Superior antitumor immune response achieved with proton over photon immunoradiotherapy is amplified by the nanoradioenhancer NBTXR3.

Recent findings suggest that immunoradiotherapy (IRT), combining photon radiotherapy (XRT) or proton radiotherapy (PRT) with immune checkpoint blockade, can enhance systemic tumor control. However, the comparative efficacy of XRT and PRT in IRT remains understudied. To address this, we compared outcomes between XRT + αPD1 and PRT + αPD1 in murine αPD1-resistant lung cancer (344SQR). We also assessed the impact of the nanoparticle radioenhancer NBTXR3 on both XRT + αPD1 and PRT + αPD1 for tumor control and examined the tumor immune microenvironment using single-cell RNA sequencing (scRNAseq). Additionally, mice cured by NBTXR3 + PRT + αPD1 were rechallenged with three lung cancer cell lines to evaluate memory antitumor immunity. PRT + αPD1 showed superior local tumor control and abscopal effects compared to XRT + αPD1. NBTXR3 + PRT + αPD1 significantly outperformed NBTXR3 + XRT + αPD1 in tumor control, promoting greater infiltration of antitumor lymphocytes into irradiated tumors. Unirradiated tumors treated with NBTXR3 + PRT + αPD1 had more NKT cells, CD4 T cells, and B cells, with fewer Tregs, than those treated with NBTXR3 + XRT + αPD1. NBTXR3 + PRT + αPD1 also stimulated higher expression of IFN-γ, GzmB, and Nkg7 in lymphocytes, reduced the TGF-ß pathway, and increased tumor necrosis factor alpha expression compared to NBTXR3 + XRT + αPD1. Moreover, NBTXR3 + PRT + αPD1 resulted in greater M1 macrophage polarization in both irradiated and unirradiated tumors. Mice achieving remission through NBTXR3 + PRT + αPD1 exhibited a robust memory immune response, effectively inhibiting growth of subsequent tumors from three distinct lung cancer cell lines. Proton IRT combined with NBTXR3 offers enhanced tumor control and survival rates over photon-based treatments in managing αPD1-resistant lung cancer, indicating its potential as a potent systemic therapy.

Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation.

Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.

Defect Engineering of Ultrasmall TiO2 Nanoparticles Enables Highly Efficient Photocatalysts for Solar H2 Production from Woody Biomass.

The conversion of woody biomass to H2 through photocatalysis provides a sustainable strategy to generate renewable hydrogen fuel but was limited by the slow decomposition rate of woody biomass. Here, we fabricate ultrasmall TiO2 nanoparticles with tunable concentration of oxygen vacancy defects (VO-TiO2) as highly efficient photocatalysts for photocatalytic conversion of woody biomass to H2. Owing to the positive role of oxygen vacancy in reducing energy barrier for the generation of •OH which was the critical species to oxidize woody biomass, the obtained VO-TiO2 achieves rapid photocatalytic conversion of α-cellulose and poplar wood chip to H2 in the presence of Pt nanoclusters as the cocatalyst. As expected, the highest H2 generation rate in α-cellulose and poplar wood chip system respectively achieve 1146 and 59 µmol h-1 g-1, and an apparent quantum yield of 4.89% at 380 nm was obtained in α-cellulose aqueous solution.

[Chemical components and in vitro anti-aging activity of Yangxue Qingnao Wan based on UPLC-Q-TOF-MS/MS].

The main chemical components of Yangxue Qingnao Wan(YXQNW) were analyzed and identified by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS/MS). According to the mass spectrometry information, Mass Hunter 10.0 analysis software was used to compare the collected quasi-molecular ion peaks and secondary fragment ions with literature and reference substances. A total of 131 compounds were identified from YXQNW, including 11 phenylpropanoids, 11 flavonoids, 42 nitrogen-containing compounds, 12 terpenoids, 17 phthalides, 23 quinones, and 15 other compounds. The anti-aging activity of YXQNW and six compounds from YXQNW, including rosmarinic acid, gallic acid, rutin, umbelliferone, hyperoside, and vanillic acid, were evaluated by D-galactose(D-gal)-induced HT22 cell senescence model. The effects of the compounds on HT22 cell damage and individual cell proliferation ability were observed from overall and individual perspectives by the Beyo Click~(TM) EdU-555 cell proliferation kit, and apoptosis was detected by the Annexin V-FITC/PI double staining apoptosis detection kit. Finally, the anti-aging effect of the compounds was tested by a cell senescence ß-galactosidase staining kit. This study provides a more comprehensive analysis of the chemical components of YXQNW and evaluates its anti-aging effect, which will provide a scientific basis for basic research on the efficacy of YXQNW for the treatment of various neurological diseases, such as Alzheimer's disease(AD), headache, and memory loss.

Effects of Leydig cell elimination on testicular interstitial cell populations: characterization by scRNA-seq and immunocytochemical techniques.

Background: The mammalian testicular interstitial cells are not well-defined. The present study characterized the interstitial cell types and their turnover dynamics in adult rats. Additionally, the heterogeneity of the mesenchymal population and the effects of Leydig cell elimination on interstitial homeostasis were further analyzed by scRNA-seq datasets and immunocytochemical techniques. Methods: Interstitial cells were defined at the transcriptomic level by scRNA-seq and then confirmed and quantified with protein markers. The dividing activity of the major cell types was determined by continuous EdU labeling of the animals for one week. Some of the rats were also treated with a dose of ethylenedimethylsulfonate (EDS) to examine how the loss of Leydig cells (LCs) could affect interstitial homeostasis for three weeks. Results: Seven interstitial cell types were identified, including cell types (percentage of the whole interstitial population) as follows: Leydig (44.6%), macrophage and dendritic (19.1%), lymphoid (6.2%), vascular endothelial (7.9%), smooth muscle (10.7%), and mesenchymal (11.5%) cells. The EdU experiment indicated that most cell types were dividing at relatively low levels (<9%) except for the mesenchymal cells (MCs, 17.1%). Further analysis of the transcriptome of MCs revealed 4 subgroups with distinct functions, including 1) glutathione metabolism and xenobiotic detoxification, 2) ROS response and AP-1 signaling, 3) extracellular matrix synthesis and binding, and 4) immune response and regulation. Stem LCs (SLCs) are primarily associated with subgroup 3, expressing ARG1 and GAP43. EDS treatment not only eliminated LCs but also increased subgroup 3 and decreased subgroups 1 and 2 of the mesenchymal population. Moreover, EDS treatment increased the division of immune cells by more than tenfold in one week. Conclusion: Seven interstitial cell types were identified and quantified for rat testis. Many may play more diversified roles than previously realized. The elimination of LCs led to significant changes in MCs and immune cells, indicating the importance of LCs in maintaining testicular interstitial homeostasis.

Development and psychometric testing of the nurses' core competencies for public health emergencies scale: A multicenter cross-sectional study.

BACKGROUND: The significance of addressing public health emergencies (PHEs) emphasizes the pivotal role of a skilled nursing workforce in effective preparedness and response. However, there's a lack of comprehensive assessments tailored to nurses' core competencies, serving as a standard for ongoing education in preparedness. OBJECTIVE: This study aimed to develop a psychometrically sound scale for identifying and measuring essential core competencies crucial for nurses during public health emergencies. DESIGN: A multicenter cross-sectional study was conducted. SETTINGS: Twelve tertiary hospitals in Shanghai. PARTICIPANTS: Affiliated nurses with prior experience and significant exposure to public health emergencies were recruited. METHODS: The study underwent development and validation in two stages, utilizing qualitative data analysis, a Delphi expert panel, and an empirical quantitative cross-sectional survey. The Nurses' Core Competencies for Public Health Emergencies (NCC-PHEs) scale and a demographic questionnaire were distributed between January 2023 and March 2023. Exploratory factor analysis, confirmatory factor analysis, Pearson correlations, and Cronbach's alpha analyses were employed to identify theoretical constructs, assess scale reliability, and establish validity. RESULTS: Analysis was conducted on valid data collected from 1481 nurses. Factor analysis identified 47 professional nursing competencies arranged within a four-factor high-order model: prevention competencies (9 items), preparation competencies (7 items), response competencies (comprising basic and advanced levels) (26 items), and recovery competencies (5 items). Structural equation modelling confirmed satisfactory factor loadings and a good model fit, validating construct integrity. The reliability of the total scale was confirmed. CONCLUSION: This study presents a valid scale that empirically measures nurses' core competencies crucial for preparedness and response during public health emergencies. The findings offer instrumental support for guiding the development of future courses and training programs in nursing research and practice.

Novel engineered IL-2 Nemvaleukin alfa combined with PD1 checkpoint blockade enhances the systemic anti-tumor responses of radiation therapy.

BACKGROUND: Combining interleukin-2 (IL-2) with radiotherapy (RT) and immune checkpoint blockade (ICB) has emerged as a promising approach to address ICB resistance. However, conventional IL-2 cytokine therapy faces constraints owing to its brief half-life and adverse effects. RDB 1462, the mouse ortholog of Nemvaleukin alfa, is an engineered IL-2 with an intermediate affinity that selectively stimulates antitumor CD8 T and NK cells while limiting regulatory T cell expansion. This study aimed to evaluate the antitumor activity and mechanism of action of the combination of RDB 1462, RT, and anti-PD1 in mouse tumor models. METHODS: Two bilateral lung adenocarcinoma murine models were established using 344SQ-Parental and 344SQ anti-PD1-resistant cell lines. Primary tumors were treated with RT, and secondary tumors were observed for evidence of abscopal effects. We performed immune phenotyping by flow cytometry, analyzed 770 immune-related genes using NanoString, and performed T cell receptor (TCR) repertoire analysis. Serum pro-inflammatory cytokine markers were analyzed by 23-plex kit. RESULTS: Compared to native IL-2 (RDB 1475), RDB 1462 demonstrated superior systemic antitumoral responses, attributable, at least in part, to augmented levels of CD4 and CD8 T cells with the latter. Our findings reveal substantial reductions in primary and secondary tumor volumes compared to monotherapy controls, with some variability observed among different dosing schedules of RDB 1462 combined with RT. Blood and tumor tissue-based flow cytometric phenotyping reveals an increase in effector memory CD8 and CD4 T cells and a decrease in immunosuppressive cells accompanied by a significant increase in IL-2, IFN-γ, and GM-CSF levels in the combination group. Transcriptomic profiling and TCR sequencing reveal favorable gene expression and T cell repertoire patterns with the dual combination. Furthermore, integrating anti-PD1 therapy with RT and RDB 1462 further reduced primary and secondary tumor volumes, prolonged survival, and decreased lung metastasis. Observations of immune cell profiles indicated that RT with escalating doses of RDB 1462 significantly reduced tumor growth and increased tumor-specific immune cell populations. CONCLUSION: The addition of Nemvaleukin therapy may enhance responses to RT alone and in combination with anti-PD1.

DCC in the cerebral cortex is required for cognitive functions in mouse.

Schizophrenia (SZ) is a highly heritable mental disorder, and genome-wide association studies have identified the association between deleted in colorectal cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p-AKT and p-GSK3α/ß were decreased, which was responsible for impaired PPI in the DCC-deficient mice. Finally, the DCC-deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta-oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ-related risky gene and when defective, may promote SZ-like pathogenesis and behavioral phenotypes in mice.

Effects of unilateral nasal obstruction on mandibular condyle in mice of different ages: An exploration based on H-type angiogenesis coupling osteogenesis.

Nasal obstruction leads to a hypoxia condition throughout the entire body. In this study, the unilateral nasal obstruction (UNO) mouse model was established by blocking the left nostril of mice. The aim of this study was to investigate the effects of UNO-induced hypoxia on mandibular condyle in juvenile (3-week-old), adolescent (6-week-old) and adult (12-week-old) male C57BL/6J mice from the perspective of H-type angiogenesis coupling osteogenesis. Firstly, UNO exerted a significant inhibitory effect on weight gain in mice of all ages. However, only in adolescent mice did UNO have an obvious detrimental effect on femoral bone mass accrual. Subsequently, micro-computed tomography (CT) analysis of mandibular condylar bone mass revealed that UNO significantly retarded condylar head volume gain but increased condylar head trabecular number (Tb.N) in juvenile and adolescent mice. Furthermore, UNO promoted the ratio of proliferative layer to cartilage layer in condylar cartilage and facilitated the chondrocyte-to-osteoblast transformation in juvenile and adolescent mice. Moreover, although UNO enhanced the positive expression of hypoxia-inducible factor (HIF)-1α in the condylar subchondral bone of mice in all ages, an increase in H-type vessels and Osterix+ cells was only detected in juvenile and adolescent mice. In summary, on the one hand, in terms of condylar morphology, UNO has a negative effect on condylar growth, hindering the increase in condylar head volume in juvenile and adolescent mice. However, on the other hand, in terms of condylar microstructure, UNO has a positive effect on condylar osteogenesis, promoting the increase of condylar Tb.N, chondrocyte-to-osteoblast transformation, HIF-1α expression, H-type angiogenesis and Osterix+ cells in juvenile and adolescent mice. Although the changes in condylar morphology and microstructure caused by UNO have not yet been fully elucidated, these findings improve our current understanding of the effects of UNO on condylar bone homeostasis.