Background and Aims:Currently,the treatment of hepatocellular carcinoma(HCC)faces significant challenges due to recurrence and metastasis,with tumor immune evasion being one of the key mechanisms underlying these issues.Signal transducer and activator of transcription 3(STAT3),an important transcription factor,is overactivated in many malignancies and is involved in both tumorigenesis and progression,closely associated with immune evasion.Programmed cell death ligand 1(PD-L1),a key immune checkpoint,helps tumor cells evade immune surveillance when its expression is upregulated,thereby suppressing anti-tumor immunity.Studies have shown that STAT3 may activate the MYC signaling pathway through interaction with DNA-activated protein kinase(PRKDC),thereby promoting PD-L1 expression and inducing immune evasion.However,the specific mechanism of the STAT3/PRKDC/MYC axis in HCC remains unclear.This study aims to elucidate the molecular mechanism by which STAT3 regulates PD-L1 expression through the PRKDC/MYC signaling pathway,potentially inducing immune evasion in HCC,with the goal of providing potential targets for HCC immunotherapy.Methods:The expressions of STAT3 in human normal liver cells(HL-7702)and human HCC cells(HuH-7,HepG2)were detected by qRT-PCR and Western blot.Plasmids with STAT3 knockdown(si-STAT3)and PRKDC overexpression(oe-PRKDC),along with their respective negative controls(si-NC,oe-NC),were constructed and transfected into HCC cells(HuH-7)according to the experimental design,with untreated HuH-7 cells as the blank control.Western blot was used to analyze the expression of STAT3,PRKDC,PD-L1,and MYC pathway-related proteins.Cell proliferation,invasion,migration,and apoptosis of HCC cells were assessed by CCK-8,Transwell,wound healing assay,and flow cytometry.After co-culturing HuH-7 cells with human peripheral blood mononuclear cells(hPBMCs),ELISA was used to detect the secretion of the immune regulatory factor interferon γ(IFN-γ).Co-immunoprecipitation and immunofluorescence co-localization were performed to verify the interaction between STAT3 and PRKDC proteins.Results:Results of qRT-PCR and Western blot showed that the mRNA and protein levels of STAT3 were significantly elevated in HCC cells(both P＜0.05).Functional experiments demonstrated that in the si-STAT3 group,HCC cell proliferation,migration,and invasion were significantly weakened,and cell apoptosis was notably increased;the expression of PD-L1 and MYC pathway-related proteins was significantly downregulated;the secretion of IFN-γ was significantly increased after co-culturing with hPBMCs(all P＜0.05).After co-culturing with oe-PRKDC plasmids,the effects of STAT3 knockdown on HCC cells were significantly reversed(all P＜0.05).Scansite 4.0 database analysis revealed that STAT3 and PRKDC have binding sites,and co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between STAT3 and PRKDC proteins.Conclusion:STAT3 is highly expressed in HCC cells and can promote HCC cell proliferation,migration,invasion,and immune evasion through interaction with PRKDC,suppress cell apoptosis,activate the MYC pathway,and increase PD-L1 expression.The STAT3/PRKDC/MYC axis may serve as a potential target for HCC immunotherapy.

Background and Aims:Currently,the treatment of hepatocellular carcinoma(HCC)faces significant challenges due to recurrence and metastasis,with tumor immune evasion being one of the key mechanisms underlying these issues.Signal transducer and activator of transcription 3(STAT3),an important transcription factor,is overactivated in many malignancies and is involved in both tumorigenesis and progression,closely associated with immune evasion.Programmed cell death ligand 1(PD-L1),a key immune checkpoint,helps tumor cells evade immune surveillance when its expression is upregulated,thereby suppressing anti-tumor immunity.Studies have shown that STAT3 may activate the MYC signaling pathway through interaction with DNA-activated protein kinase(PRKDC),thereby promoting PD-L1 expression and inducing immune evasion.However,the specific mechanism of the STAT3/PRKDC/MYC axis in HCC remains unclear.This study aims to elucidate the molecular mechanism by which STAT3 regulates PD-L1 expression through the PRKDC/MYC signaling pathway,potentially inducing immune evasion in HCC,with the goal of providing potential targets for HCC immunotherapy.Methods:The expressions of STAT3 in human normal liver cells(HL-7702)and human HCC cells(HuH-7,HepG2)were detected by qRT-PCR and Western blot.Plasmids with STAT3 knockdown(si-STAT3)and PRKDC overexpression(oe-PRKDC),along with their respective negative controls(si-NC,oe-NC),were constructed and transfected into HCC cells(HuH-7)according to the experimental design,with untreated HuH-7 cells as the blank control.Western blot was used to analyze the expression of STAT3,PRKDC,PD-L1,and MYC pathway-related proteins.Cell proliferation,invasion,migration,and apoptosis of HCC cells were assessed by CCK-8,Transwell,wound healing assay,and flow cytometry.After co-culturing HuH-7 cells with human peripheral blood mononuclear cells(hPBMCs),ELISA was used to detect the secretion of the immune regulatory factor interferon γ(IFN-γ).Co-immunoprecipitation and immunofluorescence co-localization were performed to verify the interaction between STAT3 and PRKDC proteins.Results:Results of qRT-PCR and Western blot showed that the mRNA and protein levels of STAT3 were significantly elevated in HCC cells(both P＜0.05).Functional experiments demonstrated that in the si-STAT3 group,HCC cell proliferation,migration,and invasion were significantly weakened,and cell apoptosis was notably increased;the expression of PD-L1 and MYC pathway-related proteins was significantly downregulated;the secretion of IFN-γ was significantly increased after co-culturing with hPBMCs(all P＜0.05).After co-culturing with oe-PRKDC plasmids,the effects of STAT3 knockdown on HCC cells were significantly reversed(all P＜0.05).Scansite 4.0 database analysis revealed that STAT3 and PRKDC have binding sites,and co-immunoprecipitation and immunofluorescence co-localization experiments confirmed the interaction between STAT3 and PRKDC proteins.Conclusion:STAT3 is highly expressed in HCC cells and can promote HCC cell proliferation,migration,invasion,and immune evasion through interaction with PRKDC,suppress cell apoptosis,activate the MYC pathway,and increase PD-L1 expression.The STAT3/PRKDC/MYC axis may serve as a potential target for HCC immunotherapy.

Objective:To retrieve, screen, evaluate and synthesize evidence related to the management of pregnant women during pregnancy after cervical cerclage to provide a basis for clinical practice.Methods:According to the "6S" evidence resource pyramid model, the system searched of all evidence on the management of pregnant women after cervical cerclage in databases suchas UpTo Date, BMJ Best Clinical Practice, International Guidelines Network, American Guidelines Network, World Health Organization website, Yimaitong, Metz Medical website, Clinical Guidelines website, American College of Obstetricians and Gynaecologists, Royal College of Obstetricians and Gynaecologists of the United Kingdom, Canadian College of Obstetricians and Gynaecologists, French College of Obstetricians and Gynaecologists, European Association of Perinatal Medicine, Cochrane Library, the Joanna Briggs Institute (JBI), the Centre for Evidence-Based Health Care Database, PubMed, Embase, Scopus, Web of Science, CNKI, Wanfang Database, VIP Database, and China Biomedical Literature Database, including best dicision practices, guidelines, expert consensus, evidence summary, systematic reviews, Meta-analysis. The search time limit was the establishment of the database to March 1, 2023, and the evidence was extracted and summarized according to the theme after the two researchers independently evaluate the quality of the literature.Results:A total of 8 studies were selected, including 2 expert consensuses, 2 systematic reviews and 4 guidelines. Through literature reading, evidence extraction and classification, 23 pieces of best evidence were summarized from seven aspects: systematic management, activity management, medication management, health behavior management, pregnancy supervision, supervision of the timing of cerclage removal and supervision of psychological state.Conclusions:The best evidence quality and autuority of pregnancy management for pregnamt women after cervical cerclage surgery summarized in the study are high. It was recommended to strengthen the management of pregnant women during pregnancy after cervical cerclage, dynamically and continuously assess the pregnancy status of pregnant women, and prudently selected evidence to improve the prenatal examination process, ensure the safety of mothers and babies, and reduce the occurrence of complications. Overall, effective management of pregnant women during pregnancy after cervical cerclage required a combination of many factors to ensure the health and safety of the mother and baby.

Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.

This case report described an 80-year-old male patient with Parkinson disease(PD)complicated with myasthenia gravis(MG).Six years ago,the patient was diagnosed with PD based on the motor symptoms including bradykinesia and static tremor and treated with levodopa-benserazide and piribedil sustained-release tablets.He was admitted to the hospital due to left eyelid ptosis one month ago.The result of Neostigmine test was positive and anti-acetylcholine receptor(AChR)antibodies of serum was positive,which met the diagnostic criteria for myasthenia gravis(MG).The symptom of MG improved significantly after treatment with glucocorticoid and pyridostigmine but the PD symptoms worsened.The symptoms of PD were improved after withdrawal of pyridostigmine and use of the levodopa-benserazide and his condition maintained stable at 3 years of follow-up.The PD complicated with MG was fairly rare.We also reviewed the literature on the possible comorbidity mechanism and treatment strategies to improve the comprehensive understanding and ability of diagnosis and treatment of clinicians.

Objective To establish biparameter MRI stepwiese discriminant models based on T2WI and diffusion-weighted imaging(DWI),and to observe their value for detecting clinically significant prostate cancer(CSPCa)in transitional zone.Methods Totally 224 patients with pathologically confirmed prostatic transitional zone lesions were retrospectively collected and divided into CSPCa group(n=81)and non-CSPCa group(n=143)according to pathological results and Gleason scores.Single factor and stepwise discriminant analysis were used to analyze T2WI and DWI manifestations of lesions in both groups,so as to screen the independent impact factors for distinguishing CSPCa from non-CSPCa.Discriminant functions models for CSPCa and non-CSPCa were established,respectively,and the diagnostic efficiency of models were verified using cross-verification method,while correct discriminant rate≥80％was considered as having differential diagnostic value.Results The maximum diameter,boundary,DWI signal of lesions,prostate capsule being complete or not,as well as the minimum apparent diffusion coefficient were all independent impact factors for distinguishing CSPCa from non-CSPCa,and the discriminant function models for CSPCa and non-CSPCa were established based on the above factors,respectively,with correct discrimination rates of discriminant function model for CSPCa and non-CSPCa of 90.11％and 88.81％,respectively,and the overall correct discrimination rate of 89.31％.Conclusion Biparameter MRI stepwise discriminant models could be used to detect CSPCa in transitional zone.

Objective To establish biparameter MRI stepwiese discriminant models based on T2WI and diffusion-weighted imaging(DWI),and to observe their value for detecting clinically significant prostate cancer(CSPCa)in transitional zone.Methods Totally 224 patients with pathologically confirmed prostatic transitional zone lesions were retrospectively collected and divided into CSPCa group(n=81)and non-CSPCa group(n=143)according to pathological results and Gleason scores.Single factor and stepwise discriminant analysis were used to analyze T2WI and DWI manifestations of lesions in both groups,so as to screen the independent impact factors for distinguishing CSPCa from non-CSPCa.Discriminant functions models for CSPCa and non-CSPCa were established,respectively,and the diagnostic efficiency of models were verified using cross-verification method,while correct discriminant rate≥80％was considered as having differential diagnostic value.Results The maximum diameter,boundary,DWI signal of lesions,prostate capsule being complete or not,as well as the minimum apparent diffusion coefficient were all independent impact factors for distinguishing CSPCa from non-CSPCa,and the discriminant function models for CSPCa and non-CSPCa were established based on the above factors,respectively,with correct discrimination rates of discriminant function model for CSPCa and non-CSPCa of 90.11％and 88.81％,respectively,and the overall correct discrimination rate of 89.31％.Conclusion Biparameter MRI stepwise discriminant models could be used to detect CSPCa in transitional zone.

Objective:To investigate the value of the extrahepatic bile duct and main pancreatic duct segment patterns on magnetic resonance cholangiopancreatography (MRCP) for differentiating the periampullary carcinoma (PAC).Methods:The clinicopathologic data of 125 patients with PAC who were admitted to Wuxi No.2 People’s Hospital from June 2013 to December 2021 were retrospectively analyzed, including 72 males and 53 females, aged (64.9±8.6) years. According to its anatomy, the extrahepatic bile duct (B) was divided into suprapancreatic and intrapancreatic (including ampullary) segments, and the main pancreatic duct (P) was divided into tail-body and head segments. MRCP patterns: i. the extrahepatic bile duct or main pancreatic duct visible without dilatation, ii. cutoff of the distal extrahepatic bile duct or main pancreatic duct with upstream dilatation, iii. cutoff of the intrapancreatic or head segment with upstream dilatation and remnant intrapancreatic or head segments invisible, iv. cutoff of the intrapancreatic or head segment with upstream dilatation and nondilated remnant intrapancreatic or head segments, were represented as 0, 1, 2, and 3, respectively. Segment patterns of B1/P0+ B1/P1, B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3, B3/P0, and B0/P0+ B2/P0 on MRCP were compared in PAC patients.Results:Of the 125 patients, there were 57 (45.6%) with pancreatic head carcinoma, 36 (28.8%) with ampullary carcinoma, 20 (16.0%) with distal cholangiocarcinoma, and 12 (9.6%) with periampullary duodenal carcinoma. Segment patterns of B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3 were found in 52 patients with pancreatic head carcinoma (91.2%, 52/57), with a significant difference between PAC (χ 2=110.66, P<0.001). Segment patterns of B1/P0+ B1/P1were found in 36 patients with ampullary carcinoma (100.0%, 36/36), fallowed by 11 (91.7%, 11/12) with periampullary duodenal carcinoma, with a significant difference between PAC (χ 2=129.95, P<0.001). Segment pattern of B3/P0 presented in 16 patients with distal cholangiocarcinoma (80.0%, 16/20), with a significant difference between PAC (χ 2=62.45, P<0.001). The segment patterns of B0/P0+ B2/P0 were only seen in 3 of 57(5.3%) patients with pancreatic head carcinoma. Conclusion:On MRCP, cutoff of the head segment with upstream dilatation and remnant head segment invisible or nondilated indicates the pancreatic head carcinoma. Cutoff of the intrapancreatic segment with upstream dilatation, remnant intrapancreatic segment visible, and main pancreatic duct nondilated, indicates the distal cholangiocarcinoma. And cutoff of the distal extrahepatic segment with upstream dilatation and main pancreatic duct dilatation or not, indicates the ampullary or periampullary duodenal carcinoma.

AIM: To observe the clinical efficacy of Fuzheng Xiaoliu Granules in the treatment of stage II primary liver cancer and to explore its mechanism of action from the perspective of metabolomics. METHODS: Sixty patients with stage II primary liver cancer who achieved complete remission (CR) after comprehensive interventional therapy were randomly divided into treatment group and placebo group, with 30 patients in each group. They were treated for one year and observed for one year. The one-year recurrence rate, traditional chinese medicine (TCM) syndrome score, alpha-fetoprotein and child-pugh grade were compared between the two groups. The serum metabolites of the two groups before and after treatment were screened by ultra-high liquid chromatography-mass spectrometry technology, and the metabolic pathways and related biological pathways were analyzed. RESULTS: The one-year recurrence rate of the treatment group was significantly lower than that of the placebo group, and the overall improvement rate of TCM syndrome score was significantly better than that of the placebo group (P<0.05). There was no statistical significance in the comparison of alpha-fetoprotein and child-pugh grade between the two groups after treatment (P>0.05). Metabolomics results showed that there were 39 and 33 different metabolites in the treatment group before and after treatment and in the two groups after treatment, respectively. After enrichment analysis and topological analysis of the different metabolites, it was found that Fuzheng Xiaoliu Granules could affect amino acid metabolism, fatty acid metabolism and purine metabolism and other metabolic pathways. Before and after treatment in the treatment group and after treatment in the two groups, there were the same differential metabolites and metabolic pathways in the two comparison results. The same differential metabolites with FOLD CHANGE>1 include Stearic acid, Hypoxanthine, Kynurenic acid, Arachidonic acid, and N-Arachidonoyl Dopamine. The same metabolic pathways with Impact>0.1 include Arachidonic acid metabolism and Histidine metabolism. CONCLUSION: Fuzheng xiaoliu granules can effectively reduce the recurrence rate of stage II liver cancer patients after comprehensive intervention and improve the TCM syndrome. It may inhibit the activation of PI3K/Akt and ERK signaling pathways by regulating the content of metabolites involved in metabolic pathways such as amino acids and fatty acids, thereby delaying tumor recurrence.

There is still a lack of effective strategies for the prevention and treatment of liver cancer, and a deep understanding of its pathogenesis may help to develop new treatment methods. Due to the abnormal changes of lipid metabolism in the development and progression of liver cancer, such process is closely associated with the "phlegm-turbidity" theory in traditional Chinese medicine (TCM). Starting from the changes of lipid metabolism in hepatocellular carcinoma microenvironment, this article discusses the association of the abnormal changes of lipid metabolism in tumor cells and immune cells with the "phlegm-turbidity" theory and the clinical efficacy of phlegm-eliminating therapies in clinical practice. Since the "phlegm-turbidity" theory in TCM plays an important role in the pathogenesis and pathological changes of liver cancer, the analysis of its theoretical connotation helps to clarify pathological mechanism, thereby providing a theoretical basis for the role of TCM in the prevention and treatment of liver cancer.