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*

OBJECTIVES: This study aimed to investigate the correlation between clinical symptoms and unilateral chewing habits in patients with temporomandibular disorder (TMD) accompanied by tinnitus. METHODS: A total of 285 patients diagnosed with TMD at the Department of Stomatology of the First Medical Center of Chinese People's Liberation Army General Hospital between December 2020 and May 2024 were included and divided into two groups: tinnitus group and non-tinnitus group. Analysis was conducted on the proportion of patients with unilateral chewing habits in both groups, the correlation between the side of tinnitus and the side of unilateral chewing, and the correlation of tinnitus with TMD clinical symptoms (joint clicking, joint pain, and limited mouth opening) and unilateral chewing habits. The correlation of the type of disc displacement with unilateral chewing and tinnitus was also examined. RESULTS: In the tinnitus group, the proportions of patients with and without unilateral chewing habits were 90.70% (39/43) and 9.30% (4/43), respectively. In the non-tinnitus group, the proportions of patients with and without unilateral chewing habits were 76.03% (184/242) and 23.97% (58/242), respectively. The proportion of patients with unilateral chewing habits in the tinnitus group was significantly higher than in the non-tinnitus group (χ²=4.613, P<0.05). Correlation analysis showed a positive correlation between tinnitus and unilateral chewing habits (P<0.05). In the left-sided tinnitus group, the proportion of left-sided unilateral chewers [54.55% (12/22)] was higher than that of right-sided unilateral chewers [45.45% (10/22)]. In the right-sided tinnitus group, the proportion of right-sided unilateral chewers [81.82% (9/11)] was higher than that of left-sided unilateral chewers [18.18% (2/11)]. The difference was statistically significant (χ²=7.282, P<0.05). A positive correlation was also found between the side of tinnitus and the side of unilateral chewing habits (P<0.05). The proportion of patients with pain was significantly higher in the tinnitus group than in the non-tinnitus group (P<0.05). No significant difference in the proportion of joint clicking or limited mouth opening and disc displacement (no disc displacement, unilateral disc displacement, bilateral disc displacement, reducible disc displacement, or irreducible disc displacement) was found between the tinnitus and non-tinnitus groups (P>0.05). CONCLUSIONS TMD with unilateral chewing habits may be a contributing factor to unexplained tinnitus. Unexplained tinnitus is correlated with joint pain in patients with TMD.
Humans ; Tinnitus/physiopathology* ; Temporomandibular Joint Disorders/physiopathology* ; Mastication ; Male ; Adult ; Female ; Middle Aged ; Habits

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.

Research in photodynamic therapy (PDT) primarily focuses on enhancing light penetration depth, improving oxygen supply, and optimizing photosensitizer delivery. Notably, the delivery efficiency of the photosensitizer is crucial for therapeutic efficacy. Carboxyl-substituted phthalocyanines, as important photosensitizing molecules, possess unique chemical modification sites that enable direct targeted delivery or integration into diverse delivery systems. Their synthesis predominantly employs mixed- or cross-condensation, selective synthesis, and axial modification strategies to introduce carboxyl groups. However, their inherent hydrophobicity significantly hinders effective delivery. To address this limitation, modifications with peptides or quaternary ammonium salt derivatives may facilitate precise delivery to tumor cells and pathogens. With advances in nanotechnology, carboxyl-substituted phthalocyanines can serve as key photosensitizer modules, effectively integrated into nanomaterials such as biomacromolecules, inorganic metals, and polymers for both active and passive delivery. Recently, researchers have exploited the π-π stacking and other intermolecular forces among carboxyl-substituted phthalocyanine molecules to drive their self-assembly into nano-micelles, enabling carrier-free delivery or co-delivery with other therapeutic agents for synergistic effects. This review systematically outlines the synthesis strategies for carboxyl-substituted phthalo-cyanines. Taking mono-carboxyl-substituted zinc phthalocyanine as a model molecule, the performance of three delivery modalities were compared: single-molecule targeted delivery, nanocarrier-encapsulated delivery, and carrier-free self-assembled delivery, in terms of PDT efficacy, biocompatibility, and imaging-guided tracing capabilities, to provide a systematic technical framework for the rational design of novel modular photosensitizers and to advance the clinical translation of PDT in precision oncology and anti-infective therapy.
Photochemotherapy/methods* ; Indoles/administration & dosage* ; Isoindoles ; Photosensitizing Agents/administration & dosage* ; Drug Delivery Systems ; Humans

Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer-related mortality worldwide. In recent years, metabolomics has emerged as a key systems biology approach for analyzing small-molecule metabolites in cells, tissues and organisms. It provides new strategies for early diagnosis and metabolic profiling. Additionally, metabolomics plays a crucial role in studying resistance mechanisms in lung cancer. Tumor cell metabolic reprogramming is a key driving factor in the initiation and progression of lung cancer. Metabolomics studies have revealed how lung cancer cells regulate critical pathways such as energy metabolism, lipid metabolism, and amino acid metabolism to adapt to the demands of rapid proliferation and invasive metastasis. This review summarizes the latest advances in metabolomics research in lung cancer, focusing on the characteristics of metabolic reprogramming, the identification of potential metabolic biomarkers, and the prospects of metabolomics in early diagnosis and the elucidation of resistance mechanisms in lung cancer.
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Humans ; Metabolomics/methods* ; Lung Neoplasms/pathology* ; Animals ; Biomarkers, Tumor/metabolism*

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective To analyze the clinical features of chronic obstructive pulmonary disease (COPD) patients with heart failure (HF) in Nanjing and explore the influencing factors. Methods A total of 773 COPD inpatients were selected from January 2021 to January 2024 in Nanjing Combined Hospital of Traditional Chinese and Western Medicine, Nanjing Qixia District Hospital, Nanjing Lishui District People's Hospital, Nanjing Pukou District Hospital of Traditional Chinese Medicine and Nanjing First Hospital., and were divided into 2 groups according to the presence or absence of combined HF. The general data and medical records of the two groups were compared, the clinical characteristics of COPD patients with HF were summarized, and the influencing factors of COPD patients with HF were analyzed by multivariate logistic regression. Results Among the 242 patients (31.31%) with COPD had HF, chronic paroxysmal dyspnea was the most common first symptom, 169 patients (69.83%) had left heart failure, 63 patients (30.17%) were diagnosed as right heart failure or global heart failure , 17 patients (7.02%) had myocardial infarction. Multivariate logistic regression analysis showed that the risk of HF was 1.678 times and 1.691times higher in COPD groups ≥ 50 years old and male COPD groups than in < 50 years old and female groups, respectively; the risk of HF was 1.491 times higher in COPD groups engaged in physical work than in physical work groups; the risk of HF was 1.447 times and 1.580 times higher in COPD groups with hypertension and coronary heart disease than in COPD groups without hypertension and coronary heart disease, respectively; the risk of HF was 1.859 times higher in COPD groups smoking>400 vial/year than in COPD groups≤400 vial/ year; the risk of HF was 1.757 times higher in COPD groups with acute exacerbation frequency≥2 times/year than in COPD groups<2 times/year; the above differences were statistically significant (P<0.05). Conclusion Attention should be paid to elderly, male and heavy physical work group of COPD patients. Active treatment of hypertension and coronary heart disease, effective tobacco control and reduction of the frequency of acute exacerbation are effective ways to reduce the risk of HF in COPD patients in Nanjing.

Objective To analyze the characteristics of real-world adverse drug events(ADEs)of trabectedin based on the FDA Adverse Event Reporting System(FAERS)database in order to provide references for clinical drug safety management.Methods A total of 1 349 trabectedin-related reports were extracted from the FAERS database from Q1 2007 to Q4 2024.Using the MedDRA coding classification system for system organ class(SOC)and preferred term(PT),signal detection was performed through 4 proportional imbalance methods,including reporting odds ratio(ROR)and proportional reporting ratio(PRR).Subgroup analyses by gender,age,and temporal trends were also conducted.Results Hematological and lymphatic system disorders and hepatobiliary system disorders were the primary SOCs involved.High-frequency PTs included neutropenia(123 cases)and anemia(117 cases).Eight potential ADEs that have not been listed in the drug product instruction were identified.The median onset time of ADEs was 21 d,showing an early failure pattern,with differences observed by gender(females more prone to hematological toxicity)and age(elderly more susceptible to febrile neutropenia).Conclusion Trabectedin requires close attention to hematological toxicity,hepatotoxicity,and newly identified multi-system potential risks.Clinically,monitoring should be strengthened based on time windows and population characteristics to optimize drug regimens.Countermeasure It is recommended to strengthen the full cycle monitoring of anti-tumor drugs,standardize the reporting of adverse reactions,and establish a multi-departmental collaborative research platform.

Objectives:To investigate the distribution and change of the burden of cardiovascular diseases attributable to tobacco consumption in China and the world from 1990 to 2021.Methods:Based on Global Burden of Disease(GBD)2021 database,age standardized mortality and age standardized disability-adjusted life year(DALY)rates and estimated annual percentage change(EAPC)from cardiovascular disease(including ischemic heart disease,stroke,atrial fibrillation and flutter,aortic aneurysm,peripheral artery disease)attributable to tobacco consumption were analyzed.The association of the human development index(HDI)and social demographic index(SDI)with age-standardized mortality was also analyzed.Results:Compared to 1990,the global burden of cardiovascular diseases attributable to smoking declined in 2021,age-standardized mortality decreased from 57.2/100 000 to 26.3/100 000(EAPC=-1.81%,95% CI:-2.00% to-1.63% ).The global burden of cardiovascular diseases attributable to second-hand smoke also decreased,age-standardized mortality decreased from 11.4/100 000 to 8.3/100 000(EAPC=-1.72%,95% CI:-1.91% to-1.53% ).In China,the burden of cardiovascular diseases attributable to smoking also decreased,age-standardized mortality decreased from 52.2/100 000 to 39.6/100 000(EAPC=-1.23%,95% CI:-1.44%-1.02% );the burden of cardiovascular diseases attributable to second-hand smoke decreased,age-standardized mortality decreased from 15.3/100 000 to 14.7/100 000(EAPC=-1.26%,95% CI:-1.63% to-0.90% ).Notably,the decrease in cardiovascular diseases burden attributable to second-hand smoke among Chinese women was more significant than the global level,the age-standardized mortality rate of Chinese women decreased from 17.9/100 000 to 14.5/100 000(EAPC=-2.24%,95% CI=-2.78%～-1.86% ).Among the five types of cardiovascular diseases attributable to tobacco consumption globally and in China,the age-standardized mortality and age-standardized DALY rates of aortic aneurysm,ischemic heart disease and peripheral artery disease were higher.Globally,ischaemic heart disease is the leading cause of death,accounting for 60.2% in 1990 and 61.7% in 2021,while stroke is the leading cause of death in China,accounting for 68.1% and 51.4% in 1990 and 2021,respectively.In addition,HDI and SDI are the two main factors affecting the disease burden.In regions and countries with SDI>7.2,age standardized mortality is below our forecast line.In the later part of the forecast,China's age standardized mortality showed a downward trend,possibly due to changes in tobacco control measures.Conclusions:Over the past 30 years,the burden of cardiovascular diseases attributed to tobacco consumption has decreased globally and in China.The decline in disease burden has been most pronounced among women.However,in countries and regions with an SDI below 7.2,the burden of disease remains significant high.Therefore,it is necessary to take tobacco control measures in key regions(China,East Asia,Central Europe,Central Asia and Southeast Asia)to actively reduce smoking rates and exposure to secondhand smoke in public places,so as to reduce the burden of cardiovascular diseases.

Objective To explore the clinical characteristics,antimicrobial resistance,virulence and molecular epi-demiology characteristics of carbapenem-resistant hypervirulent Klebsiella pneumoniae(CR-hvKP).Methods Car-bapenem-resistant Klebsiella pneumoniae(CRKP)strains isolated from clinical specimens in a tertiary first-class teaching hospital from 2018 to 2021 were collected.ST1 1 CR-hvKP strains were screened through the detection of antimicrobial resistance genes and virulence genes as well as multilocus sequence typing(MLST).Basic clinical in-formation,antimicrobial resistance genes and virulence genes were analyzed.Twenty-three strains of ST1 1 CR-hvKP were randomly selected for virulence phenotype analysis;45 strains of CR-hvKP were randomly selected for homology analysis by pulsed-field gel electrophoresis(PFGE).Results There were a total of 124 clinically isolated strains of ST11 CR-hvKP from 2018 to 2021,mainly from the department of neurosurgery(33.87％).The major specimen source was sputum(56.45％),the average age of infected patients were(55.2±16.4)years old,and the majority were male patients(77.42％).Antimicrobial susceptibility testing results showed these strains were resis-tant to most clinically commonly used antimicrobial agents.Virulence detection showed that virulence varied among these strains,but most of them were hypervirulence strains.PFGE analysis results showed that the strains were mainly subtype A1(63.4％).Conclusion ST1 1 CR-hvKP presents multidrug resistance and hypervirulence.Clonal transmission of some strains exists in this hospital,which poses great challenges for clinical anti-infection treatment as well as prevention and control.It is necessary to strengthen the prevention and control of healthcare-associated infection.