To analyze the treatment strategy for a 78-year-old female patient with mismatch repair deficient (dMMR) gastric cancer who achieved long-term survival. After third-line chemotherapy failed, gene testing showed ARID1A p.Gln748fs, c.2733-1G＞T variation, with PD-L1 TPS 30%, CPS 60%. The nivolumab was employed, and two weeks later, the best response was partial response (PR). During the fourth-line immunotherapy maintenance treatment, progression of left adrenal metastasis was observed. The expression of human epidermal growth factor receptor-2 (HER-2) was positive, and the antibody drug conjugate disitamab vedotin (RC48) was chosen for treatment. After 10 months of treatment with nivolumab combined with RC48, the best efficacy was assessed as stable disease (SD), with a progression free survival (PFS) of up to 12 months. Radiotherapy was employed, and immunotherapy was maintained, allowing the patient to achieve a PFS of 18 months again. During immunotherapy, a clinical pharmacist developed a personalized pharmaceutical care plan for this patient. At the last follow-up, this patient achieved 78 months of long-term survival.

Objective To study the impacts of curcumin on the proliferation, migration and cisplatin (DDP) resistance of bladder cancer cells by regulating the liver kinase B1-AMP activated protein kinase-microtubule-associated protein 1 light chain 3 (LKB1-AMPK-LC3) signaling pathway. Methods Human bladder cancer cell line T24 was cultured in vitro, and its DDP resistant T24/DDP cells were induced by cisplatin (DDP). After treating T24 and T24/DDP cells with different concentrations of curcumin, the optimal concentration of curcumin was screened by MTT assay. T24 cells were randomly grouped into control group, curcumin group, metformin group, and combination group of curcumin and metformin. After treatment with curcumin and LKB1-AMPK activator metformin, the proliferation, autophagy, migration, and apoptosis of T24 cells in each group were detected by MTT assay, monodansylcadavrine (MDC) fluorescence staining, cell scratch assay, and flow cytometry, respectively. Western blot was used to detect the expression of proteins related to LKB1-AMPK-LC3 signaling pathway in T24 cells of each group. T24/DDP cells were randomly assigned into control group, curcumin group, metformin group, and combination group of curcumin and metformin. Cells were treated with curcumin and metformin according to grouping and treated with different concentrations of DDP simultaneously. Then, the effect of curcumin on the DDP resistance coefficient of T24/DDP cells was detected by MTT assay. T24/DDP cells were randomly grouped into control group, DDP group, combination groups of DDP and curcumin, DDP and metformin, DDP, curcumin and metformi. After treatment with DDP, curcumin, and metformin, the proliferation, autophagy, migration, apoptosis, drug resistance, and the expression of proteins related to LKB1-AMPK-LC3 signaling pathway in T24/DDP cells of each group were detected with the same methods. Results Compared with the control group, the activity of T24 cells, relative number of autophagosomes, migration rate, Phosphorylated-LKB1 (p-LKB1)/LKB1, Phosphorylated-AMPK (p-AMPK)/AMPK, LC3II/LC3I, and the DDP resistance coefficient of T24/DDP cells in the curcumin group were lower, and the apoptosis rate of T24 cells was higher; the changes in various indicators in the metformin group were opposite to those in the curcumin group. Compared with the curcumin group, the activity of T24 cells, relative number of autophagosomes, migration rate, p-LKB1/LKB1, p-AMPK/AMPK, LC3II/LC3I, and the DDP resistance coefficient of T24/DDP cells in the combination group of curcumin and metformin were higher, and the apoptosis rate of T24 cells was lower. Compared with the control group, there were no obvious changes in various indicators of T24/DDP cells in the DDP group. Compared with the control group and DDP group, the viability of T24/DDP cells, relative number of autophagosomes, migration rate, P-glycoprotein (P-gp) protein expression, p-LKB1/LKB1, p-AMPK/AMPK, and LC3II/LC3I in the combination group of DDP and curcumin were lower, and the apoptosis rate of T24/DDP cells was higher; the changes in the above indicators in the combination group of DDP and metformin were opposite to those in the combination group of DDP and curcumin. Compared with the combination group of DDP and curcumin, the viability of T24/DDP cells, relative number of autophagosomes, migration rate, P-gp protein expression, p-LKB1/LKB1, p-AMPK/AMPK, and LC3II/LC3I in the combination group of DDP, curcumin and metformin were higher, and the apoptosis rate of T24/DDP cells was lower. Conclusion Curcumin can reduce the activity of LKB1-AMPK-LC3 signaling pathway, thereby inhibiting autophagy, proliferation and migration of bladder cancer cells, promoting their apoptosis, and weakening their resistance to DDP.
Humans ; Cisplatin/pharmacology* ; Curcumin/pharmacology* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Protein Serine-Threonine Kinases/genetics* ; AMP-Activated Protein Kinases/metabolism* ; Drug Resistance, Neoplasm/drug effects* ; Urinary Bladder Neoplasms/pathology* ; Cell Line, Tumor ; Cell Movement/drug effects* ; AMP-Activated Protein Kinase Kinases ; Microtubule-Associated Proteins/metabolism* ; Apoptosis/drug effects* ; Antineoplastic Agents/pharmacology* ; Metformin/pharmacology* ; Autophagy/drug effects*

Doxorubicin (Dox) is an anthracycline drug widely applied in various malignancies. However, the fatal cardiotoxicity induced by Dox limits its clinical application. Post-transcriptional protein modification via ubiquitination/deubiquitination in cardiomyocytes mediates the pathophysiological process in Dox-induced cardiotoxicity (DIC). In this study, we aimed to clarify the regulatory role and mechanism of a deubiquitinating enzyme, ubiquitin-specific peptidase 13 (USP13), in DIC. RNA-seq analysis and experimental examinations identified that cardiomyocyte-derived USP13 positively correlated with DIC. Mice with cardiac-specific deletion of USP13 were subjected to Dox modeling. Adeno-associated virus serotype 9 (AAV9) carrying cTNT promoter was constructed to overexpress USP13 in mouse heart tissues. Cardiomyocyte-specific knockout of USP13 exacerbated DIC, while its overexpression mitigated DIC in mice. Mechanistically, USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes the autolysosome-related degradation of STING, subsequently alleviating cardiomyocyte inflammation and death. Our study suggests that USP13 serves a cardioprotective role in DIC and indicates USP13 as a potential therapeutic target for DIC treatment.

Objective To explore the effects of bronchoalveolar lavage combined with microbiological rapid on-site evaluation in potential donor lung maintenance.Methods Brain death patients who met the inclusion criteria and were admitted to the Intensive Care Unit(ICU)of Calmette Hospital Affiliated to Kunming Medical University from September 2020 to December 2022 were selected for bronchoalveolar lavage(BAL)and(BAL)and the lavage fluid were collected for M-ROSE to compare the pathogen detection rate and initial diagnosis time.According to the positive results of the microbiological rapid on-site evaluation,patients with the brain death were treated with empirical anti-infective therapy,and the oxygenation index,chest X-ray score,and the infection index(WBC,CRP,PCT)of anti-infective treatment 48 hours were evaluated.Results 1.Comparison of the detection rate of pathogenic microorganisms:The results of M-ROSE were highly consistent with a routine microbiological smear(Kappa = 0.921,P<0.001).2.Comparison of diagnostic time:The initial diagnosis time of M-ROSE was significantly lower than routine microbiological smear time and microbial culture time(P<0.001).3.Comparison of therapeutic effects of anti-infective therapy for 48 hours:There was no significant difference in oxygenation index,white blood cells and hypersensitive C-reactive protein before and after the anti-infective treatment(P>0.05).There were significant differences in procalcitonin and chest X-ray before and after the anti-infective treatment(P<0.05).Conclusion Bronchoalveolar lavage combined with microbiological rapid on-site evaluation has the high timeliness in the diagnosis of potential donor pulmonary infection,which can provide a preliminary basis for the early anti-infective therapy of donor lung maintenance.

Objective:To investigate the role of TcpC, a virulence factor of uropathogenic Escherichia coli (UPEC), in immune evasion, and analyze its related pathogenic mechanism. Methods:C57BL/6 mice were injected with 10 9 colony-forming unit of wild-type (CFT073 wt) or tcpc gene-knockout (CFT073 Δ tcpc) UPEC CFT073 strains from urethra into bladder to construct a mouse model of pyelonephritis. These mice were sacrificed 5 d after infection and their kidneys were taken to observe the gross pathological changes. Hematoxylin-eosin staining was used to observe histopathological changes in kidney tissues and immunohistochemistry was performed to locate TcpC in kidney tissues. The bacterial loads in urine samples of UPEC infected-mice were counted by ten-fold dilution method, and the presence of tcpc gene in the genomic DNA of bacteria from CFT073-infected mouse kidney or urine samples was measured by PCR. The expression of TcpC at mRNA level was detected by qRT-PCR after infecting dendritic cells with CFT073 wt strains. The influences of UPEC infection on the activation of NF-κB signaling pathway and the secretion of proinflammatory factors by dendritic cells were analyzed by Western blot and ELISA, respectively. The viability of UPEC strains in dendritic cells were observed by laser confocal microscope. Results:Compared with the CFT073 Δ tcpc group, the mice in the CFT073 wt group had obvious abscess in the kidneys as well as massive neutrophil infiltration and abundant TcpC in kidney tissues. The bacterial loads in the urine of CFT073 wt-infected mice were significantly higher than those in the urine of CFT073 Δ tcpc mice. PCR results showed that tcpc gene was successfully amplified from mouse kidney and urine samples. Increased expression of TcpC at both mRNA and protein levels was detected in CFT073 wt-infected dendritic cells. CFT073 wt infection inhibited the phosphorylation of NF-κB p50 and the production of proinflammatory factors in dendritic cells. TcpC promoted the survival of CFT073 wt in dendritic cells. Conclusions:TcpC expression increases significantly during CFT073 wt infection or in mice with CFT073 wt-induced pyelonephritis. It promotes the survival of CFT073 wt in dendritic cells by inhibiting the activation of NF-κB signaling pathway and reducing the secretion of pro-inflammatory cytokines. TcpC is involved in the pathogenesis of UPEC and immune evasion.

Objective To investigate the correlation between serum microRNA(miR)-24-3p,microtubule affinity-regulating kinase 4(MARK4)level expression and cardiac function in serum of patients with coronary atherosclerotic heart disease(CHD).Methods From August 2021 to April 2023,138 CHD patients who visited Sichuan Provincial People's Hospital were collected as the study subjects(CHD group).According to the New York Heart Association(NYHA)grading,patients in the CHD group were separated into grade Ⅱ(n=39),grade Ⅲ(n=68),and grade Ⅳ(n=31).Additionally,123 individuals who underwent physical examinations were selected as the health group during the same period.Real-time fluorescence quantitative PCR(qRT-PCR)method was applied to detect the expression levels of miR-24-3p and MARK4.Cardiac function indicators in the CHD and health groups were detected.Pearson method was applied to analyze the correlation among serum miR-24-3p,MARK4,and cardiac function indicators.Results Compared with the healthy group,the levels of MARK4(1.19±0.21 vs 1.00±0.20),left ventricular end-systolic dimension(LVESd),left ventricular enddiastolic dimension(LVEDd),interventricular septal thickness(IVS),left ventricular end-diastolic volume(LVEDv),left ventricular end-systolic volume(LVESv),and left ventricular mass(LV mass)in the CHD group were increased(t=7.462,18.242,23.888,9.941,2.812,12.520,11.029),while the levels of miR-24-3p(0.62±0.11 vs 1.00±0.18),left ventricular ejection fraction(LVEF),and cardiac output(CO)were reduced(t=20.821,10.212,18.188),and the differences were statistically significant(all P＜0.05).As cardiac function grading increased,MARK4 expression levels(1.09±0.19,1.18±0.17,1.32±0.22),LVESd,LVEDd,IVS,LVEDv,LVESv and LV mass were increased(F=13.025,10.606,11.920,57.956,29.680,21.253,12.954),and miR-24-3p expression levels(0.84±0.15,0.61±0.11,0.37±0.08),LVEF and CO were decreased(F=139.227,9.720,13.411),and the differences were statistically significant(all P＜0.05).Pearson correlation analysis showed a negative correlation between miR-24-3p and MARK4 expression in the serum of patients with CHD(r=-0.540,P＜0.05).The relative expression of miR-24-3p in the serum of patients with CHD was negatively correlated with LVESd,LVEDd,IVS,LVEDv,LVESv and LV mass(r=-0.656,-0.636,-0.617,-0.576,-0.492,-0.687,all P＜0.05),but positively correlated with LVEF and CO(r=0.570,0.683,all P＜0.05).The relative expression level of MARK4 was positively correlated with LVESd,LVEDd,IVS,LVEDv,LVESv,and LV mass(r=0.503,0.542,0.508,0.624,0.516,0.560,all P＜0.05),but negatively correlated with LVEF and CO(r=-0.594,-0.525,all P＜0.05).Conclusion The expression of miR-24-3p in the serum of CHD patients was decreased,while the expression of MARK4 was increased.There was an obvious correlation between the two and cardiac function indicators.

Objective Based on the technology acceptance model,to explore the influence mechanism of technical support,perceived interactivity,perceived usefulness,perceived ease of use and perceived risk on medical staff's report intention on adverse events,and to provide path suggestions for improving medical staff's report intention adverse events.Methods The multi-stage sampling method was used to select 637 medical staffs of tertiary public hospitals in Hangzhou who used the information-based platform to report adverse events as the research respondents,and the self-developed scale of report intention on adverse events was used as the research tool,monofactor analysis were conducted by Wilcoxon rank-sum test,and the structural equation model was used to analyze the influence path of their report intention on adverse events.Results Perceived ease of use and perceived usefulness have positive effects on medical staff's report intention on adverse events(β=0.264,0.658;P＜0.001);Perceived risk negatively affected the medical staff's report intention on adverse events(β=-0.143,P＜0.001).The indirect effects of perceived usefulness and perceived ease of use on medical staff's report intention on adverse events are 0.538 and 0.205,respectively.Conclusion Perceived usefulness and perceived ease of use plays a mediating role in perceived interactivity and medical staff's report intention on adverse events.

Objective Based on the technology acceptance model,to explore the influence mechanism of technical support,perceived interactivity,perceived usefulness,perceived ease of use and perceived risk on medical staff's report intention on adverse events,and to provide path suggestions for improving medical staff's report intention adverse events.Methods The multi-stage sampling method was used to select 637 medical staffs of tertiary public hospitals in Hangzhou who used the information-based platform to report adverse events as the research respondents,and the self-developed scale of report intention on adverse events was used as the research tool,monofactor analysis were conducted by Wilcoxon rank-sum test,and the structural equation model was used to analyze the influence path of their report intention on adverse events.Results Perceived ease of use and perceived usefulness have positive effects on medical staff's report intention on adverse events(β=0.264,0.658;P＜0.001);Perceived risk negatively affected the medical staff's report intention on adverse events(β=-0.143,P＜0.001).The indirect effects of perceived usefulness and perceived ease of use on medical staff's report intention on adverse events are 0.538 and 0.205,respectively.Conclusion Perceived usefulness and perceived ease of use plays a mediating role in perceived interactivity and medical staff's report intention on adverse events.

Objective Based on the technology acceptance model,to explore the influence mechanism of technical support,perceived interactivity,perceived usefulness,perceived ease of use and perceived risk on medical staff's report intention on adverse events,and to provide path suggestions for improving medical staff's report intention adverse events.Methods The multi-stage sampling method was used to select 637 medical staffs of tertiary public hospitals in Hangzhou who used the information-based platform to report adverse events as the research respondents,and the self-developed scale of report intention on adverse events was used as the research tool,monofactor analysis were conducted by Wilcoxon rank-sum test,and the structural equation model was used to analyze the influence path of their report intention on adverse events.Results Perceived ease of use and perceived usefulness have positive effects on medical staff's report intention on adverse events(β=0.264,0.658;P＜0.001);Perceived risk negatively affected the medical staff's report intention on adverse events(β=-0.143,P＜0.001).The indirect effects of perceived usefulness and perceived ease of use on medical staff's report intention on adverse events are 0.538 and 0.205,respectively.Conclusion Perceived usefulness and perceived ease of use plays a mediating role in perceived interactivity and medical staff's report intention on adverse events.