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 study the protective effect of Wedelolactone(WEL)against inflammatory injury in human umbilical vein endothelial cells(HUVECs)and its molecular mechanism by inducing PI3K/Akt/mTOR.Methods The model of atherosclerosis(AS)oxidative stress injury in HUVECs was induced with 200 μmol·L-1 of hydrogen peroxide for 24 h.The experimental groups were as follows:normal control group,DMSO(dimethyl sulfoxide)group,H2O2 group,and WEL group.MTT was used to measure the cell survival rate of each group;flow cytometry was used to assess intracellular ROS levels;fluorescence microscopy was used to detect the expression of p62 protein;immunoblotting assay was used to determine the protein expression levels for apoptosis-related proteins associated with PI3K/Akt/mTOR signaling pathway and autophagy-related proteins.Results Compared with the H2 O2 group,the HUVEC cell survival rate was significantly inhibited in the WEL group(P＜0.05).ROS production was significantly lower,and the protein expressions of SOD1 and p62 were significantly increased in the WEL group as compared to the hydrogen peroxide group.The protein expression of p-mTOR,p-Akt,and p-PI3K was significantly decreased in hydrogen peroxide(P＜0.01);In the WEL experiment,p-mTOR,p-Akt,and p-PI3K were increased significantly in the post-injury HUVECs(P＜0.01).Conclusion Wedelolactone inhibits HUVECs'autophagy by suppressing H2O2-induced inflammatory damage in HUVECs,which may be related to the fact that WEL promotes the phosphorylation of PI3K,Akt,and mTOR proteins,inhibits autophagy and thus resists oxidative stress damage in HUVECs cells.

OBJECTIVE To rapidly analyze the chemical constituents of Rubus sachalinensis Leveille by HPLC-Q-Exactive-MS/MS. METHODS Chromatographic separation was carried out on CAPCELL PAK MGII C18(4.6 mm×250 mm, 5 μm) column at the temperature of 30 ℃. The mobile phase was acetonitrile-0.1% formic acid by gradient elution, with a flow rate of 1.0 mL∙min−1, and the injection volume of 20 µL. The MS spectrum was acquired in negative ion modes using HESI ion source. RESULTS The molecular and structural formulae of the compounds were determined based on the exact mass number and ChemSpider and PubChem databases. By comparing the retention time of the corresponding reference standards and those reported in the literature, primary mass spectra, and secondary mass spectrometry pyrolysis fragments, combined with fragmentation regularity of such compounds, a total of 71 compounds were identified from Rubus sachalinensis Leveille, including 30 organic acids, 22 flavonoids, 7 triterpenoid saponins, 5 coumarins, 1 lignan, 1 gallotannin and 2 aromatic compounds. CONCLUSION This method can quickly and accurately identify the complex chemical constituents in Rubus sachalinensis Leveille, and provide scientific basis for the basic research on the medicinal substances of Rubus sachalinensis Leveille.

Robotic natural orifice specimen extraction surgery for right colon cancer has been conducted with progressive refinements. To facilitate the standardized implementation of this surgical technique, the adoption of rigorous quality control measures is paramount. The present article outlines the key aspects of quality control for robotic natural orifice specimen extraction right hemicolectomy surgery, encompassing the preoperative, intraoperative, and postoperative phases, as well as the training and credentialing requirements for the operating surgeons, with the aim of providing a reference framework to facilitate the safe and reliable implementation and dissemination of this minimally invasive approach for right colon cancer.

Objective:To compare the surgical outcomes of robotic natural orifice specimen extraction surgery (NOSES) and robotic-assisted radical resection for rectal cancer.Methods:A retrospective analysis using propensity score matching (PSM) was conducted on 547 patients who had undergone radical resection of rectal cancer at the First Affiliated Hospital of Nanchang University from June 2018 to March 2024. The study cohort comprised 157 patients in the robotic NOSES group and 390 in the robotic-assisted group. PSM was used in a 1:1 manner to match relevant general clinical preoperative data of the study patients (age, sex, body mass index, preoperative comorbidities, abnormal preoperative carcinoembryonic antigen (>6.5 μg/L) and carbohydrate antigen 19-9 levels (>27 kU/L), preoperative American Society of Anesthesiologists score, tumor diameter, tumor distance from the anal margin, and TNM stage), with a clamp value of 0.05. After performing PSM to match the general clinical data of the two groups of patients, 77 patients in each of the robotic NOSES and robotic-assisted groups were included in the analysis. We found no statistically significant difference in preoperative general clinical data between the robot NOSES and robot-assisted groups ( P>0.05). We compared the surgical outcomes, postoperative recovery, postoperative pathological data, and incidence of complications between the robotic NOSES and robot-assisted groups. Results:Compared with the robot-assisted groups. the robot NOSES group had a significantly shorter time to first postoperative passage of flatus (48 [38, 50] hours vs. 56 [50, 60] hours, Z=-7.513, P<0.001), time to taking a liquid diet (60 [54,63] hours vs. 66 [62, 72] hours, Z=-6.303, P<0.001), lower pain scores (3 [3, 4] vs. 4 [4, 5], Z=-5.237, P<0.001), and lower incision infection rates (0 vs. 5 [6.5%], χ 2=5.237, P=0.028) within 24 hours after surgery ( P<0.05). However, there were no significant differences in surgical time, intraoperative blood loss, postoperative hospital stay, postoperative anastomotic complications, or incidence of other complications between the two groups (all P>0.05). Conclusion:Robotic NOSES surgery is a safe and feasible procedure for resecting rectal cancer and postoperative recovery is faster after robotic NOSES than after standard robot-assisted surgery.

Robotic natural orifice specimen extraction surgery for right colon cancer has been conducted with progressive refinements. To facilitate the standardized implementation of this surgical technique, the adoption of rigorous quality control measures is paramount. The present article outlines the key aspects of quality control for robotic natural orifice specimen extraction right hemicolectomy surgery, encompassing the preoperative, intraoperative, and postoperative phases, as well as the training and credentialing requirements for the operating surgeons, with the aim of providing a reference framework to facilitate the safe and reliable implementation and dissemination of this minimally invasive approach for right colon cancer.

Objective:To compare the surgical outcomes of robotic natural orifice specimen extraction surgery (NOSES) and robotic-assisted radical resection for rectal cancer.Methods:A retrospective analysis using propensity score matching (PSM) was conducted on 547 patients who had undergone radical resection of rectal cancer at the First Affiliated Hospital of Nanchang University from June 2018 to March 2024. The study cohort comprised 157 patients in the robotic NOSES group and 390 in the robotic-assisted group. PSM was used in a 1:1 manner to match relevant general clinical preoperative data of the study patients (age, sex, body mass index, preoperative comorbidities, abnormal preoperative carcinoembryonic antigen (>6.5 μg/L) and carbohydrate antigen 19-9 levels (>27 kU/L), preoperative American Society of Anesthesiologists score, tumor diameter, tumor distance from the anal margin, and TNM stage), with a clamp value of 0.05. After performing PSM to match the general clinical data of the two groups of patients, 77 patients in each of the robotic NOSES and robotic-assisted groups were included in the analysis. We found no statistically significant difference in preoperative general clinical data between the robot NOSES and robot-assisted groups ( P>0.05). We compared the surgical outcomes, postoperative recovery, postoperative pathological data, and incidence of complications between the robotic NOSES and robot-assisted groups. Results:Compared with the robot-assisted groups. the robot NOSES group had a significantly shorter time to first postoperative passage of flatus (48 [38, 50] hours vs. 56 [50, 60] hours, Z=-7.513, P<0.001), time to taking a liquid diet (60 [54,63] hours vs. 66 [62, 72] hours, Z=-6.303, P<0.001), lower pain scores (3 [3, 4] vs. 4 [4, 5], Z=-5.237, P<0.001), and lower incision infection rates (0 vs. 5 [6.5%], χ 2=5.237, P=0.028) within 24 hours after surgery ( P<0.05). However, there were no significant differences in surgical time, intraoperative blood loss, postoperative hospital stay, postoperative anastomotic complications, or incidence of other complications between the two groups (all P>0.05). Conclusion:Robotic NOSES surgery is a safe and feasible procedure for resecting rectal cancer and postoperative recovery is faster after robotic NOSES than after standard robot-assisted surgery.

Objective:To analyze the application value of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9 and CA242 in screening colorectal cancer with a meta-analysis.Methods:A literature search was conducted in the databases of Pubmed, Embase, Cochrane, CNKI, Wanfang and VIP to identify studies on applying CEA, CA19-9 and CA242 for detection of colorectal cancer from the establishment of the databases to October 2023. The Quality Evaluation Tool of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate the quality of the literature. Stata17.0 statistical software was used for meta-analysis. Deeks funnel plot was used to analyze publication bias.Results:A total of 34 articles of case-control studies met the criteria. Meta-analysis revealed that the diagnostic accuracy and sensitivity of CEA, CA19-9 and CA242 were all low, the area under the curve (AUC) of summary receiver operating characteristic curve was 0.62, 0.63 and 0.73, the sensitivity was 0.42, 0.27 and 0.36, respectively. The combined detection of CEA+CA19-9+CA242 significantly improved the pooled diagnostic accuracy (AUC: 0.92(95% CI: 0.89-0.94) and sensitivity: 0.75(95% CI: 0.65-0.83)), the specificity was mildly reduced (dropped from above 0.95 to 0.90(95% CI 0.87-0.93)). The Deek′s test indicated no publication bias. Conclusions:Combined detection of CEA+CA19-9+CA242 can significantly improve the diagnostic accuracy and sensitivity in screening colorectal cancer with a compromised specificity. However, due to the lack of data, whether it can meet the demand for opportunistic screening in the physical examination population needs to be confirmed.

Robotic surgical system natural orifice specimen extraction surgery in rectal cancer has been carried out for nearly 10 years, which has entered the mature stage of technology. Development of the surgery in a healthy, orderly, scientific and standardized manner needs systema-tic, strict and whole-process quality control. Based on relevant literatures at home and abroad, and combined with team practical experiences, the authors elaborate on the key points of quality control of robotic surgical system natural orifice specimen extraction surgery in radical resection of rectal cancer, from the aspects of preoperative, intraoperative and postoperative quality control, as well as the quality control of surgeon training and qualifications, in order to provide reference for safe implementation and promotion of the surgery.

Objective:To investigate the feasibility of active surveillance for low-risk papillary thyroid microcarcinoma.Methods:This is a cross-sectional study. From 2013 to 2017, 61 patients with pathologically confirmed papillary thyroid microcarcinoma were followed-up dynamically. The growth of nodules, newly-developed nodules and lymph node metastasis were recorded and were set as the criteria for disease progression. And the disease progression was the outcome event of survival analysis. The patients were divided into two groups based on the median age at diagnosis. Univariate analysis of factors influencing disease progression in different age groups was performed using Cox proportional hazards regression. The differences in disease progression between different age groups were compared using the Kaplan-Meier method and the log-rank test.Results:Of the 61 patients, there were 9 males and 52 females. The median age of disease onset was 43 years (ranged 23-74 years). The median follow-up time was 2 years (ranged 2-7 years), and 22 (36.1%) patients with tumor diameter increased by ≥3 mm, including 5 males and 17 females. A total of 22 cases (36.1%) showed an increase in tumor diameter of ≥3 mm, including 5 males and 17 females. Thirteen cases (21.3%) developed new malignancies, including 2 males and 11 females. Three cases (5%) had lymph node metastasis, all of which were females. In total, 24 cases (39.3%) showed disease progression, including 5 males and 19 females. Disease progression was more frequent in the <43 years age group compared to the ≥43 years age group.Conclusions:For patients with low-risk papillary thyroid microcarcinoma, strict adherence to the indications for active surveillance and consideration of patient preferences make active surveillance a feasible tumor management approach.