bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B059: Signaling Requirements for Enhanced CD8+ T Cell Responses in mRNA Cancer Vaccine Immunotherapy
Authors: Rashid Khalid , Lee Hailey R , Creech Amanda L , Luu Tony , Nguyen Katelyn , Teng Pu Lin , Zhao Weihang , Premji Alykhan M , Abt Evan R. , Le Thuc M , Wu Ting-Ting , Pardi Norbert , Radu Caius G 
Published: October 2024

Abstract
The development of nucleoside-modified mRNA vaccines in ionizable lipid-containing nanoparticles (iLNPs) has established a robust cancer immunization platform targeting tumor-associated antigens (TAAs). The substitution of uridine (U) with N1-methylpseudouridine (m1ψ) in these vaccines abrogates innate immune activation, maximizes antigen expression, and enhances the in vivo priming and expansion of adoptively transferred naïve CD8+ T cells. However, antigen-specific T cells primed under immunosilent conditions with m1ψ mRNA-iLNPs exhibit suboptimal effector functions, including impaired cytotoxic cytokine secretion and memory development. Our laboratory has demonstrated that U-mRNA-iLNP vaccines, which elicit a strong type I IFN response, achieve more prolonged tumor growth suppression compared to m1Ψ-mRNA-iLNP vaccines in a preclinical murine model of melanoma. Despite this, the clinical translation of U-mRNA-iLNP vaccines is constrained by dose-limiting toxicities in humans, mediated by cytokines such as IL-1β and IL-6. To overcome this limitation, we explored the co-delivery of a tumor antigen-encoding m1Ψ mRNA-iLNP vaccine and type I IFN in m1ψ mRNA within the context of adoptive cell transfer. Our results demonstrate that prime-boost vaccination with an mRNA-iLNP vaccine, which allows for high antigen expression and a tunable type I IFN response, significantly increases the frequency of antigen-specific CD8+ T cells in circulation and secondary lymphoid organs. Transcriptional profiling of CD8+ T cell subsets expanded by our mRNA vaccine platform revealed a polyfunctional effector signature, including Ifng, Prf1, Gzmb, Tnfα, Klrg1, and Lamp1, as well as enhanced expression of interferon-stimulated genes and costimulatory receptors. We are currently assessing the in vivo efficacy of our mRNA-vaccine platform in melanoma and PDAC orthotopic and liver metastatic models. These studies aim to provide comprehensive mechanistic insights into the requirements of a cancer mRNA-vaccine to generate potent anti-tumor CD8+ T cell responses.
Citation Format: Khalid Rashid, Hailey R Lee, Amanda L Creech, Tony Luu, Katelyn Nguyen, Pu Lin Teng, Weihang Zhao, Alykhan M Premji, Evan R. Abt, Thuc M Le, Ting-Ting Wu, Norbert Pardi, Caius G Radu. Signaling Requirements for Enhanced CD8+ T Cell Responses in mRNA Cancer Vaccine Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B059.
Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment
Authors: Singhal Deepak , Kutyna Monika M. , Hahn Christopher N. , Shah Mithun Vinod , Hiwase Devendra K. 
Published: October 2024

Abstract
Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy–induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment.
Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.
Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension
Authors: Kazmirczak Felipe , Vogel Neal T. , Prisco Sasha Z. , Patterson Michael T. , Annis Jeffrey , Moon Ryan T. , Hartweck Lynn M. , Mendelson Jenna B. , Kim Minwoo , Calixto Mancipe Natalia , Markowski Todd , Higgins LeeAnn , Guerrero Candace , Kremer Ben , Blake Madelyn L. , Rhodes Christopher J. , Williams Jesse W. , Brittain Evan L. , Prins Kurt W. 
Published: October 2024

BACKGROUND:
Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined.

METHODS:
Multiomics and physiological analyses evaluated how ferroptosis inhibition–modulated preclinical PAH. The impact of adeno-associated virus 1–mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension.

RESULTS:

Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage–associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-
Acsl4
induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository.

CONCLUSIONS:
Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.
Targeting Sphingosine-1-Phosphate Signaling to Prevent the Progression of Aortic Valve Disease
Authors: Benkhoff Marcel , Barcik Maike , Mourikis Philipp , Dahlmanns Jana , Kahmann Paulina , Wollnitzke Philipp , Hering Moritz , Huckenbeck Tim , Hoppe Julia , Semleit Nina , Deister-Jonas Jennifer , Zako Saif , Seel Jasmin , Coman Cristina , Barth Mareike , Cramer Mareike , Helten Carolin , Wildeis Laura , Hu Hao , Al-Kassis Gabrielle , Metzen Daniel , Hesse Julia , Weber Jessica , Dannenberg Lisa , Akhyari Payam , Lichtenberg Artur , Quast Christine , Gerdes Norbert , Zeus Tobias , Borst Oliver , Kelm Malte , Petzold Tobias , Ahrends Robert , Levkau Bodo , Polzin Amin 
Published: October 2024

BACKGROUND:
Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.

METHODS:
AVD progression and its consequences for cardiac function were examined in a murine wire injury–induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by liquid chromatography-mass spectrometry. Calcification of human valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by liquid chromatography-mass spectrometry.

RESULTS:
Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.

CONCLUSIONS:
Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.
Hippocampal microscopic fractional anisotropy is reduced in temporal lobe epilepsy
Authors: Arezza Nico J.J. , Abbas Hana H. , Chadwick Caroline , Johnsrude Ingrid S. , Burneo Jorge G. , Suller Marti Ana , Khan Ali R. , Baron Corey A. 
Published: October 2024

Abstract
Surgical resection is the method of choice for treating drug-resistant focal temporal lobe epilepsy (TLE). Postsurgical outcomes are better when magnetic resonance imaging (MRI) findings can localize the seizure focus for resection. However, many patients are MR-negative, meaning the focus cannot be differentiated from normal tissue in relaxation-weighted MRI. Diffusion MRI shows promise as a preoperative marker of neuronal abnormalities due to its sensitivity to cellular changes such as axon damage, indexed by fractional anisotropy. Microscopic fractional anisotropy is a recently introduced diffusion MRI metric that is sensitive to axon integrity regardless of axon orientation in both gray and white matter. In contrast, regular fractional anisotropy is only sensitive to axon integrity in coherently oriented bundles of fibers. This work investigated whether microscopic fractional anisotropy is sensitive to hippocampal abnormalities in drug-resistant TLE. Diffusion MRI was performed on a 3T scanner in 19 patients (age = 31 ± 10 years) with drug-resistant TLE (of which 10 were MR-negative) and 18 healthy volunteers (age = 38 ± 15). A deep-learning method was employed to segment the hippocampus into smaller subregions corresponding to the subiculum, cornu ammonis (CA) 1, CA2/3, and CA4 plus dentate gyrus (DG). Mean measurements of subregion volume, diffusivity, fractional anisotropy, and microscopic fractional anisotropy were compared between cohorts. In a subset of the TLE cohort suspected to have unilateral pathology (n = 15, age = 32 ± 10 years), the percentage differences between measurements ipsilateral and contralateral to the epileptogenic zone were evaluated to assess asymmetry. Microscopic fractional anisotropy was reduced in the hippocampus of drug-resistant TLE patients relative to healthy volunteers. In subregion-specific analysis, microscopic fractional anisotropy was significantly reduced in only the CA4/DG region in patients compared with healthy volunteers, after corrections for multiple comparisons. In the 15 patients with suspected unilateral pathology, microscopic fractional anisotropy was reliably and statistically lower in the ipsilateral CA4/DG region than in the contralateral side. Significant differences were not observed between TLE patients and healthy volunteers, or between hemispheres for patients with suspected unilateral pathology, for the fractional anisotropy or volume metrics. Diffusion MRI may complement standard imaging procedures by detecting abnormalities in MRI-negative patients. Due to its ability to detect abnormality regardless of axon orientation, microscopic fractional anisotropy may improve seizure focus localization in surgical candidates.
Detecting Spatiotemporal Dynamics of Western European Heatwaves Using Deep Learning
Authors: Happé T. , Wijnands J. S. , Fernández-Torres M. Á. , Scussolini P. , Muntjewerf L. , Coumou D. 
Published: October 2024

Abstract
Heatwaves over western Europe are increasing faster than elsewhere, which recent studies have attributed at least partly to changes in atmospheric dynamics. To understand the dynamical drivers of heatwaves, we develop a heatwave classification based on their spatiotemporal evolution over western Europe. We use the KNMI large-ensemble time scale (KNMI-LENTIS) large ensemble dataset of 1600 years of present-day climate and find approximately 14 000 heatwaves. To detect heatwaves, we use the Generalized Density-based Spatial Clustering of Applications with Noise (GDBSCAN) algorithm to cluster together grid points based on their surface temperature extremes. For each heatwave, we extract a 5-day window of daily sea level pressure and streamfunction at 250 hPa, capturing their near-surface and upper-level atmospheric circulation. We use a 3D variational autoencoder (VAE) to extract compact representations from this high-dimensional circulation dataset. We reduce the dimensionality to a 128-dimensional latent space, which we analyze with several algorithms (t-distributed stochastic neighbor embedding, k-means, and the Gaussian mixture model). This yields physically distinct types of heatwaves that are interpretable with known circulation patterns, i.e., U.K. high, Scandinavian high, Atlantic high, and Atlantic low. Our results indicate that the VAE can extract meaningful features from high-dimensional climate data. We find that the heatwave phase space, as found with opt-SNE, is continuous with the four circulation regimes at its corners but with soft boundaries between these circulation regimes, indicating that heatwaves are best categorized in a probabilistic way.

Significance Statement
To better understand the current mismatch in western European extreme temperature trends between observations and climate model simulations, we need to understand the different spatiotemporal atmospheric dynamics that lead to heatwaves in western Europe. We develop a method which identifies physically distinct types of heatwaves over western Europe using deep learning methods. Our method consists of a dimensionality reduction step, using a 3D variational autoencoder, and a clustering step, using k-means and the Gaussian mixture model. We identify four types of heatwaves, as well as transitional heatwaves in between, implying that heatwaves can be best categorized in a probabilistic way. This methodological framework can be applied to classify other extreme events as well.
miR-132-3p downregulates FOXO1 in CD4+ T cells and is associated with disease manifestations in patients with lupus
Authors: Qin Haihong , Chen Sunyi , Liu Xiao , Liang Jun , Wu Hao , Zhu Xiaohua 
Published: October 2024

Objective This study aimed to evaluate the expression status of miR-132-3p in CD4+ T cells in patients with systemic lupus erythematosus (SLE) and explore its potential role in SLE development. Methods The study included 60 patients with SLE and 30 healthy controls. miR-132-3p expression in CD4+ T cells was detected by real-time quantitative reverse transcription polymerase chain. Bioinformatics analyses were employed to predict target genes and explore the potential role of miR-132-3p. The associations between miR-132-3p levels and SLE Disease Activity Index (SLEDAI) score, as well as laboratory characteristics, were analyzed. Results miR-132-3p levels in CD4+ T cells were significantly higher in patients with SLE compared with healthy controls. Bioinformatics analysis identified FOXO1 as a potential target gene of miR-132-3p, with a particular emphasis on the FOXO signaling pathway. miR-132-3p up-regulation in CD4+ T cells was associated with high SLEDAI score, high anti-double-stranded DNA levels, low C3 and C4 levels, positive anti-ribosomal P, and high 24-hour urinary protein levels in patients with SLE. Conclusions miR-132-3p may contribute to CD4+ T cell dysregulation during SLE by targeting FOXO1 and could potentially be used to assess disease severity.
Effect of carbon nanotube incorporation on the mechanical and physical properties of hydroxyapatite/glass ionomer nanocomposite
Authors: Mohamed Yasser S , Abdelbary Ahmed 
Published: October 2024

This manuscript discusses the potential use of multi-walled (MW) carbon nanotubes (CNTs) as a filler material in hydroxyapatite/glass ionomer cement HA/GIC nanocomposite to enhance its properties: mechanical and physical. Four different proportions (1, 2, 3, and 5 wt%) of CNTs were added to the HA/GIC nanocomposite to determine the optimum ratio that can lead to the best properties of the new nanocomposite biomaterial. Mechanical mixing technique followed in dentistry was used in preparing all samples. FTIR, PSA, XRD, TEM, and SEM were used to characterize the fabricated Pellets. In addition, the new nanocomposite samples were evaluated using compressive and diametral tensile tests. Overall, increasing the weight ratio of CNTs added to the nanocomposite (from 1 to 5 wt%) caused about a 40% reduction in the compression strength of the samples. However, a slight increase (about 4%) was detected at 2 wt% CNTs samples. Also, a distinct increase in the elasticity of the composite (about 50%) was reported. The best results of diametral tensile strength were found at a 3 wt% CNTs. Furthermore, for all samples, adding CNTs to the composite changed the sample’s color from A2 and B2 to totally black color.
Omicron-COVID-19-Related Knowledge in Parkinson’s Disease Patients and Their Caregivers: A Cross-sectional Study
Authors: Dhiman Neetu Rani , Gyanpuri Vyom , Kumar Anand , Joshi Deepika 
Published: October 2024

Introduction The Omicron variant of SARS-CoV-2 (COVID-19) became the global community’s third major cause of worry. In the current study, we deployed a self-reported survey questionnaire to investigate the degree of comprehension, awareness and perception of the Omicron variant of COVID-19 in patients with Parkinson’s disease (PD) and their respective caregivers (CGs). Materials and Methods Using a standardised questionnaire, we conducted a prospective study on PD patients attending the neurology outpatient department prior to and during the COVID-19 pandemic. The study period was between February and August of 2022. Results A total of 114 CGs and 134 disease-affected patients were evaluated. Approximately 1.8% of the CGs and 4.5% of the patients contracted the Omicron-COVID-19. Over half of the patients (77.6%) were aware of the Omicron variant, and approximately 40.3% of them were aware of its symptoms. After receiving the Covid immunisation, patients (94.02%) reported no change in symptoms. The percentage of patients and CGs who had no symptoms of the viral infection and were not even got tested ever was 95.5% and 98.2%, respectively. Further, patients (95.5%) opted for the ‘offline’ as a preferred mode of consultation, citing the precision of treatment being the main reason. Conclusion No definite correlation between the Omicron variant infection and symptoms of PD could be established. The awareness regarding Omicron variant was largely unknown. More patient-centred research on larger population groups, incorporating literate and urban groups would unravel the knowledge gaps.
Resatovir Combined with Glycyrrhizic Acid Ameliorates Osteoarthritis and Enhances Autophagy in Chondrocytes
Authors: Mei Qijie , Xu Wenfei , Hu Qi , Guo Jinrong , Zeng Chao , Ming Chunyu , Li Chongming , Yuan Changshen , Duan Kan 
Published: October 2024

Background Osteoarthritis (OA) is a chronic disease worldwide. With resatovir usually used as an inhibitor, resatovir and glycyrrhizic acid have several pharmacological activities. Objectives We intend to explore the mechanism underlying resatovir combined with glycyrrhizic acid in OA. Materials and Methods After the establishment of an animal model of OA through anterior cruciate ligament transection and destabilization of the medial meniscus, the rats were subjected to intramuscular injection of resatovir combined with glycyrrhizic acid (60 mg/kg) or 5% glucose (60 mg/kg) every day for 4 weeks. During the progress, the rat movement and the bend score of knees were observed through behavioral studies. Additionally, the SKP2 gene expression and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB)-related signaling pathways were examined, as apoptosis and autophagy were evaluated by flow cytometry. Results With increased inflammatory cells in the model group, treatment with resatovir combined with glycyrrhizic acid significantly decreased the number of inflammatory cells. Meanwhile, the treatment resulted in decreased SKP2 expression in OA cells when hindering the migration of preosteoclast cells. Interestingly, it was observed that the bend score increased over the treatment with resatovir plus glycyrrhizic acid and TIPPI% declined dramatically. Resatovir treatment enhanced autophagy and apoptosis in OA cells and decreased pP65, P65, and LC3 expression. Conclusion Resatovir combined with glycyrrhizic acid can inhibit the inflammatory response through decreasing SKP2 expression and induce autophagy activation in OA cells through TLR4/NF-κB signaling, thereby attenuating OA progression.