BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

Insufficient alveolar bone thickness increases the risk of periodontal dehiscence and fenestration, especially in orthodontic tooth movement. Abaloparatide (ABL), a synthetic analog of human PTHrP (1-34) and a clinical medication for treating osteoporosis, has recently demonstrated its potential in enhancing craniofacial bone formation. Herein, we show that intraoral submucosal injection of ABL, when combined with mechanical force, promotes in situ alveolar bone thickening. The newly formed bone is primarily located outside the original compact bone, implying its origin from the periosteum. RNA sequencing of the alveolar bone tissue revealed that the focal adhesion (FA) pathway potentially mediates this bioprocess. Local injection of ABL alone enhances cell proliferation, collagen synthesis, and phosphorylation of focal adhesion kinase (FAK) in the alveolar periosteum; when ABL is combined with mechanical force, the FAK expression is upregulated, in line with the accomplishment of the ossification. In vitro, ABL enhances proliferation, migration, and FAK phosphorylation in periosteal stem cells. Furthermore, the pro-osteogenic effects of ABL on alveolar bone are entirely blocked when FAK activity is inhibited by a specific inhibitor. In summary, abaloparatide combined with mechanical force promotes alveolar bone formation via FAK-mediated periosteal osteogenesis. Thus, we have introduced a promising therapeutic approach for drug-induced in situ alveolar bone augmentation, which may prevent or repair the detrimental periodontal dehiscence, holding significant potential in dentistry.
Osteogenesis/drug effects* ; Periosteum/cytology* ; Parathyroid Hormone-Related Protein/administration & dosage* ; Animals ; Focal Adhesion Protein-Tyrosine Kinases/metabolism* ; Alveolar Process/drug effects* ; Cell Proliferation/drug effects* ; Phosphorylation ; Rats ; Male ; Humans ; Focal Adhesion Kinase 1/metabolism* ; Cell Movement/drug effects*

In recent years, the research on the microbial community within cancer has gradually attracted attention. The microbiota within the tumor affects the immune regulation of liver cancer and may promote the progression of liver cancer through inflammatory responses, metabolic regulation, etc. This article explores the sources and distribution characteristics of microorganisms in liver cancer, their potential mechanism of action in the occurrence and development of liver cancer, and evaluates the application prospects of intratumoral microorganisms in the early diagnosis, treatment response prediction and personalized treatment of liver cancer, especially their potential value in targeted therapy, providing new ideas for microbial intervention in future precision medicine.

Objective:To analyze the burden and trends of noncommunicable chronic disease(NCD) attributable to metabolic factors in China from 1990 to 2021.Methods:Data from the Global Burden of Diseases(GBD) 2021 database were utilized to describe changes in mortality and disability-adjusted life years(DALYs) of NCD in China from 1990 to 2021. Stratified analyses were conducted by age, sex, sociodemographic index(SDI), and related risk factors. Statistical analyses and predictions were conducted using the age-period-cohort model and the Nordpred model.Results:In 2021, the age-standardized mortality rate and age-standardized DALYs rate of NCD attributable to metabolic factors in China were 227.56 per 100 000 and 4 829.39 per 100 000, respectively. Their average annual percentage changes were -0.76%( P<0.001) and -0.77%( P<0.001). Overall, the burden decreased progressively with higher SDI levels. Analysis using the age-period-cohort model indicated reduced birth cohort and period effects for metabolic factor-attributable NCD, while age effects rose significantly. The minimum relative risk( RR) value was observed in the 15-19 age group( RR=0.01), and the maximum RR value occurred in the 95-99 age group( RR=996.86). The overall rising mortality trend indicated that age effects are the predominant driver at present. Projections estimate that by 2046, deaths from metabolic factor-attributable NCD in China will reach 8 189 563, with an age-standardized mortality rate of 236.95 per 100 000. Conclusions:China continues to face a substantial burden of NCD linked to metabolic factors, with older adults, males, and individuals with hypertension, diabetes, and prediabetes identified as key populations requiring targeted interventions.

Objective:To explore the effects of imperatorin(IMP)on airway remodeling in the bronchial asthma mice,and to elucidate the possible mechanisms.Methods:Forty SFP male BALB/c mice were randomly divided into control group,model group,low dose of IMP group(IMP-L group),high dose of IMP group(IMP-H group)and dexamethasone group,with 8 mice in each group.Except for contol group,the mice in the other groups were injected with an ovalbumin(OVA)suspension intraperitoneally to induce the asthma models.After one week,the daily asthma symptoms of the mice were observed and scored.After 8 weeks,the enhanced pause(Penh)values of the mice in various groups were detected to evaluate the airway reactivities.The percentages of eosinophils in the bronchoalveolar lavage fluid(BALF)of the mice in various groups were detected by flow cytometry.The levels of serum IgE,interleukin interferon-gamma(IL)-13,IL-5,IL-4 and interferon-gamma(IFN-γ)in BALF of the mice in various groups were measured by enzyme-linked immunosorbent assay(ELISA)method.HE,PAS and Masson staining were applied to observe the pathomorphology,the number of goblet cells and collagen deposition of the lung tissue of the mice in various groups.Immunohisto chemistry method was applied to detect the expressions of α-smooth muscle actin(α-SMA)and mouse mammary tumor virus(MMTV)wingless type MMTV intergration site family member 5A(Wnt5A)proteins in lung tissue of the mice in various groups.The expression levels of Wnt5A,cellular myelocytomatosis oncogene(c-Myc),β-catenin and α-SMA in lung tissue of the mice in various groups were detected by Western blotting method.The expression levels of α-SMA protein in lung tissue of the mice in various groups were detected by immunofluorescence method.Results:Compared with control group,the score of asthma symptoms of the mice in model group was increased(P<0.01);the Penh value was significantly increased(P<0.01);the serum IgE levels and the levels of IL-13,IL-5,IL-4 in BALF,as well as the percentage of eosinophils(EOS)in BALF were significantly increased(P<0.05 or P<0.01),and the level of IFN-γ was reduced(P<0.05);the expression levels of α-SMA and Wnt5A proteins in lung tissue were markedly increased(P<0.01);the expression levels of proteins associated with the Wnt/β-catenin signaling pathway in the lung tissue were significantly increased(P<0.01);the immofluorescence method results showed the expression level of α-SMA protein in lung tissue was significantly increased(P<0.01).Compared with model group,the scores of asthma symphtoms of the mice in IMP-L group,IMP-H group,and dexamethasone group were decereased(P<0.01),and the Penh values of the mice in IMP-H group were decreased(P<0.05);the serum IgE levels and the levels of IL-13,IL-5,IL-4 in BALF,as well as the percentages of EOS in BALF of the mice in IMP-L group,IMP-H group,and dexamethasone group were decreased(P<0.05 or P<0.01),and the levels of IFN-γ were increased(P<0.05);the expression levels α-SMA and Wnt5A proteins in lung tissue were decreased(P<0.05 or P<0.01);the expression levels of proteins related to the Wnt/β-catenin signaling pathway in the lung tissue were decreased(P<0.05 or P<0.01);the immunofluorescence method results showed that expression levels of the α-SMA protein in the lung tissue were reduced(P<0.05 or P<0.01).Conclusion:IMP has an improving effect on airway remodeling in the asthmatic mice and can inhibit the expression levels of Wnt/β-catenin pathway-related proteins.

Objective:To develop the Nurse Parenting Stress Scale and evaluate its reliability and validity.Methods:Based on Abidin's Parenting Stress Theory, scale items were generated through literature review and semi-structured interviews. The initial version was constructed via Delphi expert consultation. Using a convenience sampling method, nurses from six hospitals in Shandong Province were surveyed between August and October 2024. The first survey collected 314 questionnaires (308 valid, effective recovery rate 98.1%) for item analysis and exploratory factor analysis (EFA). The second survey collected 458 questionnaires (447 valid, effective recovery rate 97.6%) for confirmatory factor analysis (CFA) .Results:The Nurse Parenting Stress Scale consists of 4 dimensions and 31 items. The Cronbach's α coefficient of the total scale was 0.951, split-half reliability was 0.782, and test-retest reliability was 0.926. EFA extracted four common factors explaining 70.241% of the cumulative variance. CFA demonstrated a good model fit. The item-level content validity index ( I- CVI) ranged from 0.889 to 1.000, the scale-level universal agreement content validity index ( S- CVI/ UA) was 0.903, and the scale-level average content validity index ( S- CVI/ Ave) was 0.989. Conclusions:The Nurse Parenting Stress Scale shows strong reliability and validity and can serve as an effective tool for assessing parenting stress among nurses.

Based on the theory of the liver's"using bitter herbs to nourish or purge"from Huangdi Neijing,this paper systematically elucidates the theoretical foundation for treating functional constipation from liver.Focusing on the physiological characteristic of"liver desires to disperse"and the pathological manifestation of"liver bitterness and urgency,"combined with the"liver communicates with the large intestine"theory,this paper establishes a diagnostic and therapeutic framework for managing functional constipation by regulating liver function.The pathological evolution of functional constipation manifests in three distinct stages:in the early stage,liver qi stagnation leads to large intestine qi obstruction,where damaged by an excess of seven emotions resulting in symptoms such as difficult defecation,abdominal bloating,and hypochondriac pain;in the middle stage,liver depression transforms into fire,scorching bodily fluids to generate dryness,thereby creating a pathological interplay of stagnation,fire,and dryness,which is marked by anal heat,dry mouth,and yellow urine;in the late stage,yin deficiency in liver and kidney causes large intestine malnutrition,resulting in a complex pathological state where yin deficiency,collateral blockage,dryness accumulation,and blood stasis intertwine,clinically manifesting as pellet-like stools(resembling sheep feces)and soreness and weakness of the waist and knees.In treatment,the formula design follows the principle of"sweetness to relieve,acridity to tonify,and sourness to purge,"with treatment principles varying across stages.In the early stage,the focus is on dispersing liver and regulating qi,and unblocking the zang-fu viscera;in the middle stage,the priority shifts to clearing heat-fire,nourishing large intestine,and promoting fluid production;whereas,in the late stage,the emphasis lies on nourishing yin,unblocking collaterals,and promoting blood circulation.This staged treatment of functional constipation overcomes the limitations of solely focusing on nourishing large intestine and facilitating feces excretion,thereby advancing the treatment of different stages based on syndrome differentiation and personalized treatment.It provides theoretical support for improving patients' intestinal function and enhancing overall health outcomes.

Objective:To develop the Nurse Parenting Stress Scale and evaluate its reliability and validity.Methods:Based on Abidin's Parenting Stress Theory, scale items were generated through literature review and semi-structured interviews. The initial version was constructed via Delphi expert consultation. Using a convenience sampling method, nurses from six hospitals in Shandong Province were surveyed between August and October 2024. The first survey collected 314 questionnaires (308 valid, effective recovery rate 98.1%) for item analysis and exploratory factor analysis (EFA). The second survey collected 458 questionnaires (447 valid, effective recovery rate 97.6%) for confirmatory factor analysis (CFA) .Results:The Nurse Parenting Stress Scale consists of 4 dimensions and 31 items. The Cronbach's α coefficient of the total scale was 0.951, split-half reliability was 0.782, and test-retest reliability was 0.926. EFA extracted four common factors explaining 70.241% of the cumulative variance. CFA demonstrated a good model fit. The item-level content validity index ( I- CVI) ranged from 0.889 to 1.000, the scale-level universal agreement content validity index ( S- CVI/ UA) was 0.903, and the scale-level average content validity index ( S- CVI/ Ave) was 0.989. Conclusions:The Nurse Parenting Stress Scale shows strong reliability and validity and can serve as an effective tool for assessing parenting stress among nurses.

Plant virus nanoparticles(PVNPs)have inherent immune stimulation ability,which has been widely studied as an immune adjuvant to stimulate the anti-tumor immune response.PVNPs not only have the potential to be used as vaccine adjuvants for cancer immunotherapy,but also as delivery systems for single immunotherapy or combination therapies.Among them,PVNPs have achieved great success in preclinical research of cancer immunotherapy.The new immunotherapy strategy is to use PVNPs as in situ vaccination(ISV),which can effectively inhibit tumor growth and produce a widening systemic anti-tumor immune response after in-tratumoral administration;in addition,PVNPs in combination with other tumor treatment modalities may also improve the local and systemic anti-tumor immune response.In this review,the application and prospects of plant virus nanoparticles in cancer immunotherapy are reviewed,in order to provide new ideas for cancer immunotherapy.