bluuebunny/crossref_metadata_2025 huggingface dataset:
Relevant sampling in a reproducing kernel subspace of Orlicz space
Authors: Bajpeyi Shivam , Patel Dhiraj , Sivananthan S.
Published: March 2024

In this paper, we aim to provide a general paradigm for dealing with the sampling and random sampling problem in a reproducing kernel subspace of Orlicz space [Formula: see text]. We consider the function space [Formula: see text] as the image of an idempotent integral operator on [Formula: see text], where the integral kernel satisfies certain off-diagonal decay and regularity conditions. The model example of such reproducing kernel subspace of [Formula: see text] includes the finitely generated shift-invariant space and signal space with a finite rate of innovation. We show that a signal in [Formula: see text] can be stably reconstructed from its samples at distinct points separated by a sufficiently small gap. Next, we deduce that the random sampling inequality holds with a high probability for the class of functions in [Formula: see text] concentrated on a cube [Formula: see text], when the samples collected at i.i.d. random points are drawn on [Formula: see text] of order [Formula: see text].
Greedy approximation and regression analysis for the discrete TM system
Authors: Tuoheti Dilinuer , Chen Qiuping , Dong Cuiling
Published: March 2024

This note designs a statistic model involving TM system with Gaussian noise. Based on adaptive approximation of the parameters in TM system and greedy choices for the generalized Fourier coefficients, a regression function is determined for this model from the finite observed data. Finally its statistical properties are proved.
Phytomediated Synthesis of Zinc Oxide (ZnO) Nanoparticles via Vitex negundo Leaf Extract: Characterization, Antibacterial and Antibiofilm Activity
Authors: Asha Sneha , Udhayasuriyan Manimehala , Mini Minsa , Divyalekshmi S. V. , Rajan Pooja P. , Mohan Aparna , Xavier T. S. , Kumar Praveen
Published: March 2024

This study provides evidence for the green synthesis of zinc oxide nanoparticles (ZnO NPs) using Vitex negundo leaf extract. The UV–Visible (UV–Vis) spectrum of ZnO NPs and calcinated ZnO NPs (ZnO-C) showed peaks at 370[Formula: see text]nm and 374[Formula: see text]nm, respectively, confirming zinc ion reduction to zinc oxide. The ZnO NPs and calcinated counterparts were further characterized by FTIR, XRD, FE-SEM and EDX. FTIR results revealed the presence of alcoholic and aromatic groups, like flavonoids, in the leaf extract. The XRD pattern showed a distinctive Wurtzite crystalline phase with a hexagonal shape. The Brunauer–Emmett–Teller (BET) analysis data revealed that ZnO’s surface area and pore size is 22.8[Formula: see text]m2/g and 12.9[Formula: see text]nm, whereas ZnO-C exhibited a surface area of 23.5[Formula: see text]m2/g and pore size of 13.1[Formula: see text]nm. The SEM data demonstrated numerous irregular and agglomerated flakes fusing to form a roughly spherical morphology with the size, in the range of 15–20[Formula: see text]nm and 11–16[Formula: see text]nm for ZnO and ZnO-C NPs, respectively. The results of the antimicrobial assay by disc diffusion method and MIC testing revealed that ZnO and ZnO-C NPs exhibited moderate to high antimicrobial activity against various microorganisms, indicating their application against bacterial infection. In addition, the ZnO NPs significantly disrupted the biofilm of Bacillus cereus and Pseudomonas aeruginosa, as confirmed by CV assay and fluorescent microscopy.
Managing Climate Change Risks: Sea-Level Rise and Mergers and Acquisitions
Authors: Bai John Jianqiu , Chu Yongqiang , Shen Chen , Wan Chi
Published: March 2024

Using a large sample over the period 1986 to 2017, we show that companies with higher exposure to climate change risk induced by sea-level rise (SLR) tend to acquire firms that are unlikely to be directly affected by SLR. We find that acquirers with higher SLR exposure experience significantly higher announcement-period abnormal stock returns. Analyses using failed merger bids as an exogenous shock show that post-merger, analyst forecasts become more accurate and environmental-related as well as overall ESG scores improve.
Groundwater Extraction for Irrigation Purposes: The Case of Asymmetric Players
Authors: Chukaeva Valeriia , Frutos Cachorro Julia de , Marín-Solano Jesús
Published: March 2024

In this paper, we address the problem of groundwater exploitation by heterogeneous farmers for irrigation purposes. In particular, we study the possible inefficiencies that can arise in this type of common resource problem by considering the dynamic and strategic interactions between groundwater users. To this end, we build a two-player differential game in which two types of farmers (or many farmers grouped into two types, with a representative farmer for each group) display different characteristics related to their agricultural activity. More precisely, they can have different water demand functions, extraction costs, crop productivity, land types and time-preferences. Conditions are studied for the existence and uniqueness of the cooperative and non-cooperative solutions asymptotically converging to a steady state. The model is then applied to the case study of the Western La Mancha aquifer. Effects of the different heterogeneities on the degree of inefficiency of non-cooperative solutions with respect to cooperative solutions are analyzed. Numerical results show that cooperation is always beneficial for the environment and for the agents: It results in higher levels of groundwater stock and total welfare. Moreover, considering heterogeneous time preferences is crucial for reducing the inefficiency of non-cooperation with respect to cooperation, regardless of the other asymmetries between farmers.
Research on the Sustainable Cultivation Mode of Innovative Talents in Developing Countries
Authors: Chong Guoshuang , Li Li , Gao Wei , Niu Ping , Li Yuhang , Song Yanfei
Published: March 2024

The sustainable development of society and economy is in urgent need of talents with innovative qualities. Entering the information age of the 21st century, technologies such as AI, big data, cloud teaching and the internet are developing rapidly. The cultivation of innovative talents in Developing Countries should also follow the sustainable development mode. Only by discussing the current mode of fostering innovative talents can continuously change the concept of training innovative talents, which is conducive to combining theory with practice and promoting the highlighting of outstanding innovative talents.
Thirsty Fabs
Authors: Mone Gregory
Published: March 2024

How the surprising water footprint of semiconductor manufacturing, datacenters, and AI solutions is sparking sustainable development.
Floorplanning with Edge-aware Graph Attention Network and Hindsight Experience Replay
Authors: Yang Bo , Xu Qi , Geng Hao , Chen Song , Yu Bei , Kang Yi
Published: March 2024

In this article, we focus on chip floorplanning, which aims to determine the location and orientation of circuit macros simultaneously, so the chip area and wirelength are minimized. As the highest level of abstraction in hierarchical physical design, floorplanning bridges the gap between the system-level design and the physical synthesis, whose quality directly influences downstream placement and routing. To tackle chip floorplanning, we propose an end-to-end reinforcement learning (RL) methodology with a hindsight experience replay technique. An edge-aware graph attention network (EAGAT) is developed to effectively encode the macro and connection features of the netlist graph. Moreover, we build a hierarchical decoder architecture mainly consisting of transformer and attention pointer mechanism to output floorplan actions. Since the RL agent automatically extracts knowledge about the solution space, the previously learned policy can be quickly transferred to optimize new unseen netlists. Experimental results demonstrate that, compared with state-of-the-art floorplanners, the proposed end-to-end methodology significantly optimizes area and wirelength on public GSRC and MCNC benchmarks.
Beyond Relevance: Factor-level Causal Explanation for User Travel Decisions with Counterfactual Data Augmentation
Authors: Li Hanzhe , Gu Jingjing , Lu Xinjiang , Shen Dazhong , Liu Yuting , Deng YaNan , Shi Guoliang , Xiong Hui
Published: March 2024

Point-of-Interest (POI) recommendation, an important research hotspot in the field of urban computing, plays a crucial role in urban construction. While understanding the process of users’ travel decisions and exploring the causality of POI choosing is not easy due to the complex and diverse influencing factors in urban travel scenarios. Moreover, the spurious explanations caused by severe data sparsity, i.e., misrepresenting universal relevance as causality, may also hinder us from understanding users’ travel decisions. To this end, in this article, we propose a factor-level causal explanation generation framework based on counterfactual data augmentation for user travel decisions, named Factor-level Causal Explanation for User Travel Decisions (FCE-UTD), which can distinguish between true and false causal factors and generate true causal explanations. Specifically, we first assume that a user decision is composed of a set of several different factors. Then, by preserving the user decision structure with a joint counterfactual contrastive learning paradigm, we learn the representation of factors and detect the relevant factors. Next, we further identify true causal factors by constructing counterfactual decisions with a counterfactual representation generator, in particular, it can not only augment the dataset and mitigate the sparsity but also contribute to clarifying the causal factors from other false causal factors that may cause spurious explanations. Besides, a causal dependency learner is proposed to identify causal factors for each decision by learning causal dependency scores. Extensive experiments conducted on three real-world datasets demonstrate the superiority of our approach in terms of check-in rate, fidelity, and downstream tasks under different behavior scenarios. The extra case studies also demonstrate the ability of FCE-UTD to generate causal explanations in POI choosing.
A Conservative and Efficient Model for Grain Boundaries of Solid Electrolytes in a Continuum Model for Solid-State Batteries
Authors: Sinzig Stephan , Schmidt Christoph P. , Wall Wolfgang A.
Published: March 2024

A formulation is presented to model ionic conduction efficiently inside, i.e., across and along grain boundaries. Efficiency and accuracy are achieved by reducing it to a two-dimensional manifold while guaranteeing the conservation of mass and charge at the intersection of multiple grain boundaries. The formulation treats the electric field and the electric current as independent solution variables. We elaborate on the numerical challenges this formulation implies and compare the computed solution with results from an analytical solution by quantifying the convergence toward the exact solution. Towards the end of this work, the model is firstly applied to setups with extreme values of crucial parameters of grain boundaries to study the influence of the ionic conduction in the grain boundary on the overall battery cell voltage and, secondly, to a realistic microstructure to show the capabilities of the formulation.
Water/DMSO-Based Hybrid Electrolyte and Urea Additive Engineering for Performance Regulation in Aqueous Sodium Batteries
Authors: Zhou Yuxiang , Shen Hailin , Chen Xiaohui , Liu Changhai , Shan Xuelin , Wang Wenchang , Chen Zhidong
Published: March 2024

Electrochemical energy storage devices are of interest, especially aqueous sodium ion batteries (ASIBs), due to their safety, low-cost, and environmental friendliness. However, ASIBs suffer from poor cyclic stability and a narrow electrochemical window, which hinders their large-scale application. Compared to the traditional dilute saline electrolytes, high concentration electrolytes show a wider potential window. In this study, we designed a novel NaClO4-H2O/DMSO-Urea hybrid electrolyte to suppress these problems, in which DMSO and Urea create a synergistic effect. The formation of hydrogen bonds between DMSO and H2O reduced water activity, thereby suppressing the hydrogen evolution reaction. The addition of DMSO resulted in the reduction from −1.2 to −1.6 V for the hydrogen evolution potential. Therefore, we were able to expand the electrochemical window on the basis of reducing the concentration of sodium salts. Moreover, the addition of Urea facilitated formation of a stable solid electrolyte interface on the electrode surface, which improved the cycling stability of NVP/C (Na3V2(PO3)4/C) symmetric cell which exhibited a specific capacity of 59.7 mAh g−1 with the retention capacity of 80.1% after 200 cycles at 1 C. This work points out a promising strategy for developing stable and wide voltage aqueous electrolyte.
Clinical physiology: the crucial role of MRI in evaluation of peripheral artery disease
Authors: Elsaid Nahla M. H. , Peters Dana C. , Galiana Gigi , Sinusas Albert J.
Published: March 2024

Peripheral artery disease (PAD) is a common vascular disease that primarily affects the lower limbs and is defined by the constriction or blockage of peripheral arteries and may involve microvascular dysfunction and tissue injury. Patients with diabetes have more prominent disease of microcirculation and develop peripheral neuropathy, autonomic dysfunction, and medial vascular calcification. Early and accurate diagnosis of PAD and disease characterization are essential for personalized management and therapy planning. Magnetic resonance imaging (MRI) provides excellent soft tissue contrast and multiplanar imaging capabilities and is useful as a noninvasive imaging tool in the comprehensive physiological assessment of PAD. This review provides an overview of the current state of the art of MRI in the evaluation and characterization of PAD, including an analysis of the many applicable MR imaging techniques, describing the advantages and disadvantages of each approach. We also present recent developments, future clinical applications, and future MRI directions in assessing PAD. The development of new MR imaging technologies and applications in preclinical models with translation to clinical research holds considerable potential for improving the understanding of the pathophysiology of PAD and clinical applications for improving diagnostic precision, risk stratification, and treatment outcomes in patients with PAD.
Pleural Mesothelial Cells-Induced Monocytes to the Pleural Cavity through the Effect of C3 Lytic Products in Tuberculous Pleural Effusion
Authors: Luo Lisha , Feng Juntao , Deng Shuanglinzi , Hu Xinyue , Zhao Bingrong , Tang Wei , Li Xiaozhao
Published: March 2024

Background. The activation of complement is involved in monocyte recruitment in tuberculous pleural effusion (TPE), while the role of the cleavage product of complement C3 in this process needs further research. Methods. The expression of complement components in pleural biopsy specimens of TPE patients was measured. The concentration of cleavage products of complement was tested in TPE by ELISA. Moreover, the colocalizations of C3b and CR1, C3d and CR3, and CXCL12 and CXCR4 in monocytes and pleural mesothelial cells (PMCs) isolated from TPE were determined by an immunofluorescent assay. Monocyte chemotaxis assay was analyzed via transwell chambers. Results. Three pathways of the complement system were activated in tuberculous pleurisy. In patients with TPE, C3 lysis was more active than peripheral blood in pleural cavity. Tuberculous protein Mpt64 and anaphylatoxin C3a could significantly promote CXCL12 production in human PMCs isolated from TPE. C3b-CR1, C3d-CR3, and CXCL12-CXCR4 were colocalized in PMCs and monocytes from TPE. The recruitment of monocytes into TPE mediated by PMCs could be inhibited by anti-CR1, anti-CR3, and anti-CXCL12 monoclonal antibodies (mAbs). Conclusions. Complement activates strongly in TPE, and PMCs induced monocytes to the pleural cavity through C3a, C3b, and C3d.
Effects of Profortil® on Leptin‐Induced Adverse Effects on Sperm Parameters in Sprague‐Dawley Rats
Authors: Alam Malik Ifrah , Durairajanayagam Damayanthi , Henkel Ralf , Singh Harbindar Jeet
Published: March 2024

Raised leptin levels induce oxidative stress, which negatively impacts male reproduction. Profortil® is an antioxidant formulation clinically used to improve sperm quality. Whether Profortil® supplementation can prevent the detrimental effects of leptin on spermatozoa is not known. Thus, the aim of this study was to examine the effects of Profortil® on leptin‐induced adverse effects on rat spermatozoa. Adult Sprague‐Dawley rats were given either normal saline (control), leptin (60 µg/kg/day), Profortil® (50 mg/kg/day), or Profortil® + leptin once daily for 2 weeks. Sperm count and abnormal morphology were recorded. Testicular levels of 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), superoxide dismutase (SOD), and catalase (CAT) activities were measured. TUNEL and Comet assays were performed. The sperm count in the Profortil® + leptin group was comparable to that in controls but was significantly higher than that in the leptin group, which was significantly lower than that in controls. Sperm morphology was not different between leptin and Profortil® + leptin groups. 8‐OHdG level was significantly lower in the Profortil® + leptin group than that in the leptin group but was comparable to that in controls. CAT activity was not different between leptin and Profortil® + leptin groups, although activity in the former was significantly lower than that in controls. SOD activity was not different between groups. The apoptotic index was significantly higher in the leptin and Profortil® + leptin groups than in the control and Profortil® groups. Sperm DNA fragmentation was not significantly different between leptin and Profortil® + leptin groups. In conclusion, Profortil®, when given at 50 mg/kg/day for 3 weeks, was only able to reduce some, but not all the adverse effects of leptin on sperm parameters.
Variations of Carotenoids, Total Bioactive Contents, and Antioxidant Activity in Leaves of Medicago polymorpha
Authors: Zeb Alam , Ahmad Khalil
Published: March 2024

Medicago polymorpha L. (MP) is a herbaceous plant commonly known as “bur clover.” It is aboriginal to Central and Western Asia and extensively distributed around the world. This study determines the changes in carotenoids and antioxidant potential of different MP of different origins. The sample leaves were analyzed for identification and quantification of carotenoids using a reversed-phase HPLC system. The result showed nine carotenoids and pigments in each sample. The major carotenoid compounds were phytoene, phytofluene, neoxanthin and its isomer (9-Z-neoxanthin), violaxanthin, lutein along with their isomers (9-Z-lutein, 9′-Z-lutein), and all-E-β-carotene. The major pigments were 15-hydroxy-lactone chlorophyll a, pheophytin a, pheophytin a′, pyropheophytin a, divinyl chlorophyll a, chlorophyll b′, chlorophyll b, 13′-hydroxy-lactone chlorophyll b, and hydroxy pheophytin a′. The carotenoids were detected in considerable amounts in the samples from Lower Dir (213 μg/g), Swat (171 μg/g), and Buner (157 μg/g). Chlorophylls were higher in Lower Dir (203.4 μg/g), Swat (184.0 μg/g), and Buner (152.2 μg/g) and significantly lower amounts in Malakand samples (141.7 μg/g). The total carotenoids in Lower Dir (51.2%) were higher than in Swat (48.2%), Buner (50.8%), and Malakand samples (44.6%). The amounts of violaxanthin and lutein were significantly higher in Lower Dir (73.6%) samples, followed by Malakand (51.7%), whereas Buner and Swat samples showed the lowest levels. In conclusion, MP leaves are a good source of important carotenoids having potential antioxidant properties, which are highly correlated to the violaxanthin and lutein contents.
Abstract 1: Biomarkers of response and acquired resistance to TIL-ACT in solid tumors
Authors: Robinson Welles , Castro Andrea , Al-Bakir Maise , Gartner Jared J. , Chamberlain Christopher Aled , Kverneland Anders H. , Borch Troels H. , Svane Inge Marie , Donia Marco , Robbins Paul , Litchfield Kevin
Published: March 2024

Background: Cancer immunotherapy has revolutionized cancer treatment in the last decade. However, most patients either do not respond to immunotherapy or eventually relapse so there is a need to identify biomarkers of response and understand mechanisms of resistance. Most biomarker studies have analyzed patients treated with immune checkpoint inhibitors (CPI) therapy while the few studies of adoptive cell transfer of tumor infiltrating lymphocytes (TIL-ACT) have analyzed relatively small patient cohorts.

Methods: To systematically identify biomarkers of response and resistance to TIL-ACT, we collected published and unpublished whole-exome and transcriptomic data for tumors from 400 patients treated with TIL-ACT from five tumor types across four institutions and processed these datasets using a standardized bioinformatic pipeline.

Results: To identify biomarkers of response in pre-treatment tumors, we analyzed previously reported biomarkers and performed biomarker discovery in our cohorts. For the subset of 200 patients with T cell reactivities identified from the infusion products and fresh tumor, we refined our biomarkers to include neo-antigen reactivities in addition to identifying both mutational processes and transcriptional signatures associated with neo-antigens reactivity. To identify mechanisms of acquired resistance to TIL-ACT, we analyzed 15 patients with paired pre- and post-treatment tumors and found multiple mechanisms of immune evasion specific to infused reactive T cells including loss of heterozygosity of the HLA allele presenting the neo-antigen, genomic loss of the neo-antigen and inactivation of interferon-gamma signaling pathway.

Conclusions: In summary, we will present the biomarkers landscape of TIL-ACT therapy including differences between histology and across treatment modalities to improve our understanding of the mechanisms of treatment response.

Citation Format: Welles Robinson, Andrea Castro, Maise Al-Bakir, Jared J. Gartner, Christopher Aled Chamberlain, Anders H. Kverneland, Troels H. Borch, Inge Marie Svane, Marco Donia, Paul Robbins, Kevin Litchfield. Biomarkers of response and acquired resistance to TIL-ACT in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1.
Abstract 1004: Establishing lung adenocarcinoma cell lines to mitigate lung cancer health disparities
Authors: Lugo Sofia , Leon Christopher , Gladstone Matthew , Yan Chunli , Lamango Nazarius S. , Offringa Ite A. , Ofosu-Asante Kweku , Huang Yong , Mensah-Mamfo Justin K.
Published: March 2024

Lung cancer remains the leading cause of cancer death worldwide and is a pronounced source of cancer health disparities. Black/African American (B/AA) individuals demonstrate the highest lung cancer death rates when compared to other ethnic/racial groups. B/AA males exhibit a 15% higher lung cancer death rate and a 12% higher lung cancer incidence when compared to White males. Lung adenocarcinoma (LUAD) is the most common histological subtype in all races including B/AA. To study lung cancer and its related disparities, essential tools such as lung cancer cell lines are important; they can be used for molecular studies of lung cancer development, progression, development of new therapies and pre-clinical drug testing. We reviewed the literature (Leon et al. 2023, Frontiers in Oncology, Vol. 13, p. 1187585, 2023) and identified only 30 unique B/AA cell lines out of ~800 cell lines available, with the majority of cell lines being from White and Asian patients. Moreover, only 6 B/AA cell lines were derived from patients with LUAD. We are in the process of developing additional LUAD cell lines from patients as well as alveolar epithelial cell lines that can be used to model LUAD development. In addition, we are generating multiple independent isogenic cell line variants from existing lung cancer cell line NCI-H23, derived from a B/AA male patient harboring a KRASG12C heterozygous mutation. We are using CRISPR/Cas-9-based genome editing to replace the KRASG12C mutation with other KRAS mutations found in B/AA patients, including KRASG12V, KRASG12D, KRASG12A, and KRASG13C. We will perform whole genome sequencing to exclude off target effects of the CRISPR engineering. We will use isogenic cell lines to test the efficacy of polyisoprenylated cysteinyl amide inhibitors (PCAIs) and other drugs on cell lines bearing the different KRAS mutations. PCAIs were developed to target cells carrying mutant KRAS. Our efforts will provide tools to limit cancer health disparities and serve as a foundation for future research.

Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI) and the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI.

Citation Format: Sofia Lugo, Christopher Leon, Matthew Gladstone, Chunli Yan, Nazarius S. Lamango, Ite A. Offringa, Kweku Ofosu-Asante, Yong Huang, Justin K. Mensah-Mamfo. Establishing lung adenocarcinoma cell lines to mitigate lung cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1004.
Abstract 1094: Utilizing CRISPR-Cas13 as a novel functional genomics tool to characterize PAX3-FOXO1 in alveolar rhabdomyosarcoma
Authors: Zhao Andrea , Brown Lauren M. , Fareh Mohamed , Ekert Paul G.
Published: March 2024

Background: CRISPR-Cas13 (Cas13) is an RNA editing system that can knockdown gene transcripts with higher efficiency and specificity than RNA interference technologies. We are exploring the utility of Cas13 as a robust novel functional genomics tool to understand the biology of the PAX3-FOXO1(P3F1) gene fusion in alveolar rhabdomyosarcoma (ARMS). Our goal is to identify gene dependencies and novel druggable targets. [LB1]

Aim: This study aims to functionally characterize P3F1 in paediatric cancer cell lines using Cas13. [LB2]

Methods & Results: Transient transfection and viral transduction of Cas13 vector systems were used to demonstrate that Cas13 knockdown of target gene expression can be achieved in ARMS cell lines. We developed guides to specifically target P3F1 expression and tested their efficiency in HEK293T cells. Cas13 function was validated with a mCherry knockdown proof-of-concept expression in the ARMS cell lines Rh5 and Rh30. 90-95% knockdown efficiency was seen over three independent experiments. Ten P3F1 breakpoint targeting guides were designed and screened first in a HEK293T P3F1 overexpression model to select optimal high efficiency targeting guides. The highest efficiency targeting guide showed a GFP reduction of 70% in three independent experiments. High-efficiency Cas13 guides were taken forward into Rh5 cells to knockdown endogenous P3F1 expression which were validated by western blotting and RT-PCR. Western blots of Cas13 sorted Rh5 cells showed that guide 1150 was able to knockdown P3F1 protein expression by ~70%.

Discussion/Conclusion: These findings demonstrate the high efficiency and specificity of the Cas13 system to silence P3F1, and other oncogenic fusion drivers. Further studies will utilize Cas13 to characterize the molecular and cellular consequences of P3F1 gene-silencing in patient-derived ARMS cell lines.

Citation Format: Andrea Zhao, Lauren M. Brown, Mohamed Fareh, Paul G. Ekert. Utilizing CRISPR-Cas13 as a novel functional genomics tool to characterize PAX3-FOXO1 in alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1094.
Abstract 1130: Leveraging the IVIS imaging technologies for drug potency testing in orthotopic and metastatic tumor models
Authors: Huang Jingqi , Jin Jing , Duan Hongchen , Yang Xueqin , Jin Wenhao , Zhang Yiming , Zhang Lihui , Xu Gaoyang , Xie Liya , Li Wentao
Published: March 2024

Assessing anti-tumor drug potency is significantly enhanced using orthotopic and metastasis mouse tumor models. These models imitate the tumor's native environment, biological complexities, and challenges of drug delivery via blood perfusion, thereby providing a high predictive value for clinical outcomes. In this poster, we demonstrate how the IVIS optical imaging technology is employed to determine the effects of two drugs on two tumor models: •The KRAS (G12C) inhibitor, AMG510, was evaluated on the luciferase-expressing Miapaca-2 pancreatic orthotopic model •The third-generation EGFR inhibitor, AZD9291, was tested on the luciferase-expressing NIC-H1975 intracranial metastatic model Both drugs showed significant anti-tumor activity. In addition to potency testing, each drug was administered in single doses for pharmacodynamic analysis, evaluating pERK/ERK and DUSP6 levels. The pERK levels decreased after treatment, which is in line with the mechanism of action of the inhibitors. Our research illustrates that IVIS imaging offers a robust method for monitoring anti-tumor activity of drugs in orthotopic and metastatic tumor models, empowering scientists to assess new drug candidates by using biologically relevant animal models.

Citation Format: Jingqi Huang, Jing Jin, Hongchen Duan, Xueqin Yang, Wenhao Jin, Yiming Zhang, Lihui Zhang, Gaoyang Xu, Liya Xie, Wentao Li. Leveraging the IVIS imaging technologies for drug potency testing in orthotopic and metastatic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1130.
Abstract 118: Development of a novel murine model, NCG-M/hIL15, for enhanced post-HSC transplantation immunoreconstruction
Authors: Wang Huiyi , Xing Jun , Fan Jialu , Fan Yuan , Zhao Jing , Gao Xiang , Ju Cunxiang
Published: March 2024

Advances in the field of immunology and hematopoietic stem cell (HSC) transplantation have prompted the development of murine models that faithfully recapitulate human immune responses. We present the NCG-M/hIL15 model, an innovative advancement in the realm of preclinical research, addressing two key challenges associated with existing models: the limited capacity for human natural killer (NK) cell regeneration in NCG-M and the suboptimal reconstitution of T cells, myeloid lineage cells in NCG-hIL15 mice.

Compared to the conventional NCG-M model, the NCG-M/hIL15 model demonstrates a significant improvement in its ability to regenerate human NK cells post-HSC transplantation. This advancement offers a valuable tool for studying NK cell biology, immune surveillance, and antitumor responses.

Furthermore, when compared to the NCG-hIL15 model, the NCG-M/hIL15 model outperforms in the reconstitution of human T cells and myeloid lineage cells, contributing to a more comprehensive simulation of human immune responses. The overall survival of mice in this model is notably stable, further enhancing its utility for long-term immunological studies.

The NCG-M/hIL15 model not only advances our understanding of human immune responses but also has significant implications for the development of novel immunotherapies and the preclinical evaluation of HSC transplantation strategies. This novel murine model offers a more accurate representation of the human immune system, with the potential to expedite the development of innovative therapeutic interventions. We present this model as a valuable addition to the preclinical research toolkit, promising a deeper understanding of immunology and a brighter future for clinical applications.

Citation Format: Huiyi Wang, Jun Xing, Jialu Fan, Yuan Fan, Jing Zhao, Xiang Gao, Cunxiang Ju. Development of a novel murine model, NCG-M/hIL15, for enhanced post-HSC transplantation immunoreconstruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 118.
Abstract 1219: In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables ATAD3A gene depletion to enhance RAS-targeted therapy
Authors: Chen Fanghui , Lang Liwei , Li Yamin , Zheng Wei , Teng Yong
Published: March 2024

Targeting mitochondrial oncoproteins presents a new concept in developing effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme that contributes to mitochondrial dynamics, cholesterol metabolism, and signal transduction. Our previous study has demonstrated elevated expression of ATAD3A in head and neck squamous cell carcinoma (HNSCC) primary tissues and cultured cell lines. Loss of function suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice. Mechanistically, ATAD3A interacts with ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion. CRISPR-Cas9 has revolutionized genome engineering and has been intensively used to modify cancer-associated genes. However, challenges remain as CRISPR editing components must be transported into cells to exert their function. There is a need to explore effective in vivo delivery systems to accelerate the clinical use of CRISPR-Cas9. As no drug is available to target ATAD3A directly, we developed CRISPR-based ATAD3A-targeting nanodrugs by loading Cas9 mRNA and anti-ATAD3A sgRNAs into lipid nanoparticles (LNPs) that have become clinically acceptable delivery system due to low toxicity and high delivery efficacy and biocompatibility. As expected, treatment tongue tumors established in NSG mice with LNP-sgATAD3A remarkably repressed tumor growth. Most interestingly, the addition of LNP-sgATAD3A to the RAS inhibitor salirasib potentiated anticancer activity for HNSCC compared with the efficacy resulting from single-arm treatment. These novel and significant findings demonstrate a novel approach to inhibiting ATAD3A in tumor cells and provide a possible therapeutic strategy to enhance the success of multimodality therapy in cancer patients.

Citation Format: Fanghui Chen, Liwei Lang, Yamin Li, Wei Zheng, Yong Teng. In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables ATAD3A gene depletion to enhance RAS-targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1219.
Abstract 1265: Comparison of mortality- vs. stage-based endpoints in randomized trials of cancer screening: A systematic review with implications for multi-cancer screening trials
Authors: Feng Xiaoshuang , Zahed Hana , Onwuka Justina , Johansson Mattias , Etzioni Ruth , Callister Matthew E. , Robbins Hilary A.
Published: March 2024

Background: Randomized controlled trials (RCTs) assessing the endpoint of late-stage cancer incidence, rather than the gold-standard of cancer-specific mortality, are proposed for evaluation of multi-cancer early detection tests.

Methods: We conducted a systematic review to assess whether stage-based endpoints can provide a valid alternative for mortality-based endpoints (registration: PROSPERO CRD42023411132). We searched PubMed to identify RCTs of cancer screening interventions published in English before January 20, 2023. Inclusion required that RCTs report, by study arm, numbers of cancer-specific deaths and cancer cases distinguishable between stages I-II vs. III-IV. Data extraction was done by 2 separate reviewers and included the numbers of cancer cases, deaths, and participants by study arm. For each trial, we calculated the percentage reduction in the cumulative (a) late-stage cancer incidence and (b) cancer-specific mortality between the intervention and control arms. We compared these two endpoints based on Pearson correlation coefficients, fixed-effects meta-analysis, and binary statistical significance.

Results: We analyzed 41 trials ranging in size from 2,500 to 409,000 participants. Correlation between the reduction in cancer-specific mortality vs. stage III-IV cancer was strong for lung (Pearson’s ρ=0.92, n=12), breast (ρ=0.70, n=6), and ‘other’ cancers (ρ=0.69, n=8) but weak for colorectal (ρ=0.39, n=11) and prostate cancers (ρ<0, n=4). The overall correlation by fixed-effects meta-analysis across cancer types was 0.71 (95%CI=0.47-0.86) (I2=0.55). In larger trials, there was a smaller deviation between the observed reduction in cancer-specific mortality and that predicted, by cancer type, based on the trial’s reduction in stage III-IV cancer (p=0.02). Of 12 trials demonstrating a statistically significant reduction in stage III-IV cancer incidence (p<0.05), 5 also showed reduced cancer-specific mortality (42%).

Conclusions: In screening RCTs, reductions in late-stage cancer vs. cancer-specific mortality are correlated, but with important differences by cancer type. Screening interventions that reduce late-stage cancer incidence do not necessarily reduce cancer-specific mortality.

Citation Format: Xiaoshuang Feng, Hana Zahed, Justina Onwuka, Mattias Johansson, Ruth Etzioni, Matthew E. Callister, Hilary A. Robbins. Comparison of mortality- vs. stage-based endpoints in randomized trials of cancer screening: A systematic review with implications for multi-cancer screening trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1265.
Abstract 1307: Community-driven support platform BlueHQ: An innovative solution to address the needs of patients with colorectal cancer
Authors: Newcomer Kimberly Lynn
Published: March 2024

Background: Colorectal cancer (CRC) is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. To manage the disease, patients and caregivers turn to various tools and resources for financial assistance, information dissemination, emotional and peer support, and treatment planning, among other critical issues and needs they face. The Colorectal Cancer Alliance (the Alliance) created BlueHQ to provide patients and caregivers with a resource solution encompassing all potential areas of need.

Methods: A survey aimed at understanding needs, barriers, and quality improvement opportunities was disseminated via the Alliance's Blue Hope Nation community for two weeks and by email. One hundred sixty-seven colorectal cancer patients and forty caregivers of colorectal cancer patients completed the survey.

Results: Patients and caregiver respondents report reliance on external tools and resources to manage disease and support information. Of the support methods, patient respondents reported using social media (46.11%); notebooks, journals, and planners (45.41%); online articles (44.91%); the Blue Hope Nation Facebook group (41.32%); cancer discussion boards (35.33%); and spiritual or religious advice (29.94%). Patients sought financial assistance, local peer support and groups, and mental health help to minimize diagnosis-related stressors. To provide more efficient care and limit stress, the community suggested financial help, communication and support from other patients and caregivers, and informational resources.

Conclusions: These survey results are consistent with other published learnings about patient and caregiver reliance on support tools and highlight the myriad resources that patients and caregivers currently use for managing CRC. BlueHQ is a support solution that provides patients and caregivers with access to information and resources tailored to users’ specified profiles, including molecular characteristics of the tumor. Users can also store documents and information from healthcare encounters, creating a longitudinal record and tracking disease progression. In the age of precision oncology, BlueHQ ensures patients and users are presented with personalized educational materials and multimedia resources to help manage their disease and bridge the gaps in patient support. BlueHQ was explicitly designed to connect the CRC community to the latest therapeutic and clinical research resources to improve outcomes and quality of life for all CRC patients.

Citation Format: Kimberly Lynn Newcomer. Community-driven support platform BlueHQ: An innovative solution to address the needs of patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1307.
Abstract 140: Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis
Authors: Liao Weiting , Chen Xin
Published: March 2024

Hepatoblastoma (HB) is a rare, yet the most common primary malignant hepatic liver in children. A significantly portion of children with HB have tumors that are not resected at diagnosis, leading to the dismal prognosis in these patients. Concomitant YAP and β-catenin activation could be seen 80% of HB. The signaling pathways regulated by YAP and β-catenin in HB pathogenesis remain unclear. Here, we engineered a inducible HB murine model using hydrodynamic injection to deliver transposon plasmids encoding constitutive YAP and doxycycline (Dox) inducible ΔN90-β-Catenin (Yap/TRE-β-Catenin). When fed with Dox, HB formed rapidly in the mice. Upon Dox withdraw, HB regressed over the long term. We analyzed gene expression patterns in mouse HB lesions upon short term Dox withdrawal, i.e, tumors still existed yet ΔN90-β-Catenin was turned off. This approach assisted to identify genes regulated by the activated β-Catenin in HB tumors. We compared these genes with the previously identified YAP regulated genes and found the distinct gene expression programs regulated by YAP and β-Catenin in HB. Specifically, YAP off down-regulated Hippo pathway and up-regulated metabolism-related pathways, whereas β-Catenin off down-regulated protein export, DNA replication pathway and up-regulated immune-related pathways. Finally, we identified ONECUT1 as a gene down-regulated by activated β-Catenin in HB. ONECUT1 expression was down-regulated in human HBs, and co-expression of ONECUT1 strongly suppressed Yap/β-Catenin HB formation in mice. Mechanically, ONECUT1 could regulate proliferation-related downstream signaling. Altogether our studies demonstrated that suppression of activated CTNNB1 mutations could repress HB progression in vivo, and we identified distinct pathways regulated by activated β-catenin and YAP in HB. Suppression of ONECUT1 expression by β-catenin is a key genetic event leading to HB formation.

Citation Format: Weiting Liao, Xin Chen. Distinct pathways regulated by activated β-Catenin and YAP in hepatoblastoma pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 140.
Abstract 1411: Cell-type-specific transcriptomic immune aging clocks reveal clinically relevant associations with chronic illnesses including cancer
Authors: Gurevich-Schmidt Yael , Wang Kun , Wu Di , Madan Sanna , Gopalan Vishaka , Sinha Sanju , Wang Binbin , Dhruba Saugato Rahman , Schäffer Alejandro A. , Ruppin Eytan
Published: March 2024

The aging of the immune system has profound implications for individual immune responses, yet precise quantification of immune age remains a challenge. Analyzing single-cell peripheral blood mononuclear cells (PBMC) transcriptomics data from 981 healthy individuals, we developed IMMClock (IMMune Clock), a human immune age clock derived from single cell transcriptomics. IMMClock is the first to accurately assess the age of three major immune cell types, CD8+ T cells, CD4+ T cells and NK cells, at the individual level. Testing the ability of these clocks to capture the dynamic aging process, we show that they reliably predict individuals' chronological ages across seven publicly available single-cell transcriptomics datasets and the large Framingham bulk transcriptomics cohort. IMMClock identifies cell type specific age-related pathways including apoptosis, interferon gamma response, and cytokine response. The application of IMMClock reveals several associations between immune aging of different cell-types and key clinical phenotypes during aging: it recapitulates the established observation of higher immune age in males compared to females and uncovers higher immune age in CD8+ T cells of smokers and individuals with chronic illnesses including cancer. Analyzing cancer patients’ data, IMMClock readings strongly correlate with CD8+ T cell exhaustion levels, and, quite strikingly, highlights an elevated immune age in the tumor microenvironment compared to blood.

Citation Format: Yael Gurevich-Schmidt, Kun Wang, Di Wu, Sanna Madan, Vishaka Gopalan, Sanju Sinha, Binbin Wang, Saugato Rahman Dhruba, Alejandro A. Schäffer, Eytan Ruppin. Cell-type-specific transcriptomic immune aging clocks reveal clinically relevant associations with chronic illnesses including cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1411.
Abstract 1494: Clonal dominance defines metastatic dissemination in pancreatic cancer
Authors: Ho I-Lin , Li Chieh-Yuan , Wang Fuchenchu , Zhao Li , Liu Jingjing , Yen Er-Yen , Dyke Charles A. , Shah Rutvi , Liu Zhaoliang , Çetin Ali Osman , Citron Francesca , Attanasio Sergio , Giuliani Virgina , Heffernan Tim , Do Kim-Anh , Gargiulo Gaetano , Draetta Giulio , Carugo Alessandro , Lin Ruitao , Viale Andrea
Published: March 2024

Tumors represent ecosystems where subclones compete during tumor growth. While extensively investigated, a comprehensive picture of the interplay of clonal lineages during dissemination is still lacking. Using patient-derived pancreatic cancer cells, we created orthotopically-implanted clonal replica tumors to trace clonal dynamics of unperturbed tumor expansion and dissemination. This model revealed the multifaceted nature of tumor growth, with rapid changes in clonal fitness leading to continuous reshuffling of tumor architecture and alternating clonal dominance as a distinct feature of cancer growth. Regarding dissemination, a large fraction of tumor lineages could be found at secondary sites each having distinctive organ growth patterns as well as numerous undescribed behaviors such as abortive colonization. Paired analysis of primary and secondary sites revealed fitness as major contributor to dissemination. From the analysis of pro- and non-metastatic isogenic subclones, we identified a transcriptomic signature able to identify metastatic cells in human tumors and predict patients’ survival.

Citation Format: I-Lin Ho, Chieh-Yuan Li, Fuchenchu Wang, Li Zhao, Jingjing Liu, Er-Yen Yen, Charles A. Dyke, Rutvi Shah, Zhaoliang Liu, Ali Osman Çetin, Francesca Citron, Sergio Attanasio, Virgina Giuliani, Tim Heffernan, Kim-Anh Do, Gaetano Gargiulo, Giulio Draetta, Alessandro Carugo, Ruitao Lin, Andrea Viale. Clonal dominance defines metastatic dissemination in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1494.