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.

Purpose: Reduced quality of life after cystectomy has made bladder preservation a popular research topic for muscle-invasive bladder cancer (MIBC). Previous research has indicated significant tumor downstaging after neoadjuvant chemotherapy (NAC). However, maximal transurethral resection of bladder tumor (TURBT) was performed before NAC to define the pathology, impacting the real evaluation of NAC. This research aimed to assess real NAC efficacy without interference from TURBT and apply combined modality therapies guided by NAC efficacy. Materials and Methods: Patients with cT2-4aN0M0 MIBC were confirmed by cystoscopic biopsy and imaging. NAC efficacy was assessed by imaging, urine cytology, and cystoscopy with multidisciplinary team discussion. Definite responders (≤ T1) underwent TURBT plus concurrent chemoradiotherapy. Incomplete responders underwent radical cystectomy or partial cystectomy if feasible. The primary endpoint was the bladder preservation rate. Results: Fifty-nine patients were enrolled, and the median age was 63 years. Patients with cT3-4 accounted for 75%. The median number of NAC cycles was three. Definite responders were 52.5%. The complete response (CR) was 10.2%, and 59.3% of patients received bladder-sparing treatments. With a median follow-up of 44.6 months, the 3-year overall survival (OS) was 72.8%. Three-year OS and relapse-free survival were 88.4% and 60.0% in the bladder-sparing group but only 74.3% and 37.5% in the cystectomy group. The evaluations of preserved bladder function were satisfactory. Conclusion After stratifying MIBC patients by NAC efficacy, definite responders achieved a satisfactory bladder-sparing rate, prognosis, and bladder function. The CR rate reflected the real NAC efficacy for MIBC. This therapy is worth verifying through multicenter research.

Objective To investigate the dose of docetaxel appropriate for patients with metastatic castration-resistant prostate cancer and its affects to the prognosis.Methods A retrospective analysis was performed on the clinical data of 75 patients with metastatic castration-resistant prostate cancer admitted from March 2010 to July 2016 who received docetaxel combined with prednisone chemotherapy.The patients were divided into the low-dose group (n =43,docetaxel ＜ 65 mg/m2),the middle-dose group (n =21,docetaxel 65-70 mg/m2) and the high-dose group (n =11,docetaxel ＞ 70 mg/m2).The median age in the low-dose group,middle-dose group and high-dose group was 67 (53-80),66 (56-78) and 61 (47-76) years old,respectively.Among 75 patients with bone metastasis,2 patients had no evidence of bone metastasis in the low-dose group.The lymph node metastasis was found in 26,13 and 6 cases in each group,respectively.And visceral and other metastasis were founded in 11,4 and 2 cases,respectively.The Gleason score in the low-dose group was≤7 points in 15 cases,≥8 points in 22 cases and no score in 6 cases.The Gleason score inthe middle-dose group was ≤7 points in 4 cases,≥8 points in 13 cases and no score in 4 cases.The Gleason score in the high-dose group was ≤7 points in 3 cases,≥8 points in 5 cases and no score in 3 cases.The number of patients with pain in the low-dose group,middle-dose group and high-dose group was 36,12 and 9,respectively,there were no significant differences in the above indicators (P ＞ 0.05),except age,which showed relatively more aged patients in the low-dose group,(P =0.045).Kaplan-Meier method was used to compare the overall survival (OS),progression-free survival (PFS) and the incidence of ≥CTCAE-4 grade 3 adverse reactions between the two groups.The Cox regression model was adopted to analyzed the factors that might affect patient prognosis,including the effective time of first-line endocrine therapy,hemoglobin level,ECOG score,pain score,number of cycles of chemotherapy,age,dose of docetaxel and alkaline phosphatase (ALP).Kaplan-Meier method was used to analyze the effect of dose of docetaxel on the prognosis,and log-rank method was used to test the significance of the results.Results The median OS was respectively 24.1,18.5 and 23.5 months in the low-dose group,middle-dose group and high-dose group,respectively.The median PFS was 5.3 months in all three groups,which didn't show statistically significant differences.The incidence of grade 3/4 adverse reactions in the low-dose group,middle-dose group and high-dose group was 15 cases (34.9％),8 cases (38.1％) and 5 cases (45.5％) respectively.It showed an increasing trend,but no statistically significant difference.The single factors related to OS mainly include the effective time of first-line endocrine therapy,hemoglobin level,ECOG score,pain score,number of cycles of chemotherapy,there was no significant correlation with age,docetaxel dose,ALP and PSA value.Conclusions It is common to receive lower doses of docetaxel in clinical practice for patients with metastatic castration-resistant prostate cancer in China.The efficacy of low-dose docetaxel is similar to that of high doses (standard dosage).There was no significant correlation between the OS and the actual dose of docetaxel in the tolerable range.

Objective To evaluate the efficacy and safety of the modified docetaxel plus prednisone scheme for the metastatic castration resistant prostate cancer patients who got poor tolerance to chemotherapy.Method The clinical data of 50 metastatic castration resistant prostate cancer who received docetaxel + prednisone chemotherapy from March 2010 to October 2015 were analyzed retrospectively.23 cases received the modified DP regimen (modified group),27 cases received the standard DP regimen (standard group).The median age of the modified group and the standard group were 69 years (47-80 years) and 63 years (52-77 years) (P =0.005).There were 19 and 24 cases with pain in modified group and standard group respectively;10 and 19 cases with lymph node metastasis respectively;3 and 4 cases of visceral metastasis respectively;all of the 50 patients were complicated with bone metastasis.For the pathological Gleason score,there were 7 cases scored ≤7 points,13 cases scored ≥ 8 points and 3 cases unscored in the modified group;7 cases scored ≤7 points,15 cases scored ≥8 points and 5 cases unscored in standard group.There was no significant difference of the pain,metastasis,and Gleason score between the two groups (P ＞ 0.05).Progression free survival (PFS),overall survival (OS)and adverse events were analyzed using Kaplan-Meier curves,and the differences were assessed using the log-rank test.Results In the modified group and standard group,the median follow-up times were 11.0 months and 14.0 months respectively,the median chemotherapy cycles were 4.5 cycles and 5.0 cycles respectively;OS were 18.0 months and 27.5 months respectively (P =0.746).The PFS of the two groups were 6.0 months and 5.2 months,respectively (P =0.822).The PSA response were 13 cases and 17 cases in the modified group and standard group respectively (P =0.615),and the pain response were 8 cases and 7 cases (P =0.927),grade 3 to 4 adverse events were 3 cases and 14 cases (P =0.003).The main adverse events were blood toxicity,neutrophils,gastrointestinal reaction,edema,fatigue and oral mucositis etc.Conclusions Compared with the standard DP scheme,the modified DP scheme had no significant difference in OS,PFS,pain response rate and PSA response rate,while the incidence of grade 3 to 4 adverse events was significantly reduced.Modified DP scheme may be a better choice for patients with metastatic castration resistant prostate cancer who get poor tolerance to chemotherapy.

Objective To explore the effect of giving sedatives according to the circadian rhythm in prevention of occurrence of delirium and the prognosis of patients undergoing mechanical ventilation in intensive care unit (ICU). Methods A prospective double-blinded randomized controlled trial (RCT) was conducted. The patients admitted to Department of Critical Care Medicine of the Second Hospital of Lanzhou University from July 2014 to February 2015, undergoing invasive mechanical ventilation over 12 hours were enrolled. All the patients were given fentanyl for analgesia, and they were randomly divided into simulated circadian clock group (study group, n = 35) and non-simulated circadian clock group (control group, n = 35). The patients in each group were subdivided into three subgroups according to the kinds of sedative drugs, namely dexmedetomidine group (n = 8), propofol group (n = 14), and dexmedetomidine combined with propofol group (combination group, n = 13). Visual analogue scale (VAS) standard and Richmond agitation-sedation scale (RASS) were used to control the analgesic and to quantify the depth of sedation by titrating the dose of sedative drugs, the simulated circadian clock was set to control the RASS score at 0-1 during the day, and -1 to -2 at night in study group. The RASS score in the control group was set at -1 to -2 day and night. The urine 6-hydroxy acid melatonin (aMT6s) levels at different time points in the first diurnal rhythm (06:00, 12:00, 18:00, 24:00) were determined by enzyme linked immunosorbent assay (ELISA). The incidence of delirium, severe hypotension, severe bradycardia and other adverse reactions, duration of mechanical ventilation and the time of extubation, length of ICU stay, amount of sedative and analgesic drugs used were recorded. The correlation between delirium and other indexes was analyzed by using Spearman correlation analysis. Results ① There were no significant differences in gender, age, acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score among groups. ② Urine aMT6s levels did not show circadian rhythm in both groups, aMT6s level at 06:00 in study group showed an increasing tendency as compared with the control group, but the difference was not statistically significant. ③ Compared with the control group, the incidence of delirium was significantly lowered in the study group (14.3% vs. 37.1%, P = 0.029), but no significant differences were found in the incidence of severe hypotension or severe bradycardia (20.0% vs. 25.7%, 11.4% vs. 20.0%, both P > 0.05). In simulated circadian clock group, the incidence of delirium in dexmedetomidine group was significantly lower than that of the propofol group (6.3% vs. 32.1%, P < 0.05). ④ Compared with control group with the same sedative, the duration of mechanical ventilation, extubation time, length of ICU stay were significantly shortened, and the dosage of sedative drugs used was reduced in study group (all P < 0.05). In simulated circadian clock group, the duration of mechanical ventilation in dexmedetomidine group was significantly shorter than that of propofol group and combination group (hours: 75.75±26.78 vs. 102.00±26.31 and 100.31±25.38, both P < 0.05), and the length of ICU stay was significantly shorter than that of propofol group (days: 5.75±1.04 vs. 7.00±1.52, P < 0.05). ⑤ The occurrence of delirium was positively correlated with duration of mechanical ventilation (r = 0.705), extubation time (r = 0.704), length of ICU stay (r = 0.666, all P = 0.000), and no correlation was found between the occurrence of delirium and aMT6s level at 06:00, 12:00, 18:00, and 24:00 (r = -0.135, r = 0.163, r = 0.269, r = -0.077, all P > 0.05). Conclusions Administration of sedatives according to simulating circadian time could decrease the duration of mechanical ventilation, extubation time, and the length of ICU stay, decrease the dosage of sedative drugs, and reduce the incidence of delirium. Dexmedetomidine could reduce the incidence of delirium, and improve the prognosis of patients. Trial registration Registration of clinical trials in China, ChiCTR-IPR-15006644.

ObjectiveTo observe the effect on stress response to indwelling gastric tube assisted by bronchofiberoscope and traditional way in patients with severe craniocerebral injury in intensive care unit(ICU). Methods 126 patients admitted in Department of Surgery ICU in Lanzhou University Second Hospital were randomly divided into bronchofiberoscope assisted indwelling gastric tube group(experimental group) and the traditional way of indwelling gastric tube group(control group), 63 cases in each group. In the experimental group, the rod of mirror, Olypus BF-P60, was coated with lidocaine gel, through the nasal cavity it was sent into interior, when arrived at epiglottis, the operator adjusted the mirror head and let it go into the esophagus(about 10 cm), then put a steel wire as a guide into a hole for biopsy, and simultaneously, as the operator pulled out the rod, the wire was continuously pushed slowly further inside; after the bronchofiberoscope was completely withdrawn, valelinum liquidum was used to ensure sufficient lubrication to the external and internal walls of the indwelling gastric tube ready to be sent into the stomach, afterwards the tube was slowly pushed along the guide wire to an appropriate location and then the wire was pulled out, the operator injected air, when he or she heard the gurgling sound as the gas passing water, fixed the tube. In the control group, the traditional way of indwelling gastric tube was applied. Before and after indwelling gastric tube for 1, 3, 5 minutes, the changes of systolic pressure(SBP),diastolic pressure(DBP),heart rate(HR), end-expiratory carbon dioxide partial pressure(PETCO2) and plasma concentrations of norepinephrine(NE), adrenaline, angiotensinⅡ(AngⅡ), glucose(GLU) were examined.Results The plasma levels of SBP, DBP, HR, PETCO2, adrenaline, NE, AngⅡ and blood GLU had no statistical significant differences before operation in comparisons between both groups(allP>0.05). Compared to those before indwelling the tube, the levels of SBP, DBP, HR, PETCO2, NE, adrenaline, AngⅡ and GLU at various time points after the indwelling in experimental group were of no statisticalsignificant differences(allP>0.05), while the levels of SBP, DBP,HR, adrenaline, NE, AngⅡand GLU in control group at various time points after indwelling were higher obviously than those before operation, and the level of PETCO2 was decreased significantly compared with that before operation. The differences in the above indexes were significant between the treatment and control groups at 1 minute after indwelling〔SBP(mmHg, 1 mmHg=0.133 kPa): 125.1±15.4 vs. 135.5±13.6, DBP(mmHg): 85.6±16.1 vs. 91.1±17.2, HR(bpm): 99.4±13.8 vs. 107.9±16.5, PETCO2(mmHg): 32.5±2.8 vs. 29.8±4.1, NE(ng/L): 365.4±29.7 vs. 475.7±49.9, adrenaline(ng/L): 75.4±7.2 vs. 83.6±7.4, AngⅡ(ng/L): 65.3±6.9 vs. 73.3±9.1, GLU(mmol/L): 10.1±1.9 vs. 13.4±3.0, allP<0.05〕; the differences in the above indexes remained significant between the treatment and control groups till 5 minutes after indwelling〔SBP(mmHg): 123.7±14.8 vs. 129.7±15.1, DBP(mmHg): 84.3±14.6 vs. 88.4±14.2, HR(bpm): 97.7±13.6 vs. 31.6±3.9, PETCO2(mmHg): 33.5±3.1 vs. 31.6±3.9, NE(ng/L): 363.9±31.3 vs. 457.7±48.4, adrenaline(ng/L): 74.6±7.8 vs. 83.5±8.5, AngⅡ(ng/L): 64.3±8.4 vs. 71.9±5.9, GLU(mmol/L): 9.6±2.3 vs. 12.7±3.1, allP<0.05〕.ConclusionCompared with traditional way, the indwelling of gastric tube assisted by branchofiberoscopy can induce milder stress response.

OBJECTIVE: Analyse the effect of the treatment of infection in posterior tympani cavity in 168 cases with chronic otitis media. METHOD: Infection was eliminated in posterior tympani cavity of all 168 cases after surgical procedures of otitis media, and 102 tympanoplasty with autoplastic bone were operated in all cases. 22 tympanoplasty were operated without mastoidectomy, 53 with transmastoid approach, 27 with mastoidectomy and tympanoplasty. RESULT: All cases were followed up for more than one year. 160 cases were cured, the effective rate was 95% and no recurrence appeared except for 8 cases. The average threshold of hearing improvement of 87 cases > 15 dB, the effective rate was 85%. CONCLUSION To eliminate infection, the exploratory surgery of posterior tympani cavity should be done during surgical procedures of otitis media, for improving the effect of the treatment of otitis media.
Adolescent ; Adult ; Chronic Disease ; Ear, Middle ; surgery ; Female ; Humans ; Male ; Middle Aged ; Otitis Media ; surgery ; Tympanoplasty ; methods ; Young Adult

OBJECTIVE: To establish a rapid method for EBV detection with loop-mediated isothermal amplification (LAMP), and to make it as a clue for early diagnosis of nasopharyngeal carcinoma cancer. METHOD: EBV DNA was fast extracted from samples after boiling, while the whole detection will be finished within an hour with specific amplification of EBV gene by LAMP. RESULT: High specificity was shown from EBV detection of 33 clinical samples. Comparing with PCR, LAMP is more simple and convenient to perform under isothermal conditions, and require no special apparatus, thus, it is more economical and practical. CONCLUSION LAMP analysis of EBV may be an efficient and easy way for clinical diagnosis of nasopharyngeal carcinoma.
DNA Primers ; DNA, Viral ; analysis ; Herpesvirus 4, Human ; genetics ; Humans ; Molecular Sequence Data ; Nasopharyngeal Neoplasms ; diagnosis ; Nucleic Acid Amplification Techniques ; Sensitivity and Specificity

OBJECTIVE To evaluate the roles of p15,p27 gene protein and expression in nasopharyngeal carcinoma(NPC).METHODS The EnVision immunohistochemical method was used to detect the expression of p15,p27 gene protein in nasopharyngeal carcinoma tissues of 43 NPC cases and non-tumor nasopharyngeal tissues of 21 cases.RESULTS ① The positive expression rates of p15,p27 gene protein were 65%,68% in NPC respectively.There were significant differences between NPC and non-tumor group(P0.05).③The positive expression of p15 gene protein was correlated to the positive expression of p27 gene protein(P

OBJECTIVETo obtain very end full-length cDNA of hepatitis C virus (HCV) 5' untranslated region (5' UTR), and analyse its primary and secondary structure.

METHODSBy reverse transcription-nested polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP), a patient infected with genotype 2a HCV was found. Total RNA isolated from the serum as template, the cDNA of 5' noncoding region was amplified using rapid amplification of cDNA ends methods (RACE), the fragments were recombined by A-T clone strategy, the recombinants were confirmed by RFLP and PCR then sequenced. Secondary structures were analysed by RNA draw.

RESULTSVery end full-length cDNA of 2a genotype HCV 5' UTR was obtained by RACE. In five clones obtained, three contained full-length 5' UTR cDNA, and A21G, G170A, T222C, T247C, C339T substitutions were found compared with HC-J6. he homologies with HCV-1,HC-J6,HC-C2, HC-J8 were 93.6%-94.4%, 92.1%-93.0%, 98.8%-99.7%, 96.2%-96.5%, respectively; however, the substitutions did not alter the secondary structure. Two out of five clones were deleted to have 53 and 144 bases at 5' terminus of HCV 5' UTR, respectively.

CONCLUSIONSRACE is rapid and effective, works well to obtain very end of virus genome. With that, Authors obtained full-length cDNA of genotype 2a of HCV 5' UTR. There are genes deleted at 5' terminus circulated in hepatitis C patients.

5' Untranslated Regions ; genetics ; Base Sequence ; DNA, Complementary ; genetics ; DNA, Viral ; genetics ; Hepacivirus ; classification ; genetics ; isolation & purification ; Hepatitis C ; virology ; Humans ; Molecular Sequence Data ; Nucleic Acid Amplification Techniques ; methods ; Polymorphism, Restriction Fragment Length ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA