Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G_q complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.

Objective To investigate the short-term efficacy of celiac plexus block combined with the interstitial permanent implantation of 125I seeds in the treatment of advanced pancreatic cancer(inoperable locally advanced and metastatic pancreatic cancers).Methods A total of 100 patients with advanced pancreatic cancer were selected and treated with celiac plexus block combined with the interstitial permanent implantation of 125I seeds under CT guidance.Pain relief and changes in the tumor marker CA19-9 were assessed on the seventh day,the first and third months after surgery.In the third month after surgery,tumor size was assessed by CT.Results Among the 100 patients with advanced pancreatic cancer,complete response(CR)was found in 12 cases,partial response(PR)in 78 cases,stable disease in five cases,and progression of disease in five cases three months after surgery.The CA19-9 level and the sum of short and long tumor diameters were significantly decreased(both P<0.01).A total of 100 patients had severe pain before treatment(visual analogue scale(VAS)):7-10 points),59 patients reported pain disappearance(VAS:0 points),35 patients had mild pain(VAS:1-3 points),and six patients experienced moderate pain(VAS:4-6 points)in the third month after treatment.The pain relief rate was 100%.Conclusion Celiac plexus block combined with the interstitial permanent implantation of 125I seeds has good short-term efficacy and can effectively improve short-term pain in patients with advanced pancreatic cancer.

Objective:To investigate the correlation between the neoadjuvant rectal (NAR) score and long-term survival in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.Methods:Clinical and pathological data of 487 patients diagnosed with rectal adenocarcinoma from October 2004 to April 2014 at Sun Yat-sen University Cancer Center who had received neoadjuvant chemoradiotherapy were retrospectively analyzed and the impact of NAR score on prognosis studied. Disease-free-survival (DFS) was calculated by the Kaplan-Meier method and survivals compared using the log-rank test. Cox models were used for univariate and multivariate analyses. Receiver operating characteristic curves were utilized to evaluate the predictive capability of NAR and tumor regression grade scores for the risk of 10-year postoperative recurrence and metastasis. The Delong test was employed to compare the diagnostic performance of the two scores.Results:Of the 487 patients included in the study, 166 were men (34.1%). The median age was 56 years (interquartile range [IQR]: 46–63). All patients completed adequate preoperative chemoradiotherapy and underwent R0 resection.The median interval between the end of chemoradiotherapy and surgery was 51 days (IQR: 44–58). Post-chemoradiotherapy downstaging occurred in 329 patients (67.6%). Tumor regression grades (TRGs) were 1–2 in 246 patients (50.5%) and 3–4 in 241 patients (49.5%). A total of 394 patients (80.9%) received postoperative chemotherapy. NAR scores were <8 in 182 patients (37.4%), 8–16 in 180 (37.0%), and >16 in 125 (25.6%). The median follow-up time was 111.5 months (IQR: 70.7–133.7 months). One hundred and thirteen patients died of rectal cancer, among whom 13 patients developed local recurrence, 88 patients developed distant metastasis, and 12 patients had unknown recurrence patterns. The 10-year DFS and overall survival rate of f the whole group were 68.9% and 71.5% respectively. The 10-year DFS rates for patients with NAR scores <8, 8–16, and >16 were 85.1%, 80.5%, and 66.4%, respectively ( P<0.001). Multivariate analyses revealed that the Dixon operation (HR=0.606, 95%CI: 0.408–0.902, P=0.014), and >16 (HR=2.569, 95%CI: 1.559–4.233, P<0.001) were independent predictors of the 10-year DFS of patients with locally advanced rectal cancer ( P<0.05 for all). In the entire patient cohort, the AUC of the receiver operating characteristic curve for NAR score predicting 10-year recurrence and metastasis was 0.67 (95%CI: 0.62–0.72), whereas the AUC for TRG score was 0.54 (95%CI: 0.49–0.60). The two scores differed significantly in accuracy ( Z=-4.06, P<0.001), the NAR score being a significantly better predictor of risk of 10-year recurrence and metastasis than the TRG score. Conclusion:The NAR score is a reliable predictor of 10-year DFS in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy followed by curative surgery.

Objective:To compare the teaching effect of basic medical integrated courses and clinical medical integrated courses based on organ system with the traditional teaching model based on discipline,so as to provide theoretical reference for training medical talents.Methods:The program of integration of basic medical courses and clinical medical courses was formulated.The current clinical medical students who participated in the medical licensing examination were selected as the research objects under the three teaching models of basic and clinical medical integrated courses,clinical medical integrated courses,and discipline-based courses.The students'scores of comprehensive basic medicine,comprehensive clinical medicine,and medical licensing examination were analyzed to preliminarily evaluate the implementation effect of the integrated teaching model of basic medicine and clinical medicine.Result:There was no significant difference in the examination scores of students under the three teaching modes.Conclusion:The organ system-based integrated teaching model has no significant effect on students'academic performance in the short term.

Objective:To evaluate the relationship between inositol-requiring enzyme 1α-X box-binding protein 1 (IRE1α-XBP1) signaling pathway in endoplasmic reticulum and neutrophil extracellular traps during endotoxin-induced acute lung injury (ALI) in mice.Methods:Forty-eight SPF healthy male C57BL/6 mice, aged 6-8 weeks, weighing 25-30 g, were divided into 4 groups ( n=12 each) using a random number table method: control group (C group), STF-083010 group (ST group), lipopolysaccharide (LPS)-induced ALI group (ALI group) and LPS-induced ALI + STF-083010 group (ALI+ ST group). The ALI model was established by inhaling aerosolized LPS in ALI group and ALI+ ST group. The equal volume of aerosolized normal saline was inhaled in C and ST groups. IRE1α inhibitor STF-083010 50 mg/kg was intraperitoneally injected at 1 h before developing the model in ST and ALI+ ST groups, and the equal volume of normal saline was intraperitoneally injected in the other two groups. The mice were sacrificed after anesthesia at 24 h after developing the model. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected for determination of the pathological changes (by light microscopy) which were scored, wet/dry lung weight (W/D) ratio, concentrations of interleukin-1beta (IL-1β), IL-18 and myeloperoxidase (MPO) in the BALF supernatant, and expression of phosphorylated IRE1α(p-IRE1α), XBP1s and citrullinated histone H3 (Cit H3) in lung tissues (using Western blot). Results:Compared to group C, the lung injury scores and W/D ratio were significantly increased at 24 h after developing the model, the concentrations of IL-1β, IL-18 and MPO in BALF were increased, and the expression of p-IRE1α, XBP1s and Cit H3 in lung tissues was up-regulated in ALI and ALI+ ST groups. Compared to group L, the lung injury scores and W/D ratio were significantly decreased at 24 h after developing the model, the concentrations of IL-1β, IL-18 and MPO in BALF were decreased, and the expression of p-IRE1α, XBP1s and Cit H3 in lung tissues was down-regulated in group ALT+ ST ( P<0.05). Conclusions:The IRE1α-XBP1 signaling pathway in endoplasmic reticulum is involved in endotoxin-induced ALI by up-regulating the expression of neutrophil extracellular traps in mice.

Objective:To evaluate the impact of assisted reproductive technology (ART) on postpartum breastfeeding outcomes.Methods:This paper electronically retrieved the China Biology Medicine disc, China National Knowledge Infrastructure, VIP, WanFang Data, PubMed, Embase, Web of Science, and Cochrane Library. The search period was from database establishment to March 15, 2023. After independent literature search, screening, data extraction, and quality evaluation by two researchers, Meta-analysis was conducted using R 4.2.2 software.Results:A total of 11 articles were included. Meta-analysis showed that compared with naturally conceived mothers, the rates of exclusive breastfeeding at 1th week postpartum ( RR=0.84, 95% CI: 0.73-0.97), exclusive breastfeeding at 6th months postpartum ( RR=0.77, 95% CI: 0.61-0.98), and the incidence of breastfeeding for >6 months postpartum ( RR=0.71, 95% CI: 0.53-0.96) were decreased, and the rate of artificial feeding at 12th months postpartum ( RR=1.09, 95% CI: 1.02-1.17) was increased. However, there were no statistically significant differences in the rate of artificial feeding at 8th months postpartum, the incidence of breastfeeding duration >12 months, and the incidence of breastfeeding difficulties ( P>0.05) . Conclusions:ART reduces the rate of exclusive breastfeeding in postpartum 1th week and 6th months, and the incidence of postpartum breastfeeding duration>6 months, and increases the artificial feeding rate in postpartum 12th months. However, the impact of ART on the incidence of breastfeeding difficulties is not yet clear and still needs to be further demonstrated by high-quality studies.

Objective To explore the safety of minimally invasive esophagectomy (MIE) with three-field lymphadenectomy (3-FL) for esophageal squamous cell carcinoma (ESCC) by comparing the short-term outcomes between the 3-FL and the two-field lymphadenectomy (2-FL) in MIE. Methods The clinical data of patients with ESCC who underwent minimally invasive McKeown esophagectomy in our hospital from July 2015 to March 2022 were collected retrospectively. Patients were divided into a 3-FL group and a 2-FL group according to lymph node dissection method. And the clinical outcomes and postoperative complications were compared between the two groups. Results A total of 257 patients with ESCC were included in this study. There were 211 males and 46 females with an average age of 62.2±8.1 years. There were 109 patients in the 3-FL group and 148 patients in the 2-FL group. The operation time of the 3-FL group was about 20 minutes longer than that of the 2-FL group (P<0.001). There was no statistical difference between the two groups in the intraoperatve blood loss (P=0.376). More lymph nodes (P<0.001) and also more positive lymph nodes (P=0.003) were obtained in the 3-FL group than in the 2-FL group, and there was a statistical difference in the pathological N stage between the two groups (P<0.001). But there was no statistical difference in the incidence of anastomotic leak (P=0.667), chyle leak (P=0.421), recurrent laryngeal nerve injury (P=0.081), pulmonary complications (P=0.601), pneumonia (P=0.061), cardiac complications (P=0.383), overall complications (P=0.147) or Clavien-Dindo grading (P=0.152) between the two groups. Conclusion MIE 3-FL can improve the efficiency of lymph node dissection and the accuracy of tumor lymph node staging, but it does not increase the postoperative complications, which is worthy of clinical application.

Objective:To investigate the correlation between the neoadjuvant rectal (NAR) score and long-term survival in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy.Methods:Clinical and pathological data of 487 patients diagnosed with rectal adenocarcinoma from October 2004 to April 2014 at Sun Yat-sen University Cancer Center who had received neoadjuvant chemoradiotherapy were retrospectively analyzed and the impact of NAR score on prognosis studied. Disease-free-survival (DFS) was calculated by the Kaplan-Meier method and survivals compared using the log-rank test. Cox models were used for univariate and multivariate analyses. Receiver operating characteristic curves were utilized to evaluate the predictive capability of NAR and tumor regression grade scores for the risk of 10-year postoperative recurrence and metastasis. The Delong test was employed to compare the diagnostic performance of the two scores.Results:Of the 487 patients included in the study, 166 were men (34.1%). The median age was 56 years (interquartile range [IQR]: 46–63). All patients completed adequate preoperative chemoradiotherapy and underwent R0 resection.The median interval between the end of chemoradiotherapy and surgery was 51 days (IQR: 44–58). Post-chemoradiotherapy downstaging occurred in 329 patients (67.6%). Tumor regression grades (TRGs) were 1–2 in 246 patients (50.5%) and 3–4 in 241 patients (49.5%). A total of 394 patients (80.9%) received postoperative chemotherapy. NAR scores were <8 in 182 patients (37.4%), 8–16 in 180 (37.0%), and >16 in 125 (25.6%). The median follow-up time was 111.5 months (IQR: 70.7–133.7 months). One hundred and thirteen patients died of rectal cancer, among whom 13 patients developed local recurrence, 88 patients developed distant metastasis, and 12 patients had unknown recurrence patterns. The 10-year DFS and overall survival rate of f the whole group were 68.9% and 71.5% respectively. The 10-year DFS rates for patients with NAR scores <8, 8–16, and >16 were 85.1%, 80.5%, and 66.4%, respectively ( P<0.001). Multivariate analyses revealed that the Dixon operation (HR=0.606, 95%CI: 0.408–0.902, P=0.014), and >16 (HR=2.569, 95%CI: 1.559–4.233, P<0.001) were independent predictors of the 10-year DFS of patients with locally advanced rectal cancer ( P<0.05 for all). In the entire patient cohort, the AUC of the receiver operating characteristic curve for NAR score predicting 10-year recurrence and metastasis was 0.67 (95%CI: 0.62–0.72), whereas the AUC for TRG score was 0.54 (95%CI: 0.49–0.60). The two scores differed significantly in accuracy ( Z=-4.06, P<0.001), the NAR score being a significantly better predictor of risk of 10-year recurrence and metastasis than the TRG score. Conclusion:The NAR score is a reliable predictor of 10-year DFS in patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy followed by curative surgery.

Objective:To investigate the efficacy and assess the safety of transnasal nebulisation of budesonide in children with adenoid hypertrophy. Methods:Children with adenoid hypertrophy who attended the Children's Hospital of Zhejiang University School of Medicine between December 2021 and December 2022 were randomly assigned to budesonide high-dose group（Group A: budesonide 1 mg/dose + saline nasal rinse）, budesonide low-dose group（Group B: budesonide 0.5 mg/dose + saline nasal rinse）, and control group（Group C: saline nasal rinse）, and each group 20 children were collected separately, The efficacy and safety of transnasal nebulisation of budesonide in children with adenoid hypertrophy were assessed by comparing the symptomatic VAS scores, adenoidal nasopharyngeal lateral radiographs A/N values, nocturnal sleep oximetry（SaO2）, and the incidence of adverse events during the treatment period of 8-week in the three groups. Results:The 8-week baseline differences in adenoid A/N values were statistically different between groups A and B（P<0.001） and A and C（P=0.022）, with the reduced amount in adenoid volume being most pronounced in group A, which differed from the other two groups. With the increase of intervention time, SaO2 levels gradually increased（F=154.725, P<0.001） and VAS scores gradually decreased（F=165.616, P<0.001） in all three groups. After 8 weeks of treatment, there was no statistically significant difference in SaO2 level（P=0.085） between groups A and B. There was a statistically significant difference in VAS total scores between Group A and Group B （P < 0.05） . The improvement of SaO2and total VAS score in group A was higher than that in group B. There was a statistically significant difference in the comparison of SaO2 level and total VAS score between groups A and B, and between groups A and C（P<0.01）; after the intervention of the three groups, showing the greatest improvement of total VAS score and SaO2in the group A, followed by Group B. There was no statistically significant difference in the incidence of adverse events among Groups A, B, and C throughout the trial. Conclusion:The treatment of children with adenoid hypertrophy by intranasal nebulisation of budesonide suspension has good efficacy and safety, which is conducive to reducing the size of adenoids, improving the clinical symptoms of children with adenoid hypertrophy, and improving the SaO2of nocturnal sleep, and it has a certain clinical application value.
Humans ; Budesonide/administration & dosage* ; Adenoids ; Child ; Male ; Female ; Hypertrophy ; Nebulizers and Vaporizers ; Treatment Outcome ; Administration, Intranasal ; Child, Preschool

Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90α).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiation-induced cell apoptosis.It could bind to HSP90α with a high affinity,but the affinity was drastically decreased by HSP90α Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upre-gulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKe/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-Ⅱ/β ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90α and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.