Gliomas, especially high-grade gliomas such as glioblastoma multiforme (GBM), are primary malignant tumors of the central nervous system, characterized by high proliferative capacity, invasiveness, and therapeutic resistance. The development of GBM relies heavily on continuous metabolic reprogramming to adapt to the unique intracranial microenvironment, with nicotinamide adenine dinucleotide (NAD⁺) metabolic remodeling playing a pivotal role. Dysregulation of NAD⁺ and its associated metabolic pathways sustains increased intracellular NAD⁺ levels, which drive the malignant proliferation and invasive potential of GBM, correlating with worsened patient prognosis. This review systematically summarizes the current research landscape of NAD⁺ metabolic remodeling in GBM, elucidates the mechanisms by which NAD⁺ contributes to GBM pathogenesis and progression, and explores the clinical potential of NAD⁺-targeted diagnostic and therapeutic strategies to provide novel insights and directions for the clinical management of GBM.

OBJECTIVE: To analyze the time characteristics of the Ethos online adaptive radiotherapy (OART) process in clinical practice and provide guidance for the comprehensive optimization of each stage of adaptive radiotherapy. METHODS: The study involved 61 patients with cervical, rectal, gastric, lung, esophageal, and breast cancers who underwent Ethos OART. The mean ± standard deviation of segmental time, total time, and target volume for these patients were tracked. The time characteristics for different cancer types were evaluated, and the average time for target and organ at risk (OAR) modifications was compared with the average target volume for each cancer type. RESULTS: Cervical cancer born the longest total treatment time, while breast cancer had the shortest. For all cancer types except breast cancer, the modification time for target and OAR was the most time-consuming segment. The average time for target and OAR modifications aligned with the trend of the average target volume. CONCLUSION The total treatment time for various cancers ranges from 15 to 35 minutes, indicating room for improvement.
Humans ; Radiotherapy Planning, Computer-Assisted/methods* ; Neoplasms/radiotherapy* ; Female

Pharmacotranscriptomic profiles, which capture drug-induced changes in gene expression, offer vast potential for computational drug discovery and are widely used in modern medicine. However, current computational approaches neglected the associations within gene‒gene functional networks and unrevealed the systematic relationship between drug efficacy and the reversal effect. Here, we developed a new genome-scale functional module (GSFM) transformation framework to quantitatively evaluate drug efficacy for in silico drug discovery. GSFM employs four biologically interpretable quantifiers: GSFM_Up, GSFM_Down, GSFM_ssGSEA, and GSFM_TF to comprehensively evaluate the multi-dimension activities of each functional module (FM) at gene-level, pathway-level, and transcriptional regulatory network-level. Through a data transformation strategy, GSFM effectively converts noisy and potentially unreliable gene expression data into a more dependable FM active matrix, significantly outperforming other methods in terms of both robustness and accuracy. Besides, we found a positive correlation between RS_GSFM and drug efficacy, suggesting that RS_GSFM could serve as representative measure of drug efficacy. Furthermore, we identified WYE-354, perhexiline, and NTNCB as candidate therapeutic agents for the treatment of breast-invasive carcinoma, lung adenocarcinoma, and castration-resistant prostate cancer, respectively. The results from in vitro and in vivo experiments have validated that all identified compounds exhibit potent anti-tumor effects, providing proof-of-concept for our computational approach.

In the century-long evolution of insulin pharmaceuticals, each transformative advancement in this drug class has been closely tied to the ability to obtain new insulin isoforms for research. Despite this, the recently discovered naturally occurring isoforms of glycosylated human insulin have remained largely unattainable for proper characterization. Herein, we demonstrate for the first time that total chemical synthesis can be used to generate all isoforms. This achievement required maintaining the correct positions of the interchain disulfide bonds while effectively removing protecting groups on complex glycans. Notably, the availability of seven glycoforms reveals the important effects of natural sialylated glycans in suppressing insulin self-association and enhancing its solubility, surpassing the performance of currently employed rapid-acting insulin drugs. This work not only offers a readily adaptable platform for exploring natural O-glycosylation in other therapeutic proteins and peptides but also lays the groundwork for further research into harnessing natural glycosylation for therapeutic applications.

Objective To investigate the influencing factors of pulmonary and extrapulmonary acute re-spiratory distress syndrome(ARDS)caused by sepsis.Methods A total of 126 patients with ARDS admitted to the Department of Critical Care Medicine,General Hospital of Ningxia Medical University,from January 2022 to June 2024 were selected.Patients were divided into pulmonary ARDS and extrapulmonary ARDS groups based on the etiology of ARDS.General data,inflammatory indicators,and prognostic outcomes were compared between the two groups.COX regression analysis was used to identify prognostic factors.Results A-mong the 126 patients,72 were diagnosed with pulmonary ARDS and 54 with extrapulmonary ARDS.The pulmonary ARDS group had significantly lower SOFA scores,fewer organ dysfunctions,a lower incidence of arrhythmia,shorter mechanical ventilation duration,higher Murray scores,and higher Charlson Comorbidity Index(CCI)compared to the extrapulmonary ARDS group(P<0.05).Inflammatory markers,including pro-calcitonin(PCT),C-reactive protein(CRP),interleukin(IL)-4,IL-6,IL-10,and tumor necrosis factor-α(TNF-α),were significantly lower in the pulmonary ARDS group,while interferon-γ(INF-γ)levels were higher(P<0.05).For pulmonary ARDS,CCI and TNF-α were identified as independent risk factors for prog-nosis(P<0.05),with the combination of CCI and TNF-α yielding the highest predictive accuracy(AUC=0.81,95%CI:0.71-0.91).For extrapulmonary ARDS,CCI and CRP were independent risk factors(P<0.05),and their combination achieved the highest predictive performance(AUC=0.91,95%CI:0.84-0.98).Conclusion Inflammatory profiles between pulmonary and extrapulmonary ARDS caused by sepsis are different.CCI and TNF-α are independent risk factors for mortality in pulmonary ARDS,while CCI and CRP are independent risk factors in extrapulmonary ARDS.

Objective To investigate the diversity of gut microbiota in osteoporosis(OP)patients with various traditional Chinese medicine(TCM)syndrome types in the Lingnan region.Methods The analysis was carried out in 13 OP patients with blood stasis and qi stagnation syndrome(Group 1)and 13 OP patients with liver-kidney deficiency syndrome(Group 2)who were treated at Guangzhou Hospital of Chinese Medicine,the Affiliated Hospital of Guangzhou University of Chinese Medicine from January 2023 to December 2023.Fecal samples of both groups were collected,and baseline comparisons between the two groups were performed before testing.After DNA extraction,valid sequencing data were processed by operational taxonomic unit(OTU)clustering,species annotation,and microbial community composition analysis.Alpha and Beta diversity indices were employed to assess species diversity,and LEfSe was used to identify key microbial taxa.Results No significant differences in baseline characteristics such as gender and age were presented between the two groups(P＞0.05).Microbial community composition analysis revealed no significant differences in the top 15 abundant taxa at various taxonomic levels between the two groups,but structural variations were noted.Alpha diversity analysis showed that the Simpson index in Group 1 differed from that in Group 2(P＜0.05),while chao 1,ACE,richness,and coverage indices exhibited no significant differences between the two groups(P＞0.05).In Beta diversity analysis,multi-response permutation analysis(MRPP)indicated no significant intergroup differences in community structure(P＞0.05),whereas principal coordinate analysis(PCoA)suggested distinct differences in the distribution of species composition.LEfSe identified 14 taxa(e.g.,Lachnospiraceae and Lachnospirales)with significantly higher abundance and 5 taxa(e.g.,Anaeromassilibacillus and Desulfovibrio)with significantly lower abundance in Group 1.Conclusion OP patients with various TCM syndrome types in the Lingnan region exhibit distinct gut microbiota diversity and dominant microbial taxa,which will provide an objective basis for TCM syndrome differentiation of OP.

Objective To explore the regulatory mechanism of NFE2L2/KEAP1 in alveolar bone repair induced by periodontitis.Methods A rat periodontitis model was established and divided into four groups:Control group(n=6);Periodontitis model group(n=6);Periodontitis+lentivirus empty vector group(n=6);Periodontitis+NFE2L2 overexpression plasmid group(n=6).Histopathological changes in each group were observed using HE staining.TRAP staining was used to detect osteoclast positivity,while ELISA was employed to measure inflammatory cytokine levels in tissues.Immunofluorescence and qPCR were used to detect NFE2L2 expression,and western blot was used to assess the expression of osteogenic proteins ALPL2,RUNX2,and COL1.Primary periodontal ligament cells(hPDLCs)were cultured,and cells were transfected to overexpress NFE2L2 and KEAP1.The cells were divided into six groups:Normal group;Model group;pcDNA-NC group;pcDNA-NFE2L2 group;pc-NFE2L2+pcDNA-NC group;pc-NFE2L2+pcDNA-KEAP1 group.A cellular model was established,and the morphology of primary hPDLCs was observed under a microscope.Cell proliferation was assessed using CCK-8.Osteogenic mineralization was observed using alizarin red staining,and western blot was used to detect osteogenic proteins and autophagy markers.Cell migration was observed using a scratch assay.Results(1)After model induction,redness,swelling of the gums,extensive inflammatory infiltration,and alveolar bone resorption were observed,confirming successful model establishment.Partial tissue recovery occurred after NFE2L2 overexpression via lentivirus.(2)After model induction,osteoclast positivity increased,confirming successful model establishment.Overexpression of NFE2L2 reduced osteoclast positivity(P<0.001).(3)After model induction,levels of IL-1β,IL-10,and TNF-α were significantly higher than in the normal group(P<0.05),confirming successful model establishment.Transfection with NFE2L2 lentivirus reduced inflammatory cytokine levels(P<0.0001).After model induction,osteogenic protein expression decreased compared to the normal group,but overexpression of NFE2L2 increased osteogenic protein expression(P<0.05).(5)LPS treatment significantly reduced cell viability,while NFE2L2 overexpression enhanced it(P<0.0001).(6)LPS treatment reduced calcified nodules,while NFE2L2 overexpression increased them.Addition of pcDNA-KEAP1 reduced mineralized nodules.(7)LPS treatment decreased osteogenic protein expression,while NFE2L2 overexpression increased it.However,addition of pcDNA-KEAP1 reduced osteogenic protein expression(P<0.05).(8)LPS treatment reduced cell migration,whereas NFE2L2 overexpression enhanced it(P<0.0001).(9)Expression of autophagy markers decreased after LPS treatment,but increased after transfection with NFE2L2 plasmid.However,addition of pcDNA-KEAP1 reduced the expression of autophagy markers(P<0.05).Conclusion This study identified the regulatory role of NFE2L2/KEAP1 in periodontitis,providing a scientific basis for the treatment of periodontitis.

Objective To investigate the neurobehavioral development of young children aged 24 to 60 months in Shunde and explore the factors influencing the development of young children and provide reference for the interven-tion of neurobehavioral development delays in young children.Methods A retrospective cohort study was used to enroll the young children who were initially screened by the Pediatric Neuropsychological Developmental Scale(Pe-diatric Heart Scale)with a score of ≤85 was included in the study.With a score of ≤85,the young children might be at risk of developmental delays,and needed to be further diagnosed by the GESELL Developmental Diagnostic Scale,the basic information of the young children and their mothers at the time of birth were investigated,as well as basic information about the young children at the time of completing the GESELL Developmental Diagnostic Scale was collected.Results A total of 271 young children were included,196 males and 75 females.Young children had the lowest developmental quotient(DQ)in the language domain among the five domains(P＜0.001).Multiple lin-ear regression models showed:compared with girls,the language domain DQ of boys decreased by 5.321 points(P=0.049,95％CI:-10.620--0.021),and the personal-social domain DQ decreased by 4.474 points(P=0.023,95％CI:-8.316--0.631).Compared with young children via natural vaginal delivery(NVD),the gross motor domain DQ of young children via caesarean section(CS)decreased by 4.890 points(P=0.008,95％CI:-8.499--1.281),the fine motor domain DQ decreased by 3.373 points(P=0.037,95％CI:-6.532--0.213),the language domain DQ decreased by 7.621 points(P=0.004,95％CI:-12.826--2.416),per-sonal-social domain DQ decreased by 6.232 points(P=0.001,95％CI:-10.006--2.457).The results of bi-nary logistic regression models showed,compared with young children via NVD,the risk of gross motor domain retar-dation in young children increased(OR=1.763,95％CI:1.003-3.100),the risk of fine motor domain retardation increased(OR=2.217,95％CI:1.235-3.980),the risk of language domain retardation increased(OR=3.306,95％CI:1.080-10.124).Conclusion Young children with suspected neurobehavioral delays were more likely to have delayed development in language domain than in other domains,boys had lower DQ in language domain and personal-social domain than girls,and the development of young children via CS was slower than that via NVD.Fo-cus should be on the language development of young children especially on the language and personal-social devel-opment of boys.Carefully chose delivery way.Focus should be placed on assessment of young children's comprehen-sive neurobehavioral development in early time.

AIM:To explore the effects of CD38 on lysosome reformation and cholesterol efflux in macro-phages.METHODS:Bone marrow-derived macrophages from low-density lipoprotein(LDL)receptor knockout(LDLr-/-)mice were cultured as cell model.Live cell imaging system was applied to evaluate the effect of nicotinic acid adenine di-nucleotide phosphate(NAADP)on lysosome number.ELISA was conducted to measure NAADP level in macrophages.After the cells were treated with nicotinic acid(NA),RT-qPCR was conducted to detect CD38 mRNA expression,and Western blot was conducted to observe CD38 protein expression and phosphorylated transcription factor EB(TFEB)level.Laser scanning confocal microscopy was applied to evaluate the influence of CD38/NAADP signaling on lysosome number and cholesterol egression.RESULTS:NAADP remarkably increased lysosome number(P<0.05),and this effect was significantly inhibited by NAADP antagonist NED-19,Ca2+ chelator BAPTA,and calcineurin inhibitor CsA(P<0.05).CD38 markedly enhanced NAADP synthesis in macrophages(P<0.05).NAADP synthetic substrate NA prominently ele-vated the expression of CD38 mRNA and protein(P<0.05).NA significantly decreased the phosphorylated TFEB level;this effect was also attenuated by NED-19,BAPTA and CsA(P<0.05).Disrupting CD38/NAADP signaling pathway markedly inhibited NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux in macrophages(P<0.05).NA-induced enhancement of lysosome number,lysosomal free cholesterol and cytosol cholesterol ester efflux abolished in LDLr/CD38 DKO macrophages(P<0.05),whereas these effects induced by NA were recovered after CD38 gene rescue.CONCLUSION:CD38 triggers lysosome reformation via TFEB and consequently pro-motes the efflux of lysosomal free cholesterol and cytosol cholesterol ester.

At present,precise radiotherapy has been widely used through the development with many years,but the existing technique still is limited by the limitation of tolerance dose of normal tissues,which cannot achieve the optimal goal of treating tumor.Flash radiotherapy(Flash-RT)is one kind of radiotherapy technique that uses the beam with ultra-high dose rate(UHDR)to conduct irradiation,which can furthest treat tumors while significantly reduce radiation injury of normal tissues.But until now,the biological mechanism,key physical parameters and triggering mechanism of Flash-RT are still unclear,and its principle and clinical translational application are still in the stage of research.This review clarified the technological advance and clinical translational application of Flash-RT research through summarized the relevant research of Flash-RT.