Chenlu , Xie Xiaoxiao , Liu Yang , Zhou Wenrong , Chen Ziyu , Huang Dawei , Peng Bo , Peng Zhengang , Cang Yong 
Published: September 2020

Abstract
Cancer arises after somatic mutations override cellular and immunological control of cell proliferation. Mutations in oncogenes and tumor suppressor genes endow cancer cells intrinsic growth advantage over neighboring cells. Mutations can also enable cancer cells to survive immune clearance during cancer progression, but systematic analysis of such mutations is lacking. We hypothesized that some genetic alterations carried in cancer cell lines might specifically affect the cell fitness to T cell-mediated killing. By deep sequencing of syngeneic xenograft tumors receiving different levels of immune pressure, we enriched 53 mutations in clonal populations against T cell immunity. To differentiate the driver from passenger mutations, we performed in vivo and T cell co-culture CRISPR screens with a guide RNA library targeting these candidate genes. We identified ANKRD52, a promoter of miRNA-mediated silencing, as required for PD-1-independent T cell cytotoxicity by activating the JAK-STAT signaling and antigen presentation in cancer cells. ANKRD52 mutations found in prevalent cancer patients failed to activate the interferon-γ pathway and these patients exhibit poor overall survival. We hereby provide an approach for interrogating cancer genetic heterogeneity to uncover evolutionarily conserved evasion mechanism from host immunity.
Citation Format: Tianyu Y. Song, Haixin Zhao, Hongjie Fan, Min Long, Chenlu Geng, Xiaoxiao Xie, Yang Liu, Wenrong Zhou, Ziyu Chen, Dawei Huang, Bo Peng, Zhengang Peng, Yong Cang. Immune pressure selects ANKRD52 mutations for cancer cells to escape T cell-mediated killing [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 2154.
Abstract 2187: Kinetics and potency of T Cell-mediated cytolysis of glioblastoma
Authors: Chvatal Stacie A. , Logun Meghan T. , Hayes Heather B. , Millard Daniel C. , Karumbaiah Lohitash 
Published: September 2020

Abstract
Glioblastoma (GBM) is an aggressive form of brain cancer that has no effective treatments and a prognosis of only 12-15 months. Immune system effector T cells are a promising therapy due to their high specificity and innate cytotoxicity. The ability to assess the efficacy and potency of T cell therapies in vitro and with high throughput is vital for the further development of this promising therapy. Cellular impedance-based assays offer a sensitive, label-free, and nondestructive method to continuously monitor cancer cell proliferation and immune cell-mediated cytotoxicity in real-time and at high throughputs, revealing not only the potency but also the kinetics of T cell therapies. Here, we investigated the targeting potency of activated human T cells on human U87MG glioma cell monolayers across multiple cell densities.
U87MG cells were plated at 10k, 25k, and 50k cells per well on a PDL-coated CytoView-Z 96-well plate (n=12 wells per density), and their impedance was continuously monitored on the Maestro Z impedance platform. After 24 hours, activated patient-derived T Cells (ImmunoCult CD3/CD28 activation media) were added in a 10:1 effector:target ratio. Impedance and cytolysis were subsequently monitored for another 120 hours.
As expected, higher densities proliferated faster and reached a higher impedance level at 24 hours. The addition of activated human T cells resulted in a decrease of the impedance signal consistent with T cell-mediated lysis of the glioma cells. The highest density of T cells (500k) exhibited the fastest rate of U87 cytolysis, with a Kill Time 50 of 35 hours. All densities reached 100% cytolysis by 100 hours.
Overall, activated human T cells were highly effective for cytolysis of U87MG glioma cell monolayers of varying densities. The cellular impedance assay revealed high potency, with kinetics that varied across cell densities despite the same effector:target ratios.
Citation Format: Stacie A. Chvatal, Meghan T. Logun, Heather B. Hayes, Daniel C. Millard, Lohitash Karumbaiah. Kinetics and potency of T Cell-mediated cytolysis of glioblastoma [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 2187.
Abstract 2207: Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma
Authors: He Xi-Ran , Du Yang , Jin Yu-Shen , Bai Hua , Tian Jie , Wang Jie 
Published: September 2020

Abstract
Background and purpose: For squamous cell lung carcinoma (SQCLC), the survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immune checkpoint inhibitors (ICIs), also known as chemoimmunotherapy, have been confirmed in recent clinical trials. Nevertheless, the actual relationship between MTD chemotherapy and ICIs remains controversial, as most oncologists considered that MTD chemotherapeutic agents could cause immunosuppression. Hence, we attempted to optimize and assess different combinatorial patterns of chemoimmunotherapy in SQCLC.
Methods: We utilized the in vitro SQCLC cell lines, in vivo syngeneic immunocompetent mouse models, and patient samples to fully explore how to increase the ectopic lymphoid-like structures (ELSs) and the therapeutic targets for anti-programmed death 1 (PD-1) / anti PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), as well as the underlying mechanisms, in order to render SQCLC to be more sensitive to ICIs and improve the efficacy of chemoimmunotherapy.
Results: Low-dose chemotherapeutic agents induced SQCLC cells to undergo immunogenic cell death (ICD) by activating the PI3K/Akt/NF-κB signaling pathway and thereby enhancing neoantigen exposure. Following, the high mobility group box-1 released by cells undergoing ICD promoted neoantigen uptake and presentation by activating dendritic cells (DCs) and consequently invoking specific T cell responses. In vivo, low-dose chemotherapeutic agents activated systemic immune responses and immunological memory, and enhanced antitumor ELSs compared with routine MTD chemotherapy. Moreover, the upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and synergized better with the subsequent administration of anti-PD-1/PD-L1 mAbs. One possible mechanism of this synergy is increasing the activated type I macrophages, DCs, and cytotoxic CD8+ T cells, and maintaining the diversity and normal composition of intestinal gut microbiota. In contrast, when combined with ICIs, the effects of routine MTD chemotherapy appeared to be additive rather than synergistic.
Conclusion: The upfront metronomic chemotherapy better synergizes with immunotherapy over the routine MTD chemotherapy in SQCLC. This preclinical study provides a novel strategy to optimize chemoimmunotherapy, and it is worth being translated into the clinic in the future.
Citation Format: Xi-Ran He, Yang Du, Yu-Shen Jin, Hua Bai, Jie Tian, Jie Wang. Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma [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 2207.
Abstract 2228: PD1/CTLA4 humanized mice - A great model for pre-clinical toxicology and efficacy evaluation of macromolecular drugs
Authors: Ju Cunxiang , Zhang Mingkun , Mao Rui , Xiuying Ma , Tang Jin , Li Shuai , Wang Jingjing , Sun Hongyan , Zhao Jing , Gao Xiang 
Published: September 2020

Abstract
Immune checkpoint antibodies have conferred huge cancer immunotherapeutic effect (CITE). Besides, severe immunotherapy related adverse events (irAE) occurred in combination therapy such as anti-PD1 combines with anti-CTLA4 antibodies greatly limit the development of cancer therapy. Animal models which can recapitulate both clinical irAE and CITE will be benefit for developing safer immune-checkpoint-targeting reagents. However, no animal models were found can be used for preclinical safety evaluation of drugs up to now. Given this fact, PD1/CTLA4 double-humanized mice models were established in both BALB/c (BALB/c-hPD1/hCTLA4) and C57BL/6 (B6-hPD1/hCTLA4) background, which by replacing the mouse extracellular domain of CTLA4 and PD1 with human segments while retaining mouse intact intracellular part, respectively. Our data showed that strong CITE against anti-hCTLA4 treatment observed in models from both BALB/c and B6 background. Apparent inhibition of tumor growth also emerged on subcutaneously engrafted CT26 tumor in BALB/c-hPD1/hCTLA4 mice by anti-PD1/CTLA4 bispecific antibody treatment. Meanwhile, severe irAEs which have been observed in clinical patients, such as joint swelling, skin inflammation, heart damage and infiltration of inflammatory cells in different tissues and organs could be reproduced in BALB/c-hPD1/hCTLA4 mice. Consistent with previous reports, we could not observe similar irAEs under drugs treatment at the same dose in C57BL/6-hPD1/hCTLA4 mice. Our data indicated that adult BALB/c-hPD1/hCTLA4 mice, but not C57BL/6-hPD1/hCTLA4 mice, were more sensitive to irAEs. Taken together, adult PD1/CTLA4 humanized mice in BALB/c background can not only be used to screen humanized antibodies, but also have tremendous values for preclinical safety evaluation.
Citation Format: Cunxiang Ju, Mingkun Zhang, Rui Mao, Ma Xiuying, Jin Tang, Shuai Li, Jingjing Wang, Hongyan Sun, Jing Zhao, Xiang Gao. PD1/CTLA4 humanized mice - A great model for pre-clinical toxicology and efficacy evaluation of macromolecular drugs [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 2228.