Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

This study summarizes Professor Qin Zhenhua's clinical experience in treating cutaneous pruritus using a modified self-prescribed formula,Yinqiao Xingzi Decoction.Following the viewpoints from the classical Chinese medical literature and after years of clinical practice,Professor Qin proposes that the onset of cutaneous pruritus is often associated with the attack of exogenous pathogens,disharmony of qi and blood,or debility due to prolonged illness.The disease primarily involves the skin,with the fundamental pathogenesis of pathogens stagnating in the muscular superficies.Clinically,the treatment is frequently conducted from the perspective of fire-heat syndrome,and the therapeutic methods of clearing heat and removing toxins,releasing muscles and dispersing pathogens from the superficies,and dispelling wind to relieve itching are utilized.The approaches aim to cool heat in the blood,expel pathogens from the muscular layer,eliminate heat for stopping itching,and extinguish wind for calming the skin.The basic prescription,Yinqiao Xingzi Decoction(composed of Lonicerae Japonicae Flos,Forsythiae Fructus,Armeniacae Semen Amarum,Arnebiae Radix,Tribuli Fructus,Dictamni Cortex,Kochiae Fructus,and Glycyrrhizae Radix et Rhizoma),is used by modification depending on the predominance of pathogenic factors of wind,heat,dryness,or dampness-toxins,and according to the various syndromes like blood-heat,yin deficiency,or qi-blood deficiency.Yinqiao Xingzi Decoction is applicable to cutaneous pruritus with the most of clinical common syndrome types,but it is unsuitable for cases caused by yang deficiency or qi stagnation with blood stasis.

ObjectiveTo explore the effect of modified Lianpoyin formula （LPYJWF） in the treatment of Helicobacter pylori （Hp）-associated gastric mucosal damage based on mitochondrial autophagy and NLRP3 inflammasome signaling pathway. MethodsA total of 60 eight-week-old Balb/c male mice were assigned via the random number table method into control， model， high-dose LPYJWF （LPYJWF-H， 27.3 g·kg^-1·d^-1）， medium-dose LPYJWF （LPYJWF-M， 13.65 g·kg^-1·d^-1）， low-dose LPYJWF （LPYJWF-L， 6.83 g·kg^-1·d^-1）， and quadruple therapy groups. Except the control group， other groups were modeled for Hp infection. Mice were administrated with LPYJWF at corresponding doses by gavage. Quadruple therapy group was given omeprazole （6.06 mg·kg^-1·d^-1） + amoxicillin （303 mg·kg^-1·d^-1） + clarithromycin （151.67 mg·kg^-1·d^-1） + colloidal pectin capsules （30.3 mg·kg^-1·d^-1） by gavage. The control group was given an equal volume of 0.9% NaCl for 14 days. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of gastric mucosa， and Warthin-Starry （W-S） silver staining was used to detect Hp colonization. Transmission electron microscopy was employed to observe the mitochondrial ultrastructure of the gastric tissue， and immunofluorescence co-localization assay was adopted to detect the expression of mitochondrial transcription factor A （TFAM） and translocase of the outer mitochondrial membrane member 20 （TOMM20）. The water-soluble tetrazolium salt method and thiobarbituric acid method were used to determine the levels of superoxide dismutase （SOD） and malondialdehyde （MDA）， respectively， in the gastric tissue. Western blot was employed to measure the protein levels of PTEN-induced kinase 1 （PINK1）， Parkin， p62， microtubule-associated protein 1 light chain 3 （LC3）， NOD-like receptor protein 3 （NLRP3）， apoptosis-associated speck-like protein containing a CARD （ASC）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18）. Real-time quantitative PCR was employed to assess the mRNA levels of PINK1， Parkin， p62， and LC3. ResultsCompared with the control group， the model group presented obvious gastric mucosal damage， colonization of a large number of Hp， severe mitochondrial damage， vacuolated structures due to excessive autophagy， reduced TOMM20 and TFAM co-expression in the gastric mucosal tissue， and reduced SOD and increased MDA （P<0.01）. In addition， the gastric tissue in the model group showed up-regulated protein and mRNA levels of PINK1， Parkin， and LC3 and down-regulated protein and mRNA levels of p62 （P<0.01， as well as increased expression of inflammasome-associated proteins NLRP3， ASC， IL-1β， and IL-18 （P<0.01）. Compared with the model group， the LPYJWF and quadruple therapy groups showed alleviated pathological damage of gastric mucosa， reduced Hp colonization， mitigated mitochondrial damage， and increased co-expression of TOMM20 and TFAM. The SOD level was elevated in the LPYJWF-L group （P<0.01）， and the MDA levels became lowered in the LPYJWF and quadruple therapy groups （P<0.05， P<0.01）. Furthermore， the LPYJWF and quadruple therapy groups showed down-regulated mRNA levels of PINK1， Parkin， and LC3 and protein levels of PINK1 and Parkin， and up-regulated mRNA level of p62 （P<0.01）. The LPYJWF-M， LPYJWF-H， and quadruple therapy groups showcased down-regulated LC3 Ⅱ/LC3 Ⅰ level （P<0.05， P<0.01） and up-regulated protein level of p62 （P<0.01）. The expression of inflammasome-associated proteins NLRP3， ASC， IL-1β， and IL-18 were reduced in the LPYJWF and quadruple therapy groups （P<0.05， P<0.01）. ConclusionLPYJWF ameliorates gastric mucosal damage and exerts mucosa-protective effects in Hp-infected mice， which may be related to the inhibition of excessive mitochondrial autophagy， thereby inhibiting the activation of the NLRP3 inflammasome pathway.

ObjectiveTo explore the effect of modified Lianpoyin formula （LPYJWF） in the treatment of Helicobacter pylori （Hp）-associated gastric mucosal damage based on mitochondrial autophagy and NLRP3 inflammasome signaling pathway. MethodsA total of 60 eight-week-old Balb/c male mice were assigned via the random number table method into control， model， high-dose LPYJWF （LPYJWF-H， 27.3 g·kg^-1·d^-1）， medium-dose LPYJWF （LPYJWF-M， 13.65 g·kg^-1·d^-1）， low-dose LPYJWF （LPYJWF-L， 6.83 g·kg^-1·d^-1）， and quadruple therapy groups. Except the control group， other groups were modeled for Hp infection. Mice were administrated with LPYJWF at corresponding doses by gavage. Quadruple therapy group was given omeprazole （6.06 mg·kg^-1·d^-1） + amoxicillin （303 mg·kg^-1·d^-1） + clarithromycin （151.67 mg·kg^-1·d^-1） + colloidal pectin capsules （30.3 mg·kg^-1·d^-1） by gavage. The control group was given an equal volume of 0.9% NaCl for 14 days. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of gastric mucosa， and Warthin-Starry （W-S） silver staining was used to detect Hp colonization. Transmission electron microscopy was employed to observe the mitochondrial ultrastructure of the gastric tissue， and immunofluorescence co-localization assay was adopted to detect the expression of mitochondrial transcription factor A （TFAM） and translocase of the outer mitochondrial membrane member 20 （TOMM20）. The water-soluble tetrazolium salt method and thiobarbituric acid method were used to determine the levels of superoxide dismutase （SOD） and malondialdehyde （MDA）， respectively， in the gastric tissue. Western blot was employed to measure the protein levels of PTEN-induced kinase 1 （PINK1）， Parkin， p62， microtubule-associated protein 1 light chain 3 （LC3）， NOD-like receptor protein 3 （NLRP3）， apoptosis-associated speck-like protein containing a CARD （ASC）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18）. Real-time quantitative PCR was employed to assess the mRNA levels of PINK1， Parkin， p62， and LC3. ResultsCompared with the control group， the model group presented obvious gastric mucosal damage， colonization of a large number of Hp， severe mitochondrial damage， vacuolated structures due to excessive autophagy， reduced TOMM20 and TFAM co-expression in the gastric mucosal tissue， and reduced SOD and increased MDA （P<0.01）. In addition， the gastric tissue in the model group showed up-regulated protein and mRNA levels of PINK1， Parkin， and LC3 and down-regulated protein and mRNA levels of p62 （P<0.01， as well as increased expression of inflammasome-associated proteins NLRP3， ASC， IL-1β， and IL-18 （P<0.01）. Compared with the model group， the LPYJWF and quadruple therapy groups showed alleviated pathological damage of gastric mucosa， reduced Hp colonization， mitigated mitochondrial damage， and increased co-expression of TOMM20 and TFAM. The SOD level was elevated in the LPYJWF-L group （P<0.01）， and the MDA levels became lowered in the LPYJWF and quadruple therapy groups （P<0.05， P<0.01）. Furthermore， the LPYJWF and quadruple therapy groups showed down-regulated mRNA levels of PINK1， Parkin， and LC3 and protein levels of PINK1 and Parkin， and up-regulated mRNA level of p62 （P<0.01）. The LPYJWF-M， LPYJWF-H， and quadruple therapy groups showcased down-regulated LC3 Ⅱ/LC3 Ⅰ level （P<0.05， P<0.01） and up-regulated protein level of p62 （P<0.01）. The expression of inflammasome-associated proteins NLRP3， ASC， IL-1β， and IL-18 were reduced in the LPYJWF and quadruple therapy groups （P<0.05， P<0.01）. ConclusionLPYJWF ameliorates gastric mucosal damage and exerts mucosa-protective effects in Hp-infected mice， which may be related to the inhibition of excessive mitochondrial autophagy， thereby inhibiting the activation of the NLRP3 inflammasome pathway.

Objective To systematically sort out the current situation of animal model construction and evaluation of damp-heat syndrome of spleen and stomach under the pattern of combining disease and evidence,references for optimizing the standardized research of this syndrome were provided.Methods The references in the past 20 years from CNKI,Wanfang,VIP,PubMed and other databases were searched to summarize and analyze the modeling ideas,evaluation systems and problems of the animal models of spleen-stomach damp-heat syndrome.Results Most of the existing models used high-fat and high-sugar feeds combined with hot and humid environment exposure,compound pathogenic microbial infection or chemical stimulation to construct the combined disease and evidence model.The model validity was evaluated by macroscopic signs,gastrointestinal function indexes,inflammatory factors,and intestinal bacterial flora,etc.However,there were still problems of insufficient stability of the model,and inconsistencies in the criteria for evaluation of the evidence.Conclusion The combination of disease and evidence model can better simulate the clinical characteristics of spleen and stomach damp-heat syndrome,but it is necessary to strengthen the construction of multimodal evaluation system and molecular mechanism research.The standardization of animal models can be promoted through the integration of multidisciplinary technology,which can provide a more accurate method for the modernization of traditional Chinese medicine research.

Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

Dampness-heat syndrome of the spleen and stomach refers to the evil dampness-heat invading the spleen and stomach,the abnormal rise and fall of the middle jiaoqi machinery,dampness-heat depression and steaming,the physiological dysfunction of the spleen and stomach,with abdominal distention and distention,nausea and lethargy of the limbs,poor loose stool,red tongue and yellow greasy fur,and slippery pulse as the main symptoms of the syndrome,most common in digestive system diseases,among which chronic gastritis is the first.This paper summarized the research results in the past decade and related fields.In the mode of combination of disease and syndrome,based on the principle of corresponding prescription and syndrome,combined with the etiology and pathogenesis evolution of spleen and stomach damp-heat syndrome,the biological connotation of spleen and stomach damp-heat syndrome was explained from various aspects such as inflammation and immune disorders,gastrointestinal motivity disorders,water and humidity loss,endoplasmic reticulum function,and micro-ecological disorders.Enrich the research of the essence of syndrome.

Dampness-heat syndrome of the spleen and stomach refers to the evil dampness-heat invading the spleen and stomach,the abnormal rise and fall of the middle jiaoqi machinery,dampness-heat depression and steaming,the physiological dysfunction of the spleen and stomach,with abdominal distention and distention,nausea and lethargy of the limbs,poor loose stool,red tongue and yellow greasy fur,and slippery pulse as the main symptoms of the syndrome,most common in digestive system diseases,among which chronic gastritis is the first.This paper summarized the research results in the past decade and related fields.In the mode of combination of disease and syndrome,based on the principle of corresponding prescription and syndrome,combined with the etiology and pathogenesis evolution of spleen and stomach damp-heat syndrome,the biological connotation of spleen and stomach damp-heat syndrome was explained from various aspects such as inflammation and immune disorders,gastrointestinal motivity disorders,water and humidity loss,endoplasmic reticulum function,and micro-ecological disorders.Enrich the research of the essence of syndrome.

Objective To systematically sort out the current situation of animal model construction and evaluation of damp-heat syndrome of spleen and stomach under the pattern of combining disease and evidence,references for optimizing the standardized research of this syndrome were provided.Methods The references in the past 20 years from CNKI,Wanfang,VIP,PubMed and other databases were searched to summarize and analyze the modeling ideas,evaluation systems and problems of the animal models of spleen-stomach damp-heat syndrome.Results Most of the existing models used high-fat and high-sugar feeds combined with hot and humid environment exposure,compound pathogenic microbial infection or chemical stimulation to construct the combined disease and evidence model.The model validity was evaluated by macroscopic signs,gastrointestinal function indexes,inflammatory factors,and intestinal bacterial flora,etc.However,there were still problems of insufficient stability of the model,and inconsistencies in the criteria for evaluation of the evidence.Conclusion The combination of disease and evidence model can better simulate the clinical characteristics of spleen and stomach damp-heat syndrome,but it is necessary to strengthen the construction of multimodal evaluation system and molecular mechanism research.The standardization of animal models can be promoted through the integration of multidisciplinary technology,which can provide a more accurate method for the modernization of traditional Chinese medicine research.

Objective To explore the relationship between serum soluble semaphorin 4D(sSema4D),CXC chemokine ligand 12(CXCL12)levels and left ventricular diastolic function in young and middle-aged patients with essential hypertension.Methods A total of 148 young and middle-aged patients with essential hyperten-sion admitted to a hospital from November 2020 to November 2022 were selected as the study subjects,and were grouped into left ventricular diastolic dysfunction group(n=41)and normal left ventricular diastolic function group(n=107)according to their left ventricular diastolic function.The serum levels of sSema4D and CXCL12 were detected by enzyme-linked immunosorbent assay.Pearson correlation analysis was applied to analyze the correlation between the serum levels of sSema4D and CXCL12 and the left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD),left ventricular septal thickness(IVST),left ventricular end-diastolic posterior wall thickness(LVPWT),left ventricular ejection fraction(LVEF),E peak/A peak(E/A)and maximum velocity of tricuspid regurgitation(TRVmax).The predictive value of ser-um sSema4D and CXCL12 levels in left ventricular diastolic dysfunction in young and middle-aged patients with essential hypertension was analyzed by receiver operating characteristic(ROC)curve.Results There were significant differences in diastolic blood pressure and gender between the left ventricular diastolic dys-function group and the left ventricular diastolic function normal group(P＜0.05).Compared with the normal left ventricular diastolic function group,serum levels of sSema4D,CXCL12 in the left ventricular diastolic dys-function group were obviously increased,and the difference was statistically significant(P＜0.05).Compared with normal left ventricular diastolic function group,IVST and LVPWT in the left ventricular diastolic dys-function group were significantly increased,and E/A was significantly decreased,with statistical significance(P＜0.05).Pearson correlation analysis showed that serum sSema4D and CXCL12 levels were positively cor-related with LVEDD,IVST and LVPWT(P＜0.05),and negatively correlated with E/A(P＜0.05).ROC curve analysis showed that the area under the curve(AUC)of serum sSema4D and CXCL12 combined in pre-dicting left ventricular diastolic dysfunction in young and middle-aged patients with essential hypertension was 0.894(95％CI:0.833-0.939),which was significantly greater than that of sSema4D alone in predicting left ventricular diastolic dysfunction in young and middle-aged patients with essential hypertension(Z=3.142,P=0.002)and CXCL12 alone predicted the AUC of left ventricular diastolic dysfunction in young and middle-aged patients with essential hypertension(Z=3.268,P=0.001).Conclusion Serum sSema4D and CXCL12 levels are associated with left ventricular diastolic function in young and middle-aged patients with essential hypertension.