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 Zinc finger protein 335 (Zfp335) plays a crucial role in the early development of thymic T cells and the differentiation of peripheral T cell subpopulations. The objective of this study is to investigate the role and underlying mechanisms of Zfp335 in the regulation of regulatory T cell (Treg) within tumor immunity. Methods The Zfp335 gene was specifically knocked out in Treg using tamoxifen (Zfp335^fl/fl FOXP3^creERT2), and the MC38 tumor model was established. On the 7th day after tumor inoculation, tumor size was observed and measured. Tumor size was monitored and recorded daily starting from day 7 post-inoculation. On day 12, tumors were harvested, and the proportions of CD4⁺ T cells, CD8⁺ T cells, and Treg were analyzed by flow cytometry. Additionally, the mitochondrial function of effector regulatory T cell (eTreg) was assessed. Results From day 10 post-tumor inoculation, tumor volume in the Zfp335^CKO group was significantly reduced compared to that of the wild-type (WT) group. Furthermore, the infiltration of CD4⁺ and CD8⁺ T cells, along with their respective effector cells, was significantly higher in the Zfp335^CKO group than in the WT group. The proportions of CD4⁺ and CD8⁺ T cells producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were also significantly increased in the Zfp335^CKO group compared to that of the WT group. In addition, the percentage of CD8⁺ T cells secreting granzyme B (GzmB) was significantly higher in the Zfp335^CKO group than that in the WT group. In contrast, the proportion of Treg and inducible T cell co-stimulator (ICOS)⁺ Treg in the Zfp335^CKO group was significantly lower than that in the WT group. Finally, the expression level of Mitotracker Deep Red in eTreg from the Zfp335^CKO group was significantly reduced compared to that in the WT group. Conclusion During tumorigenesis, the specific deletion of Zfp335 impairs Treg activation, which is related to decreased mitochondrial function in eTreg. In Zfp335^CKO mice. Tumors exhibit increased infiltration of effector T cells, accompanied by elevated levels of cytotoxic cytokines, ultimately enhancing resistance to tumor progression.
Animals ; T-Lymphocytes, Regulatory/metabolism* ; Mice ; CD8-Positive T-Lymphocytes/immunology* ; Neoplasms/genetics* ; Cell Line, Tumor ; Mice, Inbred C57BL ; Mice, Knockout ; DNA-Binding Proteins/genetics* ; Female

OBJECTIVE: To investigate the clinical effect of transposition of gracilis muscle flap in repairing urethral perineal fistula after Miles operation. METHODS: The clinical data of 3 patients with urethral perineal fistula treated in the Second Affiliated Hospital of Zhejiang University from September 2023 to November 2024 were analyzed retrospectively. All patients were male, aged from 59 to 68 years (mean 63 years). All patients underwent Miles operation because of low rectal cancer. Urethral perineal fistula occurred after 2 months to 13 years of the operation. The underlying comorbidities included diabetes (2/3), preoperative chemoradiotherapy (1/3), and chemotherapy alone (1/3). The endourethral fistula was located in the apical and membranous part of the prostate, with a diameter of 1.5-2.0 cm and a mean of 1.7 cm. Suprapubic cystostomy was performed one month before operation. In all 3 cases, perineal inverted "Y" incision was taken under general anesthesia to expose urethral fistula, cut off necrotic tissue and suture urethral fistula. The gracilis muscle of the right thigh was taken and turned through the perineal subcutaneous tunnel. and 6 stitches were suture at the urethral fistula. RESULTS: The operations of all 3 patients were completed successfully. The follow-up period ranged from 2 months to 12 months, with an average of 8 months. There was no case of urinary incontinence after removal of catheter 3 weeks after operation. In two patients, urethrography was reviewed 1 month after surgery to show no fistula residue and urethral stenosis, and the fistula was removed. In one patient with a history of radiotherapy, urethrography was reviewed 1 month after surgery to show a small amount of contrast overflow around the urethra, and urethrography was reviewed again 3 months after surgery to show no contrast overflow around the urethra. All the 3 patients had no disturbance of movement of the right lower limb, and the pain of different degrees of thigh incision was acceptable and basically relieved half a month after operation. CONCLUSION Gracilis muscle flap is one of the effective methods for repairing urethral perineal fistula after Miles operation，which has a precise surgical result and few complications.
Humans ; Male ; Middle Aged ; Aged ; Gracilis Muscle/transplantation* ; Urinary Fistula/surgery* ; Retrospective Studies ; Surgical Flaps ; Perineum/surgery* ; Rectal Neoplasms/surgery* ; Postoperative Complications/surgery* ; Urethral Diseases/surgery* ; Urethra/surgery*

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.

Enamel demineralization, the formation of white spot lesions, is a common issue in clinical orthodontic treatment. The appearance of white spot lesions not only affects the texture and health of dental hard tissues but also impacts the health and aesthetics of teeth after orthodontic treatment. The prevention, diagnosis, and treatment of white spot lesions that occur throughout the orthodontic treatment process involve multiple dental specialties. This expert consensus will focus on providing guiding opinions on the management and prevention of white spot lesions during orthodontic treatment, advocating for proactive prevention, early detection, timely treatment, scientific follow-up, and multidisciplinary management of white spot lesions throughout the orthodontic process, thereby maintaining the dental health of patients during orthodontic treatment.
Humans ; Consensus ; Dental Caries/etiology* ; Dental Enamel/pathology* ; Tooth Demineralization/etiology* ; Tooth Remineralization

OBJECTIVE To establish an ion chromatography method for the simultaneous determination of chloride， sulfate and bicarbonate ions in Polyethylene glycol electrolyte powder （Ⅲ）. METHODS The chromatographic column was a Dionex IonpacTM AS11-HC anion analysis column， with a Dionex IonPacTM AG11-HC guard column. The mobile phase was 10 mmol/L potassium hydroxide at an isocratic elution flow rate of 1.2 mL/min. The detector was a conductivity detector， and the suppressor was a Dionex AERS with a suppressor current of 30 mA. The column temperature was maintained at 30 ° C， and the injection volume was 10 μL. Chloride and sulfate contents were calculated by external standard method， while bicarbonate content was determined by double logarithmic fitting standard curve method. RESULTS Under these chromatographic conditions， chloride， sulfate and bicarbonate ions were effectively separated with linear ranges of 0.055 to 0.219 mg/mL （r＝0.999 9）， 0.155 to 0.618 mg/mL （r＝1.000 0）， and 0.065 to 0.121 mg/mL （r＝0.999 9）， respectively. The recoveries were 98.06% to 101.34%， 97.37% to 101.25%， and 97.16% to 99.81%， respectively， with RSDs of 1.1%， 1.3% and 1.0% （n＝9）. The RSDs for the evaluation of precision， accuracy， stability and ruggedness were all less than 2%. CONCLUSIONS The established ion chromatography is simple， rapid， accurate， precise and durable， can simultaneously determine the contents of chloride， sulfate and bicarbonate ions in Polyethylene glycol electrolyte powder （Ⅲ）， which is suitable for its quality control.

Objective:To investigate the relationship between oral health and mild cognitive impairment(MCI)by using indicators that evaluate oral hypofunction.Methods:The study was conducted using a cross-sectional design.Participants were recruited from three communities(Shizi Ling, Wenyi Xincun, and Yaoling in Furong District)in Changsha in July 2021, using convenience sampling.Cognitive and oral functions were evaluated using the simple mental state examination, version 2(MMSE-2)and seven indicators of oral hypofunction, which included oral hygiene, oral dryness, occlusal force, tongue and lip movement, tongue pressure, mastication, and swallowing function.Results:A total of 144 subjects were included in this study, with 72 males.Except for education level, there were no statistically significant differences between the MCI group and the normal cognitive group in terms of demographic information and self-reported and measured oral functions(all P>0.05).There was a correlation between the subjects' self-reported oral function and the actual measured oral function.Multiple linear regression analysis revealed no significant correlation between the MMSE score and the seven indicators used to measure oral hypofunction(all P>0.05).The MMSE score of the female group showed a negative correlation with mastication( β=-0.003, P=0.043), while the MMSE score of subjects with elementary school education also showed a negative correlation with mastication( β=-0.022, P=0.016).Additionally, the MMSE score of subjects with middle school education showed a positive correlation with the number of residual teeth( β=0.090, P=0.030). Conclusions:The self-reported oral function can serve as an initial assessment of overall oral function.However, among elderly individuals who do not show significant decline in oral function, there was no significant correlation between oral function and MCI.To accurately identify individuals with MCI, a more detailed sub-analysis with a larger sample size is required.

Objective:To sinicize the Family Collaboration Scale (FCS) and test its reliability and validity.Methods:The FCS was translated into Chinese based on the forward translation-back translation proposed by Brislin model to make cross-cultural adjustment. The Chinese version of FCS was developed by forward translation, back translation, overall, expert consultation and pre-survey. From April 2022 to April 2023, 236 caregivers of the elderly patients in five tertiary hospitals in Beijing were evaluated to analyze the reliability and validity of the scale.Results:Finally, among the 230 caregivers of elderly patients, 65 males and 165 females, aged 21-84 (54.07 ± 11.17) years old. The Chinese version of FCS contained 3 dimensions and 21 items. The content validity index of the items was 0.86-1.00, scale-level content validity index/universal agreement was 0.86, the Cronbach α coefficient of the scale was 0.908. The results of confirmatory factor analysis showed that all the model fitting indexes were at acceptable level. Conclusions:The Chinese version of FCS has good reliability and validity, and it can be used as a reliable measurement tool to measure the cooperative relationship between nurses and family caregivers of elderly patients.

Objective: To understand prevalence and trend of drinking behavior among middle school students in Quzhou during 2012 to 2022, and to provide a basis for formulating scientific and effective intervention measures for adolescent drinking. Methods: By using stratified cluster sampling method, a questionnaire survey using Zhejiang adolescent health related behavior questionnaire was conducted anonymously in selected classes in May 2012, 2017 and 2022, respectively. Changes of drinking behavior of middle school students in different years were analyzed. Results: The prevalence of ever drinking, current drinking and drunkenness among middle school students in Quzhou decreased from 58.05%, 22.70% and 21.25% in 2012 to 41.83%, 15.35% and 11.54% in 2022, respectively ( χ 2 trend =82.69, 30.00，58.24, P <0.01). In the past 30 days, 66.67% of students reported drinking 1-2 days, the proportion of drinking for 3-5 days increased from 16.36% in 2012 to 26.19% in 2022, the proportion of drinking for 6-19 days decreased from 13.03% in 2012 to 3.40% in 2022. The proportion of buying alcohol increased from 22.12% in 2012 to 35.03% in 2022. The results of the three surveys showed that, now drinking rates, drinking rates, Male students (27.88%，23.96%，18.75%；24.69%，17.44%，13.75%) was higher than the girls (17.60%，17.25%，11.31%；17.87%，10.61%，8.91%)， non ordinary high schools (33.96%，34.69%，22.77%；33.65%，23.91%，19.49%) were higher than ordinary high schools (25.82%，18.80%， 12.62 %；25.82%，17.35%，9.94%) and junior middle school (16.53%，15.83%，12.22%；13.93%，8.47%，7.35%). Conclusion Progress in adolescent drinking control is being made in Quzhou, with the prevalence of ever drinking, current drinking and drunkenness significantly decreased. It is necessary to strengthen the control of drinking behavior among middle school students from the aspects of school, family and society, especially for boys and students in non ordinary high school students.

Humans ; Parkinson Disease/diagnosis* ; Machine Learning