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 investigate the role of TcpC, a virulence factor of uropathogenic Escherichia coli (UPEC), in inhibiting the formation of neutrophil extracellular traps (NETs) in mouse bone marrow neutrophils, and to analyze its pathogenic mechanism. Methods:C57BL/6 mice were injected with either wild-type (CFT073 wt) or tcpc gene-knockout UPEC CFT073(CFT073 Δ tcpc) to establish a mouse model of cystitis. Mice were sacrificed 3 d post-infection, and their bladders were collected to observe gross pathological changes. Hematoxylin-eosin (HE) staining was used to assess histopathological changes in bladder tissues, and immunohistochemistry was performed to localize TcpC in bladder tissues. Bacterial loads in urine samples were quantified using the ten-fold dilution method, and the presence of tcpc gene in genomic DNA from bladder or urine samples was confirmed by PCR. The expression of TcpC at mRNA and protein levels in mouse bone marrow nuetrophils infected with CFT073 wt was detected by qRT-PCR and Western blot. The effects of UPEC infection on expression of NETs-related proteins and the production of pro-inflammatory factors in mouse bone marrow neutrophils were analyzed by Western blot and ELISA, respectively. Reactive oxygen species(ROS) level and bacterial viability in mouse bone marrow nuetrophils were measured using ROS and bacterial viability detection kits. Results:Compared to the CFT073 Δ tcpc group, the bladder of CFT073 wt group mice exhibited significant enlargement, extensive inflammatory cell infiltration, and the presence of TcpC in bladder tissue. The bacterial load in the urine of CFT073 wt -infected mice was significantly higher than that in the CFT073 Δ tcpc group ( P<0.01). PCR confirmed the presence of the tcpc gene in bladder and urine samples from CFT073 wt-infected mice. Increased expression of TcpC at both mRNA and protein levels was observed in CFT073 wt-infected mouse bone marrow neutrophils. CFT073 wt infection inhibited the mRNA and protein expression of NETs-related proteins and reduced the production of pro-inflammatory factors in mouse bone marrow neutrophils. TcpC suppressed ROS level and promoted the survival of CFT073 wt in mouse bone marrow neutrophils. Conclusions:TcpC enhances the pathogenicity of UPEC CFT073 by inhibiting the formation and activation of NETs in mouse bone marrow neutrophils. This study provides new insights into the pathogenic mechanisms of UPEC and the immune evasion strategies of other pathogenic bacteria, as well as potential targets for clinical prevention and treatment of UPEC-induced urinary tract infections.

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 clinical efficacy of Wuhuang Shengji decoction irrigation combined with inci-sion and hanging suture in patients with perianal abscess.METHODS A total of 121 patients with perianal abscess admitted to the Anorectal Department of Ningbo Traditional Chinese Medicine Hospital from Jan.2022 to Jan.2024 were selected as the study subjects.According to the treatment methods,they were divided into a control group(n=37),a positive control group(n=41)anda research group(n=43).The control group was treated with incision and hanging suture,the positive control group was treated with recombinant human epidermal growth factor combined with incision and hanging suture,and the research group was treated with Wuhuang Shengji Decoction irrigation combined with incision and hanging suture.The clinical efficacy,the time of necrotic tissue shedding,new skin appearing,wound itch disappearing and wound healing and the recurrence rate were ob-served.The visual analogue scale(VAS),wound secretion score and expression levels of vascular endothelial growth factor(VEGF)and platelet-derived endothelial cell growth factor(PD-ECGF)in wound secretions were compared before and 14 days after treatment in the three groups.RESULTS The clinical efficacy of the study group(90.70%)was higher than that of the positive control group(87.80%)and control group(70.27%);the recur-rence rate of the study group(2.33%)was lower than that of the positive control group(9.76%)and the control group(18.92%),and the differences were statistically significant(P<0.05).The time required for necrotic tissue shedding,new skin appearing,wound itch disappearing and wound healing followed the trend of study group

OBJECTIVE To explore the clinical efficacy of Wuhuang Shengji decoction irrigation combined with inci-sion and hanging suture in patients with perianal abscess.METHODS A total of 121 patients with perianal abscess admitted to the Anorectal Department of Ningbo Traditional Chinese Medicine Hospital from Jan.2022 to Jan.2024 were selected as the study subjects.According to the treatment methods,they were divided into a control group(n=37),a positive control group(n=41)anda research group(n=43).The control group was treated with incision and hanging suture,the positive control group was treated with recombinant human epidermal growth factor combined with incision and hanging suture,and the research group was treated with Wuhuang Shengji Decoction irrigation combined with incision and hanging suture.The clinical efficacy,the time of necrotic tissue shedding,new skin appearing,wound itch disappearing and wound healing and the recurrence rate were ob-served.The visual analogue scale(VAS),wound secretion score and expression levels of vascular endothelial growth factor(VEGF)and platelet-derived endothelial cell growth factor(PD-ECGF)in wound secretions were compared before and 14 days after treatment in the three groups.RESULTS The clinical efficacy of the study group(90.70%)was higher than that of the positive control group(87.80%)and control group(70.27%);the recur-rence rate of the study group(2.33%)was lower than that of the positive control group(9.76%)and the control group(18.92%),and the differences were statistically significant(P<0.05).The time required for necrotic tissue shedding,new skin appearing,wound itch disappearing and wound healing followed the trend of study group

Objective:To investigate the role of TcpC, a virulence factor of uropathogenic Escherichia coli (UPEC), in inhibiting the formation of neutrophil extracellular traps (NETs) in mouse bone marrow neutrophils, and to analyze its pathogenic mechanism. Methods:C57BL/6 mice were injected with either wild-type (CFT073 wt) or tcpc gene-knockout UPEC CFT073(CFT073 Δ tcpc) to establish a mouse model of cystitis. Mice were sacrificed 3 d post-infection, and their bladders were collected to observe gross pathological changes. Hematoxylin-eosin (HE) staining was used to assess histopathological changes in bladder tissues, and immunohistochemistry was performed to localize TcpC in bladder tissues. Bacterial loads in urine samples were quantified using the ten-fold dilution method, and the presence of tcpc gene in genomic DNA from bladder or urine samples was confirmed by PCR. The expression of TcpC at mRNA and protein levels in mouse bone marrow nuetrophils infected with CFT073 wt was detected by qRT-PCR and Western blot. The effects of UPEC infection on expression of NETs-related proteins and the production of pro-inflammatory factors in mouse bone marrow neutrophils were analyzed by Western blot and ELISA, respectively. Reactive oxygen species(ROS) level and bacterial viability in mouse bone marrow nuetrophils were measured using ROS and bacterial viability detection kits. Results:Compared to the CFT073 Δ tcpc group, the bladder of CFT073 wt group mice exhibited significant enlargement, extensive inflammatory cell infiltration, and the presence of TcpC in bladder tissue. The bacterial load in the urine of CFT073 wt -infected mice was significantly higher than that in the CFT073 Δ tcpc group ( P<0.01). PCR confirmed the presence of the tcpc gene in bladder and urine samples from CFT073 wt-infected mice. Increased expression of TcpC at both mRNA and protein levels was observed in CFT073 wt-infected mouse bone marrow neutrophils. CFT073 wt infection inhibited the mRNA and protein expression of NETs-related proteins and reduced the production of pro-inflammatory factors in mouse bone marrow neutrophils. TcpC suppressed ROS level and promoted the survival of CFT073 wt in mouse bone marrow neutrophils. Conclusions:TcpC enhances the pathogenicity of UPEC CFT073 by inhibiting the formation and activation of NETs in mouse bone marrow neutrophils. This study provides new insights into the pathogenic mechanisms of UPEC and the immune evasion strategies of other pathogenic bacteria, as well as potential targets for clinical prevention and treatment of UPEC-induced urinary tract infections.

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.