ObjectiveTo establish a geographical origin identification model for Foeniculi Fructus from Haiyuan， providing a new technical reference for the protection of Haiyuan's geo-authentic medicinal materials and its designation as a national geographical indication agricultural product. MethodsSamples of Foeniculi Fructus were collected from eight producing areas， including Minqin （Gansu）， Bozhou （Anhui）， Qingdao （Shandong）， Dezhou （Shandong）， Urumqi （Xinjiang）， Nujiang （Yunnan）， Gutuo （Inner Mongolia）， and Haiyuan （Ningxia）. Gas chromatography-ion mobility spectrometry （GC-IMS） was used to detect the volatile organic compounds （VOCs） in samples from these geographic origins. VOCs were qualitatively analyzed through dual matching with the National Institute of Standards and Technology （NIST） mass spectral database and the IMS drift time database. Using the Reporter module and Gallery Plot visualization tools within the LAV analytical platform， VOC fingerprint profiles characterizing geographic origins were constructed. A non-targeted analytical strategy was adopted， and 97 VOCs detected via GC-IMS were subjected to principal component analysis （PCA） and partial least squares discriminant analysis （PLS-DA） based on their differential distribution patterns to construct an origin identification model for Foeniculi Fructus from Haiyuan region. Key discriminative markers were screened using variable importance in projection （VIP） values greater than 1. ResultsA total of 97 VOCs were identified， including alcohols， aldehydes， ketones， esters， organic acids， terpenoids， ethers， alkenes， and benzenes. The PLS-DA model， based on VOCs data obtained by GC-IMS， effectively distinguished Foeniculi Fructus in Haiyuan region from those of other origins. During cross-validation， the model achieved a prediction parameter （Q²） of 0.976 and a goodness-of-fit parameter （R²） of 0.936， with no overfitting observed in permutation testing. Twelve key flavor markers with VIP > 1 were identified as characteristic indicators of Haiyuan origin. ConclusionA stable and highly predictive origin identification model for Foeniculi Fructus from Haiyuan was successfully established using GC-IMS technology， PLS-DA， and VIP-based marker screening. This model provides a novel technical strategy for accurately distinguishing Foeniculi Fructus in Haiyuan region from other regional varieties and offers new technical support for its protection as a geo-authentic medicinal material and a nationally designated geographical indication agricultural product in China.

ObjectiveTo establish a geographical origin identification model for Foeniculi Fructus from Haiyuan， providing a new technical reference for the protection of Haiyuan's geo-authentic medicinal materials and its designation as a national geographical indication agricultural product. MethodsSamples of Foeniculi Fructus were collected from eight producing areas， including Minqin （Gansu）， Bozhou （Anhui）， Qingdao （Shandong）， Dezhou （Shandong）， Urumqi （Xinjiang）， Nujiang （Yunnan）， Gutuo （Inner Mongolia）， and Haiyuan （Ningxia）. Gas chromatography-ion mobility spectrometry （GC-IMS） was used to detect the volatile organic compounds （VOCs） in samples from these geographic origins. VOCs were qualitatively analyzed through dual matching with the National Institute of Standards and Technology （NIST） mass spectral database and the IMS drift time database. Using the Reporter module and Gallery Plot visualization tools within the LAV analytical platform， VOC fingerprint profiles characterizing geographic origins were constructed. A non-targeted analytical strategy was adopted， and 97 VOCs detected via GC-IMS were subjected to principal component analysis （PCA） and partial least squares discriminant analysis （PLS-DA） based on their differential distribution patterns to construct an origin identification model for Foeniculi Fructus from Haiyuan region. Key discriminative markers were screened using variable importance in projection （VIP） values greater than 1. ResultsA total of 97 VOCs were identified， including alcohols， aldehydes， ketones， esters， organic acids， terpenoids， ethers， alkenes， and benzenes. The PLS-DA model， based on VOCs data obtained by GC-IMS， effectively distinguished Foeniculi Fructus in Haiyuan region from those of other origins. During cross-validation， the model achieved a prediction parameter （Q²） of 0.976 and a goodness-of-fit parameter （R²） of 0.936， with no overfitting observed in permutation testing. Twelve key flavor markers with VIP > 1 were identified as characteristic indicators of Haiyuan origin. ConclusionA stable and highly predictive origin identification model for Foeniculi Fructus from Haiyuan was successfully established using GC-IMS technology， PLS-DA， and VIP-based marker screening. This model provides a novel technical strategy for accurately distinguishing Foeniculi Fructus in Haiyuan region from other regional varieties and offers new technical support for its protection as a geo-authentic medicinal material and a nationally designated geographical indication agricultural product in China.

Objective To investigate clinical effect of tendons pulling,poking and kneading for the treatment of external humeral epicondylitis.Metods From January 2018 to December 2021,a multicenter randomized controlled study was per-formed to collect 192 patients with external humeral epicondylitis in Wangjing Hospital,Beijing Dianli Hospital,and Beijing Fengsheng Osteotraumatology Hospital,respectively,and they were divided into treatment group and control group by random number table method.There were 96 patients in treatment group,including 36 males and 60 females,aged from 28 to 60 years old with an average of(41.20±5.50)years old;the course of disease ranged from 1 to 14 days with an average of(5.24±1.35)days;they were treated once every other day for 2 weeks.There were 96 patients in control group,including 33 males and 63 females,aged from 26 to 60 years old with an average of(43.35±7.75)years old;the course of disease ranged from 1 to 14 days with an average of(5.86±1.48)days;they were treated with topical voltaalin combined with elbow joint fixation for 2 weeks.Visual analogue scale(VAS)and Hospital for Surgery Scoring System(HSS)elbow pronation and supination angles,wrist metacarpal flexion and dorsal extension angles,elbow tenderness between two groups were compared before treatment and at 1,3,5,7,11 and 13 days after treatment;Hospital for Surgery Scoring System 2(HSS2)was compared before treatment and the final treatment.Results All patients were followed up for 10 to 14 days with an average of(12±1.6)days.VAS between treatment group and control group before treatment were 6.83±1.36 and 6.79±1.58,respectively,and decreased to 1.49±1.09 and 2.11±1.81 after the final treatment.VAS of treatment group were significantly lower than those of control group at 1,3,5,7,9,11 and 13 days after treatment(P＜0.05).HSS between two groups were 61.73±11.00 and 36.47±12.45 before treatment,respectively,and increased to 94.42±5.9 and 91.44±9.11 at the final treatment.HSS of treatment group were signifi-cantly higher than those of control group at 1,3,5,7,9,11 and 13 days after treatment(P＜0.05).On the 5th day after treat-ment,the external and internal rotation angles of elbow in treatment group were(66.41±12.69)° and(66.35±13.54)°,while those in control group were(62.08±16.03)° and(61.77±16.35)°.On the 7th day after treatment,the external and internal ro-tation angles of elbow were(69.79±12.64)° and(70.02±13.55)° in treatment group,and(65.28±15.86)° and(65.09± 16.67)° in control group.Elbow joint motion in treatment group was higher than that in control group(P＜0.05).On the 5th day after treatment,angles of wrist dorsiflexion and palm flexion were(39.43±15.94)°and(46.68±11.10)° in treatment group,and(38.51±18.49)° and(44.27±13.58)° in control group.On the 7th day after treatment,angles of wrist dorsiflexion and palm flexion were(42.52±16.50)° and(49.23±10.96)° in treatment group,and(41.18±20.09)° and(46.64±14.63)° in control group.The motion of wrist joint in treatment group was higher than that in control group(P＜0.05).On the 13th day after treatment,HSS2 in treatment group 93.61±6.32 were higher than those in control group 92.06±7.94(P＜0.05).There was no significant difference in elbow tenderness between two groups at each time point(P＞0.05).Conclusion Voltaren external treatment combined with elbow fixation and tendons pulling,poking and kneading could effectively improve symptoms of exter-nal humeral epicondylitis.Compared with voltaren external treatment,tendons pulling,poking and kneading has advantages of longer analgesic time and better elbow function recovery.

HDAC(histone deacetylase)is a class of epigenetic modifying enzymes that can deacetylate proteins by altering the acetylation status of histones in the nucleus,regulating promoter activation levels,and thereby affecting downstream gene expression.However,expression changes of HDACs during endo-thelial differentiation are still unclear.This study used a three-stage method to induce human induced pluripotent stem cells(hiPSCs)to differentiate into endothelial cells,and qRT-PCR was used to detect the expression changes of class I HDAC(HDAC1,2)and class Ⅱ HDAC(HDAC4,5)genes.It was found that HDAC5 exhibits significant expression changes during endothelial differentiation.It is downreg-ulated by 90％during the mesodermal differentiation stage(P＜0.01),upregulated by 3.7-fold during the vascular precursor stage(P＜0.01),and subsequently downregulated by 70％during the late stage of endothelial differentiation(P＜0.01).Immunoblotting experiments further confirmed that HDAC5 under-goes periodic expression changes during endothelial differentiation.Mechanistic studies have shown that HDAC5 downregulation during the differentiation stage of the mesoderm is mediated by Wnt signaling.CHIR99021 treatment and overexpression of Wnt3a can activate the Wnt signaling pathway,leading to HDAC5 downregulation.Inhibiting the Wnt signaling pathway through IWP-2 promotes the recovery of HDAC5 expression.In addition,it was found that HDAC5 is mainly localized in the nucleus,and IWP-2 restores HDAC5 expression,but it remains in the cytoplasm.Further research suggests that downregu-lation of HDAC5 during mesodermal differentiation may contribute to the expression of the mesodermal marker BraT.Treatment with the HDAC inhibitor BML210 can promote early mesodermal differentiation,interfere with endothelial differentiation of vascular precursor cells,and enhance late-stage endothelial differentiation.In conclusion,HDAC5 displays a stage-specific expression during endothelial differentia-tion,and Wnt signaling activation is the main mechanism regulating the downregulation of HDAC5 during the mesoderm stage.

Objective To explore the value of multi-parameter spectral CT for differentiating grade G2-3 pancreatic neuroendocrine tumor(pNET)and pancreatic neuroendocrine carcinoma(pNEC).Methods Preoperative double-layer detector spectral CT(DLCT)data of 35 patients with pNET(pNET group,including 25 cases of G2 grade and 10 cases of G3 grade)and 17 patients with pNEC(pNEC group)were retrospectively analyzed.Conventional CT and spectral CT parameters were compared between groups,and those being significant different between groups according to univariate analysis were respectively incorporated into multivariate logistic regression to select the independent predictors for identifying grade G2-3 pNET and pNEC.Conventional CT model and spectral CT model were constructed,and the combined model was constructed based on the two.The efficacy of each model for distinguishing grade G2-3 pNET and pNEC was evaluated.Results CT values of lesions during venous phase(OR=0.939,P=0.025)and vascular invasion(OR=5.049,P=0.027)shown on conventional CT were both independent predictors,and conventional CT model was constructed,its area under the curve(AUC)for distinguishing grade G2-3 pNET and pNEC was 0.808.Normalized iodine concentration during venous phase(OR=0.603)and normalized effective atomic number during venous phase(OR=0.847)on spectral CT were both independent predictors(both P＜0.05),and spectral CT model was constructed.The AUC of spectral CT model was 0.894,higher than that of conventional CT model(Z=2.127,P=0.033).The AUC of combined model was 0.924,higher than that of conventional CT model(Z=2.302,P=0.021)but not significantly different with that of spectral CT model(Z=0.827,P=0.408).Conclusion Multi-parameter spectral CT could effectively differentiate grade G2-G3 grade pNET and pNEC.

Objective To evaluate the bioequivalence of test product and reference product in a single dose of amoxicillin clavulanate potassium tablet under fasting and fed conditions in healthy volunteers.Methods An open label,randomized,single dose,four-period,crossover bioequivalence study was designed.Fasting and postprandial tests were randomly divided into 2 administration sequence groups according to 1:1 ratio,amoxicillin clavulanate potassium tablet test product or reference product 375 mg,oral administration separately,liquid chromatography tanden mass spectrometry was applied to determine the concentration of amoxicillin and clavulanate potassium in plasma of healthy subjects after fasting or fed administration,while Phoenix WinNonlin 8.2 software were used for pharmacokinetics(PK)parameters calculation and bioequivalence analysis.Results Healthy subjects took the test product and the reference product under fasting condition,the main PK parameters of amoxicillin are as follows:Cmax were(5 075.57±1 483.37)and(5 119.86±1 466.73)ng·mL-1,AUC0_twere(1.32 × 104±2 163.76)and(1.30 × 104±1 925.11)ng·mL-1,AUC0-∞were(1.32 × 104±2 175.40)and(1.31 ×104±1 935.86)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(3 298.27±1 315.23)and(3 264.06±1 492.82)ng·mL-1,AUC0-twere(7 690.06±3 053.40)and(7 538.39±3 155.89)ng·mL-1,AUC0-∞were(7 834.81±3 082.61)and(7 671.67±3 189.31)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-tand AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Healthy subjects took the test and reference product under fed condition,the main PK parameters of amoxicillin are as follows:Cmax were(4 514.08±1 324.18)and(4 602.82±1 366.48)ng·mL-1,AUC0-twere(1.15 × 104±1 637.95)and(1.15 × 104±1 665.69)ng·mL-1,AUC0-∞ were(1.16 × 104±1 646.26)and(1.15 × 104±1 607.20)ng·mL-1;the main PK parameters of clavulanic acid are as follows:Cmax were(2 654.75±1 358.29)and(2 850.51±1 526.31)ng·mL-1,AUC0-twere(5 882.82±2 930.06)and(6 161.28±3 263.20)ng·mL-1,AUC0-∞ were(6 022.70±2 965.05)and(6 298.31±3 287.63)ng·mL-1;the 90％confidence intervals of Cmax,AUC0-t and AUC0-∞ after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00％-125.00％.Conclusion The two formulations were bioequivalent to healthy adult volunteers under fasting and fed conditions.

Objective To observe the pharmacokinetic effect of amoxicillin and clavulanate potassium tablets on amoxicillin in Chinese healthy subjects under fasting and high fat and high calorie diet.Methods 71 healthy subjects were given a single dose of amoxicillin potassium clavulanate tablets(0.375 g)on fasting or high fat diet,and venous blood samples were collected at different time points.The concentrations of amoxicillin in human plasma were determined by HPLC-MS/MS method,and the pharmacokinetic parameters were calculated by non-atrioventricular model using PhoenixWinNonlin 8.0 software.Results The main pharmacokinetic parameters of amoxicillin potassium clavulanate tablets after fasting and high fat diet were(5 105.00±1 444.00),(4 593.00±1 327.00)ng·mL-1,and postprandial-fasting ratio 89.40％,90％confidence interval(79.55％-100.19％);t1/2 were(1.52±0.16),(1.39±0.22)h;AUC0-t were(12 969.00±1 841.00),(11 577.00±1 663.00)ng·mL-1·h,and postdietary/fasting ratio 89.20％,90％confidence interval(83.92％-94.28％);AUC0-∞ were(13 024.00±1 846.00),(11 532.00±1 545.00)ng·mL-1·h,and postprandial-fasting ratio 88.60％,90％confidence interval(83.48％-93.50％).The median Tmax(range)were 1.63(0.75,3.00)and 2.50(0.75,6.00)h,respectively,and the Tmax of postprandial medication was delayed(P＜0.01).Conclusion Compared with fasting condition,amoxicillin Tmax was significantly delayed after high fat diet,while Cmax,AUC0-t and AUC0-∞ were not significantly changed,indicating that food could delay the absorption of amoxicillin,but did not affect the degree of absorption.

Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral azvudine tablets in healthy young and elderly Chinese subjects.Methods This was a open-label and parallel-group study.The trial consisted of two groups:healthy young subjects group and healthy elderly subjects group,with 12 subjects in each group.Enrolled subjects were first given a single dose,fasting oral azvudine tablet 5 mg,after a 3-day cleansing period entered the multiple dose phase,fasting oral azvudine tablet 5 mg·d-1 for 7 days.Results After a single dose of azvudine 5 mg,Cmax and AUC0-∞ were(4.76±2.12)ng·mL-1,(6.53±2.20)ng·mL-1·h,and Tmax,t1/2 were 0.75,1.87 h in young subjects;Cmax and AUC0-∞ were(6.40±3.25)ng·mL-1,(9.50±3.70)ng·mL-1·h,and Tmax,t1/2 were 0.63,2.66 h in elderly subjects.After a multiple dose of azvudine 5 mg·d-1 for 7 d,Cmax and AUC0-∞ were(3.26±1.61)ng·mL-1,(5.38±2.19)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.88,2.13 h in young subjects;Cmax,ss and AUC0-∞,ss were(3.97±2.09)ng·mL-1,(6.71±3.26)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.75,2.56 h in elderly subjects.Elderly/young geometric mean ratios and 90％CIs were 128.37％(88.23％-186.76％),139.93％(105.42％-185.72％),140.03％(106.33％-184.41％)for azvudine Cmax,AUC0-t,AUC0-∞ after a single dose,and were 118.66％(80.83％-174.20％),118.41％(83.60％-167.69％),118.95％(84.78％-166.89％)for azvudine Cmax,AUC0-t,AUC0_∞ after a multiple dose of azvudine 5 mg·d-1 for 7 d.Conclusion After single and multiple oral administration of azvudine tablets,systemic exposure to azvudine was higher in healthy elderly subjects compared with healthy young subjects.After taking azvudine tablets,the types,severity and incidence of adverse events and adverse drug reactions in healthy elderly people were not significantly different from those in healthy young subjects.Azvudine was found to be safe and well tolerated in healthy elderly subjects.

RNA editing, an essential post-transcriptional reaction occurring in double-stranded RNA (dsRNA), generates informational diversity in the transcriptome and proteome. In mammals, the main type of RNA editing is the conversion of adenosine to inosine (A-to-I), processed by adenosine deaminases acting on the RNAs (ADARs) family, and interpreted as guanosine during nucleotide base-pairing. It has been reported that millions of nucleotide sites in human transcriptome undergo A-to-I editing events, catalyzed by the primarily responsible enzyme, ADAR1. In hematological malignancies including myeloid/lymphocytic leukemia and multiple myeloma, dysregulation of ADAR1 directly impacts the A-to-I editing states occurring in coding regions, non-coding regions, and immature miRNA precursors. Subsequently, aberrant A-to-I editing states result in altered molecular events, such as protein-coding sequence changes, intron retention, alternative splicing, and miRNA biogenesis inhibition. As a vital factor of the generation and stemness maintenance in leukemia stem cells (LSCs), disordered RNA editing drives the chaos of molecular regulatory network and ultimately promotes the cell proliferation, apoptosis inhibition and drug resistance. At present, novel drugs designed to target RNA editing(e.g., rebecsinib) are under development and have achieved outstanding results in animal experiments. Compared with traditional antitumor drugs, epigenetic antitumor drugs are expected to overcome the shackle of drug resistance and recurrence in hematological malignancies, and provide new treatment options for patients. This review summarized the recent advances in the regulation mechanism of ADAR1-mediated RNA editing events in hematologic malignancies, and further discussed the medical potential and clinical application of ADAR1.

Objective:To investigate the prospective association of sleep duration with the development of chronic obstructive pulmonary disease (COPD) in adults in Suzhou.Methods:The study used the data of 53 269 participants aged 30-79 years recruited in the baseline survey from 2004 to 2008 and the follow-up until December 31, 2017 of China Kadoorie Biobank (CKB) conducted in Wuzhong District, Suzhou. After excluding participants with airflow limitation, self-reported chronic bronchitis/emphysema/coronary heart disease history at the baseline survey and abnormal or incomplete data, a total of 45 336 participants were included in the final analysis. The association between daily sleep duration and the risk for developing COPD was analyzed by using a Cox proportional hazard regression model, and the hazard ratio ( HR) values and their 95% CI were calculated. The analysis was stratified by age, gender and lifestyle factors, and cross-analysis was conducted according to smoking status and daily sleep duration. Results:The median follow-up time was 11.12 years, with a total of 515 COPD diagnoses in the follow-up. After adjusting for potential confounders, multifactorial Cox proportional hazard regression analysis showed that daily sleep duration ≥10 hours was associated with higher risk for developing COPD ( HR=1.42, 95% CI: 1.03-1.97). The cross analysis showed that excessive daily sleep duration increased the risk for COPD in smokers ( HR=2.49, 95% CI: 1.35-4.59, interaction P<0.001). Conclusion:Longer daily sleep duration (≥10 hours) might increase the risk for COPD in adults in Suzhou, especially in smokers.