bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A043: Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme
Authors: Braun Sebastian , Oudenaarden Clara , Bolivar Paulina , Sjölund Jonas , Cordero Eugenia , Roslund Rebecca , Johansson Elinn , Pietras Alexander , Pietras Kristian 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.
Citation Format: Sebastian Braun, Clara Oudenaarden, Paulina Bolivar, Jonas Sjölund, Eugenia Cordero, Rebecca Roslund, Elinn Johansson, Alexander Pietras, Kristian Pietras. Pericytes orchestrate a tumor-suppressive microenvironment by impinging on the crosstalk between macrophages and tumor-initiating cells in glioblastoma multiforme [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A043.
Abstract B035: A compendium of syngeneic, transplantable pediatric high-grade glioma models reveals subtype-specific therapeutic vulnerabilities
Authors: McNicholas Michael , De Cola Antonella , Bashardanesh Zahedeh , Foss Amelia , Lloyd Cameron , Hebert Steven , Faury Damien , Andrade Augusto Faria , Jabado Nada , Kleinman Claudia , Pathania Manav 
Published: March 2024

Abstract
Pediatric high-grade gliomas (pHGGs) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomical locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities. Moreover, H3.3K27M tumors with PIK3CA, NF1 and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity.
Citation Format: Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron Lloyd, Steven Hebert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia Kleinman, Manav Pathania. A compendium of syngeneic, transplantable pediatric high-grade glioma models reveals subtype-specific therapeutic vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B035.
Abstract PR-010: Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors
Authors: McGrail Maura , Liu Fang , Kambakam Sekhar , Ming Zhitao 
Published: March 2024

Abstract
We generated a new zebrafish model of human brain cancer by Cre/lox regulated conditional inactivation of the tumor suppressor RB in embryonic neural progenitors. An ascl1b progenitor Cre driver was used to inactivate RB by Cre recombination of an intronic floxed mRFP gene trap cassette, leading to mRFP expression and lineage labeling of RB mutated cells. Beginning at 6 months of age adult fish developed poorly differentiated brain tumors, similar to our previous zebrafish brain tumor model generated by CRISPR targeting of RB in embryos. Tumor transcriptome analysis revealed a proneural transcription factor molecular signature of the olig2+/sox10+ human CNS primitive neuroectodermal tumor subtype. Overexpression of chromatin remodelers suggest epigenetic mechanisms may contribute to tumorigenesis. Our model will allow sorting of RB mutant cells from the earliest stage of mutagenesis in the embryo to induction of cellular transformation in juveniles. With this approach we can profile the epigenetic time course of cellular transformation and reveal new insight into the molecular mechanisms driving PNET oncogenesis. Our approach to model cancer in fish with Cre/lox conditional inactivation can be applied to other cell lineages and brain tumor types.
Citation Format: Maura McGrail, Fang Liu, Sekhar Kambakam, Zhitao Ming. Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-010.
Abstract A036: Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance
Authors: Wang Yinu , Calvert Andrea , Horacio Cardenas , Chen Fukai , Keathley Russell , Chen Ji-Xin , Thaxton Shad , Matei Daniela 
Published: March 2024

Abstract
Platinum (Pt) is the main therapy for ovarian cancer (OC); however, most patients develop Pt resistance (Pt-R). We show that Pt-R OC cells increase intracellular cholesterol through uptake via the HDL receptor, scavenger receptor type B-1 (SR-B1). SR-B1 blockade using synthetic cholesterol-poor HDL-like nanoparticles (HDL NPs) diminished cholesterol uptake leading to cell death and suppressed tumor growth. Reduced cholesterol accumulation induced lipid oxidative stress through reduction of glutathione peroxidase 4 (GPx4) leading to ferroptosis. In turn, GPx4 depletion is associated with reduced cholesterol uptake and re-sensitized OC cells to Pt. Mechanistically, GPx4 knockdown induced decreased expression of EP300, leading to reduced H3K27Ac on the SREBP2 promoter. Suppressed SREBP2 caused the downregulation of SR-B1. Thus, chemoresistance and cancer cell survival under a high ROS burden obligate high GPx4 and SR-B1 expression through SREBP2. Targeting SR-B1 to modulate cholesterol uptake inhibits this axis and causes ferroptosis in vitro and in vivo in Pt-R OC.
Citation Format: Yinu Wang, Andrea Calvert, Cardenas Horacio, Fukai Chen, Russell Keathley, Ji-Xin Chen, Shad Thaxton, Daniela Matei. Nanoparticle targeting in platinum-resistant ovarian cancer reveals dual axis of therapeutic vulnerability involving cholesterol uptake and cell redox balance [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A036.
Abstract A098: Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness
Authors: Nieddu Valentina , Melocchi Valentina , Battistini Chiara , Franciosa Giulia , Lupia Michela , Olsen Jesper , Colombo Nicoletta , Bianchi Fabrizio , Cavallaro Ugo 
Published: March 2024

Abstract
The clinical evolution of ovarian cancer (OC), with peritoneal dissemination, tumor relapse and chemoresistance, seems to be accounted for by a small population of ovarian cancer stem cells (OCSC), thus making them an attractive target for more efficacious treatments. However, this could only be achieved through the detailed characterization of the molecular and functional traits of this elusive cell subpopulation. Therefore, the identification of novel OCSC-associated targets and therapeutic approaches may offer alternative treatment options. We established a new platform of patient-derived organotypic models of OC and found that Matrix Gla Protein (MGP) was upregulated in cancer cells upon contact with the peritoneal tumor microenvironment. MGP is classically known as a vitamin K-dependent calcium chelator, mainly associated with the inhibition of tissue calcification and cardiovascular disease. In addition, MGP is also aberrantly expressed in different cancer types, but the biological mechanisms that regulate its functional contribution to cancer progression is still unknown. Our transcriptomic profiling of primary OCSC versus their non-stem counterpart pointed to MGP as a potential driver of cancer stemness. Indeed, we obtained evidence that MGP promotes, and is required for, stemness-associated biological features in vitro and in animal models, including sphere formation and tumor initiation. MGP was also implicated in the regulation of the expression of several key genes involved in stemness and/or EMT. Finally, MGP was upregulated in OC patients following chemotherapy, suggesting that the protein may be involved in OCSC-driven chemoresistance. The molecular mechanisms underlying MGP-regulated OCSC pathophysiology were investigated by RNA sequencing experiments on MGP-manipulated OC cells, which unveiled genetic networks and pathways that are orchestrated by MGP to promote OCSC function. The biological role of MGP in OC provides novel insight into the biology of OCSC, thus defining new pathways involved in OC stemness and paving the way to innovative therapeutic strategies for OC eradication.
Citation Format: Valentina Nieddu, Valentina Melocchi, Chiara Battistini, Giulia Franciosa, Michela Lupia, Jesper Olsen, Nicoletta Colombo, Fabrizio Bianchi, Ugo Cavallaro. Microenvironment-regulated matrix Gla protein drives ovarian cancer stemness [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A098.
Abstract B018: Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer
Authors: Lee Chaebin , Elias Kevin 
Published: March 2024

Abstract
Objective High grade serous ovarian cancer (HGSOC) represents the predominant subtype of epithelial ovarian cancer. Developing targeted therapies for HGSOC presents challenges due to its distinctive characteristic of copy number variation rather than recurrent somatic mutation. In our recent study, we proposed a novel approach for treating ovarian cancer by combining a gene editing system and nanotechnology, utilizing a cationic synthetic biopolymer, poly (γ-propargyl L-glutamine) (PPLQ). While our findings demonstrated promising results, we identified the presence of a negatively charged polymer layer, required for systematic delivery in vivo, significantly reduced both transfection efficiency and therapeutic efficacy. Therefore, an innovative approach to enhance transfection efficiency is desired to achieve improved treatment outcomes. Folate receptor alpha (FRα) is highly overexpressed in various epithelial cancers, including breast, lung, and ovarian cancer. Previous studies have revealed that FRα exhibits high tumor specificity, with epithelial ovarian cancers demonstrating 10 to 100-fold higher FRα expression levels compared to kidney, lung, and breast epithelial cells. Therefore, FRα is an attractive candidate for targeted therapy for ovarian cancer. Method In this study, we conjugated folic acid (FA), which has high affinity for FRα, to PPLQ to enhance gene delivery efficiency. Polyplexes were synthesized using FA conjugated PPLQ (FA-PPLQ) with pGL3 luciferase reporter vector. The particle size and the zeta potential were analyzed by Zetasizer, and transfection efficiency was evaluated by a luminescence assay. Result Compared to the positively charged PPLQ polyplexes, +55.5 mV, the FA-PPLQ polyplexes showed highly negative surface charges of -43.8 mV. The particle size was slightly increased from 35.07 ± 0.5422 for the PPLQ polyplexes to 48.63 ± 0.4239 for the FA-PPLQ polyplexes. The luminescence assay using a pGL3 luciferase reporter vector demonstrated a 74.4% improvement in transfection efficiency with FA conjugation compared to the negatively charged polymer layer. Conclusion Through the conjugation of folic acid to a cationic biopolymer, we successfully achieved enhanced transfection efficiency compared to a negatively charged polymer layer. Notably, the FA-PPLQ polyplexes exhibited a negative surface charge, which is advantageous for in vivo delivery. The results suggest that folic acid conjugation on the surface of polyplexes has a great promise as an effective approach for targeted gene therapy in HGSOC.
Citation Format: Chaebin Lee, Kevin Elias. Enhanced transfection efficiency with folic acid conjugated synthetic polymer nanoparticles for high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B018.
Abstract P28: Immunoproteasome inhibitors for the treatment of ALL
Authors: Kisselev Alexei F 
Published: March 2024

Abstract
The t(4;11)(q21;q23) chromosomal translocation that creates the MLL-AF4 fusion protein, confers a poor prognosis in infant acute lymphoblastic leukemia (ALL). This translocation also sensitizes cells to proteasome inhibitors bortezomib and carfilzomib, which are approved by the FDA for the treatment of multiple myeloma. Clinical activity of bortezomib in combination with standard chemotherapy has been documented in several clinical trials of ALL patients, and a case of a single-agent activity against relapsed leukemia driven by the MLL-AF4 translocation has been described. However, toxicities of bortezomib and carfilzomib linmit their use to treat to pediatric patients. We found that the overwhelming majority of proteasomes in this subtype of ALL are lymphoid tissue specific immunoproteasomes. Cells with MLL-AF4 translocations were sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitors ONX-0914 and M3258. Furthermore, both compounds dramatically delayed growth of orthotopic xenograft tumors in mice, and improved responce to induction chemotherapy. Thus, immunoproteasomes are therapeutic targets in ALL and replacing bortezomib and carfilzomib with immunoproteasome inhibitors in ALL should reduce toxicities associated with inhibition of the proteasomes in non-lymphoid tissues.
Citation Format: Alexei F Kisselev. Immunoproteasome inhibitors for the treatment of ALL [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P28.
Improving the Statistical Representation of Tropical Cyclone In-Storm Sea Surface Temperature Cooling
Authors: Wadler Joshua B. , Cione Joseph J. , Michlowitz Samantha , Jaimes de la Cruz Benjamin , Shay Lynn K. 
Published: March 2024

Abstract
This study uses fixed buoy time series to create an algorithm for sea surface temperature (SST) cooling underneath a tropical cyclone (TC) inner core. To build predictive equations, SST cooling is first related to single variable predictors such as the SST before storm arrival, ocean heat content (OHC), mixed layer depth, sea surface salinity and stratification, storm intensity, storm translation speed, and latitude. Of all the single variable predictors, initial SST before storm arrival explains the greatest amount of variance for the change in SST during storm passage. Using a combination of predictors, we created nonlinear predictive equations for SST cooling. In general, the best predictive equations have four predictors and are built with knowledge about the prestorm ocean structure (e.g., OHC), storm intensity (e.g., minimum sea level pressure), initial SST values before storm arrival, and latitude. The best-performing SST cooling equations are broken up into two ocean regimes: when the ocean heat content is less than 60 kJ cm−2 (greater spread in SST cooling values) and when the ocean heat content is greater than 60 kJ cm−2 (SST cooling is always less than 2°C), which demonstrates the importance of the prestorm oceanic thermal structure on the in-storm SST value. The new equations are compared to what is currently used in a statistical–dynamical model. Overall, since the ocean providing the latent heat and sensible heat fluxes necessary for TC intensification, the results highlight the importance for consistently obtaining accurate in-storm upper-oceanic thermal structure for accurate TC intensity forecasts.

Significance Statement
The ocean provides the heat and moisture necessary for tropical cyclone (TC) intensification. Since the heat and moisture transfer depend on the sea surface temperature (SST), we create statistical equations for the prediction of SST underneath the storm. The variables we use combine the initial SST before the storm arrives, the upper-ocean thermal structure, and the strength and translation speed of the storm. The predictive equations for SST are evaluated for how well they improve TC intensity forecasts. The best-performing equations can be used for prediction in operational statistical models, which can aid intensity forecasts.
Gender-Specific Pathways in Violent Crime: Investigating the Role of Demographic and Mental Health Factors Using Mixed Graphical Models and Bayesian Networks
Authors: Yan Wen-Jing , Zhao Jun-Hao , Chen Li 
Published: March 2024

This research aims to uncover gender-specific relationships and pathways that contribute to the perpetration of violent crimes, using sophisticated analytical tools to analyze the complex interactions between various factors. Employing Mixed Graphical Models and Bayesian networks, the study analyzes a sample of 1,254 prisoners (61.64% males and 38.36% females) to investigate the relationships among demographic factors, mental health issues, and violent crime. The study utilizes comprehensive measures, including the Beck Depression Inventory, Beck Anxiety Inventory, and Childhood Trauma Questionnaire, to assess participants’ mental health status. Key findings reveal significant gender differences in the pathways to violent crime. For males, incomplete parental marriages strongly correlate with criminal behavior severity, while marriage status emerges as a significant factor, with married males less likely to commit violent crimes. In contrast, these relationships are not significant for females. Bayesian network analysis indicates that living in urban areas differently influences education and emotional expression across genders, emphasizing the importance of contextual factors. The study highlights the need for gender-specific considerations in criminal justice policies and interventions. It underscores the complex interplay of demographic and mental health factors in influencing violent crime pathways, providing insights for developing more effective prevention strategies. Despite its cross-sectional design and reliance on self-reported data, the research significantly contributes to understanding the gendered dimensions of criminal behavior.
Virtual Reality simulation and Video Lecture are Equally Effective in Abscess Incision Training: A Multicentre Randomised Controlled Trial
Authors: Nuutinen Henrik , Bister Ville , Koljonen Virve 
Published: March 2024

Introduction The aim of the study was to evaluate undergraduate medical students’ knowledge and self-confidence to perform abscess incision after virtual reality-simulation or video lecture. Pre and post-knowledge assessment was conducted. Materials and Methods This was a multicentre randomised controlled trial from October 2021 to January 2022. The study was carried out at two universities providing medical education. Undergraduate medical students were randomized into either fully immersive head mounted display virtual reality-simulation (VR) or video lecture. Pre- and post-learning surveys probed self-confidence and student’s own assessment of competence. Participants were third-, fourth- and fifth-year medical students from the University of Eastern Finland and the University of Helsinki. All students were sent an email informing them of the opportunity to participate in this voluntary study. All willing students were included in the study. Results 42 medical students participated in the study. Most were fourth year medical students, 52% of the participants had previously used VR in some context and the mean age of participants was around 25 years. Both methods increased knowledge and self-confidence equally. In VR subgroup, those with technical support available experienced greater learning than those without. Conclusions Interestingly, in the present study, both VR and video lecture increased knowledge and professional self-confidence equally.