Objective:To evaluate the efficacy and safety of antaitasvir phosphate 100 mg or 200 mg combined with yiqibuvir for 12 weeks in patients with various genotypes of chronic hepatitis C, without cirrhosis or compensated stage cirrhosis.Methods:Patients with chronic hepatitis C (without cirrhosis or compensated stage cirrhosis) were randomly assigned to the antaitasvir phosphate 100 mg+yiqibuvir 600 mg group (100 mg group) or the antaitasvir phosphate 200 mg+yiqibuvir 600 mg group (200 mg group) in a 1∶1 ratio. The drugs were continuously administered once a day for 12 weeks and observed for 24 weeks after drug withdrawal. The drug safety profile was assessed concurrently with the observation of the sustained virological response (SVR12) in the two patient groups 12 weeks following the drug cessation. The intention-to-treat concept was used to define as closely as possible a full analysis set, including all randomized cases who received the experimental drug at least once. The safety set was collected from all subjects who received the experimental drug at least once (regardless of whether they participated in the randomization group) in this study. All efficacy endpoints and safety profile data were summarized using descriptive statistics. The primary efficacy endpoint was SVR12. The primary analysis was performed on a full analysis set. The frequency and proportion of cases were calculated in the experimental drug group (antaitasvir phosphate capsules combined with yiqibuvir tablets) that achieved "HCV RNA

Aim To reveal the mechanism of cross-species ischemic heart failure from the perspective of spatial and gene co-expression networks.Methods GSE210374 and GSE57338 high-throughput sequencing datas were re-trieved from the national center for biotechnology information gene expression database(NCBI-GEO),and R language soft-ware packages was used to analyze and screen differentially expressed genes(DEG)in different myocardial regions of myo-cardial infarction rats,as well as DEG of myocardial samples from patients with ischemic heart failure and healthy controls,and the regional expression of common genes was analyzed.Weighted gene co-expression network analysis(WGCNA)was used to screen the genes related to myocardial infarction and to carry out enrichment analysis,protein-protein interac-tion network(PPI)was constructed to screen core genes(HG).Results A total of 4 835 differentially expressed genes were screened out in myocardial infarction rats and normal controls,and 51 differentially expressed genes were screened out in ischemic heart failure patients and normal control samples,which revealed representative gene sets in the left ventricular myocardial infarction area(I area),border area(BZ area),and remote area(R area)after myocardial in-farction.Spatial expression analysis revealed that there were 20 co-expressed genes in each myocardial region,16 of which were expressed in all three regions,the number of genes specifically expressed in I,BZ and R regions were 2,0 and 2,respectively.Enrichment analysis showed that the functions of co-expressed genes were different in different region.The I and BZ regions were related to collagen fiber assembly,stress-induced cardiomyocyte hypertrophy,down-regulation of c-Jun amino terminal kinase(JNK signal)and cell proliferation,and complement signaling pathways;The I and R regions were enriched in the binding of Wnt and collagen;As a non-ischemic distal R region,the co-expressed genes were signifi-cantly enriched in the extracellular matrix for functions such as compressive resistance,cytolysis and inhibition of T cell proliferation.Furthermore,it was worth noting that the products of co-expressed genes in the three regions were mostly lo-cated in the extracellular space and extracellular matrix,suggesting that there may be active cellular secretion and interac-tion regulation.Further PPI analysis suggested that asporin(ASPN),osteoglycin(OGN)and collagentype ⅩⅥ alpha chain(COL14A1)gene might be the core genes of the mechanism mentioned above.Conclusions The common mechanism of ischemic heart failure in rats and human involves multiple signaling pathways such as complement and coagu-lation cascade signaling and Wnt;which may be closely related to cell apoptosis mediated by extracellular matrix and exo-somes;ASPN,OGN,and COL14A1 may be the core genes.This work is expected to provide spatial and pathway refer-ence for the selection of intervention targets and pathway in the transformation research related to ischemic heart failure.

This study aimed to observe the protective effect of momordicine I, a triterpenoid compound extracted from momordica charantia L., on isoproterenol (ISO)-induced hypertrophy in rat H9c2 cardiomyocytes and investigate its potential mechanism. Treatment with 10 μM ISO induced cardiomyocyte hypertrophy as evidenced by increased cell surface area and protein content as well as pronounced upregulation of fetal genes including atrial natriuretic peptide, β-myosin heavy chain, and α-skeletal actin; however, those responses were markedly attenuated by treatment with 12.5 μg/ml momordicine I. Transcriptome experiment results showed that there were 381 and 447 differentially expressed genes expressed in comparisons of model/control and momordicine I intervention/model, respectively. GO enrichment analysis suggested that the anti-cardiomyocyte hypertrophic effect of momordicine I may be mainly associated with the regulation of metabolic processes. Based on our transcriptome experiment results as well as literature reports, we selected glycerophospholipid metabolizing enzymes group VI phospholipase A 2 (PLA2G6) and diacylglycerol kinase ζ (DGK-ζ) as targets to further explore the potential mechanism through which momordicine I inhibited ISO-induced cardiomyocyte hypertrophy.Our results demonstrated that momordicine I inhibited ISO-induced upregulations of mRNA levels and protein expressions of PLA2G6 and DGK-ζ. Collectively, momordicine I alleviated ISO-induced cardiomyocyte hypertrophy, which may be related to its inhibition of the expression of glycerophospholipid metabolizing enzymes PLA2G6 and DGK-ζ.

Objective:To explore the feasibility and value of performing a three-sided encapsulation procedure based on fascia anatomy in laparoscopic lateral lymph node dissection (LLND) for middle and low rectal cancer.Methods:This was a retrospective review. The study cohort comprised patients who met the diagnostic criteria for rectal cancer according to the Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer, had a short lymph node diameter of >5 mm on the lateral side within the 15 days before surgery, were evaluated as feasible candidates for laparoscopic total mesorectal excision+LLND surgery, had been diagnosed with low or intermediate level rectal cancer, and whose tumor was less than 8 cm away from the anal verge according to pathological examination of the operative specimen. Patients with a history of other malignant tumors of the abdomen or with incomplete follow-up data were excluded. Forty-two patients with middle and low rectal cancer who had undergone lateral lymph node dissection in diagnosis and treatment center of Gastrointestinal Cancer of Guangdong Hospital of Chinese Medicine from Jan.2018 to Dec.2022 were enrolled. There were 24 men (57.1%) and 18 women (42.9%) aged 58.4±11.8 years and the median BMI was 22.5 (19.3–24.1) kg/m 2. The main point of the three-sided encapsulation procedure is to expand the external side medial to the external iliac artery and vein, narrowing the range of exterior side dissection. The anterior-medial side is designed to expand the vesical fascia to define the range of anterior-medial side extension. The internal side is fully extended to the ureterohypogastric nerve fascia; the distal point of the caudal extension reaches the level of the Alcock canal and the bottom reaches the piriformis, enabling dissection of the obturator nerve and No.283 lymph nodes. No.263D lymph nodes are dissected by exposing the internal iliac artery and its branches, dissecting the group No.263P lymph nodes, and severing the inferior vesical artery. Finally, the lateral lymphatic tissue is completely resected. Relevant variables were recorded, including the number of lateral lymph nodes detected, the rate of lymph node metastasis, operation duration, intraoperative blood loss, postoperative complications, postoperative hospital stay, and 3-year overall survival rate. Results:Laparoscopic surgery was successfully completed in all patients with no conversions to open surgery and no intraoperative complications. Twenty-seven (64.3%) of the study patients underwent left-sided LLND, 10 (23.8%) right-sided LLND, and five (11.9%) bilateral LLND, with lymph nodes cleared on both sides. All patients' lymph nodes were examined pathologically. A median of 17.0 (11.7, 26.0) lymph nodes was detected, the median of lateral lymph nodes being 5.0 (2.0, 10.2). The median operation time was 254.5 (199.0, 325.2) minutes. The median intra-operative blood loss was 50.0 (30.0, 100.0) mL. All patients were diagnosed with adenocarcinoma by pathological examination of the operative specimen. Two patients developed postoperative intestinal obstruction, one lymphatic leakage, and one a perineal incision infection. There were no cases of anastomotic leakage. The median postoperative hospital stay was 6.0 (5.0, 7.0) days and the median follow-up time 23.5 (9.0, 36.7) months. During follow-up, three patients (7.1%) died of tumor recurrence and metastasis. Two (4.8%) experienced mild urinary dysfunction, and one (2.4%) had moderate postoperative erectile dysfunction. One patient (2.4%) was found to have prostate and lung metastases 3 month after surgery. The 3-year overall survival rate was 74.4%.Conclusions:Three sided encapsulation is a safe and feasible procedure for LLND, achieving accurate and complete clearance of lateral lymphatic tissue.

Objective:To explore the feasibility and value of performing a three-sided encapsulation procedure based on fascia anatomy in laparoscopic lateral lymph node dissection (LLND) for middle and low rectal cancer.Methods:This was a retrospective review. The study cohort comprised patients who met the diagnostic criteria for rectal cancer according to the Chinese Guidelines for the Diagnosis and Treatment of Colorectal Cancer, had a short lymph node diameter of >5 mm on the lateral side within the 15 days before surgery, were evaluated as feasible candidates for laparoscopic total mesorectal excision+LLND surgery, had been diagnosed with low or intermediate level rectal cancer, and whose tumor was less than 8 cm away from the anal verge according to pathological examination of the operative specimen. Patients with a history of other malignant tumors of the abdomen or with incomplete follow-up data were excluded. Forty-two patients with middle and low rectal cancer who had undergone lateral lymph node dissection in diagnosis and treatment center of Gastrointestinal Cancer of Guangdong Hospital of Chinese Medicine from Jan.2018 to Dec.2022 were enrolled. There were 24 men (57.1%) and 18 women (42.9%) aged 58.4±11.8 years and the median BMI was 22.5 (19.3–24.1) kg/m 2. The main point of the three-sided encapsulation procedure is to expand the external side medial to the external iliac artery and vein, narrowing the range of exterior side dissection. The anterior-medial side is designed to expand the vesical fascia to define the range of anterior-medial side extension. The internal side is fully extended to the ureterohypogastric nerve fascia; the distal point of the caudal extension reaches the level of the Alcock canal and the bottom reaches the piriformis, enabling dissection of the obturator nerve and No.283 lymph nodes. No.263D lymph nodes are dissected by exposing the internal iliac artery and its branches, dissecting the group No.263P lymph nodes, and severing the inferior vesical artery. Finally, the lateral lymphatic tissue is completely resected. Relevant variables were recorded, including the number of lateral lymph nodes detected, the rate of lymph node metastasis, operation duration, intraoperative blood loss, postoperative complications, postoperative hospital stay, and 3-year overall survival rate. Results:Laparoscopic surgery was successfully completed in all patients with no conversions to open surgery and no intraoperative complications. Twenty-seven (64.3%) of the study patients underwent left-sided LLND, 10 (23.8%) right-sided LLND, and five (11.9%) bilateral LLND, with lymph nodes cleared on both sides. All patients' lymph nodes were examined pathologically. A median of 17.0 (11.7, 26.0) lymph nodes was detected, the median of lateral lymph nodes being 5.0 (2.0, 10.2). The median operation time was 254.5 (199.0, 325.2) minutes. The median intra-operative blood loss was 50.0 (30.0, 100.0) mL. All patients were diagnosed with adenocarcinoma by pathological examination of the operative specimen. Two patients developed postoperative intestinal obstruction, one lymphatic leakage, and one a perineal incision infection. There were no cases of anastomotic leakage. The median postoperative hospital stay was 6.0 (5.0, 7.0) days and the median follow-up time 23.5 (9.0, 36.7) months. During follow-up, three patients (7.1%) died of tumor recurrence and metastasis. Two (4.8%) experienced mild urinary dysfunction, and one (2.4%) had moderate postoperative erectile dysfunction. One patient (2.4%) was found to have prostate and lung metastases 3 month after surgery. The 3-year overall survival rate was 74.4%.Conclusions:Three sided encapsulation is a safe and feasible procedure for LLND, achieving accurate and complete clearance of lateral lymphatic tissue.

To explore the potential mechanism of frankincense volatile oil in the prevention and treatment of cardiac hypertrophy based on in vitro cell experiment and network pharmacology. METHODS: The anti-hypertrophic effect of frankincense volatile oil was investigated by isoproterenol induced H9c2 cardiomyocytes hypertrophy model. The active chemical components and targets of frankincense volatile oil and targets associated with cardiac hypertrophy were obtained by CNKI, Pubmed, Pubchem databases, etc. String database and Cytoscape 3.8.0 software were used to construct protein-protein interaction network (PPI) and a network of "drug-active component-key target-disease" of frankincense volatile oil in order to screen the key targets of frankincense volatile oil against cardiac hypertrophy. The fluorescent quantitative PCR experiments were performed to verify those key targets. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation analysis of key target genes were performed using David online analysis tool. RESULTS: In vitro cell experiments showed that frankincense volatile oil significantly inhibited the isoproterenol induced increases in cardiomyocytes surface area and protein synthesis, and upregulations of ANP and β-MHC mRNA. A total of 87 active components and 36 ingredient-disease targets of frankincense volatile oil were screened. Network analysis showed that ESR1, NOS3, PTGS2, TNF, MAPK14, and PPARG were key targets. Fluorescence quantitative PCR experiments results indicated that frankincense volatile oil inhibited isoproterenol induced upregulations of ESR1, PTGS2, TNF, and MAPK14 mRNA levels, and downregulations of NOS3, PPARG mRNA levels, respectively. In addition, the GO functional enrichment analysis showed that its biological pathways mainly included lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, enzyme binding, etc. The KEGG pathway enrichment analysis included 22 KEGG pathways, which were closely related to VEGF signaling pathway, TNF signaling pathway, sphingolipid signaling pathway and others. CONCLUSION: The active components of frankincense volatile oil may regulate VEGF signaling pathway, TNF signaling pathway, Sphingolipid signaling pathway by acting on ESR1, NOS3, PTGS2, TNF, MAPK14 and PPARG targets, thereby affecting the regulation of lipopolysaccharide-mediated signaling pathway, positive regulation of nitric oxide biosynthetic process, caveola, and enzyme binding, and improving cardiac hypertrophy.

AIM: To investigate the effect of oxypeucedanin (OPD) on doxorubicin resistance in human breast cancer MCF-7/DOX cells and its possible mechanism. METHODS: MCF-7/DOX cells were cultured in vitro, MTT assay was used to detect the effect of OPD on the survival of MCF-7/DOX cells, and the effect of OPD combined with different concentrations of doxorubicin on the proliferation of MCF-7/DOX cells were investigated. The effect of OPD combined with doxorubicin on the expression of genes including MDR1, MRP1, AGPAT2, CHKA, CEPT1, DGKA, PCYT1A, PLA2G15 in MCF-7/DOX cells was measured by qRT-PCR. The effect of OPD combined with doxorubicin on the protein expression of MDR1, MRP1, CHKA and CCTα in MCF-7/DOX cells was determined by Western blot. RESULTS: The IC

Objective:To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers.Methods:A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software.Results:(1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C max and AUC 0-tau geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C max GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C max GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC 0-t GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C max and AUC 0-t were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C max and AUC 0-72 GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion:Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.

Objective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.

Objective To explore the prognosis related genes of pancreatic ductal adenocarcinoma (PDAC)and investigate the molecular regulation mechanism.Methods Gene expression data of 102 PDAC patients with complete clinical survival data were selected from gene expression database of National Center for Biotechnology Information.The 106 transcription regulation gene collection was collected from Transfac database.The 715 microRNA (miRNA)target regulation gene collection was selected according to PicTar and TargetScanS method.Biological pathway data obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG).The known cancer genes were collected from the cancer gene census (CGC) database.Univariate Cox proportional hazards model was used to analyze the correlation between gene expression data and survival time,then obtained survival related candidate genes from the whole genome. Then the enriched genes were analyzed by hypergeometric distribution algorithm from three databases. Multiple correction testing was performed by BH-FDR method (FDR < 0.05 ).Kaplan-Meier was performed for survival curve analysis of PDAC.Results The results of data of 102 PDAC patients analyzed by univariate Cox proportional hazards model indicated that 273 genes were significantly related to the survival time of patients (P <0.000 1 ).After 273 survival genes were enrichment analyzed in 106 transcription factor regulation gene collection,12 survival genes enriched transcription factor target gene sets were found.After 273 survival genes were enrichment analyzed in 715 miRNA target regulation gene collection,11 survival genes enriched miRNAs target sets were discovered.After 273 survival genes were enrichment analyzed in pathway data of KEGG,15 survival genes enriched pathways were obtained. Period circadian clock 2 (PER2 )was regulated by CCAAT/enhancer binding protein (CEBPA)at transcription level and regulated by miRNA-32 after transcription.The prognosis of PDAC was affected by circadian rhythm pathway.The 102 patients with PDAC were ranked according to the expression of PER2 from high to low,the first 51 cases were included in PER2 higher expression group and the left were included in PER2 lower expression group.Kaplan-Meier survival analysis indicated that PER2 was significantly correlated with prognosis of PDAC (P <0.01 ).Conclusion CEBPA/miRNA-32/PER2 and its related circadian clock pathway may be the target pathway in interfering the development of PDAC,and is correlated with the prognosis of PDAC.