Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective:To construct a prior based on the inherent properties of PET to accurately segment the lesion areas.Methods:A network framework for PET tumor segmentation driven by geodesic priors was proposed (geodesic network for short). Specifically, partial differential equations were constructed to characterize the geodesic distances between different regions in PET images. Tumor marker points identified by CT labeling were used as the initial conditions for the equations. To enhance the contrast between areas of lung or breast tumors and normal tissues, a smooth Heaviside function was utilized to map the geodesic distances. The network framework adopted a dual-branch architecture, using geodesic priors to assist in PET image segmentation.Results:The proposed method achieved a Dice coefficient of 94.92% in lung cancer segmentation and 90.12% in breast cancer segmentation. With the addition of geodesic priors in the Unet, the Dice coefficient for breast cancer increased by 32.37% (from 42.50% to 74.87%).Conclusion:Geodesic priors can significantly improve segmentation outcomes and enhance the generalization capability of the network.

[摘 要] 目的：探讨白蛋白结合型紫杉醇联合PD-1抑制剂用于治疗一线化疗失败的骨与软组织肉瘤的疗效及安全性。方法：回顾性分析北京积水潭医院骨肿瘤科2017年8月至2020年8月收治的一线化疗失败的晚期骨与软组织肉瘤患者。患者接受白蛋白结合型紫杉醇（125~140 mg/m2，第1天和第8天）与PD-1抑制剂（信迪利单抗或特瑞普利单抗，每21 d一次）联合治疗。每2个治疗周期评估1次疗效，按RECIST 1.1标准评估肿瘤疗效，按NCI-CTCAE5.0标准评估不良反应。结果：共20名患者纳入研究，完成1至8个治疗周期，中位治疗周期数为3个。所有患者均可评估疗效，完全缓解4例（20%），部分缓解0例，稳定9例（45%），疾病进展7例（35%）。客观缓解率（ORR）为20%，疾病控制率（DCR）为65%。中位无进展生存期（PFS）为3.0个月。治疗期间主要不良反应包括2级白细胞减少（40%）、1-2级神经毒性反应（20%），以及2级甲状腺功能减退（10%）。结论：白蛋白结合型紫杉醇联合PD-1抑制剂治疗为一线化疗失败的晚期骨与软组织肉瘤患者提供了一种潜在的治疗选择，其不良反应可控，值得开展更大样本的前瞻性研究进一步验证其疗效。

Objective:To construct a biosafety evaluation index system for major emergency public health events in medical institutions.Methods:Based on previous laboratory biosafety evaluation work, relevant regulations and standards on biosafety in China were collected through literature research and expert consultations. Candidate indicators for constructing the biosafety evaluation system for major emergency public health events in medical institutions were selected, and a framework was established. Two rounds of expert questionnaires were conducted to determine the content of the index system based on experts′ evaluation, and each indicator′s relevance and importance were scored. Finally, two rounds of Delphi consultations were carried out, and the Analytic Hierarchy Process (AHP) was applied to calculate the weights of indicators.Results:The response rates for the total four rounds of questionnaire surveys were all 100%. The first two rounds focused on determining the framework, while the latter two focused on determining the weights for each indicator. The authority coefficients of the expert consultations for the two rounds of weights were 0.65 and 0.70, respectively, indicating the reliability of the research results. In the final round of survey, the Kendall′s coefficients of concordance at each level were all greater than 0.1. Through statistical testing, the P-values were all less than 0.05, indicating good coordination of expert opinions. Ultimately, we established an operational biosafety evaluation system for major emergency public health events in medical institutions, consisting of 4 primary indicators, 26 secondary indicators, and 119 tertiary indicators, with additional deduction items, bonus items, unacceptable items, and monitoring indicators.Conclusions:Based on scientific theory, a biosafety evaluation system for major emergency public health events in medical institutions was constructed, achieving the integration of routine and emergency measures. This system can be used for self-assessment of laboratory biosafety during emergency public health events, addressing the lack of unified standards in biosafety evaluation. Through regular self-assessment, it can enhance the level of biosafety management in medical institution laboratories, to realize the value of application and dissemination.

OBJECTIVE To explore the association of the expressions of tissue forkhead box transcription factor(FOX)F2,angiopoietin-like protein 4(ANGPTL4)and FOXP3 with the pathological features and recurrence of the cervical cancer patients with human papillomavirus(HPV)infection undergoing radical hysterectomy.METHODS Totally 69 cervical cancer patients with HPV infection who underwent radical hysterectomy in Danzhou People's Hospital from Nov.2018 to Jul.2021 were randomly assigned as the cervical cancer group,meanwhile,72 patients who had cervical intraepithelial neoplasia(CIN)were chosen as the CIN group.The patients of the cer-vical cancer group were divided into the recurrence group with 25 cases and the no recurrence group with 44 cases according to the prognosis.The levels of tissue FOXF2,ANGPTL4 and FOXP3 were compared among the groups.The levels of FOXF2,ANGPTL4 and FOXP3 were compared among the cervical cancer patients with dif-ferent clinical pathological features,and the pathological features were compared among the patients with different treatment outcomes.The values of the three indexes in diagnosis of the postoperative recurrence in the cervical cancer patients with HPV infection undergoing radical resection were analyzed.RESULTS There were significant differences in the levels of tissue FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA between the cervical cancer group and the CIN group(P＜0.05).There were significant differences in the levels of FOXF2 mRNA,ANGPTL4 mR-NA and FOXP3 mRNA among the cervical cancer patients with HPV infection who varied in federation international of gynecology and obstetrics(FIGO)stage,lymphatic metastasis and infiltration depth(P＜0.05).There were significant differences in the FIGO stage,lymphatic metastasis,infiltration depth,FOXF2 mRNA level,ANGPTL4 mRNA level and FOXP3 mRNA level between the recurrence group and the no recurrence group(P＜0.05).The area under the curve(AUC)value of the joint detection of FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA was higher than that of the single detection in diagnosis of the postoperative recurrence in the cervical cancer patients with HPV infection under-going radical resection(P＜0.05).CONCLUSIONS The cervical cancer patients with HPV infection undergoing radi-cal resection show the abnormal expressions of tissue FOXF2 mRNA,ANGPTL4 mRNA and FOXP3 mRNA.There is association between the three indexes and the FIGO stage,lymphatic metastasis and infiltration depth.The joint detection of the three indexes has high value in diagnosis of the postoperative recurrence.

Objective To systematically evaluate the effect of inspiratory muscle training(IMT)on weaning outcomes in patients with weaning failure.Methods Literatures in Chinese and English were retrieved from databases such as PubMed,Cochrane Library,Web of Science,Embase,CNKI,VIP,Wanfang data and CBM for researches on the effect of IMT in mechanical ventila-tion weaning failure,from the inception of the databases to October 22,2024.The methodological quality of the researches was evaluated with PEDro scale,and data were extracted for a systematic review.Results Nine randomized controlled trials were included,published between 2011 and 2023,from Brazil,China,the United States,Iran and Australia,with a total of 499 patients.The scores of the PEDro scale ranged five to eight.The population included patients with prolonged weaning,difficult weaning and tracheostomy.The IMT methods included threshold load training and tapered flow resistance training.The training intensity was 30%to 80%of maximal inspiratory pressure(MIP),and some researches did not set the training intensity based on MIP.The pro-gression of intensity varied widely across researches.The intervention frequency ranged from five to 30 breaths per set,with at least one minute rest between sets,two to six sets per session,one to two sessions per day,and five to seven days per week.The duration of the intervention ranged from successful weaning,one week after weaning,extubation,or four days to eight weeks.Regarding the efficacy of the intervention,IMT was not benefi-cial for the duration of mechanical ventilation and intensive care unit(ICU)length of stay on weaning failure pa-tients.However,the effect of IMT on weaning successful rates,duration of weaning,MIP and mortality was in-consistent.Conclusion IMT can not improve the duration of mechanical ventilation and ICU length of stay for weaning failure pa-tients,and there is still debate regarding its effect on successful rate of weaning,duration of weaning,MIP and mortality.

Objective:To explore the potential category characteristics of social participation in colorectal cancer patients with stoma and analyze the influencing factors of different potential categories, so as to provide references for formulating and implementing targeted nursing measures.Methods:By using the convenience sampling method, colorectal cancer patients with stoma who were hospitalized or had outpatient follow-up visits at Guilin Hospital of Integrated Traditional Chinese and Western Medicine and the Second Affiliated Hospital of Guilin Medical University from January to December 2024 were selected as the survey subjects. A cross-sectional survey was conducted using the general information questionnaire, the voluntary participation Questionnaire, the Existential Anxiety Scale, the Family Support Scale and the Social Support Rating Scale. Potential profile analysis was used to identify the categories of social participation characteristics of colorectal cancer stoma patients, and multivariate Logistic regression was used to analyze the related influencing factors.Results:A total of 240 valid questionnaires were finally retrieved. Among the 240 colorectal cancer patients with stoma, 126 were male and 114 were female, aged 34-75 (55.63 ± 6.52) years. The social participation score of colorectal cancer patients with stoma was (55.84 ± 8.62) points. The results of potential profile analysis showed that the social participation of colorectal cancer patients with stoma could be divided into three potential categories: low participation-inefficient social life type accounted for 38.3% (92/240), medium participation-efficient indoor participation type accounted for 36.3% (87/240), and high participation-efficient outdoor participation type accounted for 25.4% (61/240). The results of multivariate Logistic regression analysis showed that, taking the high participation-efficient outdoor participation type as the reference, age, educational level, presence absence of stoma-related complications, existence of meaningless anxiety, family support, and social support were the influencing factors of low participation-inefficient social life type and medium participation-efficient indoor participation type ( OR values ranged from 0.163 to 1.879, all P<0.05). Conclusions:There are obvious classification characteristics in the social participation of colorectal cancer patients with stoma. Nursing staff can formulate and implement targeted intervention strategies based on different classification characteristics. Starting from the existence of meaningless anxiety in patients, an effective family and social support system should be established to improve their social participation.

Objective:To understand the hindrance and promoting factors of colonoscopy compliance in high-risk adenoma patients 3 months after resection, and to provide reference for formulating targeted nursing intervention strategies.Methods:An interview outline was formulated based on the health action process approach theory. A descriptive qualitative research method was used to select 13 patients with high-risk adenoma after resection in Guilin Integrated Traditional Chinese and Western Medicine Hospital from April to May 2024 for semi-structured interviews according to the purposive sampling method. Content analysis was used to analyze the data and refine the themes.Results:Among the 13 patients, there were 8 males and 5 females, aged 42-70 years old.A total of 2 themes and 8 sub-themes were extracted, including hindering factors (fear of disease outcome, risk perception barriers, low self-efficacy and lack of behavior plan) and promoting factors (establishing correct health beliefs, perceiving the benefits of health behavior, enhancing personal efficacy and advocating health behavior plan).Conclusions:The compliance of colonoscopy in patients with high-risk adenoma after resection is affected by a series of obstacles and promoting factors. In the future, targeted intervention strategies can be formulated based on the health action process approach theory to improve their compliance with colonoscopy.

Objective To systematically evaluate the effect of inspiratory muscle training(IMT)on weaning outcomes in patients with weaning failure.Methods Literatures in Chinese and English were retrieved from databases such as PubMed,Cochrane Library,Web of Science,Embase,CNKI,VIP,Wanfang data and CBM for researches on the effect of IMT in mechanical ventila-tion weaning failure,from the inception of the databases to October 22,2024.The methodological quality of the researches was evaluated with PEDro scale,and data were extracted for a systematic review.Results Nine randomized controlled trials were included,published between 2011 and 2023,from Brazil,China,the United States,Iran and Australia,with a total of 499 patients.The scores of the PEDro scale ranged five to eight.The population included patients with prolonged weaning,difficult weaning and tracheostomy.The IMT methods included threshold load training and tapered flow resistance training.The training intensity was 30%to 80%of maximal inspiratory pressure(MIP),and some researches did not set the training intensity based on MIP.The pro-gression of intensity varied widely across researches.The intervention frequency ranged from five to 30 breaths per set,with at least one minute rest between sets,two to six sets per session,one to two sessions per day,and five to seven days per week.The duration of the intervention ranged from successful weaning,one week after weaning,extubation,or four days to eight weeks.Regarding the efficacy of the intervention,IMT was not benefi-cial for the duration of mechanical ventilation and intensive care unit(ICU)length of stay on weaning failure pa-tients.However,the effect of IMT on weaning successful rates,duration of weaning,MIP and mortality was in-consistent.Conclusion IMT can not improve the duration of mechanical ventilation and ICU length of stay for weaning failure pa-tients,and there is still debate regarding its effect on successful rate of weaning,duration of weaning,MIP and mortality.