Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Objective:To explore the effectiveness and application value of focused ultrasound ablation surgery (FUAS) combined with hysteroscopic surgery in treating solitary type Ⅱ submucosal uterine fibroids with maximum diameter >5 cm.Methods:Clinical data of 35 patients with a single type Ⅱ submucosal uterine fibroid with maximum diameter greater than 5 cm who underwent FUAS combined with hysteroscopic surgery at Qingdao Women and Children′s Hospital from June 2020 to December 2023 were collected. The clinical characteristics, treatments and treatment outcomes were retrospectively analyzed.Results:(1) Clinical characteristics: the mean age of the 35 patients was (36.7±6.6) years, with a median maximum diameter of fibroids of 56 mm (range: 51-80 mm). All patients presented with symptoms of menorrhagia, median menstrual bleeding score was 5 points (ranged from 3 to 5 points), and 34 cases (97.1%, 34/35) had concomitant anemia, the mean hemoglobin was (83.1±13.8) g/L of 35 patients. (2) Treatments: all 35 patients underwent FUAS treatment initially, with a lesion ablation rate ranging from 69.7% to 97.9% (median:90.7%), and no complications occurred. After FUAS treatment, the volume of fibroids decreased in all patients, with a volume reduction rate ranging from 30.57% to 87.22% (median:76.03%). Hysteroscopic surgery was performed 3-14 months (median: 5 months) after FUAS to remove the necrotic fibroid tissue, achieving a 100.0% (35/35) fibroid resection rate. Only 1 patient developed complications of hyperhyderation syndrome during hysteroscopic surgery, and no complications occurred in the remaining patients. (3) Evaluation of efficacy: after FUAS pretreatment, the maximum diameter of fibroids in the 35 patients decreased significantly ( Z=-5.171, P<0.001), as did the volume of fibroids ( Z=-5.159, P<0.001). The hemoglobin level increased significantly compared to the level before FUAS in all cases ( t=-8.657, P<0.001), and median menstrual bleeding score decreased to 2 points (range: 1-3 points), significantly lower than original level ( Z=-5.292, P<0.001). At the 3-month follow-up after hysteroscopic surgery, all patients were free of anemia symptoms, with menstrual bleeding scores totally decreased to 1 point, significantly lower than that before hysteroscopic surgery ( Z=-4.786, P<0.001); hemoglobin level [(118.7±5.6) g/L] significantly increased compared to that before hysteroscopic surgery ( t=-9.258, P<0.001). All patients underwent gynecological transvaginal ultrasound re-examination, which did not reveal any residual fibroids. Conclusion:FUAS combined with hysteroscopic surgery is effective in treating solitary type Ⅱ submucosal uterine fibroids with maximum diameter >5 cm, providing a new treatment option for patients.

Objective:To compare the efficacy, safety, and cost-effectiveness of the trastuzumab originator (HST) versus its biosimilar (HLX02) combined with pertuzumab and chemotherapy as neoadjuvant treatment in patients with HER-2-positive breast cancer.Methods:This retrospective cohort study included 175 patients with HER-2-positive breast cancer who received neoadjuvant therapy followed by curative surgery at the Cancer Hospital Chinese Academy of Medical Sciences between October 2020 and January 2024. Patients were divided into two groups based on the trastuzumab formulation used: the HST group ( n=89) and the HLX02 group ( n=86).The efficacy, safety, and trastuzumab-related treatment costs were compared between the two groups. Moreover, using Logistic regression model to identify the factors influencing total pathological complete response (tpCR) rates. Results:There were statistically significant differences in clinical T stage and surgical approach between the HST and HLX02 groups ( P＜0.05). Other clinicopathological characteristics, such as age and histological grade, showed no statistically significant differences ( P＞0.05), with most baseline characteristics remaining balanced between the two groups. There were no significant differences in tpCR rates ( P=0.957) or Miller-Payne (MP) grading rates ( P=0.991) between the HST and HLX02 groups. The tpCR rates for the two groups were 55.1% (49/89) and 54.7% (47/86), respectively. The rates of achieving grade 5 (G5) in the postoperative MP pathological grading system were 55.1% (49/89) and 55.8% (48/86), respectively, with no statistically significant difference ( P=0.991). Univariate and multivariate Logistic regression analyses showed that hormone receptor status is an independent risk factor affecting tpCR ( OR=0.31, 95% CI; 0.16-0.61, P＜0.001). The incidence of adverse event during neoadjuvant therapy was similar between the groups, with no occurrences of trastuzumab-related cardiac toxicity. The HLX02 regimen showed a lower cost-effectiveness ratio (586.48 vs. 604.96) and reduced trastuzumab treatment costs during neoadjuvant therapy compared to HST [tpCR:(31 208.37±2 191.00) CNY vs. (33 224.49±2 741.00) CNY; non-tpCR: 33 030.05±5 787.00) CNY vs. (33 412.50±4 203.00) CNY, P＜0.05]. Conclusions:In the neoadjuvant treatment of early-stage HER-2-positive breast cancer, HLX02 combined with pertuzumab and chemotherapy demonstrates similar efficacy and safety to the trastuzumab originator, while offering a significant cost advantage.

Healthy female rabbits aged 3.5 to 4.0 months were randomly divided into four groups:the white light group(control group A),the green light group(treatment group B),the red light group(treatment group C)and the blue light group(treatment group D)with 3 replicates in each group,and 12 rabbits in each replicate.The light intensity was set to 80 lx,and the light was 16 h per day for 6 days before artificial insemination.Three reproductive cycles were carried out to de-termine the reproductive performance of female rabbits under different light colors,such as the number of fetuses,total litter size,weaning litter weight and serum reproductive hormone content.The results showed that,according to the comprehensive statistics of three breeding cycles:(1)the melatonin levels in the green group and red group were significantly lower than those in white group(P＜0.01),and the green group was significantly lower than the blue group(P＜0.05);the levels of luteinizing hormone in green group and red group were significantly higher than those in white group(P＜0.01);the follicle stimulating hormone in the green group was significantly high-er than in white group(P＜0.05);the estradiol content in the green group was significantly higher than that in the white group and blue group(P＜0.01),and significantly higher than that in the red group(P＜0.05).(2)the conception rate of the group was significantly higher than that of the white group(P＜0.01),and significantly higher than that of the red group and blue group(P＜0.05).(3)the number of rabbits in the green group at 30 days of age was significantly higher than that in the red group and the blue group(P＜0.05),and the litter weight at 30 days of age was significantly higher than that in the red group and the blue group(P＜0.01),and significantly higher than that in the white group(P＜0.05).In conclusion,the LED light belt is controlled by a dynamic light control system,the light intensity is set to 80 lx,and the light is 16 h a day for 6 d before artificial insemination.Green light can reduce the serum melatonin of Fujian white rabbits,which has the best comprehensive effect on the same period of conception rate and reproductive performance of Fujian white rabbits.

Healthy female rabbits aged 3.5 to 4.0 months were randomly divided into four groups:the white light group(control group A),the green light group(treatment group B),the red light group(treatment group C)and the blue light group(treatment group D)with 3 replicates in each group,and 12 rabbits in each replicate.The light intensity was set to 80 lx,and the light was 16 h per day for 6 days before artificial insemination.Three reproductive cycles were carried out to de-termine the reproductive performance of female rabbits under different light colors,such as the number of fetuses,total litter size,weaning litter weight and serum reproductive hormone content.The results showed that,according to the comprehensive statistics of three breeding cycles:(1)the melatonin levels in the green group and red group were significantly lower than those in white group(P＜0.01),and the green group was significantly lower than the blue group(P＜0.05);the levels of luteinizing hormone in green group and red group were significantly higher than those in white group(P＜0.01);the follicle stimulating hormone in the green group was significantly high-er than in white group(P＜0.05);the estradiol content in the green group was significantly higher than that in the white group and blue group(P＜0.01),and significantly higher than that in the red group(P＜0.05).(2)the conception rate of the group was significantly higher than that of the white group(P＜0.01),and significantly higher than that of the red group and blue group(P＜0.05).(3)the number of rabbits in the green group at 30 days of age was significantly higher than that in the red group and the blue group(P＜0.05),and the litter weight at 30 days of age was significantly higher than that in the red group and the blue group(P＜0.01),and significantly higher than that in the white group(P＜0.05).In conclusion,the LED light belt is controlled by a dynamic light control system,the light intensity is set to 80 lx,and the light is 16 h a day for 6 d before artificial insemination.Green light can reduce the serum melatonin of Fujian white rabbits,which has the best comprehensive effect on the same period of conception rate and reproductive performance of Fujian white rabbits.

Objective:To explore the effectiveness and application value of focused ultrasound ablation surgery (FUAS) combined with hysteroscopic surgery in treating solitary type Ⅱ submucosal uterine fibroids with maximum diameter >5 cm.Methods:Clinical data of 35 patients with a single type Ⅱ submucosal uterine fibroid with maximum diameter greater than 5 cm who underwent FUAS combined with hysteroscopic surgery at Qingdao Women and Children′s Hospital from June 2020 to December 2023 were collected. The clinical characteristics, treatments and treatment outcomes were retrospectively analyzed.Results:(1) Clinical characteristics: the mean age of the 35 patients was (36.7±6.6) years, with a median maximum diameter of fibroids of 56 mm (range: 51-80 mm). All patients presented with symptoms of menorrhagia, median menstrual bleeding score was 5 points (ranged from 3 to 5 points), and 34 cases (97.1%, 34/35) had concomitant anemia, the mean hemoglobin was (83.1±13.8) g/L of 35 patients. (2) Treatments: all 35 patients underwent FUAS treatment initially, with a lesion ablation rate ranging from 69.7% to 97.9% (median:90.7%), and no complications occurred. After FUAS treatment, the volume of fibroids decreased in all patients, with a volume reduction rate ranging from 30.57% to 87.22% (median:76.03%). Hysteroscopic surgery was performed 3-14 months (median: 5 months) after FUAS to remove the necrotic fibroid tissue, achieving a 100.0% (35/35) fibroid resection rate. Only 1 patient developed complications of hyperhyderation syndrome during hysteroscopic surgery, and no complications occurred in the remaining patients. (3) Evaluation of efficacy: after FUAS pretreatment, the maximum diameter of fibroids in the 35 patients decreased significantly ( Z=-5.171, P<0.001), as did the volume of fibroids ( Z=-5.159, P<0.001). The hemoglobin level increased significantly compared to the level before FUAS in all cases ( t=-8.657, P<0.001), and median menstrual bleeding score decreased to 2 points (range: 1-3 points), significantly lower than original level ( Z=-5.292, P<0.001). At the 3-month follow-up after hysteroscopic surgery, all patients were free of anemia symptoms, with menstrual bleeding scores totally decreased to 1 point, significantly lower than that before hysteroscopic surgery ( Z=-4.786, P<0.001); hemoglobin level [(118.7±5.6) g/L] significantly increased compared to that before hysteroscopic surgery ( t=-9.258, P<0.001). All patients underwent gynecological transvaginal ultrasound re-examination, which did not reveal any residual fibroids. Conclusion:FUAS combined with hysteroscopic surgery is effective in treating solitary type Ⅱ submucosal uterine fibroids with maximum diameter >5 cm, providing a new treatment option for patients.

Objective:To compare the efficacy, safety, and cost-effectiveness of the trastuzumab originator (HST) versus its biosimilar (HLX02) combined with pertuzumab and chemotherapy as neoadjuvant treatment in patients with HER-2-positive breast cancer.Methods:This retrospective cohort study included 175 patients with HER-2-positive breast cancer who received neoadjuvant therapy followed by curative surgery at the Cancer Hospital Chinese Academy of Medical Sciences between October 2020 and January 2024. Patients were divided into two groups based on the trastuzumab formulation used: the HST group ( n=89) and the HLX02 group ( n=86).The efficacy, safety, and trastuzumab-related treatment costs were compared between the two groups. Moreover, using Logistic regression model to identify the factors influencing total pathological complete response (tpCR) rates. Results:There were statistically significant differences in clinical T stage and surgical approach between the HST and HLX02 groups ( P＜0.05). Other clinicopathological characteristics, such as age and histological grade, showed no statistically significant differences ( P＞0.05), with most baseline characteristics remaining balanced between the two groups. There were no significant differences in tpCR rates ( P=0.957) or Miller-Payne (MP) grading rates ( P=0.991) between the HST and HLX02 groups. The tpCR rates for the two groups were 55.1% (49/89) and 54.7% (47/86), respectively. The rates of achieving grade 5 (G5) in the postoperative MP pathological grading system were 55.1% (49/89) and 55.8% (48/86), respectively, with no statistically significant difference ( P=0.991). Univariate and multivariate Logistic regression analyses showed that hormone receptor status is an independent risk factor affecting tpCR ( OR=0.31, 95% CI; 0.16-0.61, P＜0.001). The incidence of adverse event during neoadjuvant therapy was similar between the groups, with no occurrences of trastuzumab-related cardiac toxicity. The HLX02 regimen showed a lower cost-effectiveness ratio (586.48 vs. 604.96) and reduced trastuzumab treatment costs during neoadjuvant therapy compared to HST [tpCR:(31 208.37±2 191.00) CNY vs. (33 224.49±2 741.00) CNY; non-tpCR: 33 030.05±5 787.00) CNY vs. (33 412.50±4 203.00) CNY, P＜0.05]. Conclusions:In the neoadjuvant treatment of early-stage HER-2-positive breast cancer, HLX02 combined with pertuzumab and chemotherapy demonstrates similar efficacy and safety to the trastuzumab originator, while offering a significant cost advantage.

OBJECTIVE To establish the fingerprint of Pinghuo tea standard decoction and a method for determination of multi-component to clarify the transfer relationship of quantities and quality from pieces and standard decoction.METHODS Fifteen batches of Pinghuo tea standard decoction were prepared and the extract rate was determined;the fingerprint of the preparation was established by using high-performance liquid chromatography(HPLC);the similarity evaluation and the determination of common peaks were performed,and chemometric analysis was performed;the same method was used to determine the content of indicator components and the transfer rate was calculated.The chromatographic column was Venusil C18 column with mobile phase consisted of acetonitrile-0.1％ phosphoric acid solution (gradient elution);the column temperature was 30 ℃,and the detection wavelengths were 238 nm (0-37 min,85-102 min) and 330 nm (37-85 min) at a flow rate of 1.0 mL/min with an injection volume of 10 μL.RESULTS The similarity of HPLC fingerprints for 15 batches of Pinghuo tea standard decoction was not lower than 0.968.A total of 24 common peaks were calibrated and 9 peaks were recognized,which were as follows neochlorogenic acid (peak 3),chlorogenic acid (peak 6),geniposide (peak 9),glycyrrhizin (peak 10),galuteolin (peak 11),isochlorogenic acid A (peak 14),luteolin (peak 21),kaempferol (peak 23) and glycyrrhizic acid (peak 24).Cluster analysis,principal component analysis and orthogonal partial least squares discriminant analysis showed consistent results,all of which could classify the 15 batches of samples into three categories.The linear range of indicator components in 15 batches of Pinghuo tea standard decoction,such as geniposide,luteolin,isochlorogenic acid A,glycyrrhizin,and glycyrrhizic acid,were 0.020580-0.411600,0.001617-0.080850,0.006076-0.607600,0.005125-0.071740,and 0.017288-0.432200 mg/mL,respectively;RSDs of precision,repeatability,stability and recovery rate tests were all not higher than 4％ (n=6).The mass fractions ranged 3.2279-10.0022,0.2974-0.5546,3.3501-6.1596,0.7206-1.0733,2.0031-3.0301 mg/g;transfer rates from the pieces and standard decoction were 19.7628％-35.8405％,12.1233％-21.2540％,46.0972％-82.8694％,58.7088％-91.6296％,39.1143％-63.7106％.The transfer rates of the extract from 15 batches of Pinghuo tea standard decoction ranged from 61.15％-84.68％.CONCLUSIONS Established HPLC fingerprint and content determination methods in this study are simple and accurate,which can provide reference for the quantitative value transfer study,quality control,clinical application and the development of subsequent formulations of Pinghuo tea standard decoction.

Objective:To explore the effectiveness and safety of focused ultrasound ablation surgery (FUAS) for abdominal wall endometriosis.Methods:From November 2019 to October 2022, a total of 34 patients with abdominal wall endometriosis who underwent FUAS were collected, and their clinical features, imaging features, intraoperative treatment and side effects after treatment were analyzed retrospectively, and the improvement of symptoms and re-intervention were followed up.Results:(1) Characteristics of clinical data: the average age of 34 patients with abdominal wall endometriosis was (32.8±3.8) years old. The largest diameter of the lesion was 48 mm, and the median lesion diameter was 24 mm. Thirty cases (88%, 30/34) had moderate to severe periodic pain in abdominal incision before FUAS. All patients were diagnosed by preoperative magnetic resonance imaging, including 19 cases (56%, 19/34) of superficial type, 8 cases (24%, 8/34) of intermediate type and 7 cases (21%, 7/34) of deep type. (2) FUAS treatment parameters: ablation was completed with average operation time of (64±18) minutes, average sonication time was (385±108) s, (103±11) W of average power, (38 819±16 309) J of average total energy, the average treatment area volume of (3.11±1.42) cm 3, and (377.79±106.34) s/h of average treatment intensity. (3) Efficiency: the pain of patients after FUAS was significantly relieved, and the pain scores of patients after 1 month, 3 months, 6 months and 1 year after FUAS were significantly decreased ( Z=-4.66, -5.13, -5.11 and -4.91, all P<0.01). One year after FUAS, the near relief and effective pain relief rate was 74% (25/34), and the clinical effective rate was 85% (29/34). Five patients recurred after one year, including 3 patients who underwent abdominal wall endometriosis lesion resection and 2 patients who received drug treatment. One month after FUAS, the size of the lesion did not change significantly compared with that before FUAS ( P>0.05), and the size of the lesion decreased significantly after FUAS at 3 months, 6 months and 1 year ( Z=-2.15, -2.67 and -3.41, all P<0.05). It has no difference in pain relief among different types ( P>0.05), but has significant difference in focus reduction among three types ( P<0.01). (4) Safety: there were 34 cases (100%, 34/34) of skin burning sensation, 19 cases (56%, 19/34) of pain in the treatment area and 2 cases (6%, 2/34) of hematuria. All patients got better after corresponding treatments. Conclusion:FUAS is safe and effective for the treatment of abdominal wall endometriosis, which has clinical application value.

Objective:To compare the mid-term clinical effects of AngioJet rheolytic thrombectomy assisted catheter-directed thrombolysis (ART+CDT) with catheter-directed thrombolysis (CDT) in the treatment of acute deep venous thrombosis of lower extremities.Methods:Ninety-one patients admitted to the Department from Jan 2016 to Dec 2017 were placed with inferior vena cava filters and divided into ART+CDT group (30 cases)and CDT group (61 cases). Total urokinase dosge, thrombolytic time, operative cost, length of hospital stay, detumescence rate, thrombus clearance rate, cumulative patency rate of lower limb veins, Villalta score at 2 years and 5 years, thrombosis recurrence rate and chronic venous insufficiency quality of life questionnaire were compared between the two groups.Results:The success rate of surgery was 100% in both groups, there was no mortality. There were significant differences in the short-term postoperative outcomes between the two groups in terms of total dosage of urokinase, thrombolysis time, total cost of surgery, length of hospital stay, detumescence rate, venous patency scores before and after treatment, and venous patency rate (all P<0.05). For the mid- and long-term postoperative outcomes of 2 and 5 years, there were no significant differences in the incidence of PTS, recurrence rate of thrombus, chronic venous function scale, and cumulative patency rate at 2 years (all P>0.05). Conclusions:ART+CDT has a significant advantage over CDT alone in terms of early efficacy and early reopening of blood flow in patients. Both ART+CDT and CDT have a low incidence of PTS and a low recurrence rate of thrombus in the mid-term follow-up, and both have satisfactory performance in the mid- and long-term efficacy of interventional treatment of deep venous thrombosis of lower limbs.