bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 688: Targeting tumor associated host cells by modifiers of integrated endoplasmic reticulum stress response
Authors: Upcin Berin , Szi-Marton Daniel , Henke Erik , Ergün Süleyman , Aktas Bertal Huseyin 
Published: September 2020

Abstract
Solid tumors are composed of cancer cells, tumor associated host cells (TAHCs) and extracellular matrix components. TAHCs form tumor vasculature, secrete extracellular matrix components, provide protection from host immune-defense, and contribute to therapy resistance. Agents that can abrogate the survival and/or proliferation of both cancer cells and TAHCs would be more potent and less vulnerable to acquired resistance.
Solid tumors are under stress due to host immune surveillance, lagging vascularization, and an unstable nascent vasculature that results in nutrients and oxygen restriction. Tumors utilize adaptive pathways including hypoxia activated signaling, integrated endoplasmic reticulum (ER) stress response (IERSR) signaling, and immune evasion for survival and progression. The IERSR is a double-edged sword that is pro-survival if activated transiently but cause cell death if activated in a sustained manner. In particular, sustained activation by eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation (eIF2α-P) arm of the IERSR causes cell death. eIF2α-P reduces overall protein synthesis while inducing expression of some pro-apoptotic and tumor suppressor genes. Because TAHCs actively synthesize proteins in supporting tumor cells, we hypothesized that specific activators of eIF2α kinases will abrogate tumor survival and/or progression by dual effect on TACHs and cancer cells. We tested this hypothesis by evaluating chemical activators of eIF2α kinase heme regulated inhibitor (HRI) in ex-vivo aortic ring angiogenesis assay and against tumor organoids formed by co-culture of macrophages, fibroblasts, endothelial cells, and human breast or melanoma cancer cells. All HRI activators inhibited angiogenesis in the aortic ring assay (ARA) and had profound effects on tumor angiogenesis and macrophages. At sublethal concentration, HRI activators disrupted tumor vasculature and significantly reduced macrophages in the tumor organoids. These agents also significantly inhibited cell migration as measured by wound healing assay and by cell-migration assay of xCELLigence® RTCA DP instrument. These data indicate that HRI activators can target both tumor and TAHCs in a dose dependent manner and support further development of these agents for cancer therapy.
Citation Format: Berin Upcin, Daniel Szi-Marton, Erik Henke, Süleyman Ergün, Bertal Huseyin Aktas. Targeting tumor associated host cells by modifiers of integrated endoplasmic reticulum stress response [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 688.
Abstract 748: The small leucine-rich proteoglycan fibromodulin is a potential, novel serum and urinary biomarker for the detection of prostate cancer
Authors: Reyes Niradiz , Bettin Alfonso , Geliebter Jan 
Published: September 2020

Abstract
Background: Prostate cancer (PCa) is the most common malignant tumor diagnosed in males and the fifth leading cause of cancer deaths worldwide. The impact of this cancer in the population is due, in part, to the lack of satisfactory methods for early diagnosis and accurate prognosis, which results in delayed clinical treatment of patients. Effective therapy exists for early stages, but it is practically incurable in advanced stages. Therefore, new and better molecular biomarkers are urgently needed for the opportune diagnosis and adequate prediction of the clinical course of the disease. We have previously identified the small leucine-rich proteoglycan, fibromodulin, as a novel, potential tissue biomarker for prostate cancer. Fibromodulin is a secreted proteoglycan which can be detected in different body fluids, such as blood, urine, or prostatic secretions. The aim of the present study was to determine whether fibromodulin concentration in serum and/or urine is able to differentiate PCa patients from patients with benign disease.
Methods: Serum and urine samples were collected from a cohort of patients newly diagnosed with PCa (n=44) or with other prostatic disorders (n=46). Samples were also obtained from a group of control healthy individuals within the same age range. The concentration of fibromodulin in the blood and urine samples was measured with a commercial ELISA kit. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of fibromodulin in serum and urine. This work was approved by the Institutional Review Board of the University of Cartagena.
Results: Both serum and urinary levels of fibromodulin were significantly higher in PCa patients compared to patients with benign disorders and healthy controls (p&lt;0.05). Overall, urinary levels were higher than serum levels for each of the three groups.
Conclusion: Our results support the potential of fibromodulin as a novel serum and urinary biomarker for PCa. Validation of these results requires prospective studies using a larger cohort of patients, as well as multicenter clinical trials, to define the real value of this protein as a biomarker for PCa.
Keywords: Prostate cancer, fibromodulin, biomarkers, proteoglycan.
Citation Format: Niradiz Reyes, Alfonso Bettin, Jan Geliebter. The small leucine-rich proteoglycan fibromodulin is a potential, novel serum and urinary biomarker for the detection of prostate 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 748.
Abstract 810: Beyond genomics - A precision oncology approach utilizing multiplex protein profiling for tumor and tumor organoid samples
Authors: Erdmann Gerrit , Dudys Przemylaw , Arndt Anja , Regenbrecht Christian , Templin Markus , Sachse Christoph 
Published: September 2020

Abstract
Precision medicine's goal of achieving a better response rate by avoiding ineffective therapies has sparked new approaches, including the testing of patient-derived 3d (PD3Ds) tumor cultures for modeling individual patient response, and the use of various molecular pathology techniques for advanced tumor profiling. An intrinsic limitation of well-established genomics methodologies is, however, that they cannot directly assess cell-signaling activity within the tumor cells defined by the phosphorylation status of cellular signaling pathway networks.
Here we present the development of a robust protein profiling strategy utilizing the DigiWest immuno-assay platform, to obtain data on the activation status of key cellular signaling networks implicated in cancer, and on proteins targeted by FDA-approved drugs. This includes targeted cancer therapies for e.g. EGFR, HER2, PI3K, mTOR, ALK and AKT.
Accordingly, we compiled a list of relevant pathway nodes and their phosphorylation sites that yield activity information on RAS/RAF/ERK, PI3K/AKT and mTOR signaling pathways. Based on this, we validated 242 total and phospho antibodies in a pre-set oncoproteomic DigiWest panel that yields information on the activity of all major signaling pathways from the receptor level down to transcription factors, apoptosis and proliferation. This oncoproteomic panel can be utilized for elucidating drug response in pre-clinical cell models, in PD3D organoid models or in clinical tumor samples. Exemplary, we show differential activation states in cancer cell lines representing the most prevalent cancer types and the impact of pathway activation in different models. Finally, we tested this panel in PD3D organoids that were subjected to screening against common targeted therapies.
While the initial results are promising, further work on evaluating how such an oncoproteomic panel profiling might contribute to the rationale for personalized therapy decisions is required.
Disclosure Statement: NMI TT Pharmaservices offers DigiWest protein profiling as a service. CELLphenomics offers PD3D cell cultures and drug testing as a service.
Citation Format: Gerrit Erdmann, Przemylaw Dudys, Anja Arndt, Christian Regenbrecht, Markus Templin, Christoph Sachse. Beyond genomics - A precision oncology approach utilizing multiplex protein profiling for tumor and tumor organoid samples [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 810.
Abstract 823: Gene expression analysis reveals a pitfall in the molecular research of prostate tumors relevant to Gleason score
Authors: Zhang Wensheng , Dong Yan , Zhang Kun 
Published: September 2020

Abstract
Gleason score (GS) is a powerful prognostic factor in prostate cancer (PCa). A GS-7 tumor typically has the primary architectural pattern and secondary prevalent one being graded as 3 and 4 or 4 and 3, respectively. Due to the well-known multifocal occurrence of different patterns, a biological sample from a GS-7 tumor used in a molecular experiment will be uncertain regarding the actually represented pattern if no special attention is given to specimen preparation. In this study, by an integrative analysis of public gene expression datasets for PCa, we demonstrate that such an uncertainty is not uncommon. First, based on a unique dataset (Sowalsky, et.al, Clin. Cancer Res., 2017) of paired Gleason pattern 3 (GP-3) and Gleason pattern 4 (GP- 4) specimens of 13 GS-7 tumors, we identify 303 differentially expressed genes with respect to those two architectural patterns. Then, using the TCGA data, we show that the profile of these genes is a strong signature for distinguishing the GS-6 (3+3) tumors from the GS-8 (4+4) ones (AUC = 0.96, p-value = 9*10E-17), implying that the differences of transcription program between the GS-8 (4+4) and GS-6 (3+3) samples resemble the differences between the GP-3 and GP-4 specimens. We further demonstrate that the co-expression pattern of the signature genes in the subset of the GS-7 samples resembles that present in the aggregate of GS-6 and GS-8 samples. Finally, we verify the findings using the GSE21032 data. Our results suggest that the GS-7 specimens used to generate two frequently-cited genome-wide expression datasets largely are individual GP-3 or GP-4 specimens rather than the “intermediate” specimens of GP-3 and GP-4. This provides molecular evidence for the aforementioned uncertainty of GS-7 tumor samples, indicating a potential pitfall in the existing molecular and translational research of prostate tumors relevant to GS.
Citation Format: Wensheng Zhang, Yan Dong, Kun Zhang. Gene expression analysis reveals a pitfall in the molecular research of prostate tumors relevant to Gleason score [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 823.
Abstract 828: gDR suite: an integrative solution for handling cell line drug response data
Authors: Hafner Marc , Gladki Arkadiusz , Li Jane , Lin Eva , Lun Aaron , Martin Scott , Potocka Natalia , Scigocki Dariusz , Vartanian Steffan , Vogel Jan , Vuong Allison 
Published: September 2020

Abstract
Assessing the response of cancer cell lines to drugs and treatments that affect their growth is the cornerstone of drug discovery and development. On one hand, large screens are performed across many lines and drugs in a semi-automated manner. On the other hand, small-scale studies, for example focused on factors that contribute to sensitivity and resistance, are generally performed in labs with limited automation. Data from these complementary approaches are rarely handled in the same manner: commercial software are available for the former case, whereas experimentalists in the latter case often handle files manually and process data in spreadsheets. Here we propose a suite of computational tools that enable the processing, archiving, and visualization of drug response data from any experiment, thus ensuring reproducibility and implementation of the FAIR principles.
The core of the gDR suite is a database designed to host drug response data from large screens, single-agent treatments, combination experiments, as well as data from complex experimental designs including ligand co-treatments or shRNA. Experimentalists can upload metadata files along with unprocessed output files from plate readers in an interactive web application built with R Shiny. Data normalization and quality control are performed by the software before the data is stored in the database. Data from commercial software or other databases can also be easily pushed into the database through a REST API. To fetch the processed data, we developed an R package as well as another R shiny-based web application. Both tools allow users to efficiently search the database, easily plot the data from the selected experiments, and perform basic analyses. Overall, the gDR suite is a modular software that provides an end-to-end solution for managing drug response data.
At the conference, we will describe our implementation and demonstrate how to use the gDR suite. We hope that this tool will facilitate the handling of drug response data and thus contribute to the quality of published data. In addition, we hope that the community will contribute to the gDR suite by adding new functionalities for either importing, plotting, or analyzing the data.
Citation Format: Marc Hafner, Arkadiusz Gladki, Jane Li, Eva Lin, Aaron Lun, Scott Martin, Natalia Potocka, Dariusz Scigocki, Steffan Vartanian, Jan Vogel, Allison Vuong. gDR suite: an integrative solution for handling cell line drug response data [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 828.
Abstract 84: E2F8 tumor suppressive role in Non-Alcoholic Steatohepatitis
Authors: Ochoa-Rios Shaaron L. , Kent Lindsey N. , Leone Gustavo 
Published: September 2020

Abstract
Non-Alcoholic Steatohepatitis (NASH) is the aggressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is the accumulation of extra fat in liver cells, most commonly known as fatty liver. Some of the main conditions that distinguish NAFLD from NASH are severe liver inflammation, increased lipid accumulation and fibrosis. NASH is caused by an excess of fat in the liver which is linked to obesity and diet. Diets high in fats and sugars, typical of a Western diet, have been shown to induce NASH. Approximately 25% of NASH cases progress to Hepatocellular Carcinoma (HCC). Currently, there is no approved therapy for NASH and complications due to NASH is estimated to be the main reason for liver transplant. E2F8, a member of a family of transcription factors that are well known for regulating the cell cycle, has been shown to promote hepatic steatosis in a zebrafish model. Previous research from our lab has demonstrated that E2F8 has a tumor-suppressive role and loss of E2F8 leads to HCC in a carcinogen-induced model. Here, we use a mouse model to conditionally delete E2f8 in hepatocytes to sensitize to liver cancer and evaluate the effects of E2F8 on NASH development. Mice were fed with a low-fat diet (LFD), high-fat diet (HFD), choline-deficient high-fat diet (CDHFD) or Western diet (WD). Our results show that control mice in a LFD maintained a normal liver and E2F8 had a tumor-suppressive role for all diets including LF. However, a HFD induced NAFLD while a CDHFD and WD caused NASH by inflammation and fibrosis, respectively. We demonstrate that E2f8 ablation influences collagen deposition, lipid accumulation, and E-cadherin expression. Additionally, experimental mice fed a HFD had an incidence of less than 40% of spontaneous HCC, while experimental mice fed a WD had an incidence of more than 50% of spontaneous HCC; demonstrating that E2F8 tumor-suppressive role is essential to prevent progression to HCC in a NASH model. We hypothesize, that E2F8 has a role in the regulation of liver metabolism. Collectively, our study demonstrates that a WD and E2F8 hepatocyte deletion leads to an increase in lipid and collagen accumulation and HCC occurrence.
Citation Format: Shaaron L. Ochoa-Rios, Lindsey N. Kent, Gustavo Leone. E2F8 tumor suppressive role in Non-Alcoholic Steatohepatitis [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 84.
Abstract 896: Enhanced sensitivity detection of replication competent lentivirus by qPCR
Authors: Burke David , Drafahl Kristine , Fjeld Clark , Galderisi Chad , Spittle Cindy 
Published: September 2020

Abstract
Introduction: Chimeric antigen receptor T (CAR T) cells are an important emerging therapy for hematologic malignancies and are currently being investigated for other cancer types as well. CAR-T cells require a retrovirus or lentivirus to introduce the chimeric antigen receptor gene into the activated T cells. Safety measures are put in place by design to eliminate any chance to create replication competent virus. Multiple plasmids carrying specific components of the virus are used to reduce the chances of creating a replication competent lentivirus. Despite these measures, safety concerns have been posed by the FDA regarding use of a lentivirus for this treatment due to the potential for replication competent lentiviruses (RCL) to arise. FDA requires monitoring of both CAR T products as well as patients undergoing therapy. It has proven to be difficult to achieve acceptable detection sensitivity of the VSV-G sequence in a background of gDNA due to the high level of homology to many areas in gDNA.
Methods: We have developed a new rapid and sensitive qPCR assay targeting the vesicular stomatitis virus G glycoprotein (VSV-G), an envelope protein on lentiviral vectors. Incorporation of the envelope gene would be required to generate a replication competent virus. The intended use of the validated assay is to detect and monitor for RCL presence in human blood samples collected during clinical monitoring. A validated reference assay targeting RPPH1 will be used to quantify the amount of amplifiable genomic DNA in each extracted DNA sample. The size of the amplicons are 66 and 87 base pairs for VSV-G and RPPH1 respectively. The VSV-G assay test includes one positive and one negative control per assay run. The VSV-G positive control is composed of plasmid containing the VSV-G target sequence spiked into a background of VSV-G negative human gDNA. The negative control is composed of negative gDNA without VSV-G plasmid.
Results: Improved sensitivity without non-specific amplification was achieved by optimized primer and probe selection. Additionally sensitivity and specificity were enhanced by employing a step-down PCR protocol whereby the annealing and extension temperature is lowered in stepwise fashion over the first five cycles of PCR. Genomic DNA inputs up to 200ng per reaction showed high efficiency of amplification from 10 to 1e6 copies target sequence per reaction.
Conclusion: This assay will provide a rapid and sensitive method for safety monitoring of patients undergoing CAR-T therapy with therapeutic cells generated using lentiviral vectors.
Citation Format: David Burke, Kristine Drafahl, Clark Fjeld, Chad Galderisi, Cindy Spittle. Enhanced sensitivity detection of replication competent lentivirus by qPCR [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 896.
Abstract 909: The role of checkpoints in Rituximab-mediated NK cell activation
Authors: Wang Zhaoming , Weiner George J. 
Published: September 2020

Abstract
Purpose: Despite the remarkable clinical success of anti-CD20 monoclonal antibody (mAb) therapy, the mechanisms of action by which such mAb mediate their anti-tumor effects are not completely understood. This includes a need to better understand the role of various NK cell subtypes and checkpoint molecules in anti-CD20 mAb therapy.
Experimental procedures:
Raji B cell lymphoma cells and peripheral blood mononuclear cells (PBMCs) from normal donors (n=21) were co-cultured with rituximab (RTX) or trastuzumab as a control mAb for up to 15 days. Analysis included assessment of proliferation, remaining viable cells and phenotype of various cell types.
Results:
As expected, RTX was superior to trastuzumab in eliminating Raji cells. RTX also induced proliferation of NK cells and a shift of NK cells from a CD56dim to CD56bright population. Both NK cell proliferation and the increase in the CD56bright population occurred at day 5-7 when elimination of Raji cells was largely complete. Addback of additional Raji cells at day 5 delayed proliferation of NK cells and the shift from a CD56dim to CD56bright population suggesting this shift occurs once activation of the NK cell via Fcγ;;R is complete. Evaluation of checkpoint molecule expression by NK cells demonstrated RTX, in the presence of Raji target cells, upregulates NK cell expression of TIGIT and TIM3, but not PD1, CTLA-4, or LAG-3. This upregulation was maintained for the full duration of incubation (up to 15 days). The level of expression of TIGIT and TIM3 on NK cells induced by RTX was dose dependent and peaked at 1-5 ug/ml. NK cells induced by RTX to express TIGIT or TIM3 degranulated (CD107a), produced cytokines (IFNγ, TNFα) and expressed activation markers (CD69 and CD25) to a greater degree than did TIGIT or TIM3 negative NK cells. Anti- TIGIT mAb enhanced CD107a expression and TNFα production by RTX-activated NK cells.
Conclusion:
NK cells proliferate and shift from CD56dim to CD56bright population after being activated and eliminating RTX-coated target cells.
TIGIT and TIM3 are biomarkers for RTX-mediated NK cell activation.
Blocking TIGIT can enhance RTX-mediated NK cell degranulation and cytokine production.
Citation Format: Zhaoming Wang, George J. Weiner. The role of checkpoints in Rituximab-mediated NK cell activation [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 909.