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.

Lateral organ boundaries (LOB) domain (LBD) genes encode a family of transcription factors ubiquitous in higher plants, playing crucial roles in the growth, development, and stress responses. Hippophae rhamnoides, known for its drought, cold, and saline-alkali tolerance, offers significant economic benefits and ecological values. Utilizing the whole genome data and bioinformatics approaches, this study identified and analyzed the LBD gene family in H. rhamnoides. Additionally, we examined the expression pattern of HrLBD genes by integrating the transcriptome data from male and female flower buds in development. Eleven LBD genes were identified in H. rhamnoides, and these genes were distributed on five chromosomes. The HrLBD proteins showed the lengths ranging from 159 aa to 302 aa, the molecular weights between 18 249.91 Da and 33 202.01 Da, and the subcellular localization in the nucleus or chloroplasts. LBD protein domains and gene structures were highly conserved, featuring similar motifs. The phylogenetic analysis of HrLBD genes and the LBD genes in Arabidopsis thaliana and Hordeum vulgare revealed that HrLBD genes falled into two major categories: Class Ⅰ and Class Ⅱ. The transcriptome data and RT-qPCR showed that HrLBD genes were highly expressed in male flower buds, with up-regulated expression levels throughout bud development, indicating a role in the specific stage of male flower bud development. This study lays a theoretical foundation for exploring the roles of HrLBD genes in the growth, development, and sex differentiation of H. rhamnoides flower buds.
Flowers/genetics* ; Hippophae/metabolism* ; Phylogeny ; Gene Expression Regulation, Plant ; Plant Proteins/genetics* ; Transcription Factors/genetics* ; Multigene Family ; Genes, Plant

Acute skin failure is a common condition of skin damage in critically ill patients, which seriously affects the prognosis of patients. This article summarizes the evaluation indicators, techniques, and comparison of evaluation indicators and techniques for acute skin failure, in order to provide references for the development of acute skin failure evaluation tools and the formulation of nursing measures.

This paper interprets the background, content overview and characteristics, clinical practice significance and disciplinary development of Nursing Standards for Clinical Operation Techniques in Critical Care Ultrasound (hereinafter referred to as the Standards) and puts forward reflections on the clinical application of the Standards, aiming to improve the critical care ultrasound techniques of clinical nursing staff, solve nursing challenges and make clinical nursing ultrasound techniques more scientific, standardized and homogenized.

Objective:To gain a deep understanding of the current cognition and training needs of nursing undergraduates regarding their emergency response teamwork skills, and to provide reference for the development of courses on emergency response teamwork among nursing undergraduates.Methods:From September to October 2023, purposive sampling was used to select 15 senior nursing undergraduates from Peking Union Medical College, Beijing University of Chinese Medicine, and Beijing City University as subjects for semi-structured interviews. Colazizzi 7-step analysis method was used to summarize and extract themes.Results:Three themes were extracted, including insufficient cognition and skill in emergency response, lack of emergency response teamwork cultivation, and the need for systematic and comprehensive training courses.Conclusions:Universities, hospitals, and other training institutions should work together to develop a systematic emergency response teamwork training course for nursing undergraduates, to cultivate the skills of nursing undergraduates and reserve talents for high-quality emergency response nursing teams.

Objectives To explore the establishment and effects of a multilevel and inter-disciplinary management scheme for specialist nurses.Methods The multilevel and inter-disciplinary management scheme included establishing the pyramid hierarchical training model,exploring superimposed training mechanism for specialist nurses with horizontal expansion,vertical extension,and deep development,and constructing stereoscopic clinical evaluation and quantitative assessment system.Four hundred-forty two specialized nurses have been recruited to join the multilevel and inter-disciplinary management scheme from July 2021 to August 2023.The core competencies of specialized nurses were compared before and after the implementation of management scheme.Results The quality development of specialized nursing have been improved,and the total scores and the scores of 3 dimensions(research innovation,management,and professional development)in core competencies of specialized nurses after the intervention of multilevel and inter-disciplinary management scheme were higher than those before(P＜0.05).Conclusion The multilevel and inter-disciplinary management scheme can effectively improve the core competencies of specialized nurses,and promote the high-quality development of specialized nursing.

Objective:To explore the current situation of nursing human caring in hospital wards and analyze its influencing factors, so as to facilitate the development of nursing human caring practice.Methods:From July to November 2022, a total of 107 hospitals were surveyed through stratified convenience sampling method, and 4 072 ward nursing managers were recruited to finish the general information questionnaire and the ward nursing human caring status questionnaire. The general information included the region, class and type of the hospital, etc. The ward nursing human caring status questionnaire included 38 items in 5 dimensions of nursing human caring system and process, humanistic quality and training of nursing staff, humanistic environment and facilities, human caring procedures and measures, and human caring quality evaluation and improvement, with a full score of 190 points. Descriptive statistics were used to analyze the general data, independent samples t-test, ANOVA and correlation analysis were used to analyze the factors influencing the current status of nursing human caring in the ward, while multiple linear regression analysis was used to conduct a multivariate analysis. Results:The score of nursing human caring in hospital wards was 156.91±27.78. Whether the hospital had carried out nursing human caring pilot(demonstration) wards, whether the ward had previously been a hospital nursing human caring pilot(demonstration) nursing unit, the type of ward, and whether nursing managers had participated in human caring training were the influencing factors of the implication of nursing humanistic caring in wards( P<0.05). Conclusions:The practice of nursing human caring in hospital wards is at a good level, but needs to be further strengthened. Nursing managers should take systematically strategies to promote the development of nursing human caring practice.

Indocyanine Green/therapeutic use* ; Photochemotherapy ; Combined Modality Therapy ; Anti-Infective Agents

Objective:To analyze the clinical characteristics of patients with de-novo non-alcoholic fatty liver disease (de-novo NAFLD) and patients with de-novo NAFLD combined with metabolic syndrome (MS) after liver transplantation (LT) , and to determine the related risk factors.Methods:Patients who underwent LT at the Organ Transplantation Center, the Affiliated Hospital of Qingdao University, from Jan. 2016 to Oc. 2020 and were monitored until Oct. 2021 were gathered. The recipients were divided into the group with/without de-novo NAFLD, and LT recipients with de-novo NAFLD were divided into the group with/without combined MS. Clinical characteristics of the LT recipients with de-novo NAFLD combined with MS were analyzed. Logistic regression analyses were performed to identify the risk factors for LT recipients with de-novo NAFLD and those with combined MS.Results:A total of 324 LT recipients with a median follow-up of 2.9 years (range: 2.0-4.3 years) were included in the study. De-novo NAFLD was diagnosed in 21.0% (68/324) of the LT recipients, and MS was diagnosed in 44.1% (30/68) of these patients. Compared with LT recipients without de-novo NAFLD, those with de-novo NAFLD had higher preoperative body mass index (BMI) , blood glucose, glycated hemoglobin levels and lower platelet levels, and longer postoperative follow-up, higher BMI, waist circumference, albumin, triglycerides (TG) , low-density lipoprotein (LDL) , blood glucose, glycated hemoglobin levels, and the incidence of MS (all P<0.05) . Preoperative platelets, glucose, postoperative albumin, LDL and BMI were independent risk factors for predicting de-novo NAFLD after LT (all P<0.05) . Preoperative glucose performed well in predicting the occurrence of de-novo NAFLD (threshold: 5.5mmol/L, P<0.001, AUC=0.678) . The differences in Pre-LT blood glucose, post-LT BMI, waist circumference, prevalence of prediabetes or diabetes, fatty liver index (FLI) , and NAFLD fibrosis score (NFS) between de-novo NAFLD LT recipients with and without combined MS were significantly different (all P<0.05) . Conclusions:The incidence of de-novo NAFLD after LT is noteworthy, and LT recipients with de-novo NAFLD are more likely to have a combination with MS. In preoperative treatment, keeping blood glucose to 5.5 mmol/L or below trends helps to lower the risk of de-novo NAFLD following LT. LT recipients’ nutritional state and lipid levels require prompt care. High albumin levels might not be a desirable thing. De-novo NAFLD LT recipients with concomitant prediabetes or diabetes may imply an increased risk of developing comorbid MS during the post-LT follow-up. Controlling FLI levels in LT recipients with de-novo NAFLD may reduce the risk of developing comorbid MS.

BACKGROUND: The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. METHODS: 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. RESULTS: Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. CONCLUSIONS Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.
Humans ; Male ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Immune Checkpoint Inhibitors/therapeutic use* ; Programmed Cell Death 1 Receptor/genetics* ; Retrospective Studies ; Antineoplastic Agents, Immunological/therapeutic use* ; Prognosis ; DNA Helicases/genetics* ; Nuclear Proteins/genetics* ; Transcription Factors/genetics*