bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5408: AI powered-platform to predict gene modifications from prostate and breast cancer whole slide images
Authors: Huang Wei , Jain Parag , Xie Chensu , Muhammad Hassan , Basu Hirak , Wilding George , Roy Rajat 
Published: April 2023

Abstract
There is little published evidence of predicting cancer genotypes directly from tissue histology, especially for breast and prostate cancers. Artificial intelligence (AI) enables discriminating and extracting morphological features reflective of the underlying genomic alterations at visual and subvisual levels. We have built a morphology-based and AI-powered platform for cancer genotyping, risk stratification and outcome prediction that addresses the needs for treatment decision-making in a cost effective and timely fashion. A cohort of 390 prostate and 742 invasive breast cancer patients with known molecular status of key genes, such as TP53, PIK3CA, MYC, ERBB2, TMPRSS2-ERG and PTEN from The Cancer Genome Atlas were included in this study. Hematoxylin and eosin (H&E) stained whole slide images (WSI) of the cancer tissue sections were available at 20x or 40x. The WSI from the two cancer cohorts were split 2:1 into a training and test dataset, respectively. Our platform involved two different deep Convolutional Neural Network (DCNN) architectures. The platform first divided each WSI into multiple tiles. Each tile was then analyzed using a DCNN that graded the tile and generated a high dimensional vector to provide a mathematical representation of the morphology. The combination of high dimensional vectors across the WSI was then fed into a second DCNN that generated a morphological score, which predicted whether the gene under consideration was wild type or modified. Our platform has achieved 70 - 80% accuracy as defined by the Area under the Curve for the receiver operating characteristics curves for the genetic markers on the test cohorts (Table 1). Our platform can predict genotypes/molecular alterations directly from H&E stained WSI with high accuracy. This technology presents a novel, practical and cost-effective approach for cancer molecular classification and risk stratification, enabling timely and optimal treatment decision-making for positive clinical outcomes.
Genotype Prediction for Breast Cancer (BrCa) and Prostate Cancer (PCa) from WSI Cohort Molecular Biomarker Training Dataset (n) Test Dataset (n) Test ROC AUC Score (%) Gene Modification/Loss Intact/Wild type Gene Modification/Loss Intact/Wild type BrCa TP53 196 302 96 149 80 PIK3CA 153 344 75 170 74 MYC 68 414 33 204 77 ERBB2 66 416 32 205 78 PCa TMPRSS2-ERG 104 157 51 78 70 PTEN 57 201 28 99 73
Citation Format: Wei Huang, Parag Jain, Chensu Xie, Hassan Muhammad, Hirak Basu, George Wilding, Rajat Roy. AI powered-platform to predict gene modifications from prostate and breast cancer whole slide images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5408.
Abstract 5410: Predictive biomarker discovery method to bridge the gap between preclinical disease model dose-response and clinical trials
Authors: Futorian David , Fischman Oren , Arad Gali , Simchi Nitzan , Erez Omri , Seger Eran , Groen Rozanne , Pevzner Kirill 
Published: April 2023

Abstract
The translational gap of drug and biomarker discovery remains one of the biggest challenges in the pharmaceutical industry. On one hand high throughput screening and omics methods facilitate the generation of in-vitro and in-vivo data of dose-response for a particular drug or combinations. On the other hand, clinical omics techniques allow for the creation of large scale treatment-naive clinical datasets, with the TCGA and CPTAC as prominent examples. However, the question of which disease model best represents the response/resistance mechanisms of an oncology patient remains challenging.
In this study we present a machine learning (ML) based computational technique for integrating omics from preclinical dose-response studies with clinical treatment-naive samples to create putative predictive biomarkers, and exemplify its application 2 case studies - PARP or AKT inhibitors.
We utilize the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) as a resource for in-vitro dose response data for PARPi and AKTi, coupled with multi-omic molecular data. We utilize the treatment naive molecular characterization from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data of Breast cancer patients. Multi-omic analysis of these datasets derived 2 putative predictive biomarkers for PARPi and AKTi. The multi-omic analysis resembles the data availability at the critical drug development stage of transition from preclinical response models to a clinical trial. These biomarkers are tested on a validation dataset obtained from the iSPY adaptive clinical trial and achieve superior results compared to the original enrolment biomarkers and even the retrospectively derived biomarkers.
This study presents a novel computational approach to bridge the gap between preclinical dose-response and clinical datasets and suggests an efficient way to discover predictive biomarkers based on data accessible in a preclinical setting.
Citation Format: David Futorian, Oren Fischman, Gali Arad, Nitzan Simchi, Omri Erez, Eran Seger, Rozanne Groen, Kirill Pevzner. Predictive biomarker discovery method to bridge the gap between preclinical disease model dose-response and clinical trials. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5410.
Abstract 5791: Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis
Authors: Manupati Kanakaraju , Hao Mingang , Haas Michael , Yeo Syn Kok , Guan Jun-Lin 
Published: April 2023

Abstract
Autophagy is a self-degradation process, it is essential for growth of heterogenous of breast cancer cells. Breast tumor heterogeneity majorly comprises bulk cancer cells & cancer stem cells (CSCs). Targeting either CSCs or cancer cells could lead to interconversion between these cells due to EMT/MET transitions. Therefore, it is important to identify a common molecular targets & its mechanism of regulation in these populations for improvement of breast cancer therapy. Here, we utilized a PCR based screen & identified NUMA1 downregulation in FIP200 KO (autophagy gene) cells of three major breast cancer subtypes, FF99 (luminal), N418 (Her2+) & BF3M (basal). Further, NUMA1 KO in these cells reduced tumor formation & CSCs indicating the role of NUMA1 on regulation of CSCs. Therefore, we sorted breast CSCs, ALDH+ and CD29hi CD61+ from WT & NUMA1 KO cells, tail-vein injected nude mice depicted reduced metastatic potential with NUMA1 KO than WT CSCs. Mechanistically, NUMA1 regulation by PIM1 kinase was observed in CSCs but not in bulk cancer cells. Cell viability assays revealed that combination treatment of autophagy & PIM1 inhibitor showed higher efficacy against cancer cells of three breast cancer subtypes than individual treatments alone. Finally, the combination treatment of autophagy inhibitor, Lys05 & PIM1 inhibitor, SMI-4a reduced tumor formation & metastasis of breast cancer. Human tissue microarray results depicted high expression of NUMA1 & PIM1 in different breast cancer subtypes than non- tumor tissues. Our study demonstrated that inhibition of autophagy & PIM1 in bulk cancer cells & CSCs showed attenuation of tumor formation & metastasis, suggesting this combination treatment serves as an important therapeutic approach for treating breast cancer.
Citation Format: Kanakaraju Manupati, Mingang Hao, Michael Haas, Syn Kok Yeo, Jun-Lin Guan. Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5791.
Abstract 5794: Targeting CD133+/CD90+ liver cancer stem cells by piperlongumine: A novel strategy for liver cancer treatment
Authors: Abdelaziz Basma A. , Sadek Omayma M. , Sultan Ahmed S. 
Published: April 2023

Abstract
Liver cancer is an aggressive malignant disease. It’s the most common cancer worldwide and the leading cause of cancer death. Because of the atypical early symptoms of liver cancer, the majority of liver cancer patients are diagnosed with advanced-cancer stage, decreasing the chance of resection and resulting in a poor survival rate. Liver cancer stem cells (LCSCs) are a small subpopulation inside the tumor bulk, characterized by the maintenance of self-renewal and pluripotency. Thus, LCSCs are responsible for cancer initiation, metastasis, relapse, and chemoresistance. Elucidating LCSC characteristics and disclosing their regulatory mechanism might facilitate the development of prognostic, diagnostic, and therapeutic approaches to improve the clinical management of liver cancer. Piperlongumine (PL) an active biological pyridine alkaloid has anti-angiogenic, anti-diabetic, and anti-bacterial activities. The present study aimed to isolate highly tumorigenic and aggressive subpopulation of LCSCs (CD133+/CD90+) from primary tumors and different cell lines and investigate the effect of (PL), a novel targeting therapy, on LCSCs proliferation. The isolated LCSCs were treated with different concentrations of PL and its effect was examined by cell viability, cell morphological changes, western blot, caspase-3 activity, apoptotic induction, and clonogenic formation. By using Immunocytochemistry (ICC) analysis, the localization of nuclear and cytoplasmic Aldehyde dehydrogenase (ALDH6A1) was detected. PL inhibited the viability of CD133+/CD90+LCSC-sub-popupation and caused morphological changes after 48 hours while enhancing the pre-apoptotic signals and caspase-3 activity. In addition, PL decreased the colonies’ formation ability compared to control group. Furthermore, PL suppressed the protein expression levels of ALDH6A1, Notch-1, β-catenin, ERK1/2, and Cyclin-D1 in the dose and time-dependent manners. Besides, PL decreased the localization and intensity of nuclear and cytoplasmic ALDH6A1 compared to the control group, indicating that PL decreased the proliferation and stemness markers of LCSCs. Overall, Piperlongumine as a novel targeting therapy has an important role in targeting CD133+/CD90+ LCSCs sub-population proliferation.
Citation Format: Basma A. Abdelaziz, Omayma M. Sadek, Ahmed S. Sultan. Targeting CD133+/CD90+ liver cancer stem cells by piperlongumine: A novel strategy for liver cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5794.
Abstract 5816: Tensin1 tension sensor reveals novel features associated with actomyosin, focal adhesion dynamics, and mechanosensitivity
Authors: Jang Yoon-Kwan , Suh Jung-Soo , Choi Gyuho , Ahn Sanghyun , Han Ki Seok , Kim EunHye , Lee Yerim , Hu Xiaoqi , Hwang Eunbae , Kim Tae-Jin 
Published: April 2023

Abstract
Cellular responses to mechanical stimuli play an imperative role in the regulation of physiological and pathological functions. Unlike other integrin-mediated adhesion proteins, the force transmission mechanism of tensin1 is not well understood. In this study, we describe the development and visualization of a tensin1 tension sensor. A signal from this sensor indicates that tensin1 is under greater tension at peripheral adhesions than at central adhesions, and that it is controlled by actomyosin in fibroblasts. In a bidirectional manner, tension in tensin1 is regulated by focal adhesion kinase (FAK) activity. Our findings demonstrate that tensin1 is capable of sensing the extracellular matrix through alterations in the tension it receives from the extracellular matrix. Furthermore, tensin1 depletion increases the tension of talin1, but the absence of talin1 decreases the tension applied to tensin1. These results indicate that tensin1 is complementary and dependent on the tension received by talin1. Overall, our data, together with the prognosis following tensin1 expression in colorectal and urothelial cancer, elucidate the tension-receiving function of tensin1 and highlight the necessity of tensin1-mediated mechanotransduction studies.
Citation Format: Yoon-Kwan Jang, Jung-Soo Suh, Gyuho Choi, Sanghyun Ahn, Ki Seok Han, EunHye Kim, Yerim Lee, Xiaoqi Hu, Eunbae Hwang, Tae-Jin Kim. Tensin1 tension sensor reveals novel features associated with actomyosin, focal adhesion dynamics, and mechanosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5816.
Abstract 593: Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity
Authors: Liang Jiabei , Gao Xiao , Zhang Cong , Zhao Hui , Peng Hao , Hao Feng , Ning Jinying , Wu Guojin 
Published: April 2023

Abstract
T cell immunoreceptor with Ig and ITIM domains (TIGIT) and poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG) are two immune checkpoint receptors. They compete with CD226 for binding to CD155 or CD112 and suppress the activity of NK cells and T cells. Here we developed a bispecific antibody KA-1874 targeting TIGIT with an anti-PVRIG scFv fused to the C-terminus. KA-1874 is a fully human IgG4 with high binding affinity to TIGIT (KD=0.08nM) and PVRIG (KD=0.17nM). KA-1874 blocks both bindings of PVRIG-mFc to PVRL2 and TIGIT-mFc to CD155. In cell-based luciferase reporter assays, KA-1874 blocks PVRIG and TIGIT-mediated inhibitory signaling and enhances CD3 signaling with EC50 of 1.1nM and 1.4nM respectively, while COM701 against PVRIG and EOS488 against TIGIT both with EC50 above 2nM. In a CMV recall assay, PBMC increases INF-γ secretion when cultured with KA-1874, suggesting KA-1874 enhances primary T cell function. Immunodeficient mice humanized with PBMC are transplanted with A374 tumor cells. Co-injection of KA-1874 and pembrolizumab, which against PD-1, suppress established tumor growth. In comparison, KA-1874 or pembrolizumab alone fails to inhibit tumor growth. The above results indicate KA-1874 is an excellent candidate therapeutical antibody for cancer immunotherapy.
Citation Format: Jiabei Liang, Xiao Gao, Cong Zhang, Hui Zhao, Hao Peng, Feng Hao, Jinying Ning, Guojin Wu. Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 593.
Abstract 5940: Enhanced mast cell abundance is associated with the enrichment of CCR2+ cytotoxic T cells and favorable prognosis in lung adenocarcinoma
Authors: Fan Fan , Zhang Xiaoming , Chen Haiquan 
Published: April 2023

Abstract
Mast cells constitute indispensably immunoregulatory sentinel cells in tumor microenvironment, however, their functions are poorly characterized in lung adenocarcinoma (LUAD). Here, we performed flow cytometry and single-cell RNA sequencing to comprehensively characterize LUAD infiltrating MCs. MCs exhibited remarkably functional heterogeneity and were enriched in ground-glass opacity featured LUAD (gLUAD). The MCs in gLUAD exhibited proinflammatory and chemotactic properties while the MCs in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. MCs were an important source of CCL2 that correlated with the recruitment of CCR2+ cytotoxic T lymphocytes (CTLs), which represent a specific subcluster of pre-exhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of MCs-CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of MCs in LUAD and their potential crosstalk with CTLs, suggesting that targeting MCs may be a novel immunotherapeutic strategy for LUAD.
Citation Format: Fan Fan, Xiaoming Zhang, Haiquan Chen. Enhanced mast cell abundance is associated with the enrichment of CCR2+ cytotoxic T cells and favorable prognosis in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5940.
Abstract 5957: Chemotherapy-induced extracellular matrix remodeling in HGSOC
Authors: Kotantaki Panoraia , Laforêts Florian , Maniati Eleni , Berlato Chiara , Malliouri Anna , Devlin Michael John , Malacrida Beatrice , Elorbany Samar , Manchanda Ranjit , Balkwill Frances R. 
Published: April 2023

Abstract
In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic models of HGSOC, one that displays excellent response to carboplatin/paclitaxel (60577) and one that is resistant to treatment (HGS2)1. Using immunohistochemistry, we stained omental tumors from both models for the ECM components fibronectin (FN1), collagen 1A1 (COL1A1) and versican (VCAN), also using Masson’s Trichrome to stain for collagen. We analyzed their abundance, textural features (Haralick features) and structure with the image analysis softwares, QuPath and TWOMBLI respectively. A compilation of 44 ECM metrics, which we named the “structure index”, correlated with response to chemotherapy, as measured by reduction in omental tumor weight. In parallel, we performed RNAseq on the omental tumors, identifying clusters of genes that change over time with chemotherapy treatment of the responsive model 60577, while the chemoresistant model HGS2 displayed limited alteration of gene expression. We integrated RNAseq and ECM structure and texture data, and showed the structure index was correlated with 144 core matrisome genes. To identify potential therapeutic targets, we then focused our study on genes that remained highly expressed in resistant tumors post chemotherapy, but were originally low or decreased with treatment in the sensitive tumors. Members of the LOX and P4HA family were found amongst these genes. We confirmed by immunohistochemical analysis that expression of LOX, LOXL2, P4HA1 and P4HA2 was downregulated by chemotherapy in the 60577 chemo-sensitive tumors while their levels remained relatively unaffected in the resistant HGS2 tumors. This study refines our understanding of the mechanisms of microenvironmental chemoresistance in HGSOC, highlighting putative therapeutic targets to increase the efficacy of platinum-based chemotherapy in ovarian cancer.
1 Maniati, E. et al. Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep 30, 525-540.e527, doi:10.1016/j.celrep.2019.12.034 (2020).
Citation Format: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill. Chemotherapy-induced extracellular matrix remodeling in HGSOC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5957.
Abstract 5958: Analysis of MDSCs as a diagnostic and therapeutic target for gastric cancer
Authors: Yamauchi Suguru , Iwasawa Takumi , Ito Tomoaki , Brock Malcom V. , Fukunaga Tetsu , Orita Hajime , Kato Kazunori 
Published: April 2023

Abstract
Background: Gastric cancer (GC) is the second most common cancer in Japan in terms of incidence and the third most common in terms of deaths. The onset and progression of cancer are generally suppressed by the action of immune cells, which is an inflammatory response. MDSCs are thought to promote cancer progression and invasion by suppressing the function of immune cells, making them potential therapeutic and diagnostic targets. We measured MDSCs in GC patients and observed more monocyte-derived MDSCs in peripheral blood in advanced GC than in early GC. However, granulocyte-derived MDSCs showed no difference in GC progression when markers for classical MDSCs were used. We considered that granulocyte-derived MDSCs were much more abundant than monocyte-derived MDSCs in peripheral blood and were involved in cancer progression. We hypothesized that we had a new granulocyte-derived marker for advanced GC that did not show differences in classical markers, but may have different functions, and aimed to identify a novel subset that may be a therapeutic and diagnostic target.
Method: For GC patients, we used heparin blood samples provided by patients who consented to Juntendo University. We analyzed the expression of various cell surface proteins against populations of CD33high, CD66bhigh, and HLA-DRlow as classical markers of MDSCs derived from granulocytes of GC patients using FACS (Melody). MDSCs were isolated by a cell sorter and used for experiments such as RNA-Seq. Novel markers and involved cytokines were quantified in plasma components by cytometric bead array.
Result: The chemokine receptors CCR2, CCR5, CXCR4, and CXCR5 were highly expressed in MDSCs of advanced GC patients. The ability to suppress T-cell activation was also found to be stronger in MDSCs with advanced GC. In addition, IL-10 produced by MDSCs was also more abundant in the plasma of patients with advanced GC, as well as chemokines according to chemokine receptors.
Conclusion: The high expression of chemokine receptors on MDSCs in advanced GC may indicate that chemokines produced at the cancer site facilitate the migration of MDSCs. These novel subsets of MDSCs found in advanced GC suggest that they may be new therapeutic targets.
Citation Format: Suguru Yamauchi, Takumi Iwasawa, Tomoaki Ito, Malcom V. Brock, Tetsu Fukunaga, Hajime Orita, Kazunori Kato. Analysis of MDSCs as a diagnostic and therapeutic target for gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5958.