bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Cement Treatment on Water Retention Behavior and Collapse Potential of Gypseous Soils: Experimental Investigation and Prediction Models
Authors: Abdulameer AlNaddaf Hussein Q. , Kouzegaran Saeed , Fattah Mohammed Y. , Akhtarpour Ali
Published: January 2024

Gypseous soil poses a significant challenge in geotechnical engineering due to its susceptibility to collapse under saturation. This type of soil covers approximately 33% of regions in Iraq, primarily in unsaturated conditions. This study focuses on two types of gypseous soils: one with moderate gypsum content from Karbala city (G1) and the other with high‐gypsum content from Tikrit city (G2), to investigate the effects of cement treatment on their water retention behavior and potential for reducing collapse. Different percentages of cement were mixed with both soils to determine the optimum soil–cement mixture for reducing collapse potential (CP) through single oedometer tests. The water retention characteristics and water retention behavior of samples with varying gypsum content and different levels of cement treatment were examined and compared using a controlled‐suction oedometer. The soil–water retention curve (SWRC) of these natural and treated gypseous soils was also investigated and compared in both wetting and drying paths. Additionally, multiple pedotransfer functions (PTFs) were assessed to identify or adapt prediction equation(s) for the SWRC of gypseous soil both with and without cement treatment with acceptable accuracy. The results show that adding cement can decrease the CP of gypseous soils; it also affects their SWRC significantly. By making some simple modifications, the PTFs demonstrate acceptable estimations for the water retention curve of both natural and cement‐treated gypseous soils.
Molecular Docking, Dynamics Simulations, ADMET, and DFT Calculations: Combined In Silico Approach to Screen Natural Inhibitors of 3CL and PL Proteases of SARS-CoV-2
Authors: Mohanasundaram Sugumar , Karthikeyan Porkodi , Sampath Venkatesan , Anbazhagan M. , Prabhu Sundramurthy Venkatesa , Khaled Jamal M. , Thiruvengadam Muthu
Published: January 2024

Considering natural compounds for the antiviral effect is another opportunity for exploring novel drug candidates for severe acute respiratory syndrome coronavirus 2. The selected natural compounds were interacted using a molecular docking approach. The 3D structures of the main protease and papain-like protease were used for the virtual screening to detect the potent inhibitor against SARS-CoV-2. The top-scored compounds were further analyzed for absorption, digestion, metabolism, excretion, and toxicity properties and density functional theory analysis. Our results indicated that glycyrrhizin exhibited better docking scores of -9.5 kcal/mol with main protease and -9.7 kcal/mol with papain-like protease. Next to glycyrrhizin, rutin showed a better docking score of -9.1 kcal/mol and -9.2 kcal/mol with 3-chymotrypsin-like and papain-like proteases. Violaxanthin and naringin occupied the subsequent position in the docking score table with 3CL and PL proteases, respectively. In addition, the crucial properties like drug likeliness and pharmacokinetics of the compounds were determined. There is no significant toxicity identified.
A Review of Over-the-Air Testing Methods for Performance Measurement of Antennas and Devices in Communication Systems
Authors: Duan Siqi , Wang Weimin , Tang Bihua , Wu Yongle , Liu Yuanan
Published: January 2024

With the fast development of communication techniques, over-the-air testing has developed into the main testing method for current communication systems due to its advantages including no cable connection, high measurement efficiency, and independence from environment. OTA testing has become almost the only solution for 5G system testing especially after the popularity of 5G massive multiple-input-multiple-output. In this paper, we summarize the three main methods of OTA testing including the reverberation chamber-based method, the radiation two-step method, and the multiprobe anechoic chamber- (MPAC-) based method, among which we focus on the MPAC method systematically. In the MPAC method, there are two main channel synthesis techniques that have been heavily studied, namely, prefaded signal synthesis and plane wave synthesis. We summarize the current main research based on these two techniques including probe configurations, probe selection algorithms, and probe design based on the PFS technique and the design of plane wave generators based on PWS technique. The main comparisons are made for the performance of different probe selection algorithms and the performance of different plane wave generators as well as the latest advances.
Intelligent Collaborative Optimal Scheduling for Water Intake‐Supply Pump Groups in Drinking Water Treatment Plants
Authors: Wang Dongsheng , Zhang Peng , Ma Haixiang , Li Zhixuan , Xu Suqian , Tan Chaoqun
Published: January 2024

Up to 80% of the electrical energy is consumed by pump groups in water purification plants. Optimizing the scheduling of water intake‐supply pump groups is crucial for saving electrical energy and reducing carbon dioxide emissions while ensuring water supply and security requirements are met. Herein, an intelligent collaborative optimal scheduling method is proposed for the water intake pump groups, clean‐water reservoirs, and water supply pump groups. A long short‐term memory (LSTM) network is applied to predict the flow of the water supply pump group, and a data‐driven approach is used to plan the flow of the water intake pump group and model the working characteristics of working pump configurations. Furthermore, based on the dynamic programming (DP) algorithm, the optimal scheduling scheme of the water intake‐supply pump groups as well as the working pump configuration at each moment can be obtained. The proposed approach dynamically updates data on an hourly basis to enhance the precision of collaborative optimal scheduling outcomes. The experimental results of long‐term operation showed that pump efficiency was increased by 10.68% and 10.70% of electric energy was effectively saved as compared to the results of previous manual scheduling. This study provides a solution for energy conservation and efficiency enhancement of multiple energy‐consuming equipment and carbon emission reduction.
Psychometric Properties of the Subhealth Measurement Scale V1.0 for Assessing Suboptimal Health Status of Midwives: A Multicentre Cross-Sectional Study
Authors: Chen Xiao-Qian , Jiang Xiu-Min , Zheng Qing-Xiang , Huang Xin-Xin , Liu Gui-Hua , Pan Yu-Qing , Bian Yan
Published: January 2024

Aim. Midwives are prone to suboptimal health status (SHS), while there is a lack of unified measurement standard of SHS for them to early detect and prevent SHS. This study aimed to evaluate validity and reliability of Subhealth Measurement Scale V1.0 (SHMS V1.0) in midwives. Design and Methods. The cross-sectional study had 842 midwives from 46 midwifery institutions in southeastern China completing the SHMS V1.0 with 39 items. Internal consistency, test-retest reliability, and concurrent validity of SHMS V1.0 were assessed. Project analysis and confirmatory factor analysis (CFA) were performed to assess construct validity. Results. SHMS V1.0 had acceptable reliability with Cronbach’s alpha and a test-retest reliability coefficient of 0.908 and 0.804, respectively. The correlation coefficients between each item and corresponding dimension and those between dimension and corresponding subscale were all greater than 0.4. The CFA supported the structure of SHMS V1.0 with strong factor loadings and excellent fit indexes in the first-order and modified second-order factor model, illustrating that SHMS V1.0 had good construct validity among midwives. The concurrent validity for SHMS V1.0 showed large correlation with FS-14, but the social subscale showed medium correlations with fatigue, inferring that SHMS V1.0 can more comprehensively reflect SHS of midwives than FS-14, especially for social health symptoms. Practice Implications. SHMS V1.0 with excellent psychometric properties can accurately and reliably evaluate the SHS of midwives. These findings of our study provide an important measurement tool and inspiration for midwives to early detect and prevent SHS.
Table S6 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S6
Table S12 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Table S12
Figure S4 from Glucose Deprivation Promotes Pseudohypoxia and Dedifferentiation in Lung Adenocarcinoma
Authors: Saggese Pasquale , Pandey Aparamita , Alcaraz Martín , Fung Eileen , Hall Abbie , Yanagawa Jane , Rodriguez Erika F. , Grogan Tristan R. , Giurato Giorgio , Nassa Giovanni , Salvati Annamaria , Shirihai Orian S. , Weisz Alessandro , Dubinett Steven M. , Scafoglio Claudio
Published: January 2024

Figure S4
Supplementary Table 1 from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong
Published: January 2024

Supplementary Table 1
Figure S4 from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong
Published: January 2024

Figure S4
Supplementary Figure 2 from Small Cell Lung Cancer Plasticity Enables NFIB-Independent Metastasis
Authors: Ko Julie H. , Lambert Kyle E. , Bhattacharya Debadrita , Lee Myung Chang , Colón Caterina I. , Hauser Haley , Sage Julien
Published: January 2024

NFIB is not required for metastasis in tumors initiated from a neuroendocrine cell of origin in the RPR2 mouse model
Data from The Chromatin Remodeler CHD4 Sustains Ewing Sarcoma Cell Survival by Controlling Global Chromatin Architecture
Authors: Graca Marques Joana , Pavlovic Blaz , Ngo Quy A. , Pedot Gloria , Roemmele Michaela , Volken Larissa , Kisele Samanta , Perbet Romain , Wachtel Marco , Schäfer Beat W.
Published: January 2024

Abstract
Ewing sarcoma is an aggressive cancer with a defective response to DNA damage leading to an enhanced sensitivity to genotoxic agents. Mechanistically, Ewing sarcoma is driven by the fusion transcription factor EWS-FLI1, which reprograms the tumor cell epigenome. The nucleosome remodeling and deacetylase (NuRD) complex is an important regulator of chromatin function, controlling both gene expression and DNA damage repair, and has been associated with EWS-FLI1 activity. Here, a NuRD-focused CRISPR/Cas9 inactivation screen identified the helicase CHD4 as essential for Ewing sarcoma cell proliferation. CHD4 silencing induced tumor cell death by apoptosis and abolished colony formation. Although CHD4 and NuRD colocalized with EWS-FLI1 at enhancers and super-enhancers, CHD4 promoted Ewing sarcoma cell survival not by modulating EWS-FLI1 activity and its oncogenic gene expression program but by regulating chromatin structure. CHD4 depletion led to a global increase in DNA accessibility and induction of spontaneous DNA damage, resulting in an increased susceptibility to DNA-damaging agents. CHD4 loss delayed tumor growth in vivo, increased overall survival, and combination with PARP inhibition by olaparib treatment further suppressed tumor growth. Collectively, these findings highlight the NuRD subunit CHD4 as a therapeutic target in Ewing sarcoma that can potentiate the antitumor activity of genotoxic agents.
Significance:
CRISPR/Cas9 screening in Ewing sarcoma identifies a dependency on CHD4, which is crucial for the maintenance of chromatin architecture to suppress DNA damage and a promising therapeutic target for DNA damage repair-deficient malignancies.
Data from Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong
Published: January 2024

Abstract
Stromal cells are physiologically essential components of the tumor microenvironment (TME) that mediates tumor development and therapeutic resistance. Development of a logical and unified system for stromal cell type identification and characterization of corresponding functional properties could help design antitumor strategies that target stromal cells. Here, we performed a pan-cancer analysis of 214,972 nonimmune stromal cells using single-cell RNA sequencing from 258 patients across 16 cancer types and analyzed spatial transcriptomics from 16 patients across seven cancer types, including six patients receiving anti–PD-1 treatment. This analysis uncovered distinct features of 39 stromal subsets across cancer types, including various functional modules, spatial locations, and clinical and therapeutic relevance. Tumor-associated PGF+ endothelial tip cells with elevated epithelial–mesenchymal transition features were enriched in immune-depleted TME and associated with poor prognosis. Fibrogenic and vascular pericytes (PC) derived from FABP4+ progenitors were two distinct tumor-associated PC subpopulations that strongly interacted with PGF+ tips, resulting in excess extracellular matrix (ECM) abundance and dysfunctional vasculature. Importantly, ECM-related cancer-associated fibroblasts enriched at the tumor boundary acted as a barrier to exclude immune cells, interacted with malignant cells to promote tumor progression, and regulated exhausted CD8+ T cells via immune checkpoint ligand–receptors (e.g., LGALS9/TIM-3) to promote immune escape. In addition, an interactive web-based tool (http://www.scpanstroma.yelab.site/) was developed for accessing, visualizing, and analyzing stromal data. Taken together, this study provides a systematic view of the highly heterogeneous stromal populations across cancer types and suggests future avenues for designing therapies to overcome the tumor-promoting functions of stromal cells.
Significance:
Comprehensive characterization of tumor-associated nonimmune stromal cells provides a robust resource for dissecting tumor microenvironment complexity and guiding stroma-targeted therapy development across multiple human cancer types.
Abstract A025: Autotaxin-lysolipid signaling suppresses a CCL11- eosinophil axis to promote pancreatic cancer progression
Authors: Bhattacharyya Sohinee , Oon Chet , Sandborg Holly , Morgan Terry , Sherman Mara H.
Published: January 2024

Among all cancer types, pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes. In recent studies, metabolic and microenvironmental reprogramming in PDAC has been shown to facilitate tumor progression by promoting immune escape mechanisms, however these mechanisms are still poorly understood. Recently, our lab established that autotaxin (ATX) - lysophosphatidic acid (LPA) signaling in PDAC enhances tumorigenicity, but the immunomodulatory function of this signal pathway remains largely unexplored. We now show that ablation of the LPA-producing enzyme autotaxin (ATX) in PDAC cells can reduce tumor burden in mice and reprogram the tumor immune microenvironment by increasing tumor eosinophil infiltration. The functional role of eosinophils in the context of PDAC is a poorly understood area. The presence of eosinophils in pancreatic cancer has been reported in a few case reports: for example, prior studies identified neutrophils and eosinophils together as a group, expressing high levels of CD66b. We confirmed the presence of eosinophils in PDAC in mice as well as patients, and we found that rare patient samples with the highest intratumoral eosinophil abundance had the longest survival rates. Genetic or pharmacologic ATX inhibition increased intratumoral eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. When eosinophils were present, primary tumor growth was modestly reduced, but metastatic spread was greatly reduced. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop wherein ATX-LPA signaling negatively regulates activity of AP-1 transcription factor c-Jun, in turn suppressing expression of potent eosinophil chemoattractant CCL11 (Eotaxin-1). This is the first study that highlights the anti-tumor potential of eosinophils in pancreatic cancer.

Citation Format: Sohinee Bhattacharyya, Chet Oon, Holly Sandborg, Terry Morgan, Mara H. Sherman. Autotaxin-lysolipid signaling suppresses a CCL11- eosinophil axis to promote pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A025.
Abstract A034: Thermoregulation alters adipose influence of pancreatic cancer growth
Authors: Eades Austin , Bye Bailey , Walsh R. McKinnon , VanSaun Michael
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States and has an abysmal 5-year overall survival of 12%. A major risk factor for PDAC is obesity- which has increased 12% between 1999-2018 in the United States. This rise correlates with the projection that PDAC is to become the second leading cause of cancer death by 2025. Clinically, reports show obese PDAC patients have a three-month decrease in overall survival when compared to lean PDAC patients. Multiple studies have implicated obese white adipose tissue (WAT) as promoting tumor progression. Yet only one study has investigated the effects of brown adipose tissue (BAT) on PDAC, which exhibited cold-mediated BAT activation steals glucose from the tumor. Aside from potential metabolic regulation, our group discovered that cold-mediated activated BAT elicited the release of anti-tumorigenic factors. We discovered this by exposing diet-induced obese mice to a subthermal environment via a thermogenic shift (TS) from thermoneutral (TN) housing. The TS BAT-conditioned media (CM) inhibited PDAC cell proliferation (EdU) and increased apoptosis (via cleaved caspase-3). Using a cytokine array, we identified endostatin as the most upregulated molecule in TS BAT-CM compared to TN BAT-CM. Incubation of PDAC cell lines with recombinant endostatin showed increased cleaved caspase-3. A shotgun-based proteomics screen uncovered novel endostatin binding partners and signaling mediators. In conclusion, we have identified a novel anti-tumorigenic role for activated BAT that further suggests its importance in relation to PDAC progression.

Citation Format: Austin Eades, Bailey Bye, R. McKinnon Walsh, Michael VanSaun. Thermoregulation alters adipose influence of pancreatic cancer growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A034.
Abstract A044: Tumor-infiltrating lymphocyte density correlates with survival in pancreatic adenosquamous carcinoma
Authors: Haldar Saurav D. , Jakubowski Christopher D. , Lim Su Jin , Wang Hao , Burkhart Richard A. , Lafaro Kelly , Burns William R. , He Jin , Laheru Daniel A. , Thompson Elizabeth D. , Azad Nilofer S.
Published: January 2024

Background: Pancreatic adenosquamous carcinoma (PASC) is a rare and aggressive form of pancreatic cancer, representing only 1-5% of cases. Histologically, it is defined by the presence of at least 30% squamous differentiation mixed with ductal adenocarcinoma. No standard therapies or prognostic biomarkers have been validated to date in this understudied disease. Methods: All patients diagnosed with pancreatic cancer in the Johns Hopkins Cancer Registry from 2013 to 2018 were queried for adenosquamous histology. Archived slides of available tumor specimens were examined to quantify the percentage of squamous differentiation and tumor-infiltrating lymphocyte (TIL) density. Descriptive statistics were used to summarize clinical, pathologic, and molecular characteristics. Kaplan-Meier estimates and log-rank tests were used for survival analyses. Results: Among a total of 8,908 patients queried, 155 patients with adenosquamous histology were identified. Median overall survival (OS) was 14.2 months and 7.5 months for resectable and unresectable/metastatic disease, respectively. Molecular tumor testing revealed frequent somatic mutations in KRAS, TP53, and SMAD4 in addition to multiple DNA damage repair genes. The percentage of squamous differentiation and TIL density was correlated with survival outcomes in a subset of 28 patients with evaluable tumor specimens. No association between the percentage of squamous differentiation and OS was identified. Of note, compared to those with low TIL density (0-10%), patients with an intermediate/high TIL density (>10%) exhibited significantly improved survival (median OS 36.3 vs 14.2 months, p = 0.011). Conclusions: For the first time, intermediate/high TIL density is associated with prolonged OS in a single-institution cohort of PASC patients. Prospective validation in larger cohorts is needed to establish prognostic biomarkers that can guide therapeutic decision-making in this lethal and under-examined disease subtype.

Citation Format: Saurav D. Haldar, Christopher D. Jakubowski, Su Jin Lim, Hao Wang, Richard A. Burkhart, Kelly Lafaro, William R. Burns III, Jin He, Daniel A. Laheru, Elizabeth D. Thompson, Nilofer S. Azad. Tumor-infiltrating lymphocyte density correlates with survival in pancreatic adenosquamous carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A044.
Abstract A045: Persistence of the splanchnic gene signature along the mesenchymal cell trajectory during pancreatic cancer progression
Authors: Han Lu , Walter Tom , Beaudet Joseph , Everett Caroline , Piermattei Julia , Adams Alex , Fang Kun , Zimmermann Michael , Mathison Angela , Urrutia Raul , Jin Victor , Leone Gustavo , Ostrowski Michael
Published: January 2024

In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. While fibroblasts are sparse in the normal adult pancreas, CAFs are a major component in the desmoplastic stroma of PDAC and may account for half of the entire tumor tissue. Here we aimed to investigate the origin, diversification, and function of CAFs. We constructed a dual-DNA-recombinase mouse genetic model, which allowed for genetic alternations in pancreatic epithelial cells and fibroblasts independently and simultaneously. The splanchnic mesenchyme is a layer of tissue adjacent to the pancreatic endoderm during fetal development. Our lineage tracing studies demonstrated that the splanchnic mesenchyme is the fetal origin of adult pancreatic fibroblasts during homeostasis and tumorigenesis. Notably, the other two postulated CAF sources, bone marrow and epithelial cells, have minimal contributions to fibroblasts. We further compared mice carrying no genetic mutations, only Kras mutation, and Kras/p53 dual mutations in pancreatic epithelial cells. We found that fibroblasts in all three conditions are derived from the splanchnic mesenchyme, suggesting a continuous mesenchymal trajectory in coordination with the pancreatic epithelium. Additionally, single cell transcriptomic analysis indicated persistent and dynamic gene expressions along the pancreatic mesenchymal trajectory during development, homeostasis, precancer lesion and cancer. Intriguingly, certain splanchnic factors are expressed in adult pancreatic fibroblasts in temporally and spatially distinct patterns. To determine the function of splanchnic factors in fibroblasts, we constructed mouse genetic models to delete GATA6 specifically in CAFs, which resulted in increased tumor burden in the pancreas. This suggests a non-cell autonomous function of GATA6 in CAFs to restrain pancreatic cancer progression. In summary, this study delineated a continuous cell trajectory of the mesenchymal lineage in the pancreas across different life stages. Furthermore, persistent gene expressions along the mesenchymal trajectory contributes to pancreatic CAF heterogeneity. Importantly, such persistence may constitute an inherent mechanism to restrain pancreatic cancer.

Citation Format: Lu Han, Tom Walter, Joseph Beaudet, Caroline Everett, Julia Piermattei, Alex Adams, Kun Fang, Michael Zimmermann, Angela Mathison, Raul Urrutia, Victor Jin, Gustavo Leone, Michael Ostrowski. Persistence of the splanchnic gene signature along the mesenchymal cell trajectory during pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A045.
Abstract A081: The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies
Authors: Ahmed Ahmed , Arshad Tariq , Neidle Stephen
Published: January 2024

Quadruplexes (G4s) are formed from G-rich elements widely prevalent in the human and other genomes. They comprise repetitive G-tracts of varying length, interspersed with short general sequences, which can fold into higher-order four-stranded G4 structures under appropriate circumstances. Their prevalence is non-random, and they are over-represented in the promoter and untranslated regions of genes involved in replication and replication pathways, especially in cancer-related events and pathways. Promoter G4s have been characterised in, for example, the RAS, MYC, KIT, B-RAF, HIF, VEGF genes. The existence of stable G4 structures within duplex DNA is likely to be transient since they can be effectively unwound by helicases. However, it is now well-established that they can be stabilised by appropriate small molecules, leading to impairment of polymerase precession and transcription factor binding, and then to down-regulation of the expression of the affected gene. This therapeutic strategy has been exploited in the design of a series of potent G4-binding compounds based on the naphthalene diimide framework, culminating in the development of the compound QN-302, which has selectivity to PDAC cell lines with low nM potency. It is also active in several in vivo models of PDAC. Its transcriptional profile shows that it affects multiple G4 promoter genes and thus acts as a pan-G4 agent. QN-302 has been undergoing pre-clinical development by Qualigen Inc and in 2022 was granted Orphan Drug designation for PDAC by the FDA. It is currently being evaluated for clinical development in solid tumors including PDAC. As part of this program, several potential biomarkers are currently being considered. These in large part are suggested by the transcriptome analyses of QN-302 in cells and in vivo. They are established markers of progressive PDAC and thus may be useful for indicating the success of QN-302 therapy in humans. In addition, our orthotopic study of the effects of QN-302 on orthotopically implanted BX-PC3 tumors has indicated that circulating tumor DNA may be a useful indicator of tumor regression by QN-302.

Citation Format: Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The pan-quadruplex experimental drug QN-302 in pancreatic ductal adenocarcinoma (PDAC): Potential biomarkers for clinical studies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A081.
Abstract A093: Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma
Authors: Dilly Julien , Abbassi Laleh , Hennessey Connor J. , Uribe Giselle A. , Parent Brendan , Yang Annan , Kapner Kevin S. , Li Ziyue , Dasgupta Shatavisha , Jordan Alexander , Hoffman Megan T. , Qiang Li , Hambitzer Felix P. , Chugh Seema , Shalek Alex K. , Dougan Stephanie K. , Wolpin Brian M. , Nowak Jonathan A. , Raghavan Srivatsan , Winter Peter S. , Aguirre Andrew J.
Published: January 2024

KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) and is mutationally activated in approximately 90% of cases, with the glycine-to-aspartic acid substitution at position 12 (p.G12D) being the most prevalent alteration. Mutations in this oncogene have been associated with more aggressive disease and poorer outcomes and have remained “undruggable” for more than three decades. However, the recent development of mutant-specific small molecule inhibitors of KRAS has given hope for the treatment of this highly lethal and treatment-refractory malignancy. Here we evaluated the genomic and transcriptional mechanisms of resistance to MRTX1133, a first-in-class inhibitor of KRASG12D, in an autochthonous mouse model of PDAC. We leveraged single-nucleus RNA sequencing and whole-exome sequencing on 16 samples from KPC mouse specimens (LSL-KrasG12D/+; LSL-Trp53R172H/+; p48-Cre) that were treated with either MRTX1133 or the vehicle, including 6 samples from mice that developed resistance to KRASG12D inhibition. Our analysis has uncovered that resistance is multifaceted and characterized by both emergent genomic and transcriptional features. Genetically, resistant tumors harbored clonal and subclonal amplifications in the HIPPO pathway, cell cycle regulators, and ABC transporters. Transcriptionally, we employed non-negative matrix factorization and identified recurrent gene expression programs in resistant and vehicle samples. Using this approach, we uncovered the existence of an intermediate phenotype between classical and mesenchymal cell states that is enriched in tumors with evolved resistance to MRTX1133. In summary, our study provides a high resolution genomic and transcriptional landscape of resistance to KRAS targeting in a preclinical in vivo model of PDAC, highlighting the complexity of treatment resistance and identifying various pathways and effectors that may serve as potential new targets for combination therapy.

Citation Format: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Shatavisha Dasgupta, Alexander Jordan, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre. Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A093.
Abstract A096: PIKfyve as a potential therapeutic target in pancreatic cancer
Authors: Grenier Shea , Galapate Cheska , Zhang Yijuan , Arora Gurpreet , Olson Steven , Emerling Brooke , Commisso Cosimo
Published: January 2024

A lack of effective treatments beyond surgical resection and chemotherapy contributes to the 12% five-year survival rate of pancreatic ductal adenocarcinoma (PDAC), underscoring the need to identify novel therapeutic approaches. Pharmacological inhibition of phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) with small molecules has been demonstrated to have therapeutic effects in tauopathies, viral infection, and cancer; however, these compounds have not been evaluated in PDAC. The PIKfyve lipid kinase generates PI5P and/or PI(3,5)P2 from phosphoinositol (PI) or PI3P, respectively, and is associated with cellular signaling, membrane homeostasis, and vesicular trafficking. Evidence suggests that PIKfyve inhibitors exhibit anti-cancer effects through autophagy inhibition and lysosomal impairment in non-Hodgkin’s B cell lymphoma, multiple myeloma, and prostate cancer, among other cancer types. Here, we report that the treatment of PDAC cells with apilimod, a PIKfyve-specific inhibitor, results in increased cytoplasmic vacuolization, a characteristic phenotype, increased expression of transcription factor EB (TFEB), and antiproliferative effects in vitro. We also demonstrate that apilimod is a novel inhibitor of macropinocytosis, an endocytic mechanism of nutrient uptake in PDAC. YM201636, another PIKfyve inhibitor, exhibits similar vacuolization and cytostatic effects in PDAC cells. Importantly, preliminary data suggests that genetic knockdown of PIKfyve phenocopies the observed pharmacological effects in vitro. Future experiments will assess the mechanistic underpinnings of PIKfyve function using agonists and endosomal inhibitors and will investigate the in vivo therapeutic potential of targeting PIKfyve in PDAC. Combined, this study will assess PIKfyve as a potential target in the treatment of PDAC for which novel therapeutics are urgently needed.

Citation Format: Shea Grenier, Cheska Galapate, Yijuan Zhang, Gurpreet Arora, Steven Olson, Brooke Emerling, Cosimo Commisso. PIKfyve as a potential therapeutic target in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A096.
Abstract A118: Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignancy and rapid recurrence
Authors: MacPherson Kevin , Link Jason M. , Worth Patrick , Sheppard Brett , Fields Andrew , Daniel Colin , Nishida Andrew , Pelz Carl , Waugh Trent , Agritelle Ethan , Muschler John , Adey Andrew , Sears Rosalie
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) disease progression involves complex cell state transitions in both malignant and non-malignant populations within the tumor microenvironment. To uncover PDAC cell states and epigenetic features associated with clinical outcome, we studied 42 PDAC samples (35 primary tumors and 7 metastases) from 41 patients with single cell ATAC-seq, along with 10 sample-matched single cell RNA-seq profiles. Our work uncovered thousands of chromatin regions with altered accessibility in malignant cells relative to normal ductal and acinar cells. Numerous epigenetic changes were universal to all PDAC clusters regardless of patient-of-origin and occurred proximal to genes involved in glycolysis, regulation of MYC, hypoxic response, extracellular matrix remodeling, and repression of transposable elements. Topic modeling of high dimensional chromatin data revealed networks of co-accessible cis-regulatory regions active in malignant cells, as well as networks specific to basal-like and classical PDAC molecular subtypes. Furthermore, our epigenomic data also suggest alternate paths of lineage infidelity across the classical-basal continuum: while basal-like PDAC cells acquire chromatin accessibility mimicking that of skin or mammary epithelial tissue, several classical subtype tumors featured a subpopulation of malignant cells with increased accessibility of neural-associated chromatin regions genome-wide. Within the immune compartment, we also identified a cis-regulatory network with increased activity in T-cells sampled from rapidly recurring PDAC tumors. Motif analysis of this network revealed enrichment for SMAD and FOXP1 motifs, suggesting widespread modification of T-cells by TGF-β. To our knowledge, our work is the largest single-cell resolution study of chromatin state in human PDAC to date, revealing key epigenetic features associated with PDAC subtype and clinical outcome.

Citation Format: Kevin MacPherson, Jason M. Link, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelle, John Muschler, Andrew Adey, Rosalie Sears. Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignancy and rapid recurrence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A118.
Abstract B007: Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker
Authors: Honda Kazufumi , Kashiro Ayumi H. , Kobayashi Michimoto , Takeuchi Keiko , Shizume Yuya , Oh Takanori , Morizane Chigusa , Hijioka Susumu , Nara Satoshi
Published: January 2024

To reduce the mortality rate of pancreatic cancer, there is an urgent need to develop a biomarker that can efficiently screen for pancreatic cancer in blood tests. We had identified the unique processing of C-terminal amino acids of apolipoprotein A2 homodimers, we named it apolipoprotein A2-isoforms (apoA2-i). ApoA2-i consists of three isoforms with different C-terminal amino acids. Especially, we had reported that apoA2-ATQ/AT, known as the intermediate isoform, was significantly reduced in the bloodstream of pancreatic adenocarcinoma (PDAC) patients compared to healthy controls. However, previous reports were investigated using a research use only (RUO) reagent, which could not be used in clinical settings. We generated a novel ELISA for measuring apoA2-i under the Japanese medical device Quality Management System requirements, and measured the concentration of apoA2-i in 2,732 of plasma samples. The clinical equivariance and significance of apoA2i were evaluated by pre-specified endpoints. The point estimate of the area under the curve to distinguish between PDAC and healthy controls was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832–0.925] than for CA19-9 (0.849, 95%CI: 0.793–0.905) and achieved the primary endpoint. The cut-off apoA2-ATQ/AT of 59.5 μg/mL was defined based on 95% specificity in 2,000 healthy samples. The sensitivity of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) of PDAC was higher than that of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cut-off, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. ApoA2-ATQ/AT has equivalent or better clinical performance to CA19-9 as a blood biomarker.

Citation Format: Kazufumi Honda, Ayumi H. Kashiro, Michimoto Kobayashi, Keiko Takeuchi, Yuya Shizume, Takanori Oh, Chigusa Morizane, Susumu Hijioka, Satoshi Nara. Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B007.
Abstract B008: Secretome labeling identifies gelsolin as a potential pro-tumorigenic PDAC biomarker
Authors: Kastan Jonathan P. , Standring Oliver , Cifani Paolo , Gaeth Victoria , Jensen Amanda , Park Youngkyu , Tuveson David
Published: January 2024

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy with a 5-year survival rate around 10% due to late detection and therapeutic resistance. Thus, new methods to detect PDAC earlier in high-risk and general populations are greatly needed. Early detection tests have historically relied on circulating nucleic acids or proteins that have been identified as enriched in patients with PDAC by large-scale studies, but they often lack a firm basic biological context that would bolster the sensitivity and specificity of these tests. To this end, we have introduced a construct into PDAC organoid and 2D lines that enables the labeling of PDAC-secreted proteins with biotin (Sec61-BioID) in vitro and in vivo. With this system, we can specifically isolate the PDAC secretome and identify the proteins via mass spectrometry. From this approach, we have identified Gelsolin (GSN), an enzyme that regulates actin dynamics, as a highly secreted protein by a panel of PDAC cell lines in vitro and in vivo. We have explored the biological role of secreted GSN in PDAC tumorigenesis via CRISPR knockout. GSN knockout abrogated the growth of PDAC tumors in NSG mice, and we are delineating the potential mechanisms that explain this defect via histological analysis and in vitro cell proliferation and invasion assays. Additionally, we have analyzed purified secreted GSN from PDAC lines by mass spectrometry to identify potential post-translational modifications that may differentiate PDAC-derived GSN from other GSN molecules, secreted by healthy tissue, in circulation. We are currently utilizing biochemical approaches to validate these putative modifications and define their specificity in PDAC patient blood as compared to healthy age-matched controls.

Citation Format: Jonathan P. Kastan, Oliver Standring, Paolo Cifani, Victoria Gaeth, Amanda Jensen, Youngkyu Park, David Tuveson. Secretome labeling identifies gelsolin as a potential pro-tumorigenic PDAC biomarker [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B008.
Abstract B023: Hypoxia supports CAF-mediated epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma
Authors: Kowalewski Karl , Lazzara Matthew
Published: January 2024

The pancreatic ductal adenocarcinoma (PDAC) microenvironment is populated by distinct subtypes of cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) that synthesize and remodel the stromal matrix and inflammatory CAFs (iCAFs) that secrete cytokines and growth factors. Subpopulations of CAFs reside in regions of tumor hypoxia, which may play a role in determining CAF behaviors. We tested the hypothesis that iCAFs preferentially drive ductal cell epithelial-mesenchymal transition (EMT), which promotes PDAC chemoresistance, and that hypoxia promotes the iCAF phenotype. Cell-cell communication analysis using publicly available single-cell RNA sequencing (scRNA-seq) data of human tumors indicated that iCAFs secrete growth factors predicted to promote ductal cell EMT. This inference was confirmed in experiments showing that PDAC cells exhibit stronger EMT in response to conditioned medium from iCAFs than from myCAFs. Publicly available scRNA-seq data further indicated a correlation between hypoxia and the iCAF phenotype. qRT-PCR and immunofluorescence microscopy confirmed that hypoxia promotes the iCAF phenotype, and conditioned medium experiments demonstrated the preferential ability of hypoxic CAFs to utilize an NFκB-dependent pathway to secrete cytokines that promote EMT. A screen of 430 kinase inhibitors nominated specific growth factors that we validated to be EMT-inducing and generated by hypoxic CAFs. Finally, iterative indirect immunofluorescence imaging (4i) of tumor sections from KrasLSL-G12D/+; Trp53LSL-R172H/+, Pdx1-Cre; Rosa26YFP/YFP (KPCY) mice and quantitative image analysis demonstrated a spatial correlation in PDAC tumors between mesenchymal neoplastic cells and hypoxic CAFs. Our results raise the intriguing possibility that hypoxia cooperates with CAFs to promote EMT in PDAC and identify drug targets whose antagonism may interfere with a PDAC-stromal signaling process that promotes chemoresistance.

Citation Format: Karl Kowalewski, Matthew Lazzara. Hypoxia supports CAF-mediated epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B023.
Abstract B056: Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs
Authors: Jara Carlos P. , Al-Gahmi Al-Murtadha , Le Binh , Carlson Mark A.
Published: January 2024

An innovative approach in pancreatic cancer (PC) research is to utilize large animal models which (i) would be useful for development of technologies that require a human-sized platform and (ii) would produce data that could have greater clinical relevance and accuracy compared to data produced by murine models. To this end, our group has been developing porcine PC models and has reliably induced PC in the KRAS G12D/p53 R167H Oncopig model. The objective of the present study was to generate a slower-growing, early-stage PC model with intraductal injection of adenoviral vector with a Keratin 8 promoter driving the expression of the Cre-Recombinase protein (Ad5mK8-nlsCre) in oncopigs which, we hypothesized, would produce pancreatic neoplasia restricted to the epithelium. Results We first confirmed with scRNA-seq and immunohistochemistry that Keratin-8 expression in the porcine pancreas was restricted to ductal and acinar cells. Using an ex vivo infection assay with the Ad5mK8-nlsCre vector in wild-type porcine pancreas, we then demonstrated that expression of Cre-recombinase was confined to epithelial cells. We then performed a dose-response study of ductal injection (laparotomy) of Ad5mK8-nlsCre (10(7)-10(10) pfu) in Oncopigs. At the planned 2-month endpoint, all Ad5mK8-nlsCre concentrations produced microscopic evidence of ductal hyperplasia, metaplasia, and nuclear atypia, with KRAS-G12D expression by immunohistochemistry. At the higher Ad5mK8-nlsCre concentration, there was increased ductal mucin production. Using an epithelial-specific AdCre vector, we produced microscopic epithelial neoplasia within the pancreas of the Oncopig. Conclusion While further follow-up and characterization is needed, this induction technique may yield a porcine model of early-stage PC, which could be useful to (i) study early tumor biology and progression and (ii) develop diagnostic and interventional technologies for early tumor management.

Citation Format: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson. Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B056.