Aim To study the active ingredients and mechanism of action of Xinkeshu tablets against myo-cardial ischemia by network pharmacology and ze-brafish model.Methods The anti-myocardial ische-mia activity of Xinkeshu tablets was evaluated by iso-prenaline hydrochloride(ISO)-induced zebrafish myo-cardial ischemia model and H2O2-induced H9c2 dam-age model.The active ingredients of Xinkeshu tablets were retrieved using databases such as TCMSP.The potential targets were predicted by PharmaMapper data-base.Myocardial ischemic disease targets were searched by OMIM database.The potential therapeutic targets of Xinkeshu tablets against myocardial ischemia were analyzed.GO and KEGG enrichment analysis were conducted on core targets.The active ingredients were verified by zebrafish and cell model.qRT-PCR was used to detect the expression of key targets.Re-sults Xinkeshu tablets could significantly alleviate ISO-induced pericardial edema and bradycardia.It al-so could increase sinus venous-bulb aortic(SV-BA)distance and improve the cell viability.The 30 poten-tial active ingredients of Xinkeshu tables mainly acted on 30 core targets,including ALB,AKT1 and MAPK1,to regulate 627 GO items,including protein phosphorylation,negative regulation of apoptosis and positive regulation of PI3K signal transduction.KEGG results showed that 117 signaling pathways,including PI3K/Akt,FOXO and Ras,exerted anti-myocardial ischemia effect.Salvianolic acid A,lithospermic acid,rosmarinic acid,salvianolic acid D,salvianolic acid B,ginsenoside Rg2,hyperoside,3'-methoxypuerarin,3'-hydroxypuerarin and ginsenoside Rg1 could alleviate ISO-induced zebrafish myocardial ischemia and im-prove the cell viability.Xinkeshu tablets could upregu-late the expression of genes such as ras and akt1,and downregulate the expression of genes such as mapk1 and mapk8.Conclusion The active ingredients,in-cluding salvianolic acid A in Xinkeshu tablets,exert anti-myocardial ischemia effects by targeting targets,such as AKT1,MAPK1,and regulating signaling path-ways,such as PI3K/Akt,MAPK and Ras.

Eclipta prostrata L.has been used in traditional medicine and known for its liver-protective properties for centuries.Wedelolactone(WEL)and demethylwedelolactone(DWEL)are the major coumarins found in E.prostrata L.However,the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease(NAFLD)still remains to be explored.Utilizing a well-established zebrafish model of thioacetamide(TAA)-induced liver injury,the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis.Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver.The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped,and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized.Based on spatial metabolomics and transcriptomics,we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL.Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD,and presents a"multi-omics"platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.

Objective To construct a three-dimensional statistical shape model of the pelvis and analyze the individual variation and gender differences of the three-dimensional shape of the pelvis.Methods We collected CT data from 201 Chinese individuals and used deep learning to automatically reconstruct three-dimensional models of the pelvis.Through three-dimensional model registration,dense correspondence mesh mapping,and the use of statistical shape modelling(SSM)and principal component(PC)analysis method,we extracted models of variations(MoV)of pelvic shape changes and statistically compared the shape MoV between males and females.Results We analysed the top 10 principal components of shape variations,which accounted for 86.1％of the total variability.Among them,PC01,PC02,and PC04 showed significant differences between genders(P＜0.001),accounting for a total variability of 60.1％.PC08 and PC 10 demonstrated pelvic asymmetry,accounting for a total variability of 3.8％.Conclusion We constructed a three-dimensional statistical shape model of the pelvis in Chinese individuals,revealing the morphological variation and sex differences of Chinese pelvis.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Nucleus Accumbens/metabolism* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Sleep ; Sleep Wake Disorders ; Stress, Psychological/complications*

The purpose of this study was to explore transrectal ultrasound (TRUS) findings of prostate cancer (PCa) guided by multiparametric magnetic resonance imaging (mpMRI) and to improve the Prostate Imaging Reporting and Data System (PI-RADS) system for avoiding unnecessary mpMRI-guided targeted biopsy (TB). From January 2018 to October 2019, fusion mpMRI and TRUS-guided biopsies were performed in 162 consecutive patients. The study included 188 suspicious lesions on mpMRI in 156 patients, all of whom underwent mpMRI-TRUS fusion imaging-guided TB and 12-core transperineal systematic biopsy (SB). Univariate analyses were performed to investigate the relationship between TRUS features and PCa. Then, logistic regression analysis with generalized estimating equations was performed to determine the independent predictors of PCa and obtain the fitted probability of PCa. The detection rates of PCa based on TB alone, SB alone, and combined SB and TB were 55.9% (105 of 188), 52.6% (82 of 156), and 62.8% (98 of 156), respectively. The significant predictors of PCa on TRUS were hypoechogenicity (odds ratio [OR]: 9.595, P = 0.002), taller-than-wide shape (OR: 3.539, P = 0.022), asymmetric vascular structures (OR: 3.728, P = 0.031), close proximity to capsule (OR: 3.473, P = 0.040), and irregular margins (OR: 3.843, P = 0.041). We propose subgrouping PI-RADS score 3 into categories 3a, 3b, 3c, and 3d based on different numbers of TRUS predictors, as the creation of PI-RADS 3a (no suspicious ultrasound features) could avoid 16.7% of mpMRI-guided TBs. Risk stratification of PCa with mpMRI-TRUS fusion imaging-directed ultrasound features could avoid unnecessary mpMRI-TBs.
Male ; Humans ; Prostatic Neoplasms/pathology* ; Multiparametric Magnetic Resonance Imaging ; Magnetic Resonance Imaging/methods* ; Prostate/pathology* ; Image-Guided Biopsy/methods*

Objective: We aimed to determine the epidemiological characteristics of asymptomatic AF in elder community population (≥65 years old) to analyze the detection rate of different screening methods. Methods: The study was a prospective cohort study. The elder (≥65 years old) residents who voluntarily participated in free physical examination in Dalian community were selected. The participants were randomly divided into screening group (including intensive screening group and single screening group) and control group. The control group received interrogation, medical history collection and routine 12-lead electrocardiogram (ECG) examination. Screening group received an additional single-lead ambulatory ECG equipment worn for 5-7 days. Intensive screening group received two equal-length wearings in 2020 and 2021 respectively, while one screening group only wore once in 2020. Results: Finally 3 340 residents ((70.7±5.0) years old) which consisted of 1 488 males (44.55%) were enrolled. There were 1 945 residents in screening group, including 859 in intensive screening group and 1 086 in one-time screening group. The control group included 1 395 people. Detection rate of asymptomatic AF was significantly higher in screening group than control group (79(4.06%) vs. 24(1.72%), P<0.001). Higher detection rate was found in screening group than control group in AF risk factors (1 or 2-3) subgroups and CHA₂DS₂-VASc score (2-3 or≥4) subgroups (P<0.05). Additionally, no difference was found between intensive screening group and single screening group (42(4.89%) vs. 37(3.41%), P=0.100). Intensive screening increased detection rate (7(6.93%) vs. 1(0.58%), P=0.009) only in residents those with low thrombosis risk (CHA₂DS₂-VaSc<2). Conclusions: Screening in elderly (≥65 years old) can significantly improve the detection rate of asymptomatic AF by wearing single lead dynamic ECG device. The rate increased significantly with the increase of risk factors associated with AF by single screening. In addition, repeat screening of the same method may only improve detection rates in the group with low risk thrombotic scores and non-combination of AF risk factors.Screening methods that are appropriate for different populations may require further exploration.
Male ; Humans ; Aged ; Atrial Fibrillation/epidemiology* ; Prospective Studies ; Electrocardiography ; Risk Factors ; Stroke ; Risk Assessment ; Mass Screening/methods*

Objective: We aimed to determine the epidemiological characteristics of asymptomatic AF in elder community population (≥65 years old) to analyze the detection rate of different screening methods. Methods: The study was a prospective cohort study. The elder (≥65 years old) residents who voluntarily participated in free physical examination in Dalian community were selected. The participants were randomly divided into screening group (including intensive screening group and single screening group) and control group. The control group received interrogation, medical history collection and routine 12-lead electrocardiogram (ECG) examination. Screening group received an additional single-lead ambulatory ECG equipment worn for 5-7 days. Intensive screening group received two equal-length wearings in 2020 and 2021 respectively, while one screening group only wore once in 2020. Results: Finally 3 340 residents ((70.7±5.0) years old) which consisted of 1 488 males (44.55%) were enrolled. There were 1 945 residents in screening group, including 859 in intensive screening group and 1 086 in one-time screening group. The control group included 1 395 people. Detection rate of asymptomatic AF was significantly higher in screening group than control group (79(4.06%) vs. 24(1.72%), P<0.001). Higher detection rate was found in screening group than control group in AF risk factors (1 or 2-3) subgroups and CHA₂DS₂-VASc score (2-3 or≥4) subgroups (P<0.05). Additionally, no difference was found between intensive screening group and single screening group (42(4.89%) vs. 37(3.41%), P=0.100). Intensive screening increased detection rate (7(6.93%) vs. 1(0.58%), P=0.009) only in residents those with low thrombosis risk (CHA₂DS₂-VaSc<2). Conclusions: Screening in elderly (≥65 years old) can significantly improve the detection rate of asymptomatic AF by wearing single lead dynamic ECG device. The rate increased significantly with the increase of risk factors associated with AF by single screening. In addition, repeat screening of the same method may only improve detection rates in the group with low risk thrombotic scores and non-combination of AF risk factors.Screening methods that are appropriate for different populations may require further exploration.
Male ; Humans ; Aged ; Atrial Fibrillation/epidemiology* ; Prospective Studies ; Electrocardiography ; Risk Factors ; Stroke ; Risk Assessment ; Mass Screening/methods*

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis ; Chemoradiotherapy ; Female ; Humans ; Male ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Recurrence, Local ; Programmed Cell Death 1 Receptor/antagonists & inhibitors* ; Rectal Neoplasms/therapy* ; Retrospective Studies ; Risk Factors ; Treatment Outcome

Aortic Valve/surgery* ; Aortic Valve Stenosis/surgery* ; China/epidemiology* ; Heart Valve Prosthesis Implantation ; Humans ; Severity of Illness Index ; Treatment Outcome

OBJECTIVE: To explore the influencing factors of low back pain and the relationship of the influence of bad working posture, weight load and frequency of load and the dose-response relationship among the occupational workers of key industries in China. METHODS: A total of 57 501 employees from 15 key industries in China were selected as research subjects using stratified cluster sampling method. The occurrence of low back pain in the past one year, as well as occupational factors such as job type, labor organization and work posture were investigated by using the Chinese version Musculoskeletal Disorders Questionnaire. RESULTS: The prevalence of low back pain in the occupational population of key industries in China was 16.4%(9 448/57 501). Multivariate Logistic regression analysis showed that the risk of low back pain in females was higher than that in males(P<0.01). Married, obese, occasional and frequent smokers, and a history of lower back disease were associated with increased risk of low back pain(all P<0.05). The risk of low back pain was associated with older age, higher education level, and lower frequency of physical exercise(all P<0.01). The risk of low back pain was higher with longer working time, greater back curvature, and the high frequency of long standing and sitting position work, uncomfortable working posture, repeated operation per minute, and lifting>5 kg weight(all P<0.01). CONCLUSION: The influencing factors of low back pain in the occupational population of key industries in China include bad working posture, high frequency load, weight load and other individual factors. There is a dose-response relationship with low back posture load and frequency of load.