bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3940: Acute total body ionizing radiation induces long-term adverse effects and immediate changes in cardiac protein oxidative carbonylation in the rat
Authors: Rosen Elliot T. , Kryndushkin Dmitry , Aryal Baikuntha , Gonzalez Yanira , Chehab Leena , Dickey Jennifer , Mog Steven , Rao V Ashutosh 
Published: August 2019

Abstract
Radiation-induced heart disease presents a significant challenge in the event of an accidental radiation exposure as well as to cancer patients who receive acute doses of irradiation as part of radiation therapy. We utilized the Wistar-Kyoto and spontaneously hypertensive rat model, previously shown to demonstrate drug-induced cardiomyopathy, to evaluate the acute and long-term effects of sub-lethal total body irradiation at two, four, and fifty-two weeks. We further examined irreversible oxidative protein carbonylation in the heart immediately following irradiation. Both males and females sustained reduced growth and anemic conditions over a one-year period as reflected by reduced body weight and low red blood cell count. Increased inflammation was detected by elevated IL-6 serum levels in males at four weeks. Serum cardiac troponin T and I analyses revealed indications of cardiomyopathy at earlier time points while more variability in the troponin levels was observed at one year. Echocardiography at two weeks following 5.0Gy treatment revealed hypertrophy and decrease in cardiac output in the short term, but significant differences were not observed at the one-year timepoint. Cardiac output was decreased in both males and females after two weeks, and statistically significant in females. Following irradiation, the heart tissue showed an increase in total protein carbonylation accompanied by DNA damage indicated by an increase in γ-H2AX. We present novel findings of several proteins that showed a marked change in carbonylation profile including those of mitochondrial origin. Overall, we present findings of acute oxidative protein, DNA damage, and long-term cardiomyopathy in the irradiated animals.
Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao. Acute total body ionizing radiation induces long-term adverse effects and immediate changes in cardiac protein oxidative carbonylation in the rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3940.
Abstract 3964: Chemotherapeutic drug-induced tumor neoantigen discovery
Authors: Rumble Julie M. , Mobley James L. , Jones Richard , Ford Michael , Pisano Michael 
Published: August 2019

Abstract
Checkpoint inhibitors have shown significant efficacy against a variety of cancers, changing the way many cancers are treated. However, only a subset of patients can benefit from these therapies currently, and finding ways to increase the number of patients who can is a primary interest. Tumor mutational burden is one biomarker for checkpoint inhibitor efficacy, which may point to effective strategies for increasing tumor response to therapy. Combination of checkpoint inhibitors with existing chemotherapy is being pursued in several clinical trials, and has been shown to have synergistic effects in a mouse tumor model. Chemotherapeutic drugs work in many ways to kill tumor cells, notably by attacking DNA and its replication machinery to prevent proliferation. These DNA-targeting drugs can cause mutations in cells that are not killed outright. We hypothesize that some chemotherapeutics can cause DNA mutations that are translated into proteins and peptides that make their way into the HLA class I peptide presentation pathway. If these neoantigens are seen by CD8+ T cells as foreign, T cells will attack these tumor cells. This could provide one mechanism of action for an increase in therapeutic efficacy in tumors treated with combinations of chemotherapeutics and checkpoint inhibitors. We test the ability of two drugs, SN-38 (an active metabolite of irinotecan) and oxaliplatin to induce neoantigens by sequencing peptides from class I molecules in a colon cancer cell line.
Citation Format: Julie M. Rumble, James L. Mobley, Richard Jones, Michael Ford, Michael Pisano. Chemotherapeutic drug-induced tumor neoantigen discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3964.
Abstract 397: SMARCA4 is a selective vulnerability in SMARCA2-deficient esophageal squamous cell carcinoma cell lines
Authors: Ehrenhöfer-Wölfer Katharina , Puchner Teresa , Blaha-Ostermann Silvia , Hörmann Alexandra , Sommergruber Wolfgang , Schweifer Norbert , Zichner Thomas , Schlattl Andreas , Neumüller Ralph A. , Koegl Manfred , Petronczki Mark P. , Pearson Mark , Wöhrle Simon 
Published: August 2019

Abstract
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent tumor type with poor prognosis and limited treatment options. In this study, we aimed to discover potential novel drug targets using a pooled epigenome sgRNA viability screen in a panel of ESCC cell models. We identify the BAF chromatin remodeling helicase subunit SMARCA4/BRG1 as a novel dependency in a subset of ESCC cell lines. In line with the established synthetic lethal interaction of SMARCA4 and SMARCA2/BRM, the two mutual exclusive catalytic subunits of the BAF complex, SMARCA4-dependent cell lines display low or absent expression of SMARCA2. In rescue studies using SMARCA4 variants, we demonstrate that SMARCA4-dependency is linked to its ATPase/helicase activity, but not to bromodomain function. Similarly, ectopic expression of wild-type and bromodomain-mutant SMARCA2, but not a helicase-dead variant, rescues from loss of SMARCA4 in SMARCA2-low ESCC cells. SMARCA2-proficient ESCC cell models are rendered SMARCA4-dependent upon CRISPR/Cas9-mediated knock-out of SMARCA2. We further identify SMARCA4-dependent cell models from additional tumor types (colon, ovarian and pancreas carcinoma) with low or absent SMARCA2 expression. These findings expand the concept of SMARCA2/SMARCA4 paralog dependency and indicate pharmacological inhibition of SMARCA4 as a novel opportunity for targeted therapy of SMARCA2-deficient cancers.
Citation Format: Katharina Ehrenhöfer-Wölfer, Teresa Puchner, Silvia Blaha-Ostermann, Alexandra Hörmann, Wolfgang Sommergruber, Norbert Schweifer, Thomas Zichner, Andreas Schlattl, Ralph A. Neumüller, Manfred Koegl, Mark P. Petronczki, Mark Pearson, Simon Wöhrle. SMARCA4 is a selective vulnerability in SMARCA2-deficient esophageal squamous cell carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 397.
Abstract 3974: In vivo CRISPR-Cas9 library screen for liver cancer therapeutic targets essential for T cell killing
Authors: Zhao Haixin , Geng Chenlu , Zhou Wenrong , Peng Zhengang , Ji Qunsheng , Cang Yong 
Published: August 2019

Abstract
T-cell checkpoint inhibition by antibodies blocking programmed cell death protein 1 (PD1) has been a major breakthrough in cancer therapeutic development. However, anti-PD1 drugs approved by FDA are ineffective in treating all cancer types or in all patients in a responsive cancer type. Therefore, it is important to stratify responsive patient population and identify synergistically effective combination therapies. Primary hepatocellular carcinoma (HCC) is a human malignancy with a high incidence, mortality and recurrence rate worldwide. We established a syngeneic mouse HCC model using a murine hepatoma cell line, Hepa1-6, which, interestingly, shrunk in volume shortly after reaching up to 400 mm3. The tumor failed to resume growth unless treated with anti-CD4/CD8 antibodies to deplete endogenous T cells, suggesting that an adaptive T cell immunity suppresses the late-stage tumor growth. To identify the genetic regulators of the cancer elimination, we employed CRISPR-Cas9 based genome-wide knockout screening strategy to identify the potential targets essential for cancer cell sensitivity to the T cell immunity. Mouse xenograft models derived from hepa1-6 cells infected with the library were treated with anti-CD4/CD8 antibodies or anti-mPD1 antibody. Deep sequencing of the tumors revealed T cell-dependent enrichment of guide RNAs targeting 241 genes with variable functions. We have performed a second round of in vivo screen with a CRISPR library focused on these candidate genes. We will discuss the technical challenges of the in vivo screen as well as the broad application of the technology for discovery of immune oncology targets.
Citation Format: Haixin Zhao, Chenlu Geng, Wenrong Zhou, Zhengang Peng, Qunsheng Ji, Yong Cang. In vivo CRISPR-Cas9 library screen for liver cancer therapeutic targets essential for T cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3974.
Abstract 3983: An efficient new detection method of colorectal cancers from blood samples
Authors: Kim Joon , Kim Seon Hahn , Cho Kyung-Hwan , Kwon Yeongkeun , Kim Tae-Sung , Jung YouJin , Kim Hag Dong 
Published: August 2019

Abstract
Colorectal cancer incidence in Korea is known to be one of the highest in the world. However, the detection methods from patients’ blood samples show relatively inefficient. Ribosomal protein S3 (rpS3), a multifunctional protein with a DNA repair endonuclease activity, has been known to be overexpressed and secreted from cancer cells but not from normal cells. Western blotting using antibodies against rpS3 protein revealed that this protein is overexpressed from cancer tissues of colorectal cancer patients comparing to normal tissues from the same patients. However, other proteins including other ribosomal proteins did not show this phenomenon. We also tested the secretion level of the protein using newly developed S3-1 antibody in the serum samples from 50 colorectal cancer patients and 50 healthy people to test the possibility as a cancer marker. All the diagnosed blood samples which were randomly selected among subjects in National Biobank of Korea were collected and serum was acquired by centrifugation. Samples were analyzed by dot blotting and ELISA methods. The detection level of S3-1 from the serum of colorectal cancer patients showed significantly higher than that from healthy control group. Also more than 60% from colorectal cancer patients’ serum showed sensitivity signals with 90% specificity which are significantly better than those of CEA or CA19-9 showing a possibility as a novel colorectal cancer biomarker.
Citation Format: Joon Kim, Seon Hahn Kim, Kyung-Hwan Cho, Yeongkeun Kwon, Tae-Sung Kim, YouJin Jung, Hag Dong Kim. An efficient new detection method of colorectal cancers from blood samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3983.
Abstract 3993: Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival
Authors: Ho Won Jin , Danilova Ludmila , Zhu Qingfeng , Vithayathil Teena , Jesus-Acosta Ana De , Azad Nilo , Laheru Daniel , Fertig Elana , Anders Robert , Jaffee Elizabeth , Yarchoan Mark 
Published: August 2019

Abstract
Unselected cases of pancreatic adenocarcinoma (PDAC) have not shown clinical benefit from single agent immune checkpoint therapy, but a subset of PDAC are known to upregulate pathways involved in acquired immune suppression. Further delineation of immunologic subtypes of PDAC is key to smarter trial designs and progress toward improved immunotherapy strategies. To accomplish this, we first employed clinical survival and RNA expression data from 155 patients in The Cancer Genome Atlas (TCGA) to investigate the relationship between immune modulating checkpoints and immune subset marker, CD8A, and their impact on survival in PDAC patients. Among the markers explored, overexpression of PD-L1 (HR=2.55, p=0.001) and IDO1 (HR=2.24, p&lt;0.01) were individually associated with poor survival. PD-L1 expression was not significantly associated with stage or tumor mutational burden of the PDACs. While CD8A expression alone was not correlated with survival, stratifying the analysis based on PD-L1 and CD8 expression identified a subtype characterized by low PD-L1 and high CD8A with favorable survival (p=0.004). Similarly, the combination of low IDO1 and high CD8A expression was associated with favorable survival (p=0.038). We further extended these observations using an independent PDAC cohort of 33 patients from our institution via immunohistochemistry, again observing that low PD-L1 / high CD8 subtype associates with positive prognosis (p=0.021). Although PDAC is regarded as a poorly immunogenic cancer type, these findings infer that baseline T cell infiltration into PDAC is a feature of long term survival and highlights the importance of developing future immunotherapeutic strategies based on data-supported biomarkers to refine patient selection.
Citation Format: Won Jin Ho, Ludmila Danilova, Qingfeng Zhu, Teena Vithayathil, Ana De Jesus-Acosta, Nilo Azad, Daniel Laheru, Elana Fertig, Robert Anders, Elizabeth Jaffee, Mark Yarchoan. Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3993.
Abstract 3994: Genomic characterization of melanoma in the elderly reveals molecular drivers of progression and prognosis associated with immunotherapy response
Authors: Smith Stephen P. , Gaudy-Marqueste Caroline , Kumar Rajive , Marais Richard , Nagore Eduardo , Viros Amaya 
Published: August 2019

Abstract
Melanoma incidence and mortality particularly affects elderly patients. 85% of melanoma deaths occur in patients older than 60, and age is a powerful independent predictor of outcome. The genomic characteristics driving melanoma in the aged population have not been previously investigated.
We have undertaken a comprehensive genomic analysis of age-specific molecular characteristics in metastatic cutaneous melanoma and discovered a core set of 4 driver genes that when mutated in older patients is a powerful predictor of poor outcome. We validate these findings in international independent primary melanoma replication cohorts. This signature stratifies patient prognosis more accurately than the current staging guidelines from early to late stages, making it relevant to immediate clinical practice.
Checkpoint inhibitors are showing promising results in the adjuvant setting to treat early stage melanoma patients, and the cost burden to health care will limit access to these drugs. Importantly, elderly patients benefit from immune checkpoint inhibitor therapies, and there are currently no accepted predictors of response used to prioritize patients for these costly therapies in the adjuvant or advanced disease stages. Previous studies have shown a higher mutation burden and neo-antigen load are indicators of response.
Critically, we show elderly melanoma patients are the population subset most likely to present with a higher mutation burden, and our signature strongly correlates with melanomas of higher mutation burden and neo-antigen load. We validate these findings across multiple primary and metastatic melanoma cohorts. Finally, stratifying old patients by our 4-gene outcome signature is also associated with immunotherapy response in the metastatic stage. Our study demonstrates that stratifying patients by age will allow improved discrimination of prognosis and association with response to treatment.
Current selection of patients is based on AJCC stage alone, which means more patients have to be enrolled and more time is required to discriminate the effect of novel adjuvant immunotherapy strategies. Our work, validated across multiple cohorts, directly proposes enrolling patients with high genetic risk of poor outcome and improved rate of immunotherapy response using a simple 4-gene DNA signature that can be easily translated into clinical practice.
Citation Format: Stephen P. Smith, Caroline Gaudy-Marqueste, Rajive Kumar, Richard Marais, Eduardo Nagore, Amaya Viros. Genomic characterization of melanoma in the elderly reveals molecular drivers of progression and prognosis associated with immunotherapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3994.
Abstract 3996: Search for prognosis prediction factors in treatment selection for elderly patients with EGFR negative advanced stage non-small cell lung cancer patients
Authors: Kaneko Yoshiko , Mouri Takako , Tamiya Nobuyo , Yamada Tadaaki , Uchino Junji , Takayama Koichi 
Published: August 2019

Abstract
Introduction: Since 40% of Japanese lung cancer patients are older than 75 years old, it is necessary to consider a specific strategy to treat such elderly lung cancer patients. From that aspect, it is very important to define frail or vulnerable elder populations who have lots of heterogenic health background in treatment of lung cancer. In this study, we have tried to identify prediction factors which significantly correlates to overall survival (OS) of such elderly advanced lung cancer patients by using of patient status and laboratory data before treatment.
Objects and methods: Patients more than 75 years old who enrolled in this retrospective study were diagnosed as an advanced and EGFR negative non-small cell lung cancer during 2013-2017, and they were not available for any molecular targeted therapeutics. OS of best supportive care (BSC) cohort and chemotherapy with Docetaxel monotherapy and more cohort from those elderly patients were analyzed by Kaplan-Meier analysis.
Results: Clinical Question 1; What is a prediction factor for OS of BSC patients?
Answer 1; From analysis of 29 BSC patients (age 15-94 years old, median 82), it is revealed that low performance status (PS =0,1) stage at diagnosis (p=0.03) are significantly correlated to longer OS, and also hypoalbuminemia is significantly correlated to worse OS (11 wks vs 35 wks). Age at diagnosis did not correlate to duration of OS. ( more vs less than 80 years old:15 wks vs 37 wks, P=0.13)Clinical Question 2; Does chemotherapy significantly prolong OS of elderly patients?
Answer 2; Kaplan-Meier analysis of elderly patients (PS 0-2) less than 80 years old who were treated by chemotherapies at least with DOC monotherapy showed longer OS than that of 29 BSC patients ( 84 wk vs 15 wk, p=0.006). However, no significant difference to OS (p=0.378) has been observed to BSC patients in advanced stage with better PS (0-2). Multivariate analysis for OS indicated significant correlation of hypoalbuminemia (p=0.002), but no correlation of chemotherapy (p=0.202) has been observed.
Conclusion: 1, EGFR mutation-negative advanced NSCLC patients elder than 80 years old who were treated by chemotherapies did not showed significantly longer OS than that of BSC patients. 2, PS and hypoalbuminemia before treatment may be prediction factors for longer OS of elder lung cancer patients.
Citation Format: Yoshiko Kaneko, Takako Mouri, Nobuyo Tamiya, Tadaaki Yamada, Junji Uchino, Koichi Takayama. Search for prognosis prediction factors in treatment selection for elderly patients with EGFR negative advanced stage non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3996.
Abstract 40: Biomaterials and systems biology to guide breast cancer drug screening
Authors: Schwartz Alyssa , Barney Lauren , Jansen Lauren , Hall Christopher , Meyer Aaron , Peyton Shelly R. 
Published: August 2019

Abstract
Improved in vitro models are needed to better understand cancer progression and bridge the gap between in vitro proof-of-concept studies, in vivo validation, and clinical application. Many methods exist to create biomaterial platforms, including hydrogels, which we use to study cells in contexts more akin to what they experience in vivo. Our lab has multiple approaches to create such biomaterials, based on combinations of poly(ethylene glycol) (PEG) with peptides and zwitterions. In this presentation, I will discuss our findings in using these cell culture environments to understand the role of the extracellular matrix (ECM) in controlling cancer cell innate drug response via adaptive signaling. Specifically, I will present data comparing the behavior of breast, prostate, and ovarian cancer cells to chemotherapy and targeted drugs when cultured as 3D spheroids, on 2D gels, and as a function of the stiffness of the tumor microenvironment. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments. Our work suggests that different model systems are important for evaluating cell response to receptor tyrosine kinase inhibitors, whose efficacy depends on cell-ECM interactions.
Citation Format: Alyssa Schwartz, Lauren Barney, Lauren Jansen, Christopher Hall, Aaron Meyer, Shelly R. Peyton. Biomaterials and systems biology to guide breast cancer drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 40.