bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 101: Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma
Authors: Nakano Yusuke , Kitagawa Akihiro , Hashimoto Masahiro , Abe Tadashi , Hisamatsu Yuichi , Toshima Takeo , Yonemura Yusuke , Masuda Takaaki , Inoue Akira , Eguchi Hidetoshi , Doki Yuichiro , Mimori Koshi 
Published: April 2023

Abstract
Background & Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC.
Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material.
Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly.
Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.
Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [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 101.
Abstract 1041: Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies
Authors: Zhang Qu , Houseman Andy , Yuan Sammy , Harding Joe , Zhou Helen , Feng Bin , Washburn Michael L. 
Published: April 2023

Abstract
Background: Previous studies have shown that ctDNA MR defined by 50% reduction of ctDNA levels after immune checkpoint inhibitor (ICI) treatment is significantly associated with improved survival. However, discordance between MR and radiologic response was observed, hindering the potential use of MR as a surrogate endpoint. We report a meta-analysis of MR rate (MRR) and radiologic objective response rate (ORR) with ICI intervention. The relationship between MRR difference and hazard ratio of survival has also been assessed using two independent approaches.
Methods: MRR, ORR and overall survival (OS) data were compiled from 9 study arms where metastatic solid tumors were treated by ICI. Weighted least squares linear regression method was used to study the relationship between MRR and ORR. Patient level MR and OS data were downloaded from the original report (Set 1) or by digitizing Kaplan-Meier plot using Guyot algorithm (Set 2). The correlation of MRR difference between two arms and hazard ratio for OS was assessed using samples generated by bootstrapping with replacement. Similarly, a parametric simulation by fitting a piecewise exponential curve was also performed to confirm the above finding.
Results: A total of 958 patients were eligible for this analysis. A significant correlation between MRR and ORR was identified across 9 study arms after adjusting sample size (Adjusted R2=0.91, P&lt;0.0001). Under a hypothetical scenario of two randomized study arms, an inverse correlation between MRR difference and hazard ratio was observed using both bootstrapping and parametric simulation approaches across different conditions. A stronger negative trend was found in Set 1 compared with Set 2, where MR showed a better association with OS in the former (HR=0.27 versus HR=0.41)
Conclusions: This meta-analysis showed for the first time that ctDNA molecular response rate may be a surrogate for radiologic objective response rate in ICI and could enable early decision making. Since most of the data analyzed here is from patients with non-small cell lung cancer, the extrapolation of these findings to other tumor types needs further validation.
Citation Format: Qu Zhang, Andy Houseman, Sammy Yuan, Joe Harding, Helen Zhou, Bin Feng, Michael L. Washburn. Circulating tumor (ct)DNA molecular response rate (MRR) as a potential surrogate for radiologic objective response rate (ORR): A meta-analysis of immunotherapy studies [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 1041.
Abstract 1050: Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum
Authors: Vymetalkova Veronika , Siskova Anna , Vodicka Pavel , Jungwirth Jiri , Bruha Jan 
Published: April 2023

Abstract
Colorectal cancer (CRC) is a worldwide health burden with nearly 1.2 million new cases expected each year globally. When CRC is identified early, there is a five-year survival rate of about 90% but it drops to near 12% once there are distant metastases. Early detection of colorectal adenoma is warranted as it represents the precancerous lesion of CRC. The removal of colorectal adenoma can effectively prevent the subsequent development of CRC. The only preventive strategy is to undergo appropriate endoscopic surveillance and early detection of adenoma or CRC In this study, we focused on the transcriptome profile in patients with colon adenomas, incident colorectal cancer (CRC) and in the healthy population. MRNA transcripts were, in addition to tissues, isolated from the plasma and stool. Plasma and stool analyses should reveal potential mRNA signatures capable of non-invasive determination of the average individual risk of predisposition to adenomas or CRCs. Relevant plasma/stool mRNA will be further validated in another group of individuals with similar clinical characteristics and analyzed in relation to diet and lifestyle factors. For patients with CRC, plasma and stool specimens are collected repeatedly to reveal whether the transcripts identified by us will decrease or diminish in CRC patients after successful surgery. We hypothesize that altered mRNA signatures in plasma and stool may serve as a robust, powerful non-invasive and sufficiently sensitive tool in the early detection of adenomas or CRCs. The bioinformatic analysis is currently running and the results will be presented during the meeting. The long-term significance of the project lays on improvement of the therapy efficacy in colon cancer patients. Supported by grant GACR 22-05942S and by the Ministry of Health of the Czech Republic, grant nr. NU22J-03-00033.
Citation Format: Veronika Vymetalkova, Anna Siskova, Pavel Vodicka, Jiri Jungwirth, Jan Bruha. Non-invasive detection of circulating mRNA markers in diseases of the colon and rectum [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 1050.
Abstract 1077: Porcupine inhibition enhances enzalutamide efficacy in drug resistant prostate cancer
Authors: Jones Katelyn Makayla , Liu Xiaoqi 
Published: April 2023

Abstract
Androgen receptor (AR) signaling continues to participate as a vital component of castration-resistant prostate cancer (CRPC). Subsequently, this has led to the development of Androgen Signaling Inhibitors (ASI), specifically Enzalutamide (ENZ), which is a direct inhibitor of AR, to clinically manage CRPC. Inevitably, ENZ treatment only provides improvement for approximately two months before advancing to an incurable form, ENZ-resistant CRPC. With PCa ranking as the second leading cause of cancer-related deaths in USA males, there is an urgency and necessity for the discovery and development of novel therapeutic approaches for CRPC. Wnt signaling has been extensively documented in its involvement in PCa and the tumor microenvironment (TME), however the mechanism of how the Wnt signaling cascades contribute to ENZ resistance is still ambiguous. Recently we have published that the activation of the canonical Wnt pathway contributes to the progression of ENZ resistance in CRPC and using a combination of β-catenin inhibitor with ENZ resulted in the synergistic inhibition of patient derived xenograft (PDX) tumor growth. Regarding the non-canonical Wnt pathway, we confirmed its contribution to invasion and migration which leads to metastasis in ENZ-resistant CRPC, and when the downstream effector ROCK is depleted or depleted ROCK cells are treated with ENZ, there is a significant hindering of cell migration and invasion. Also, utilizing a combination therapy of ROCK inhibitor with ENZ synergistically inhibited the growth of PDX tumors. Hence the reasoning that by simultaneously inhibiting both the canonical and non-canonical Wnt signaling cascade will result in the inhibition of cell proliferation, migration, and invasion. The goal of this study was to define the mechanism of PORCN in ENZ-resistant CRPC and develop a therapeutic approach to combat this disease. My research has determined that Porcupine (PORCN) is associated with CRPC progression to ENZ-resistance, and that an inhibition or loss of PORCN has resulted in the regain of ENZ sensitivity in ENZ-resistant models. This model has also demonstrated that PORCN and Wnt signaling engage in a paramount role contributing to AR activation, promoting CRPC progression, and the development of ENZ resistance.
Citation Format: Katelyn Makayla Jones, Xiaoqi Liu. Porcupine inhibition enhances enzalutamide efficacy in drug resistant prostate 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 1077.
Abstract 108: Spatio-temporal view of malignant histogenesis and cancer evolution via formation of polyploid giant cancer cell
Authors: Li Xiaoran , Zhong Yanping , Zhang Xudong , Sood Anil , Liu Jinsong 
Published: April 2023

Abstract
To understand how malignant tumors develop from single cells, we used long-term, time-lapse, live-cell imaging to track the dynamics of the cell membrane, nucleus, spindle, and cell cycle regulators during the development of high-grade, serous, carcinoma-derived organoids. Organoids are highly heterogeneous and include 2 major subtypes. Type-1 organoids are relatively homogeneous and develop via traditional mitosis, whereas type-2 organoids are highly heterogenous and are composed of differently sized polyploid giant cancer cells (PGCCs). Tracking the origin of PGCCs in type-2 organoids shows single cells first undergo asymmetric mitosis and nuclear fusion, followed by endoreplication, multipolar restitution mitosis, multipolar endomitosis, and karyokinesis. At the cellular level, the formation of PGCCs was associated with the formation of transient intracellular cells, termed fecundity cells. The fecundity cells underwent decellularization via the dissolution of the cell membrane, which allowed a giant nucleus to form via nuclear fusion. Different PGCCs underwent nuclear budding, decellularization, or entosis to form Russian doll-like tissue structures that facilitated rapid tumor growth and evolution. The uncoupling of nuclear augmentation from cytokinesis led to a rapid increase in the nuclear-to-cytoplasmic ratio and increased the genomic content of PGCCs, which facilitated macro-genomic evolution during tumor development. Our live-cell imaging evidence allows us to link nuclear replication and cancer evolution to the nuclear morphologies observed by pathologists under the microscope. PGCCs may be the central regulators of malignant histogenesis, cancer evolution, and physical barriers conferring resistance to immune therapy.
Citation Format: Xiaoran Li, Yanping Zhong, Xudong Zhang, Anil Sood, Jinsong Liu. Spatio-temporal view of malignant histogenesis and cancer evolution via formation of polyploid giant cancer cell [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 108.
Abstract 1092: Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC)
Authors: Nenwani Minal , Achreja Abhinav , Animasahun Olamide , Sarangi Itisam , Roy Jyotirmoy , Choppara Srinadh , Wuchu Fulei , Paserba Miya , Mittal Anjali , Quispe Sergio , Mohan Aradhana , Morgan Meredith , Lawrence Theodore S. , Nagrath Deepak 
Published: April 2023

Abstract
One of the most challenging aspects of PDAC is intense therapeutic resistance towards radiotherapy. Cellular signaling pathways are tightly regulated to protect and withstand constant DNA-damaging insults. Similarly, pancreatic cancer cells are known to activate important metabolic events in the advent of cellular stress. Fuel sources obtained via the high metabolic flexibility of PDAC cells confer on them enhanced survival and the ability to escape therapy-induced cell death. To this end, we aim to dissect the role of altered metabolic reprogramming in radioresistant PDAC cells. Investigation of systemic metabolic changes post-radiation of 8Gy in in vitro systems revealed reduced total NAD/NADH ratio and hinted at the increased dependency of PDAC cells on the one-carbon metabolic pathway. Using combinatorial stable-isotope tracing techniques, we confirmed the role of methylene tetrahydrofolate dehydrogenase (MTHFD1/2) enzymes as key regulators in maintaining total NAD/NADH ratio in irradiated cells. Moreover, inhibition of the one-carbon metabolic pathway hindered the ability of PDAC cells to resolve radiation-induced DNA damage. In summary, we propose that PDAC cells modulate the flux of MTHFD1/2 enzymes to reprogram their metabolic state and generate intermediates for DNA repair and cell survival, thus establishing MTHFD1/2 enzymes as potential therapeutic targets to tackle radioresistance.
Citation Format: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath. Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC) [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 1092.
Abstract 1162: Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia
Authors: Ferrer Miriam , Mourikis Nicholas , Davidson Emma E. , Kleeman Sam O. , Zaccaria Marta , Habel Jill , Rubino Rachel , Flint Thomas R. , Connell Claire M. , Lukey Michael J. , White Eileen P. , Coll Anthony P. , Venkitaraman Ashok R. , Janowitz Tobias 
Published: April 2023

Abstract
The dependency of cancer cells on glucose can be targeted with high-fat low-carbohydrate ketogenic diet (KD). However, hepatic ketogenesis is suppressed in IL-6 producing cancers, which prevents the utilization of this nutrient source as energy for the organism. In two IL-6 associated murine models of cancer cachexia we describe delayed tumor growth but accelerated onset of cancer cachexia and shortened survival when mice are fed KD. Mechanistically, we find this uncoupling is a consequence of the biochemical interaction of two simultaneously occurring NADPH-dependent pathways. Within the tumor, increased production of lipid peroxidation products (LPPs) and, consequently, saturation of the glutathione (GSH) system leads to ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impairs the biosynthesis of corticosterone, the main regulator of metabolic stress, in the adrenal glands. Administration of dexamethasone, a potent glucocorticoid, improves food intake, normalizes glucose homeostasis and utilization of nutritional substrates, delays onset of cancer cachexia and extends survival of tumor-bearing mice fed KD, while preserving reduced tumor growth. Our study highlights that the outcome of systemic interventions cannot necessarily be extrapolated from the effect on the tumor alone, but that they have to be investigated for anti-cancer and host effects. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.
Citation Format: Miriam Ferrer, Nicholas Mourikis, Emma E. Davidson, Sam O. Kleeman, Marta Zaccaria, Jill Habel, Rachel Rubino, Thomas R. Flint, Claire M. Connell, Michael J. Lukey, Eileen P. White, Anthony P. Coll, Ashok R. Venkitaraman, Tobias Janowitz. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia [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 1162.
Abstract 121: In situ mutational mapping of tumor cells and tissues at subcellular resolution
Authors: Östlin Jessica , Chitnis Debashish , Olofsson Mimmi , Hernández-Neuta Iván , Kuhnemund Malte 
Published: April 2023

Abstract
In situ techniques enable studying cells and tissues within their cellular context. This is of great importance in cancer, often displaying genetic and phenotypic heterogeneity with distinct subclones harboring different capacity to grow and spread. It was recently shown that by spatially mapping dozens of mutations within tumor tissues, tumor evolution and microenvironmental impact could be studied at the subclonal level (1). We have developed an in situ technique that spatially maps multiple expressed mutations simultaneously at subcellular resolution. The technique is based on single-nucleotide discriminating probes hybridized to mRNA. Correctly hybridized probes get ligated, amplified by rolling circle amplification, and decoded on our Xenium In situ platform. The technique was validated in well characterized cell lines, targeting multiple single nucleotide variants of the KRAS codons 12 and 13. As a proof of concept, we then applied the technique on FFPE breast tumor tissue sections that were previously characterized by targeted NGS onco-gene panels on extracted tumor DNA. In addition to the 280 plex Xenium Human Breast Gene Expression Panel, we targeted several mutations in situ and successfully mapped their spatial distribution in the tumor tissue sections. In summary, we demonstrate that the Xenium In Situ technology can spatially resolve the genetic and phenotypic landscape of breast tumors. The technology will enable researchers to unravel tumor evolution, growth and spread as well as the microenvironmental impact in detail, potentially refining patient stratification and treatment decisions.
Citation Format: Jessica Östlin, Debashish Chitnis, Mimmi Olofsson, Iván Hernández-Neuta, Malte Kuhnemund. In situ mutational mapping of tumor cells and tissues at subcellular resolution [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 121.
Abstract 1231: A stochastic data-driven model predicts the timing and distribution of the epithelial-mesenchymal transition
Authors: Najafi Annice , Jolly Mohit K. , George Jason T. 
Published: April 2023

Abstract
The Epithelial-Mesenchymal Transition (EMT) is a key contributor to cancer metastasis and morbidity. During this process, epithelial cells acquire migratory and stem-like characteristics, which allow them to travel through vasculature and form distant metastases in a secondary organ site via the reverse process of MET. Initially thought of as a binary process, it is now well established that cells can be stably arrested en route to EMT in an intermediate hybrid state (H) with characteristics falling on a spectrum between the epithelial (E) and mesenchymal (M) phenotypes. This non-transient intermediate state is stabilized by phenotypic stability factors and is associated with more tumor aggressiveness, worse treatment response, and patient outcomes. Although abundant time-course single-cell RNA sequencing data exists, enabling dynamical single-cell analysis of EMT, current methods of EMT state inference are optimized on microarray data. Thus, there is a large need for a computational framework that infers and predicts the E, H, and M fractions at transient and steady states from single-cell RNA sequencing data. Here, we introduce a fully stochastic continuous-time Markov model to predict the dynamics of EMT transitions from time-course data. We fit our continuous-time model on a multi-replicate time-course flow cytometry data of MCF10A cell line where TGF is withdrawn at different days following treatment for each replicate. We then demonstrate that our model is extendable to time-course single-cell RNA sequencing data utilizing a novel data-driven pipeline. Our data-driven pipeline infers the three E, H, and M trajectories from time-dependent and dose-dependent single-cell RNA sequencing data. We confirm our trajectories accurately reflect the E, H, and M states via gene-set enrichment analysis. We find the fraction of cells in each state at stationary distribution using our data-driven pipeline and show that they match the predictions of a previous simulation study. By applying the stochastic model to time-course single-cell RNA sequencing trajectories of four cancer cell lines (A549, MCF7, OVCA420, and DU145), we show that the stochastic model accurately predicts context-specific EMT dynamics over time. Our model is the first RNA sequencing-based method for tracking EMT from longitudinal data at the single-cell resolution and therefore is of immediate utility for studying metastatic signatures in cancer.
Citation Format: Annice Najafi, Mohit K. Jolly, Jason T. George. A stochastic data-driven model predicts the timing and distribution of the epithelial-mesenchymal transition [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 1231.