bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6209: TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements
Authors: Flechner Marie , Loskutov Juergen , Pfohl Ulrike , Osman Katja , Regenbrecht Christian R. , Uhlig Katja , Wedeken Lena 
Published: June 2022

Abstract
Colorectal carcinomas (CRC) are one of the most common malignant tumors. Due to its heterogeneity and high probability to metastasize, the disease is often incurable and novel, improved therapies are needed. Enhanced, physiologically relevant in-vitro tumor models significantly increase the success rate in new drug development, reduce the number of animal experiments and result finally in better therapies for cancer patients. Furthermore, they have the potential to offer new approaches to personalized oncology. In recent years, 3D cell cultures were established as relevant preclinical cancer models, suitable for high-throughput-screening. However, their capacity to model and/or measure physiological processes can still be enhanced. In this project, we developed a tumor organoid-on-chip platform (TumOC) by combining most recent technological advances: We integrated patient-derived 3D cell cultures (organoids) from colorectal carcinomas and microsensor particles measuring oxygen concentration and therefore allowing assessment of cell vitality in real time in a microfluidic system. The resulting TumOC platform allows for defined exposition of cytostatic drugs including dynamic treatments. Measurements of cell vitality in real time enables analysis of not only the final effect of a drug treatment, but also the kinetics of drug response. At the same time, utilizing organoids allows for recapitulating tumor architecture and heterogeneity. Here we report the first proof of principle results generated with this system. We measured the cell vitality in real time over 72 hours during treatment with classic chemotherapeutics or targeted cancer drugs and compared the results to end-point measurements on the same organoids in a static system. In conclusion, our TumOC platform with its ability to recapitulate tumor heterogeneity in combination with dynamic treatments and real-time cell vitality assessment is an in-vitro tumor model closely recapitulating the physiological situation in a patient. TumOC provides an impressive opportunity to test and, consequently, predict the effectiveness of anti-cancer therapies. Therefore, this system is of interest not only for pre-clinical drug development but also for personal oncology.
Citation Format: Marie Flechner, Juergen Loskutov, Ulrike Pfohl, Katja Osman, Christian R. Regenbrecht, Katja Uhlig, Lena Wedeken. TumOC: A tumor organoid-on-chip platform for real-time cell vitality measurements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6209.
Abstract 6215: The immune cell atlas of human neuroblastoma
Authors: Verhoeven Bronte Manouk , Mei Shenglin , Olsen Thale K. , Gustafsson Karin K. , Valind Anders , Lindström Axel , Nord David G. , Fard Shahrzad S. , Hagerling Catharina , Kharchenko Peter V. , Kogner Per , Johnsen John I. , Baryawno Ninib 
Published: June 2022

Abstract
Our current knowledge of the different immune cells in neuroblastoma is based on in vitro and in vivo studies mainly focusing on a single cell type. Different studies have conveyed conflicting results and despite the use of anti-GD2 immunotherapy in the clinic, a comprehensive immune cell overview at the single-cell level is still missing and understanding the complete composition of immune cells neuroblastoma will be crucial for the development of novel immunotherapeutics against the disease. In this study, we performed single-cell RNA-sequencing on human neuroblastoma coupled with multiplex immunohistochemistry and survival analysis to provide a complete cellular and molecular immune cell landscape of human neuroblastoma. Further, we contrasted the neuroblastoma data with single-cell RNA-sequencing data from normal fetal adrenal gland to characterize cell-state changes from normal tissue to neuroblastoma. Our analysis revealed 27 immune cell subtypes including distinct subpopulations of myeloid, NK, B and T cells that were associated with a survival benefit. Multiple subtypes of B and NK cells, not seen in neuroblastoma before, were identified. We propose the presence of tertiary lymphoid structures and showed that Active NK cells correlated with improved survival. In contrast to adult cancers, we detected no difference in cytotoxicity and exhaustion score for cytotoxic T cells, nor Treg activity. However, we demonstrated an increase in inflammatory monocyte signature score from normal to tumor derived myeloid cells. Finally, we performed receptor-ligand interaction analysis between tumor, stroma and immune cells, where we highlight several interactions that we suggest for future studies of how to exploit immune cells as a therapeutic option in neuroblastoma. Our findings significantly broaden the understanding of the immune composition in neuroblastoma and provides a resource for the development of novel immunotherapeutics.
Citation Format: Bronte Manouk Verhoeven, Shenglin Mei, Thale K. Olsen, Karin K. Gustafsson, Anders Valind, Axel Lindström, David G. Nord, Shahrzad S. Fard, Catharina Hagerling, Peter V. Kharchenko, Per Kogner, John I. Johnsen, Ninib Baryawno. The immune cell atlas of human neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6215.
Abstract 6242: Association of prostate cancer risk variants with gene expression in prostate stroma
Authors: Ma Chaoran , Zhou Yinglu , Plym Anna , Fanelli Giuseppe Nicolò , Loda Massimo , Mucci Lorelei , Tyekucheva Svitlana , Penney Kathryn 
Published: June 2022

Abstract
Background: Prostate cancer genome-wide association studies have identified &gt;260 germline risk variants which provide strong risk prediction for prostate cancer. Functional interpretation and biological mechanisms of these risk variants are not always clear. Many of the prostate cancer risk variants are expression quantitative trait loci (eQTLs), but studies have mostly been performed in tumor or epithelial-enriched normal prostate tissue. Given emerging evidence supporting that stroma contributes to the carcinogenic process, we examined the associations of prostate cancer risk variants with the expression of genes in prostate stroma.
Methods: We generated mRNA expression data for 13,577 genes with the Illumina TruSeq RNA Exome library preparation kit from stromal samples in specimens from participants of the Health Professionals Follow-up Study and Physicians’ Health Study cohorts. Specifically, we profiled 172 stromal samples adjacent to tumor and 86 paired stroma distant from tumor. We included 264 prostate cancer risk variants genotyped data and imputed using a common reference panel (1,000 Genomes Phase I release). We performed cis- (≤1 Mb from the SNP (single nucleotide polymorphism) to the gene) and trans- eQTL analyses using a linear regression model in the R package Matrix eQTL.
Results: Thirty-four SNPs were significantly (P &lt; 0.01) associated with cis-expression of 41 nearby genes in prostate stroma adjacent to tumor, and 41 SNPs with 52 nearby genes for stroma distant from tumor. Genome-wide, 86 SNPs were significantly (FDR &lt; 0.10) associated with the expression of 126 genes in stroma adjacent to tumor, and 64 SNPs with 291 genes for stroma distant from tumor.
Conclusions: This is the first study to comprehensively examine associations between prostate cancer risk variants and gene expression in prostate stroma. We observed some previous reported associations but also novel associations which may suggest genes that contribute to prostate cancer risk within the stromal tissue. Identifications of eQTLs within prostate stroma may suggest potential mechanisms in specific cell types for their effect on disease.
Citation Format: Chaoran Ma, Yinglu Zhou, Anna Plym, Giuseppe Nicolò Fanelli, Massimo Loda, Lorelei Mucci, Svitlana Tyekucheva, Kathryn Penney. Association of prostate cancer risk variants with gene expression in prostate stroma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6242.
Abstract 6249: PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc
- (SLC7A11)
Authors: Saini Krishan K. , Chaturvedi Priyank , Verma Ayushi , Nengroo Mushtaq A. , Sinha Abhipsa , Singh Akhilesh , Meena Sanjeev , Khan Muqtada A. , Singh Manish P. , Datta Dipak 
Published: June 2022

Abstract
Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis is induced in cancer cells by inhibition of lipid peroxide quencher GPx4. System xc - imports cystine into cytosol for the biosynthesis of glutathione. Tumor cells that are resistant to chemotherapeutic drugs called ‘drug tolerant’ or ‘Persister’ cells which have distinct vulnerability towards iron mediated cell death or ferroptosis. Unfolded Protein Response (UPR) plays critical role for cancer cells to become drug tolerant. Tweaking the balance of UPR to make drug tolerant cells susceptible to Ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER-stress in ferroptosis, we investigated the status of UPR following treatment of potent ferroptosis inducer RSL3 (Ras Selective Lethal) in colon cancer cells. We observed an overall up-regulation of UPR activators (ATF6, IRE1α and PERK) and their downstream effectors along with a marked overexpression of cystine-glutamate transporter (System xc -). To further delineate the contribution of particular UPR arm in modulating System xc - expression and subsequent ferroptosis, we made stable knock down cells of each UPR arm and discovered that PERK is selective and critical in inducing ferroptosis in colon cancer cells. Loss of PERK function not only promotes ferroptosis via increasing lipid peroxidation but also limits in vivo tumor growth in colon xenograft model. Further, we find that low PERK expression is associated with higher patient survival as per TCGA COLON CANCER (COAD) database. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and genetic silencing of PERK sensitizes colon cancer cells to selective Ferroptotic cell death. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics that can sensitize apoptosis resistant cancer cells towards Ferroptotic cell death.
Citation Format: Krishan K. Saini, Priyank Chaturvedi, Ayushi Verma, Mushtaq A. Nengroo, Abhipsa Sinha, Akhilesh Singh, Sanjeev Meena, Muqtada A. Khan, Manish P. Singh, Dipak Datta. PERK arm of UPR selectively regulates ferroptosis in colon cancer cells by modulating the expression of system xc - (SLC7A11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6249.
Abstract 6329: Using low-resolution, low-cost histopathology images to predict esophageal squamous cell carcinoma via deep learning
Authors: Alam Mansoor , Amin Ibrar , Sajjad Ayesha , Zamir Hina , Zaheer Saad , Khattak Maria T. , Muhammad Iqbal , Khan Faisal F. 
Published: June 2022

Abstract
Like many cancers, esophageal squamous cell carcinoma, has a substantially better survival rate if detected in early stages, making early detection a critical element in successful treatment. On the other hand, deep learning tools that employ high-resolution whole slide images and therefore substantially greater compute power and are not easily accessible in low-resource settings. In this study we train and test deep learning models using low-resolution and low-cost digital histopathology images acquired using a 5-megapixel Leica ICC50 camera mounted on a Leica DM500 binocular microscope, at two different magnification levels, Under IRB approvals, we acquired a total of 64 Hematoxylin and Eosin (H&E) stained tissue slides of biopsies taken from patient presenting at Rehman Medical Institute from 2016 to 2020 that were anonymized. A total of 2370 images were captured at two different magnification levels, i.e. 10x and 40x, and were labelled with four classes by at least one expert pathologist (677 well differentiated, 1066 moderately differentiated, 152 poor differentiated and 475 normal) to develop the ESCC image dataset. Preprocessing was performed to clean the dataset, generate patches and resize the images. Deep learning models were trained on the ESCC image dataset for feature extractions. This was followed by machine learning classifier for the diagnosis of ESCC. Deep learning models that were used in this study are Resnet50, VGG16, VGG19, and Inception_Resnet_V2 with Logistic Regression (LR) used as classifier. An ensemble model which stacks up the Inception and Resnet. This model preformed with the highest accuracy at 96% with Precision, Recall, and f1 score values at 96%, 96%, and 96%, respectively. This study reports 1) a local ESCC image repository for research purposes, 2) an ensemble ML/DL model that predicts ESCC with 96% accuracy and 3) also a computer-aided diagnosis (CAD) system for ESCC with a user-interface which will assist histopathologists in diagnosing ESCC with higher speed, efficiency and accuracy.
Citation Format: Mansoor Alam, Ibrar Amin, Ayesha Sajjad, Hina Zamir, Saad Zaheer, Maria T. Khattak, Iqbal Muhammad, Faisal F. Khan. Using low-resolution, low-cost histopathology images to predict esophageal squamous cell carcinoma via deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6329.
Abstract 634: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks
Authors: Schenck Ryan O. , Jakobsen Niels A. , Turati Virginia , Shibata Darryl , Vyas Paresh , Leedham Simon , Anderson Alexander R. 
Published: June 2022

Abstract
Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning method that allows us to diagnose CHIP without DNA sequencing. This method allows for the identification of patients who may have CH driven by structural variants such as copy number variants. We use this method to examine a cohort of 656 normal patients without evidence of CHIP based on mutation showing that we identify the presence of CHIP roughly a third of these patients. Clonal hematopoiesis is driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates for stim cell numbers differing by orders of magnitude.Finally, using a mechanistic model of clonal hematopoeisis and fCpGs we examine the temporal ability to diagnose CHIP given single and multiple expanding clones. We illustrate that multiple driver mutations within the same clone leads to an increased detection ability with an increased expansion rate (i.e. fitness) and in cases where drivers are found in separate, competing clones.
Citation Format: Ryan O. Schenck, Niels A. Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 634.
Abstract 6378: The cross-talk between FTH1 and PYCR1 drives pancreatic cancer progression
Authors: Park Ji Min , Chiu Ching-Feng 
Published: June 2022

Abstract
This study is designed to explore the effect of FTH1 on PDAC human pancreatic cancer cells, proline metabolism, and their crosstalk. Considering the high prevalence of pancreatic cancer with an absence of efficient therapy against PDAC, the present study may provide experimental evidence in support of the novel role of FTH1 in proline metabolism and suggest FTH1 as a potential target for PDAC patients. We further focus on the underlying molecular mechanism of how FTH1 cross-talks with PYCR1 and leads KRAS-mutated PDAC cell growth, investigating whether miRNAs regulation involves in FTH1 mediating PYCR1 expression. Taken together, our study provides a novel function of FTH1 and its cross-talk with PYCR1 may be a novel target for pancreatic cancer research and thus these findings will help us to find metabolite-based therapeutic strategies to improve KRAS-mutated PDAC.
Citation Format: Ji Min Park, Ching-Feng Chiu. The cross-talk between FTH1 and PYCR1 drives pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6378.
Abstract 6401: PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state
Authors: WATANABE RYUTA , MAEKAWA MASASHI , KIYOI TAKASHI , KURATA MIE , MIURA NORIYOSHI , KIKUGAWA TADAHIKO , HIGASHIYAMA SHIGEKI , SAIKA TAKASHI 
Published: June 2022

Abstract
Introduction & objectives: Prostate-specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration-resistant prostate cancers. Recently, 68Ga-PSMA Positron Emission Tomography/Computed Tomography (PET/CT) has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear.
Materials & methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium derived from a PSMA-positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the conditioned medium. We assessed angiogenic activities by treatment of HUVECs with LNCaP-derived conditioned medium using a tube formation assay that mimics angiogenesis. Results: Immunohistochemical positivity of PSMA and CD31, a marker of endothelial cells, and PSMA-expressing tumor endothelial cells were observed in four of 33 prostate cancer patients (12.1%). We also found that the 10,000 × g pellet fraction of the LNCaP-derived conditioned medium containing PSMA-positive membranes, including microvesicles, transformed HUVECs from “PSMA-negative” to “PSMA-positive.” Mass spectrometry revealed that the fraction contained an important growth factor. Furthermore, treating HUVECs with the 10,000 × g pellet fraction of the LNCaP-derived conditioned medium significantly promoted tube formation, mimicking angiogenesis in a PSMA-dependent manner.
Conclusions: Our findings revealed the existence of PSMA-positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues. The endocytic process of the PSMA-positive microvesicles in normal endothelial cells may be an attractive target to develop novel anti-angiogenic drugs, which could inhibit transformation of normal endothelial cells to tumor endothelial cells (Watanabe et al., The Prostate. 2021. in press).
Citation Format: RYUTA WATANABE, MASASHI MAEKAWA, TAKASHI KIYOI, MIE KURATA, NORIYOSHI MIURA, TADAHIKO KIKUGAWA, SHIGEKI HIGASHIYAMA, TAKASHI SAIKA. PSMA-positive membranes secreted from prostate cancer cells have potency to transform vascular endothelial cells into an angiogenic state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6401.