Along with more research into the mechanisms of pulmonary fibrosis,anti-pulmonary fibrosis drugs under development are becoming diversified.Over the past decade,multiple phase Ⅱ/Ⅲ clinical trials have been terminated due to insufficient efficacy,with seven single-target monoclonal anti-body drugs failing to meet expectations.In contrast,multi-target drugs such as nintedanib and pirfeni-done have been successfully marketed,demonstrating favorable clinical outcomes.However,drugs directly targeting transforming growth factor-β have raised safety concerns.Ongoing phase Ⅲ candi-dates,such as lysophosphatidic acid receptor 1 antagonists and phosphodiesterase 4B inhibitors,do not directly intervene in the transforming growth factor-β signaling pathway.Given the potential limita-tions of single-target drugs,future drug development is expected to prioritize multi-target and multi-cell strategies while exploring synergistic multi-drug therapies.This article reviews the current clinical trials for anti-pulmonary fibrosis drugs worldwide and the challenges they face in order to provide references for the research and development of new anti-pulmonary fibrosis drugs.

Objective To observe the value of intratumoral and peritumoral radiomics based on dynamic contrast-enhanced MRI(DCE-MRI)combined with clinical indexes for predicting Ki-67 expression of prostate cancer(PCa).Methods Totally 294 PCa patients were retrospectively enrolled and randomly divided into training set(n=205)and test(n=89)set at a ratio of 7∶3,who were stratified into low-expression subgroup(Ki-67≤10%)and high-expression subgroup(Ki-67＞10%)based on pathological findings.ROIintratumoral and ROIperitumoral were delineated on DCE-MRI,and radiomics features were extracted from ROIintratumora,l ROIperitumoral and ROIintratumoral+peritumora,l respectively.Radiomic features significantly associated with Ki-67 expression status were selected to construct radiomics models.A multivariate logistic regression analysis was performed to develop a clinical predicting model,then a combined model was established combined with the optimal radiomics model.Receiver operating characteristic(ROC)curves were plotted,and the area under the curve(AUC)were calculate to evaluate the predictive efficacy of the models and compared between each two models.Decision curve analysis(DCA)was used to assess the clinical net benefit of each model.Results The AUC of modelintratumora,l modelperitumoral and modelintratumoral+peritumoral for predicting Ki-67 expression in training set was 0.905,0.867 and 0.930,and the last one was the best.In clinical model,total prostate-specific antigen(t-PSA)and T stage≥3 were both independent predictors of high Ki-67 expression of PCa(both P＜0.05).The AUC of combined model based on modelintratumoral+peritumoral and clinical model was 0.911 in test set,being not significantly different with that of modelintratumoral+peritumoral(AUC=0.906;Z=0.349,P=0.727)but higher than that of clinical model(AUC=0.684;Z=4.370,P＜0.05).DCA revealed that the combined model provided higher clinical net benefit than clinical model and modelintratumoral+peritumoral across risk thresholds of 0.10-0.70.Conclusion DCE-MRI intratumoral+peritumoral radiomics model could effectively predict Ki-67 expression status of PCa.Combining with clinical indexes could further enhance its clinical net benefit.

Objective To observe the value of intratumoral and peritumoral radiomics based on dynamic contrast-enhanced MRI(DCE-MRI)combined with clinical indexes for predicting Ki-67 expression of prostate cancer(PCa).Methods Totally 294 PCa patients were retrospectively enrolled and randomly divided into training set(n=205)and test(n=89)set at a ratio of 7∶3,who were stratified into low-expression subgroup(Ki-67≤10%)and high-expression subgroup(Ki-67＞10%)based on pathological findings.ROIintratumoral and ROIperitumoral were delineated on DCE-MRI,and radiomics features were extracted from ROIintratumora,l ROIperitumoral and ROIintratumoral+peritumora,l respectively.Radiomic features significantly associated with Ki-67 expression status were selected to construct radiomics models.A multivariate logistic regression analysis was performed to develop a clinical predicting model,then a combined model was established combined with the optimal radiomics model.Receiver operating characteristic(ROC)curves were plotted,and the area under the curve(AUC)were calculate to evaluate the predictive efficacy of the models and compared between each two models.Decision curve analysis(DCA)was used to assess the clinical net benefit of each model.Results The AUC of modelintratumora,l modelperitumoral and modelintratumoral+peritumoral for predicting Ki-67 expression in training set was 0.905,0.867 and 0.930,and the last one was the best.In clinical model,total prostate-specific antigen(t-PSA)and T stage≥3 were both independent predictors of high Ki-67 expression of PCa(both P＜0.05).The AUC of combined model based on modelintratumoral+peritumoral and clinical model was 0.911 in test set,being not significantly different with that of modelintratumoral+peritumoral(AUC=0.906;Z=0.349,P=0.727)but higher than that of clinical model(AUC=0.684;Z=4.370,P＜0.05).DCA revealed that the combined model provided higher clinical net benefit than clinical model and modelintratumoral+peritumoral across risk thresholds of 0.10-0.70.Conclusion DCE-MRI intratumoral+peritumoral radiomics model could effectively predict Ki-67 expression status of PCa.Combining with clinical indexes could further enhance its clinical net benefit.

Along with more research into the mechanisms of pulmonary fibrosis,anti-pulmonary fibrosis drugs under development are becoming diversified.Over the past decade,multiple phase Ⅱ/Ⅲ clinical trials have been terminated due to insufficient efficacy,with seven single-target monoclonal anti-body drugs failing to meet expectations.In contrast,multi-target drugs such as nintedanib and pirfeni-done have been successfully marketed,demonstrating favorable clinical outcomes.However,drugs directly targeting transforming growth factor-β have raised safety concerns.Ongoing phase Ⅲ candi-dates,such as lysophosphatidic acid receptor 1 antagonists and phosphodiesterase 4B inhibitors,do not directly intervene in the transforming growth factor-β signaling pathway.Given the potential limita-tions of single-target drugs,future drug development is expected to prioritize multi-target and multi-cell strategies while exploring synergistic multi-drug therapies.This article reviews the current clinical trials for anti-pulmonary fibrosis drugs worldwide and the challenges they face in order to provide references for the research and development of new anti-pulmonary fibrosis drugs.

Objective To investigate the effect of type 2 dengue virus(DENV-2)infection on autophagy in human umbilical vein endothelial cells(HUVECs)and the mechanism mediating the inhibitory effect of baicalin against DENV-2 infection.Methods Cultured HUVECs with DENV-2 infection were treated with different concentrations of baicalin,and the changes in autophagy of the cells were detected using transmission electron microscopy.Lyso Tracker Red staining was used to examine pH changes in the lysosomes of the cells,and the expressions of ATG5,beclin-1,LC3,P62,STX17,SNAP29,VAMP8,and PI3K/AKT signaling pathway-related proteins were detected by Western blotting.DENV-2 replication in the cells were evaluated using RT-qPCR.The differentially expressed proteins in DENV-2-infected HUVECs were identified by proteomics screening.Results Treatment with baicalin did not significantly affect the viability of cultured HUVECs.Proteomic studies suggested that the PI3K-AKT pathway played an important role in mediating cell injury induced by DENV-2 infection.The results of RT-qPCR demonstrated that baicalin dose-dependently inhibited DENV-2 replication in HUVECs and produced the strongest inhibitory effect at the concentration of 50 μg/mL.Transmission electron microscopy,Lyso Tracker Red staining,RT-qPCR,and Western blotting all showed significant inhibitory effect of baicalin on DENV-2-induced autophagy in HUVECs.DENV-2 infection of HUVECs caused increased cellular expressions of LC3 and P62 proteins,which were significantly lowered by treatment with LY294002(a PI3K inhibitor).Conclusion Baicalin inhibits DENV-2 replication in HUVECs and suppresses DENV-2-induced cell autophagy by inhibiting the PI3K/AKT signaling pathway.

Objective To investigate the effect of type 2 dengue virus(DENV-2)infection on autophagy in human umbilical vein endothelial cells(HUVECs)and the mechanism mediating the inhibitory effect of baicalin against DENV-2 infection.Methods Cultured HUVECs with DENV-2 infection were treated with different concentrations of baicalin,and the changes in autophagy of the cells were detected using transmission electron microscopy.Lyso Tracker Red staining was used to examine pH changes in the lysosomes of the cells,and the expressions of ATG5,beclin-1,LC3,P62,STX17,SNAP29,VAMP8,and PI3K/AKT signaling pathway-related proteins were detected by Western blotting.DENV-2 replication in the cells were evaluated using RT-qPCR.The differentially expressed proteins in DENV-2-infected HUVECs were identified by proteomics screening.Results Treatment with baicalin did not significantly affect the viability of cultured HUVECs.Proteomic studies suggested that the PI3K-AKT pathway played an important role in mediating cell injury induced by DENV-2 infection.The results of RT-qPCR demonstrated that baicalin dose-dependently inhibited DENV-2 replication in HUVECs and produced the strongest inhibitory effect at the concentration of 50 μg/mL.Transmission electron microscopy,Lyso Tracker Red staining,RT-qPCR,and Western blotting all showed significant inhibitory effect of baicalin on DENV-2-induced autophagy in HUVECs.DENV-2 infection of HUVECs caused increased cellular expressions of LC3 and P62 proteins,which were significantly lowered by treatment with LY294002(a PI3K inhibitor).Conclusion Baicalin inhibits DENV-2 replication in HUVECs and suppresses DENV-2-induced cell autophagy by inhibiting the PI3K/AKT signaling pathway.

Objective:To investigate the relationship between histone deacetylase (HDAC) gene polymorphism and type 2 diabetes mellitus (T2DM) in Bai and Han populations in Dali of Yunnan province.Methods:A total of 148 patients with T2DM of Bai and Han nationalities who received treatment in Dali Bai Autonomous Prefecture People's Hospital from May 2019 to March 2021 were included in the T2DM group. An additional 100 healthy controls of Bai and Han nationalities who concurrently received physical examination in the same hospital from May 2019 to December 2020 were included in the normal control group. The susceptibility genes of T2DM were detected using the Taqman MGB probe method. The susceptibility gene loci were amplified using polymerase chain reaction. The whole sequence of susceptibility gene was sequenced.Results:There were no significant differences in the distribution frequencies of rs2530223 genotype, rs11741808 genotype, rs2547547 genotype, and rs1741981 genotype between Bai and Han populations (all P > 0.05). There was a significant difference in blood lipid level between four loci ( t = -1.06, -0.19, 0.39, -2.12, -2.04, 0.16, 1.47, < 0.01, -0.16, -3.17, -2.93, 0.69, -2.58, -2.33, all P < 0.05). There was a significant difference in homeostasis model assessment of insulin resistance between different states (all P < 0.05). The frequency distributions of each genotype and each allele did not differ significantly between healthy control people of Bai nationality and T2DM patients of Bai nationality and between healthy control people of Han nationality and T2DM patients of Han nationality (all P > 0.05). Logistic regression analysis showed that the polymorphism was not an independent risk factor for T2DM. Conclusion:The relationships between HDAC gene polymorphism and T2DM, obesity and dyslipidemia differ between Bai and Han populations.

【Objective】 To establish a co-expression lncRNA-mRNA ceRNA network and explore the potential molecular mechanism of lncRNA in dengue fever. 【Methods】 DENV-2-infected and normal pHUVEC were sequenced and screened for differentially expressed lncRNA and mRNA by gene microarray technology. Differentially expressed mRNA was analyzed by protein-protein interaction (PPI), and significantly related co-expressed lncRNA-mRNA was screened by Pearson’s correlation coefficient. The microRNA (miRNA) that bound to co-expressed lncRNA-mRNA was predicted by the database. The ceRNA network of co-expressed lncRNA-mRNA was constructed by Cytoscape software. Finally differentially expressed mRNAs and co-expressed lncRNA-mRNA were analyzed by GO and KEGG enrichment, and co-expressed lncRNA-mRNA was verified by RT-qPCR. 【Results】 At 48 h and 72 h after infection, 105 and 51 differentially expressed mRNAs were obtained, respectively, while 59 and 29 differentially expressed lncRNAs were obtained, respectively. Furthermore, at the two time intervals, there were 10 differential mRNAs and 5 differential lncRNAs, respectively. PPI analysis of differential mRNAs showed that isocratic values of interleukin 6 (IL6), interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), and 2’-5’-oligoadenylate synthetase 2 (OAS2) were relatively high. The pairing results of lncRNA-mRNA co-expression analysis with the highest correlation coefficients at 48 h and 72 h after infection were XLOC_001966-SMTNL1 and XLOC_001966-ESR2, respectively. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the functions of differentially expressed mRNA and co-expressed lncRNA-mRNA were mainly involved in virus epidemic prevention response, immune response, and signal transduction, as well as the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, type I interferon, and cytokine receptor interaction. RT-qPCR revealed that lncRNA XLOC-I2-8991 was upregulated in the co-expressed lncRNA-mRNA, whereas all the other lncRNA and mRNA were downregulated. 【Conclusion】 This study initially revealed the potential lncRNA-mRNA co-expression network during dengue virus infection, and found that co-expressed lncRNA-mRNA was mainly enriched in the immune regulation and signal transduction pathways during virus infection. The findings will help further exploration into the infection mechanism of DENV-2.

Objective: To explore the role of miR-30b in the trigeminal ganglion( TG) of trigeminal neuralgia( TN) model rats. Methods: An infraorbital nerve-chronic constriction injury( ION-CCI) model of TN was produced in the rat. Von Frey hair was used to determine the time-course of changes in mechanical pain threshold.qRT-PCR and Western blot were used to detect the expression of miR-30b and activating transcription factor 3( ATF3) in the TG. In addition,miR-30b agomir and agomir NC were injected into ION-CCI rats by the infraorbital foramen injection. The mechanical pain threshold and the expression changes of ATF3 were determined after intervention. Results: Compared with the sham-operated group,the ION-CCI group had a decreased mechanical pain threshold 2 days after surgery,reached the lowest observed level by day 12,and this threshold reduction lasted more than 28 days( P<0. 05). Compared with the sham-operated group,the ION-CCI group had a lower miR-30b expression and a higher ATF3 expression in postoperative TG( P<0. 05). After the overexpression of miR-30b in ION-CCI group,the mechanical pain threshold increased,and the expression of ATF3 decreased in TG( P<0. 05). Conclusion These results suggest that miR-30b may participate in the regulation of TN. miR-30b may be a potential therapeutic target for TN.

Objective:To investigate the epidemiological characteristics, diagnosis, treat-ment and prognosis of gallbladder cancer in China from 2010 to 2017.Methods:The single disease retrospective registration cohort study was conducted. Based on the concept of the real world study, the clinicopathological data, from multicenter retrospective clinical data database of gallbladder cancer of Chinese Research Group of Gallbladder Cancer (CRGGC), of 6 159 patients with gallbladder cancer who were admitted to 42 hospitals from January 2010 to December 2017 were collected. Observation indicators: (1) case resources; (2) age and sex distribution; (3) diagnosis; (4) surgical treatment and prognosis; (5) multimodality therapy and prognosis. The follow-up data of the 42 hospitals were collected and analyzed by the CRGGC. The main outcome indicator was the overall survival time from date of operation for surgical patients or date of diagnosis for non-surgical patients to the end of outcome event or the last follow-up. Measurement data with normal distribu-tion were represented as Mean±SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(range), and com-parison between groups was conducted using the U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Univariate analysis was performed using the Logistic forced regression model, and variables with P<0.1 in the univariate analysis were included for multivariate analysis. Multivariate analysis was performed using the Logistic stepwise regression model. The life table method was used to calculate survival rates and the Kaplan-Meier method was used to draw survival curves. Log-rank test was used for survival analysis. Results:(1) Case resources: of the 42 hospitals, there were 35 class A of tertiary hospitals and 7 class B of tertiary hospitals, 16 hospitals with high admission of gallbladder cancer and 26 hospitals with low admission of gallbladder cancer, respectively. Geographical distribution of the 42 hospitals: there were 9 hospitals in central China, 5 hospitals in northeast China, 22 hospitals in eastern China and 6 hospitals in western China. Geographical distribution of the 6 159 patients: there were 2 154 cases(34.973%) from central China, 705 cases(11.447%) from northeast China, 1 969 cases(31.969%) from eastern China and 1 331 cases(21.611%) from western China. The total average number of cases undergoing diagnosis and treatment in hospitals of the 6 159 patients was 18.3±4.5 per year, in which the average number of cases undergoing diagnosis and treatment in hospitals of 4 974 patients(80.760%) from hospitals with high admission of gallbladder cancer was 38.8±8.9 per year and the average number of cases undergoing diagnosis and treatment in hospitals of 1 185 patients(19.240%) from hospitals with low admission of gallbladder cancer was 5.7±1.9 per year. (2) Age and sex distribution: the age of 6 159 patients diagnosed as gallbladder cancer was 64(56,71) years, in which the age of 2 247 male patients(36.483%) diagnosed as gallbladder cancer was 64(58,71)years and the age of 3 912 female patients(63.517%) diagnosed as gallbladder cancer was 63(55,71)years. The sex ratio of female to male was 1.74:1. Of 6 159 patients, 3 886 cases(63.095%) were diagnosed as gallbladder cancer at 56 to 75 years old. There was a significant difference on age at diagnosis between male and female patients ( Z=-3.99, P<0.001). (3) Diagnosis: of 6 159 patients, 2 503 cases(40.640%) were initially diagnosed as gallbladder cancer and 3 656 cases(59.360%) were initially diagnosed as non-gallbladder cancer. There were 2 110 patients(34.259%) not undergoing surgical treatment, of which 200 cases(9.479%) were initially diagnosed as gallbladder cancer and 1 910 cases(90.521%) were initially diagnosed as non-gallbladder cancer. There were 4 049 patients(65.741%) undergoing surgical treatment, of which 2 303 cases(56.878%) were initially diagnosed as gallbladder cancer and 1 746 cases(43.122%) were initial diagnosed as non-gallbladder cancer. Of the 1 746 patients who were initially diagnosed as non-gallbladder cancer, there were 774 cases(19.116%) diagnosed as gallbladder cancer during operation and 972 cases(24.006%) diagnosed as gallbladder cancer after operation. Of 6 159 patients, there were 2 521 cases(40.932%), 2 335 cases(37.912%) and 1 114 cases(18.087%) undergoing ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) examination before initial diagnosis, respec-tively, and there were 3 259 cases(52.914%), 3 172 cases(51.502%) and 4 016 cases(65.205%) undergoing serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis, respectively. One patient may underwent multiple examinations. Results of univariate analysis showed that geographical distribution of hospitals (eastern China or western China), age ≥72 years, gallbladder cancer annual admission of hospitals, whether undergoing ultrasound, CT, MRI, serum carcinoembryonic antigen, CA19-9 or CA125 examination before initially diagnosis were related factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.45, 1.98, 0.69, 0.68, 2.43, 0.41, 1.63, 0.41, 0.39, 0.42, 95% confidence interval as 1.21-1.74, 1.64-2.40, 0.59-0.80, 0.60-0.78, 2.19-2.70, 0.37-0.45, 1.43-1.86, 0.37-0.45, 0.35-0.43, 0.38-0.47, P<0.05). Results of multivariate analysis showed that geographical distribution of hospitals (eastern China or western China), sex, age ≥72 years, gallbladder cancer annual admission of hospitals and cases undergoing ultrasound, CT, serum CA19-9 examination before initially diagnosis were indepen-dent influencing factors influencing initial diagnosis of gallbladder cancer patients ( odds ratio=1.36, 1.42, 0.89, 0.67, 1.85, 1.56, 1.57, 0.39, 95% confidence interval as 1.13-1.64, 1.16-1.73, 0.79-0.99, 0.57-0.78, 1.60-2.14, 1.38-1.77, 1.38-1.79, 0.35-0.43, P<0.05). (4) Surgical treatment and prognosis. Of the 4 049 patients undergoing surgical treatment, there were 2 447 cases(60.435%) with complete pathological staging data and follow-up data. Cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb were 85(3.474%), 201(8.214%), 71(2.902%), 890(36.371%), 382(15.611%), 33(1.348%) and 785(32.080%), respectively. The median follow-up time and median postoperative overall survival time of the 2 447 cases were 55.75 months (95% confidence interval as 52.78-58.35) and 23.46 months (95% confidence interval as 21.23-25.71), respectively. There was a significant difference in the overall survival between cases with pathological staging as stage 0, stage Ⅰ, stage Ⅱ, stage Ⅲa, stage Ⅲb, stage Ⅳa and stage Ⅳb ( χ2=512.47, P<0.001). Of the 4 049 patients undergoing surgical treatment, there were 2 988 cases(73.796%) with resectable tumor, 177 cases(4.371%) with unresectable tumor and 884 cases(21.833%) with tumor unassessable for resectabi-lity. Of the 2 988 cases with resectable tumor, there were 2 036 cases(68.139%) undergoing radical resection, 504 cases(16.867%) undergoing non-radical resection and 448 cases(14.994%) with operation unassessable for curative effect. Of the 2 447 cases with complete pathological staging data and follow-up data who underwent surgical treatment, there were 53 cases(2.166%) with unresectable tumor, 300 cases(12.260%) with resectable tumor and receiving non-radical resection, 1 441 cases(58.888%) with resectable tumor and receiving radical resection, 653 cases(26.686%) with resectable tumor and receiving operation unassessable for curative effect. There were 733 cases not undergoing surgical treatment with complete pathological staging data and follow-up data. There was a significant difference in the overall survival between cases not undergoing surgical treatment, cases undergoing surgical treatment for unresectable tumor, cases undergoing non-radical resection for resectable tumor and cases undergoing radical resection for resectable tumor ( χ2=121.04, P<0.001). (5) Multimodality therapy and prognosis: of 6 159 patients, there were 541 cases(8.784%) under-going postoperative adjuvant chemotherapy and advanced chemotherapy, 76 cases(1.234%) under-going radiotherapy. There were 1 170 advanced gallbladder cancer (pathological staging ≥stage Ⅲa) patients undergoing radical resection, including 126 cases(10.769%) with post-operative adjuvant chemotherapy and 1 044 cases(89.231%) without postoperative adjuvant chemo-therapy. There was no significant difference in the overall survival between cases with post-operative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.23, P=0.629). There were 658 patients with pathological staging as stage Ⅲa who underwent radical resection, including 66 cases(10.030%) with postoperative adjuvant chemotherapy and 592 cases(89.970%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemotherapy and cases without postoperative adjuvant chemotherapy ( χ2=0.05, P=0.817). There were 512 patients with pathological staging ≥stage Ⅲb who underwent radical resection, including 60 cases(11.719%) with postoperative adjuvant chemotherapy and 452 cases(88.281%) without postoperative adjuvant chemotherapy. There was no significant difference in the overall survival between cases with postoperative adjuvant chemo-therapy and cases without post-operative adjuvant chemo-therapy ( χ2=1.50, P=0.220). Conclusions:There are more women than men with gallbladder cancer in China and more than half of patients are diagnosed at the age of 56 to 75 years. Cases undergoing ultrasound, CT, serum CA19-9 examination before initial diagnosis are independent influencing factors influencing initial diagnosis of gallbladder cancer patients. Preoperative resectability evaluation can improve the therapy strategy and patient prognosis. Adjuvant chemotherapy for gallbladder cancer is not standardized and in low proportion in China.