Cholangiocarcinoma (CCA) is a fatal malignancy with steadily increasing incidence and poor prognosis. Since most CCA cases are diagnosed at an advanced stage, systemic therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, play a crucial role in the management of unresectable CCA. The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA. This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA, summarizes crucial clinical trials, and describes the efficacy and safety of different drugs, which may help further develop precision and individualization in the clinical treatment of unresectable CCA.
Humans ; Cholangiocarcinoma/drug therapy* ; Immunotherapy/methods* ; Bile Duct Neoplasms/drug therapy* ; Molecular Targeted Therapy/methods*

Objective To investigate the expression of blood basophil activation markers in patients with allergic rhinitis (AR) and the effects of allergens on their expression. Methods The blood samples were collected from the following four groups: healthy control (HC), AR patients with negative skin prick test (nAR), seasonal AR patients (sAR) and perennial AR patients (pAR). Flow cytometry was employed to analyze the expression of basophil activation markers Immunoglobulin E receptor I alpha(FcepsilonRIα), CD63 and CD203c in AR patients. Plasma levels of interleukin 4 (IL-4) and IL-8 were measured by liquid-phase chip technology, and their correlations with the percentages of activated basophils were further analyzed. An ovalbumin-induced AR mouse model was established, and the expression levels of FcepsilonRIα and CD63 on blood basophils were detected. Results The expression of FcepsilonRIα, CD203c and CD63 on basophils were increased in nAR, sAR and pAR patients. Allergens enhanced the mean florescence intensity expression of CD63 and CD203c on basophils of sAR and pAR patients. The plasma levels of IL-4 and IL-8 were elevated in nAR, sAR and pAR patients, showing moderate to high correlations with the expression levels of basophil activation markers. The FcepsilonRIαand CD63 expression on basophils of AR mice were increased. Conclusion Allergens may contribute to AR pathogenesis by upregulating the expression of FcepsilonRIα, CD63 and CD203c, as well as promoting the secretion of IL-4 and IL-8.
Basophils/metabolism* ; Humans ; Allergens/immunology* ; Animals ; Rhinitis, Allergic/blood* ; Female ; Male ; Adult ; Mice ; Biomarkers/blood* ; Tetraspanin 30/blood* ; Interleukin-4/blood* ; Interleukin-8/blood* ; Receptors, IgE/blood* ; Phosphoric Diester Hydrolases ; Young Adult ; Pyrophosphatases ; Middle Aged ; Mice, Inbred BALB C

Objective To investigate how culture duration affects the expression of immune membrane proteins in human monocyte-derived dendritic cells (DCs) and their exosomes (DEXs). Methods Human monocytes were induced with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) to differentiate into DCs and were subsequently matured with tumor necrosis factor α(TNF-α). Exosomes were isolated by ultracentrifugation, and DEXs were identified by transmission electron microscopy and Amnis imaging flow cytometry, which were also used to quantify the expression of immune membrane proteins on DCs and DEXs. Results On the 10th day of culture, DCs displayed high surface expression of CD11c, CD80, CD86, major histocompatibility complex class I (MHC-I), and MHC-II. Expression peaked at day 18(CD11c: 78.66%±20.33%, CD80: 76.41%±10.02%, CD86: 96.43%±0.43%, MHC-I: 84.71%±2.96%, MHC-II: 80.01%±7.03%). After day 24, the overall expression showed a declining trend, with statistically significant differences observed for all markers except CD80 and MHC-II. By day 30, 80% of the DCs still expressed CD80, CD86, and MHC-II. The expression of immune membrane proteins on DEX surfaces also reached its peak on day 18, followed by an overall decline with prolonged culture time, with statistically significant differences observed for all markers except CD80. Correlation analysis revealed a significant positive relationship between the expression levels of immune membrane proteins on DC and DEX surfaces (CD11c: r=0.98; CD80: r=0.65; CD86: r=0.82; MHC-I: r=0.86; MHC-II: r=0.93). Conclusion Human monocyte-derived DCs in vitro express high expression of immune membrane proteins and maintain stable expression over a specific period. The exosomes secreted by these cells similarly demonstrate high surface expression of immune membrane proteins, with temporal trends aligned with those of the parent DCs.
Humans ; Dendritic Cells/immunology* ; Exosomes/immunology* ; Monocytes/metabolism* ; Cells, Cultured ; Time Factors ; B7-1 Antigen/metabolism* ; Membrane Proteins/immunology* ; Cell Culture Techniques/methods* ; B7-2 Antigen/metabolism* ; Cell Differentiation ; CD11c Antigen/metabolism* ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology*

Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

Cancer stands as a significant global public health challenge,and cancer screening serves as a pivotal strategy for reducing its mortality.Presently,only a limited number of cancer types have appropriate screening methods available.Traditional single-cancer screen-ing approaches are fraught with limitations,including invasiveness,low accuracy,and poor patient compliance.Multi-cancer early detection(MCED)leveraging liquid biopsy technology enables non-invasive and efficient early detection of multiple cancers by analyzing biomarkers such as cell-free DNA,cell-free RNA,proteins,and metabolites in blood and other bodily fluids.This innovative approach substantially broadens the spectrum of detectable cancers and enhances population coverage,showcasing immense potential for improving existing can-cer screening strategies.This expert consensus comprehensively reviews the progress of liquid biopsy-based MCED,biomarker selection and detection technologies,the criteria for cancer type selection,research design and clinical utility evaluation,as well as implementation path-ways.The overarching goal of this consensus is to offer scientific guidance for further research and the widespread adoption of MCED,thereby facilitating the continuous optimization of cancer screening strategies.

With the growing emphasis on maternal and child oral health, the significance of managing oral health across preconception, pregnancy, and infancy stages has become increasingly apparent. Oral health challenges extend beyond affecting maternal well-being, exerting profound influences on fetal and neonatal oral development as well as immune system maturation. This expert consensus paper, developed using a modified Delphi method, reviews current research and provides recommendations on maternal and child oral health management. It underscores the critical role of comprehensive oral assessments prior to conception, diligent oral health management throughout pregnancy, and meticulous oral hygiene practices during infancy. Effective strategies should be seamlessly integrated across the life course, encompassing preconception oral assessments, systematic dental care during pregnancy, and routine infant oral hygiene. Collaborative efforts among pediatric dentists, maternal and child health workers, and obstetricians are crucial to improving outcomes and fostering clinical research, contributing to evidence-based health management strategies.
Humans ; Pregnancy ; Female ; Infant ; Consensus ; Mouth Diseases/therapy* ; Pregnancy Complications/therapy* ; Oral Health ; Infant, Newborn ; Delphi Technique ; Oral Hygiene

OBJECTIVE: To explore the relationship between the geriatric nutritional risk index (GNRI) and cognitive function. METHODS: A cross-sectional study method was conducted. People aged ≥ 60 years from the National Health and Nutrition Examination Survey (NHANES) databases from 1999 to 2002 and 2011 to 2014 were included as study subjects. The participants were divided into three groups based on their GNRI scores: a medium-high risk group (82 ≤ GNRI < 92), a low risk group (92 ≤ GNRI < 98), and a no-risk group (GNRI ≥ 98). Demographic characteristics (gender, age, race, education), chronic diseases [chronic bronchitis, emphysema, thyroid problems, coronary heart disease, angina pectoris, stroke, hypertension, diabetes mellitus, and depression score on the patient health questionnaire (PHQ-9)], lifestyle habits (history of smoking, hours of sleep), etc., were collected. Cognitive function was assessed using the consortium to establish a registry for Alzheimer's disease word learning subtest (CERAD-WL), animal fluency test (AFT), and digit symbol substitution test (DSST) for the 2011-2014 data, while only the DSST was used for the 1999-2002 data. Differences in the above information among the GNRI cohorts were compared. Factors affecting cognitive function in the population were analyzed using multifactorial Logistic regression. RESULTS: 2 653 participants from 2011 to 2014 and 2 380 participants from 1999 to 2002 were enrolled, with a total of 5 033 participants in the study. There were statistically significant differences in age, stroke, diabetes mellitus, DSST score, AFT score, CERAD score test 1 recall (Cst1), and CERAD score test 2 recall (Cst2) among the GNRI groups. Multifactorial Logistic regression analysis of data from 2011 to 2014 showed that in model 3 (DSST score, age, gender, race, marriage, education, hours of sleep, history of smoking, emphysema, thyroid problems, chronic bronchitis, coronary heart disease, angina pectoris, hypertension, diabetes mellitus, depression score on the PHQ-9, and stroke) adjusted for all covariates, GNRI was a protective factor for DSST [odds ratio (OR) = 1.03, 95% confidence interval (95%CI) was 1.00 to 1.05, P = 0.03]; Logistic regression analyse for 1999 to 2002 and 2011 to 2014 showed a significant association even after adjustment for covariates (OR = 1.02, 95%CI was 1.00 to 1.03, P = 0.02). Subgroup Logistic regression analyses of the total population from 2011 to 2014 showed a significant association between GNRI and DSST scores (OR = 1.02, 95%CI was 1.01 to 1.03, P < 0.001), with significant associations in the age subgroups of 60 to 64 years old, across gender, non-Hispanic Whites and Blacks, by education, and by marital status associations were significant (all P < 0.05). Subgroup Logistic regression analyse of the total populations from 1999 to 2002 and 2011 to 2014 showed a significant association between the GNRI and DSST score (OR = 1.01, 95%CI was 1.01 to 1.02, P < 0.001), but did not show a significant year difference (interaction P = 0.503), and the newly found in the smoking population the association was also more significant (P < 0.01). CONCLUSION The GNRI correlates with the presence of cognitive functions related to processing speed, sustained attention, and executive function, and may be able to serve as an indicator for the assessment or prediction of related cognitive functions.
Humans ; Cross-Sectional Studies ; Aged ; Middle Aged ; Nutrition Surveys ; Cognition ; Female ; Male ; Nutritional Status ; Risk Factors ; Geriatric Assessment

Objective To investigate the factors influencing the efficacy of intravesical Bacille Calmette-Guérin(BCG)instillation after transurethral resection of bladder tumor(TURBT)in patients with intermediate-and high-risk non-muscle invasive bladder cancer(NMIBC),and to construct a prediction model for recurrence after BCG treatment.Methods A retrospective cohort study was conducted on the subjected patients diagnosed with intermediate-and high-risk NMIBC undergoing TURBT followed by standard BCG instillation.The 110 patients treated in Department of Urology of Army Medical Center of PLA from January 2018 to December 2023 were assigned into a training set,while the 52 patients treated at Department of Urology of General Hospital of Central Theater Command from January 2015 to December 2020 were into an external validation set.A total of 17 variables were included and analyzed.Univariate and multivariate Cox regression analyses were performed to identify factors associated with recurrence after BCG instillation,and nomograms were plotted to predict 1-year,3-year,and 5-year recurrence-free survival(RFS).Calibration curve,decision curve analysis(DCA),and receiver operating characteristic(ROC)curve analysis were conducted for internal and external validation to evaluate the predictive performance and clinical utility of the model.Results In the training set,26 patients(23.64%)experienced recurrence during the follow-up period,with a median RFS of 32.00(18.00～50.50)months.Univariate Cox regression analysis suggested that platelet count,eosinophil to lymphocyte ratio(ELR),neutrophil to lymphocyte ratio(NLR),platelet to lymphocyte ratio(PLR),systemic immune inflammation(SII)index,and neutrophil-monocyte to lymphocyte ratio(NMLR),pathological T1 stage(pT1)tumor and hemoglobin,albumin,lymphocyte,and platelet(HALP)score were potential factors influencing recurrence after BCG instillation.Multivariate Cox regression analysis identified high HALP score(HR=0.185,95%CI:0.046～0.736,P=0.017)as an independent protective factor,while high ELR(HR=3.599,95%CI:1.505～8.608,P=0.004)and pT1 stage(HR=3.240,95%CI:1.191～8.818,P=0.021)were independent risk factors for recurrence.Based on this,a nomogram prediction model was constructed.The calibration curves demonstrated good agreement between predicted and actual 1-,3-,and 5-year recurrence risks.Decision curve analysis indicated clinical utility across a wide threshold probability range.In the training set,the model showed strong predictive performance for 1-(AUC=0.842),3-(AUC=0.847),and 5-year(AUC=0.887)recurrence risks,which was further validated in the external cohort.Conclusion Higher HALP score prior to BCG instillation therapy is a protective factor against tumor recurrence,while higher ELR and pT1 stage are risk factors.Our nomogram prediction model based on HALP score,ELR and pathological T stage,can identify individuals at high risk of recurrence after BCG instillation therapy.

Objective To investigate risk factors for residual lesions after initial transurethral resection of bladder tumors(TURBT)and risk factors for tumor recurrence after second TURBT in patients with non-muscle-invasive bladder cancer(NMIBC)in order to provide reference for clinical management.Methods A case-control study design was adopted to include 120 NMIBC patients who underwent initial TURBT and then second surgery within 2～8 weeks in our department from January 2017 to January 2025.Based on the presence of residual lesions after the initial TURBT or not,the patients were divided into a residual lesion group(n=34)and a non-residual lesion group(n=86).Chi-square test and multivariate logistic regression analysis were performed to identify potential risk factors for residual lesions following the initial TURBT.Univariate and multivariate Cox regression models were used to analyze potential risk factors for tumor recurrence after the second TURBT.Results The residual lesion rate after initial TURBT was 28.33％.Chi-square test analysis revealed that tumor stage T1(Chi-square=5.756,P=0.016)and broad tumor base(Chi-square=4.331,P=0.037)were factors influencing residual lesions after initial TURBT.Multivariate logistic regression analysis identified tumor stage T1(OR=3.047,95％CI:1.128～8.226,P=0.028)as an independent risk factor for residual lesions after initial TURBT.The tumor recurrence rate after second TURBT was 17.5％.Multivariate Cox regression analysis identified tumor stage T1(OR=4.258,95％CI:1.248～14.532,P=0.021),intravesical chemotherapy instillation after second TURBT(OR=3.539,95％CI:1.284～9.752,P=0.015),history of urinary system tumors(OR=3.002,95％CI:1.145～7.873,P=0.025)and high platelet-to-lymphocyte(PLR)ratio(OR=2.798,95％CI:1.115～7.023,P=0.028)as independent risk factors for tumor recurrence after second TURBT.Conclusion Tumor stage T1 and broad tumor base are risk factors for residual lesions after initial TURBT,while tumor stage T1,intravesical chemotherapy instillation after second TURBT,history of urinary system tumors and high PLR ratio are risk factors for tumor recurrence after second TURBT.Comprehensive analysis on above 4 indicators can effectively assess the risk of tumor recurrence in NMIBC patients following second TURBT,and timely early medical intervention is beneficial for improving patient outcomes.

Objective To observe the therapeutic effects and mechanisms of acupuncture at"Yanglingquan"(GB34)and"Zusanli"(ST36)on knee osteoarthritis(KOA)rats,focusing on the regulation of PTEN-induced kinase 1/Parkin(PINK1/Parkin)-mediated mitophagy in chondrocytes.Methods Ten out of 40 male SD rats were randomly selected as the normal group,and the remaining 30 rats were used to construct a KOA model.A total of 27 rats were successfully modeled.The successfully modeled rats were randomly divided into a model group,an acupuncture group(acupuncture at Yanglingquan and Zusanli),and an acupuncture+autophagy inhibitor(3-MA)group(acupuncture at Yanglingquan and Zusanli combined with intraperitoneal injection of 3-MA),with 9 rats in each group.After intervention,the morphology of cartilage tissue in each group was observed,and the Mankin's score of cartilage was assessed.The apoptosis rate of chondrocytes was calculated.Enzyme-linked immunosorbent assay(ELISA)was used to detect inflammatory factors[cyclooxygenase 2(COX-2),interleukin 1β(IL-1β),and tumor necrosis factor α(TNF-α)],oxidative damage indicators[nitric oxide(NO),superoxide dismutase(SOD),malondialdehyde(MDA),and glutathione peroxidase(GSH-Px)],and the levels of matrix metalloproteinase 3(MMP-3)and tissue inhibitor of metalloproteinase 1(TIMP-1).The DHE probe was used to measure reactive oxygen species(ROS)level.Polymerase chain reaction(PCR)was used to detect the mRNA expression levels of PTEN-induced kinase 1(PINK1),Parkin,and microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)in cartilage tissue.Western blot was used to measure the protein expression levels of PINK1,Parkin,and LC3-Ⅱ in cartilage tissue.Results Compared with the normal group,the model group showed increased Mankin's score,apoptosis rate,COX-2 level,IL-1β and TNF-α levels,NO and MDA levels,MMP-3 and TIMP-1 levels,and ROS content,as well as decreased SOD and GSH-Px levels,and reduced mRNA and protein expressions of PINK1,Parkin and LC3-Ⅱ,with statistically significant differences(P＜0.05).Compared with the model group,the acupuncture group showed decreased Mankin's score,apoptosis rate,COX-2 level,IL-1β and TNF-α levels,NO and MDA levels,MMP-3 and TIMP-1 levels,and ROS content,as well as increased SOD and GSH-Px levels,and elevated mRNA and protein expressions of PINK1,Parkin and LC3-Ⅱ,with statistically significant differences(P＜0.05).Compared with the acupuncture group,the acupuncture+3-MA group showed increased Mankin's score,apoptosis rate,COX-2 level,IL-1β and TNF-α levels,NO and MDA levels,MMP-3 and TIMP-1 levels,and ROS content,as well as decreased SOD and GSH-Px levels,and mRNA and protein expressions of PINK1,Parkin and LC3-Ⅱ,with statistically significant differences(P＜0.05).Conclusion Acupuncture at"Yanglingquan"and"Zusanli"can inhibit chondrocyte apoptosis by activating PINK1/Parkin-mediated mitophagy,thus improving the condition of KOA rats.