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 correlation between hearing loss and cognitive decline in community-dwelling older adults and to analyze the influencing factors.Methods:Using Pure-tone audiometry, the Hearing Handicap Inventory for the Elderly (HHIE), Mini-Mental State Examination (MMSE), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder, a survey was conducted with 492 community-dwelling older adults aged 60 years and above in Beijing. Age, gender, education level, hearing loss, levels of anxiety and depression, and other factors were used as independent variables, and the MMSE scores were used as dependent variables. Analysis of variance and multiple linear regression were performed.Results:Among the 492 subjects, based on the better ears, 418 (85.0%) had hearing loss and 160 (32.5%) had disabled hearing loss. Factors such as age (β=-0.33, P<0.01), gender (β=0.09, P=0.04), education level (β=0.31, P<0.01), hearing loss (β=-0.11, P=0.02) and marital status (β=0.56, P=0.02) were significantly related to cognitive decline. Gender (β=-0.17, P<0.01) and hearing loss (β=0.08, P=0.02) correlated with anxiety indicators; gender (β=-0.84, P=0.02) and hearing loss (β=0.04, P=0.01) also correlated with depression indicators. Conclusion:Results indicated a correlation between hearing loss and cognitive decline, and between hearing loss and anxiety and depression among community-dwelling older adults in Beijing.

Objective:To investigate a 3D method of radiological evaluation of extra-articular scapular fracture and the treatment outcomes.Methods:A total of 19 patients with extra-articular scapular fracture were operatively treated and completely followed up at Department of Orthopaedics and Traumatology, Beijing Jishuitan Hospital from January 2014 to January 2020. They were 17 males and 2 females with an average age of 41 years (from 24 to 65 years). The medial-lateral displacement, antero-posterior angulation and glenopolar angle were measured on images of 3D reconstruction of the fractured scapulae by Mimics software. 3D reconstructions of the intact scapulae were made as controls in the patients with proximal humerus fracture matched in time and age (17 males and 2 females with an average age of 41 years). Operations were carried out via the modified Judet approach in the experimental group. The treatment outcomes in the experimental group were evaluated by the Constant-Murley absolute value scoring at 6 months after operation.Results:All the patients in the experimental group obtained a mean follow-up of 48 months (from 11 to 73 months). All fractures in the experimental group acquired anatomical reduction and fixation intraoperatively and bony union within 6 months after operation. In the experimental group, the medial-lateral displacement averaged 17.9 mm and the antero-posterior angulation 26.9° before operation while the anteflexion lifting angle 162.2°, the lateral external rotation 41.6°, and the Constant-Murley absolute value scores 93.2 points at 6 months after operation. Pre-operatively, the glenopolar angles were 34.4°±6.3° and 40.6°±6.6° for the experimental and control groups respectively, showing a significant difference between the 2 groups ( P<0.05). At 6 months after operation, the glenopolar angle was 38.4°±5.0° for the experimental group, showing a significant difference between pre- and post-operation ( P<0.05). Conclusions:3D reconstruction measurements with Mimics software help accurate characterization of extra-articular scapular fracture and evaluation of surgical indications. Open reduction and internal fixation of scapular fractures via the modified Judet approach may promise a satisfactory union rate and functional outcomes.

Objective:To analyze the treatment of scapular glenoid fractures via the modified Judet approach.Methods:A retrospective study was conducted of the 25 patients who had been treated for scapular glenoid fractures via the modified Judet approach and completely followed up at Department of Orthopaedic Trauma, Beijing Jishuitan Hospital from January 2014 to January 2020. They were 19 males and 6 females with an average age of 46 years (from 29 to 66 years). According to the Goss-Ideberg classification, 8 cases were diagnosed as type Ⅱ, 2 cases as type Ⅳ, 10 cases as type Ⅴ and 5 cases as type Ⅵ. 3D reconstruction of the CT scans by software Mimics 16.0 was made to confirm the diagnoses and classifications of the fractures. Articular step-off and displacement of the scapular glenoid were calculated and recorded. The functional outcomes were evaluated by Constant-Murley scoring system at 6 months postoperatively.Results:Preoperatively, the mean articular step-off was 5.8 mm (from 1.2 to 6.3 mm) and the mean displacement 7.7 mm (from 2.1 to 12.9 mm). All fractures obtained bony union within postoperative 6 months. The mean follow-up period was 58.8 months (from 7 to 92 months). The forward flexion was 158.6° (from 125° to 180°) and the external rotation 39.0° (from 30° to 45°) at 6 months postoperatively. The mean Constant-Murley score was 92.6 (from 75 to 100) at 6 months post-operatively; 19 cases were excellent (76%), 5 were good (20%) and one was fair (4%), giving an excellent to good rate of 96% (24/25).Conclusion:For scapular glenoid fractures of Goss-Ideberg types Ⅱ/Ⅳ/Ⅴ/Ⅵ, surgery via the modified Judet approach may promise satisfactory reduction and fixation and fine clinical outcomes.

Objective To evaluate the predictors of gleason score pathological downgrading after radical prostatectomy in patients with biopsy-proven level 2 of grading groups (Gleason Score 3 + 4 =7).Methods Data of 252 patients,diagnosed with level 2 of grading groups(Gleason score 3 + 4 =7) prostate cancer by biopsy,with subsequent laparoscopic radical prostatectomy,were retrospectively analyzed.The mean age was 64.3,ranged from 46 to 82 years.The average body mass index (BMI) was 23.2 kg/m2,ranged from 15.2 to 30.4 kg/m2.The median prostate volume,transition zone volume(TZV) and transition zone index(TZI) were 48.9 ml (30.3-73.1 ml),21.4 ml(13.5-31.2 ml) and 0.46％ (0.37％-0.58％),respectively.The median value of tPSA,fPSA and PSAD were 1.53 ng/ml(0.67-3.92 ng/ml),9.65 ng/ml (4.13-18.68 ng/ml) and 0.18 ng/(ml · cm3) [0.09-0.50 ng/ (ml · cm3)],respectively.Clinical T stage was also evaluated,including 153 (60.7％) diagnosed as T1e stage,78 (3 1.0％) diagnosed as T2 stage,and 21 (8.3％) diagnosed as T3 stage.There were 58(23.0％) with extracapsular extension,47 (18.7％) patients with seminal vesicle invasion,and 2(0.8％) with lymph node metastasis.Pathological T stage includes 112 (44.4％) diagnosed as T2 stage,55 (21.8％) diagnosed as T3a stage,35 (13.9％) diagnosed as T3b stage,and 50(19.8％) diagnosed as T4 stage.The patients were assigned Prostate ImagingReporting and Data System version 2 scores of 1,2,3,4,and 5 were 45 (17.9％),36 (14.3％),51 (20.2％),68(27.0％)and 52(20.6％),respectively.The patients were categorized into 2 groups with and without pathological downgrading,including downgrade and no downgrade group.Univariate and multivariate logistic regression analysis were done to determine the predictors of pathological downgrading.Results The patients were categorized into downgrade(n =31) and no downgrade group(n =221) of 252 patients.The pathological downgrading was identified in 31 (12.3％).The tPSA,PSAD and PI-RADS scores in patients with downgrade group which were lower than those in without downgrade group (P ＜ 0.05).The logistic regression analysis revealed PI-RADS score was the independent predictor of downgrading(OR =0.364,95％ CI 0.253-0.522,P ＜ 0.01).The area under the ROC curve of PI-RADS score was 0.810 and the diagnostic value was the best.Conclusions These findings suggested that PI-RADS scores was predictor for pathological downgrading after radical prostatectomy in patients with biopsy-proven level 2 of grading groups,reduced PI-RADS score (PI-RADS score ≤ 3) is correlated with increased pathological downgrading after radical prostatectomy.

Objective: To investigate the effect of miR-144-3p modulating proliferation, migration and apoptosis of liver cancer Huh-7 cells through blocking frizzled class receptor 4 (FZD4)/Wnt/β-catenin pathway and the possible mechanism. Methods: A total of 18 pairs of cancer tissues and corresponding para-cancerous tissues from liver cancer patients, who underwent surgery in Workers' Hospital of Liuzhou City from March 2012 to July 2017, were collected for this study; in addition, hepatic cancer cell lines (Huh-7, SMMC7721 and MHCC97) and human normal liver epithelial cell line THLE-3 were also collected. The expression of miR-144-3p in liver cancer tissues and cell lines was detected by qPCR. MiR-144-3p mimics/inhibitor and FZD4 siRNA were transfected into liver cancer Huh-7 cells; the proliferation, migration and apoptosis of Huh-7 cells were evaluated by CCK-8 assay, Transwell assay, wound healing assay and Annexin V-FITC/PI double staining flow cytometry assay, respectively. The interaction between miR-144-3p and FZD4 was verified by dual-luciferase reporter gene assay. Results: The expression of miR-144-3p was down-regulated in liver cancer tissues and cell lines (P<0.05 or P<0.01). Over-expression of miR-144-3p significantly inhibited cell proliferation viability, migration but induced apoptosis of Huh-7 cells (all P<0.01). Moreover, dual-luciferase reporter gene assay showed that miR-144-3p directly interacted with FZD4 and suppressed its expression. Furthermore, in vitro experiments verified that miR-144-3p targeted FZD4 to suppress the proliferation, migration and promote apoptosis of Huh-7 cells via blocking Wnt/β-catenin pathway (all P<0.01). Conclusion: miR-144-3p inhibits malignant biological behaviors of liver cancer Huh-7 cells via blocking Wnt/FZD4/β-catenin signaling pathway, which may provide potential molecular targets for early diagnosis or treatment of liver cancer.

Objective: To explore the effects of various forms of prostatic apex on positive apical margin rate (PAM) and biochemical recurrence (BCR) after laparoscopic radical prostatectomy. Methods: A retrospective analysis of 309 patients (aging (65±6) years) who were experienced laparoscopic radical prostatectomy from January 2010 to December 2016 at the Department of Urology, First Affiliated Hospital of Fujian Medical University. According to the relationship between prostate apex and membrane urethra at the mid-sagittal plane of preoperative MRI, all patients were classified into 4 categories. There were 31 patients for type 1, apex covering both anterior and posterior aspects of membranous urethra, 139 patients for type 2, apex covering anterior side of membranous urethra, 63 patients for type 3, apex covering posterior aspect of membranous urethra, 76 patients for type 4, apex not covering membranous urethra. PAM and BCR after operation were compared between this four groups respectively. The χ² test was used to compare PAM among the 4 types. Logistic regression analysis were undertaken to analyze the factors affecting PAM. Cox′s proportional hazards regression model was undertaken to identify the variables influencing BCR. Results: There was no significant difference in the 4 groups concerning age, body mass index, prostate volume, preoperative prostate-specific antigen (PSA) value, postoperative Gleason score and pathological stage (P>0.05).The median follow-up time was 32 months (ranged from 12 to 60 months).The data showed that the apical type 3 patients has the highest PAM. There was statistical difference among the 4 groups in PAM (χ²=15.592, P=0.001). Preoperative level of PSA (OR=20.356, 95% CI: 2.440 to 169.810, P=0.005), postoperative Gleason score (OR=4.113, 95% CI: 1.911 to 8.849, P=0.001), pathological stage (OR=3.422, 95% CI: 1.600 to 7.319, P=0.002) and apical type 3 (OR=6.134, 95% CI: 2.196 to 17.132, P=0.001) were independent relactive factors of PAM. Preoperative level of PSA (HR=1.362, 95% CI: 1.006 to 1.843, P=0.045), postoperative Gleason score (HR=1.920, 95% CI: 1.384 to 2.665, P=0.001), pathological stage (HR=1.476, 95% CI: 1.098 to 1.983, P=0.010), PAM (HR=3.497, 95% CI: 2.407 to 5.081, P=0.001)and apical type 3 (HR=1.828, 95% CI: 1.266 to 2.639, P=0.001) were independent prognosis factors of BCR. Conclusion Prostate apical type 3 could be a significant independent predictor of PAM, and an independent prognosis factor for BCR.

Objective To discuss the clinical value of CT combined electronic level guided percutaneous transthoracic needle biopsy in diagnosis of small pulmonary nodules.Methods 44 cases of lung mini-nodule underwent CT combined electronic level guided percutaneous transthoracic needle biopsy.After operation the tissue was sent for pathologic examination.The nodules were divided into two groups,including Group A (diameter 0.5-1.0 cm,N=10) and Group B (diameter 1.1-2.0 cm,N=34),according to the different sizes of diameter.The excision of postoperative pathological and diagnosis result of clinical diagnosis and treatment of more than 12 months follow up were taken as the final result.The sensitivity,specificity,veracity and complications were compared and analyzed using paired x2 test,taking P＜0.05 as significant difference.Results (1)The arrival rate of target puncture were 100 ％ in 44 cases,with the sensitivity rate of 90.9％,specificity rate of 100 ％,veracity rate of 88.6 ％,positive predictive value of 97.5 ％,and negative predictive value of 100 ％.The sensitivity,specificity and veracity of Group A were 77.8％,100％ and 70.0％ respectively.And the sensitivity,specificity and veracity of Group B were 94.1％,100％ and 94.1％ respectively.The sensitivity,veracity of Group A was higher than Group B (P＜0.05),while there was no difference in specificity.(2)Complication:the incidence rate of pneumothorax,pulmonary bleeding symptoms and hemothorax were 9.1％,11.4％,2.3％,respectively.The incidence rate of total complication was 22.7％,and all be cured after the treatment.The lesions with emphysema around is a risk factor for pneumothorax and pulmonary bleeding symptoms (x2 =11.2,10.2,P＜0.05).However,the position,size and deepness was not correlated with the complications mentioned above (P ＞0.05).Conclusion CT combined electronic level guided percutaneous transthoracic needle biopsy is a safe,effective and accurate diagnostic method for lung mini-nodule lesion.

Long non-coding RNA ( lncRNA ) is a group of RNAs that exceed 200 nt in length without protein coding capacity .The tumorigenesis and progression of colorectal carcinoma relate to the aberrant expres-sion of lncRNAs closely.In this review,we summarize researches in the current status of lncRNAs in human color-ectal carcinoma to provide potential evidences for future diagnosis and gene therapies .

BACKGROUNDPartial tandem duplication of mixed lineage leukaemia (MLL-PTD) is detected both in patients with acute leukemia and in healthy people. However, MLL-PTD in relatives of patients with MLL-PTD has not been reported. The objective of this study was to investigate the expression of MLL-PTD in patients with acute leukemia and in their relatives.

METHODSThe bone marrow or peripheral blood was collected from patients with acute leukaemia and their relatives. Nested reverse transcription-polymerase chain reaction (RT-PCR) was applied to detect the mRNA expression of the MLLPTD fused gene, and further confirm in genomic DNA level.

RESULTSAnalysing MLL-PTD in case 1, the patient's older brother and his younger brother were positive, while his mother and his son were negative. The exon type in case 1 was e9/3 fusion, but in his older brother, it was e9/3 and e11/3 fusion, and in his younger brother, it was e9/3, e10/3, and e11/3 fusion. MLL-PTD in case 2 was negative, but in the patient's older sister was positive, and the exon type was e9/3, e10/3, and e11/3.

CONCLUSIONSThe expression of MLL-PTD was present in cases with acute leukaemia with a single expression type. However, various expression types were detected in their healthy relatives. MLL-PTD can couple with other chromosome aberrations, and its impact on disease prognosis remains to be studied further.

Acute Disease ; Chromosome Aberrations ; Female ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Male ; Myeloid-Lymphoid Leukemia Protein ; genetics ; Reverse Transcriptase Polymerase Chain Reaction