Objective:To assess the efficiency and safety of combining lenvatinib with DEB-TACE for the treatment of unresectable large hepatocellular carcinoma,accompanied by PVTT,in order to provide insights into its potential as a therapeutic approach.Method:Patients with hepa-tocellular carcinoma and portal vein tumor thrombus,who were diagnosed and treated at Linyi Can-cer Hospital between June 2019 and June 2021,were chosen as the subjects of this study.Patient allocation into the experimental group(23 cases)and control group(27 cases)was based on indi-vidual preferences,ensuring a random distribution of participants.The DEB-TACE treatment was administered to the control group,while the experimental group received a combination of DEB-TACE and lenvatinib.The effectiveness of lenvatinib was assessed in the immediate post-surgery period,the patients'survival was monitored,and any associated side effects were documented.Result:3 months after treatment,the objective remission rates of the experimental group and the control group were 91.31％and 66.67％,and the disease control rates were 100％and 77.78％.The difference was statistically significant(P＜0.05).3 months after treatment,the regression rates of tumor thrombus in the experimental group and the control group were 60.87％and 29.63％,the difference was statistically significant(P＜0.05).The progression free survival time of the experi-mental group and the control group was 11 months and 8 months,the difference was statistically significant(P＜0.05);The median survival time of the experimental group and the control group was 20 months and 14 months,and the difference was statistically significant(P＜0.05).The main ad-verse reactions of the experimental group were hypertension,diarrhea,hand foot syndrome,rash,fatigue,loss of appetite,etc.,all of which were less than or equal to grade 3,and could be basically relieved after symptomatic treatment.Conclusion:The combination of DEB-TACE and lenvatinib is proven to be a safe and well-tolerated treatment for unresectable large hepatocellular carcinoma with portal vein tumor thrombus.This therapy not only effectively controls tumor progression but also prolongs survival time.

OBJECTIVE: The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker. METHODS: A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL). RESULTS: The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m ³. The OELs for COEs exposure using the BBMD were 0.00170 mg/m ³ for the total population, 0.00158 mg/m ³ for males, and 0.00174 mg/m ³ for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m ³, respectively. CONCLUSION Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m ³. This value will provide a benchmark for determining possible OELs.
Male ; Female ; Animals ; Coke ; Polycyclic Aromatic Hydrocarbons ; DNA Copy Number Variations ; Benchmarking ; Occupational Exposure/analysis* ; DNA, Mitochondrial/genetics* ; DNA Damage

To study the quality control of three traditional Chinese medicines derived from Gleditsia sinensis [Gleditsiae Sinensis Fructus(GSF), Gleditsiae Fructus Abnormalis(GFA), and Gleditsiae Spina(GS)], this paper established a multiple reaction monitoring(MRM) approach based on ultra-high performance liquid chromatography-triple quadrupole-linear ion-trap mass spectrometry(UHPLC-Q-Trap-MS). Using an ACQUITY UPLC BEH C_(18) column(2.1 mm × 100 mm, 1.7 μm), gradient elution was performed at 40 ℃ with water containing 0.1% formic acid-acetonitrile as the mobile phase running at 0.3 mL·min~(-1), and the separation and content determination of ten chemical constituents(e.g., saikachinoside A, locustoside A, orientin, taxifolin, vitexin, isoquercitrin, luteolin, quercitrin, quercetin, and apigenin) in GSF, GFA, and GS were enabled within 31 min. The established method could quickly and efficiently determine the content of ten chemical constituents in GSF, GFA, and GS. All constituents showed good linearity(r>0.995), and the average recovery rate was 94.09%-110.9%. The results showed that, the content of two alkaloids in GSF(2.03-834.75 μg·g~(-1)) was higher than that in GFA(0.03-10.41 μg·g~(-1)) and GS(0.04-13.66 μg·g~(-1)), while the content of eight flavonoids in GS(0.54-2.38 mg·g~(-1)) was higher than that in GSF(0.08-0.29 mg·g~(-1)) and GFA(0.15-0.32 mg·g~(-1)). These results provide references for the quality control of G. sinensis-derived TCMs.
Flavonoids/analysis* ; Alkaloids ; Chromatography, High Pressure Liquid/methods* ; Mass Spectrometry ; Drugs, Chinese Herbal

OBJECTIVES: To investigate the value of CCKBR^fl/fl villin-Cre mice as a mouse model of salt-sensitive hypertension (SSH). METHODS: In the first part, 2-month-old CCKBR^fl/fl villin-Cre mice (CKO) and control CCKBR^fl/fl mice (WT) were fed with normal diet (0.4% NaCl) or high salt diet (4% NaCl), separately for 6 weeks. In the rescue study, one week of hydrochlorothiazide or saline injection were treated with the CKO mice fed high salt diet. The blood pressure, biochemical indexes, and the expression of small intestinal sodium transporters (NHE3, NKCC1, eNaC) was detected. The organ injury markers (MMP2/MMP9) and the histopathological changes of kidneys were observed, whereas the changes of duodenal sodium absorption were detected by small intestinal perfusion in vivo. RESULTS: The CCKBR^fl/fl villin-Cre mice with high salt intake exhibited high blood pressure, increased duodenal sodium absorption and urinary sodium excretion, and with renal injury. The protein expression of NHE3, NKCC1 and eNaC were also significant increase in the intestine of CKO-HS mice. Treatment with hydrochlorothiazide remarkably attenuated the elevated blood pressure by high salt absorption in the CCKBR^fl/fl villin-Cre mice, but no significant histopathological changes were observed. CONCLUSIONS These results support a crucial role of intestinal Cckbr deficiency on SSH development and the diuretic antihypertension effect in CCKBR^fl/fl villin-Cre mice. The CCKBR^fl/fl villin-Cre mice with the high salt intake may serve as a stable model of salt-sensitive hypertensive induced by sodium overloading.

Objective: To examine the safety and effectiveness of laparoscopic individualized surgical treatment for chronic traumatic diaphragmatic hernia (CTDH). Methods: The clinical data and follow-up data of 29 CTDH cases admitted to the Qilu Hospital of Shandong University or the First Affiliated Hospital of Shandong First Medical University from June 2015 to January 2023 were retrospectively analyzed. There were 21 males and 8 females, aged (49.4±17.8) years (range: 19 to 79 years). The main clinical manifestations were symptoms of the digestive system and respiratory system, and only 4 cases were asymptomatic. All patients received laparoscopic treatment (conversion to open surgery was not excluded). Intraoperative exploration (location of the hernia, contents of the hernia, diameter of the hernia ring), surgical conditions (surgical repair plan, operation time, blood loss, postoperative complications) and postoperative follow-up were analyzed and discussed. Results: Laparoscopic repair was successfully completed in 27 cases, including simple suture in 6 cases, suture and patch repair in 17 cases, the anterior abdominal wall muscle flap reversal suture and patch repair of in 3 cases, and patch bridge repair in 1 case. The operation time was (112.8±44.7) minutes (range: 60 to 200 minutes). The amount of bleeding (M(IQR)) was 35 (58) ml (range: 10 to 300 ml). The other 2 patients were converted to laparotomy. Except for one patient with transverse colon strangulation necrosis who died of aggravated pulmonary infection after surgery, the remaining 28 patients were discharged successfully. The follow-up time was 36 (24) months (range: 1 to 60 months). During the follow-up period, only two patients had occasional left upper abdominal discomfort. Twenty-seven patients with left diaphragmatic hernia had no recurrence, and the symptoms of 1 patient with right diaphragmatic hernia were relieved. Conclusion: Customized laparoscopic surgical repair for CTDH according to the location and size of the diaphragmatic defect can achieve good surgical results.
Male ; Female ; Humans ; Hernia, Diaphragmatic, Traumatic/surgery* ; Retrospective Studies ; Laparoscopy/methods* ; Postoperative Complications ; Laparotomy ; Surgical Mesh

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

Humans ; Female ; Coronary Artery Disease/complications* ; Hyperlipoproteinemia Type II/complications* ; Aortic Valve Stenosis/etiology* ; Treatment Outcome

Multicollinearity is an important issue affecting the results of regression analysis. LASSO developed in recent years has great advantages in selecting explanatory variables, processing high-dimensional data, and solving multicollinearity problems. This method adds a penalty term to the model estimation, which can compress the regression coefficients of some unnecessary variables to zero and then remove them from the model to achieve the purpose of variable screening. This paper focuses on the LASSO method and compares it with optimal subsets, ridge regression, adaptive LASSO, and elastic net results. It is found that both LASSO and adaptive LASSO have good performance in solving independent variable multicollinearity problems and enhancing model interpretation and prediction accuracy.
Humans ; Regression Analysis

Chinese patent medicines(CPMs) are unique therapeutic drugs in China. Establishing and improving the evaluation criteria is an important measure to promote the high-quality development of CPMs. Based on the "evaluation criteria of high-grade CPMs with quality as the core index" established by our group in 2018, the "high-quality evaluation criteria for CPMs based on whole process control" was proposed in the present study in 2022. The scope of application and basic principles of the new criteria were clarified. A quality evaluation scoring table was established in the new criteria, including five parts: raw material selection, production process, quality control, efficacy evaluation, and brand building. The technical evaluation indexes involved have increased from 20% in the original criteria to 70% in the new criteria, and efficacy evaluation has been added in the new criteria. The subjective evaluation indicators account for a large proportion in the original criteria, which is prone to bias. The improved criteria overcome this shortcoming. It is expected that the new criteria as a basis can play a better role in the selection of high-quality products of CPMs, guide enterprises and institutions to participate actively in the evaluation and research of high-quality CPMs, and promote the high-quality development of CPMs.
Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Nonprescription Drugs ; Chlorobenzenes ; China

Aim To prepare prostate cancer exosomes containing melittin and observe their uptake by prostate cancer cells. Methods Cells treated with starvation for different time were screened for exosome extraction. Exosomes from PC-3 cells were extracted by ultracentrifugation, and the extracted particles were examined by transmission electron microscopy, nanoparticle tracking analyzer(NTA), and Western blot. Melittin exosome system was prepared by repeated freeze-thaw method, incubation at room temperature as well as electroporation, and the size of encapsulation efficiency was measured by centrifugation. A high-performance liquid chromatography(HPLC)method was applied to assay the content of melittin exosomes(exo-mel). Fluorescence inverted microscopy was employed to evaluate the uptake of melittin exosomes by PC-3 cells, DU145 cells as well as LNCaP cells. Results The results of starvation treatment showed that 24 h starvation treatment was the optimal time point. TEM results showed that the exosomes were round or oval in shape with a distinct membranous structure, and the diameter was around 100 nm. The reagent protein concentration for NTA analysis of exosomes was 0.222 g·L-1. The results of Western blot for the marker proteins of exosomes showed that Alix and CD63 were positively expressed, which indicated that the exosomes could be obtained by starvation culture of PC-3 cells and ultracentrifugation. The results of entrapment efficiency showed that the entrapment efficiency of electroporation method was 17.51% ± 2.39%, that of repeated freeze-thaw method was 11.46% ± 1.02%, and that of room temperature incubation method was 3.93% ± 2.44%. The encapsulation efficiency of electroporation was the highest with significant difference(P<0.05). The uptake assay showed that PC-3 cells could efficiently take up exo-mel in a time-dependent manner, and DU145 cells and LNCaP cells also could take up exo-mel over time. Conclusions Exosomes can be accessed by starvation treatment and high-speed centrifugation, and the prostate cancer melittin exosome system prepared by electroporation method could be taken up by prostate cancer cells.