Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

OBJECTIVE To establish the HPLC fingerprint of Xintong granules and the quantitative analysis of multi- components by single-marker method （QAMS） to determine the contents of 7 components， so as to provide a scientific basis for their quality control. METHODS HPLC method was used to establish the fingerprints for 10 batches of Xintong granules （No. S1- S10）， and similarity evaluation， cluster analysis （CA） and partial least squares-discriminant analysis （PLS-DA） were performed. At the same time， the contents of seven components， including puerarin， daidzin， calycosin-7-O- β -D-glucoside， stilbene glycoside， naringin， icariin and tanshinone ⅡA， were determined by QAMS method， and were compared with the results of external standard method. RESULTS A total of 18 common peaks were marked and 7 peaks were identified in the HPLC fingerprints for 10 batches of Xintong granules， namely puerarin （peak 4）， daidzin （peak 7）， calycosin-7-O-β-D-glucoside （peak 9）， stilbene glycoside （peak 10）， naringin （peak 12）， icariin （peak 17）， and tanshinone ⅡA （peak 18）； the similarities among them were more than 0.990， and CA and PLS-DA results showed that S4-S5，S8-S10，S1-S3 and S6-S7 were clustered into three categories， respectively. Using naringin as the internal standard， the contents of puerarin， daidzin， calycosin-7-O-β-D-glucoside， stilbene glycoside， icariin and tanshinone ⅡA were determined to be 7.868 1-10.181 2， 1.709 2-2.374 1， 0.285 2-0.326 3， 1.024 1- 1.523 9， 0.140 2-0.290 4， and 0.077 1-0.219 4 mg/g， respectively， by the QAMS. These results showed no significant differences compared to those obtained by the external standard method. CONCLUSIONS Established HPLC fingerprint and QAMS method are convenient， stable and accurate， which can provide a basis for the quality evaluation of Xintong granules.

BACKGROUND: Lung cancer is currently the most prevalent malignancy and the leading cause of cancer deaths worldwide. Although the early stage non-small cell lung cancer (NSCLC) presents a relatively good prognosis, a considerable number of lung cancer cases are still detected and diagnosed at locally advanced or late stages. Surgical treatment combined with perioperative multimodality treatment is the mainstay of treatment for locally advanced NSCLC and has been shown to improve patient survival. Following the standard methods of neoadjuvant therapy, perioperative management, postoperative adjuvant therapy, and other therapeutic strategies are important for improving patients' prognosis and quality of life. However, controversies remain over the perioperative management of NSCLC and presently consensus and standardized guidelines are lacking for addressing critical clinical issues in multimodality treatment. METHODS: The working group consisted of 125 multidisciplinary experts from thoracic surgery, medical oncology, radiotherapy, epidemiology, and psychology. This guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The clinical questions were collected and selected based on preliminary open-ended questionnaires and subsequent discussions during the Guideline Working Group meetings. PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNKI) were searched for available evidence. The GRADE system was used to evaluate the quality of evidence and grade the strengths of recommendations. Finally, the recommendations were developed through a structured consensus-building process. RESULTS: The Guideline Development Group initially collected a total of 62 important clinical questions. After a series of consensus-building conferences, 24 clinical questions were identified and corresponding recommendations were ultimately developed, focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assement, and follow-up protocols for NSCLC. CONCLUSIONS This guideline puts forward reasonable recommendations focusing on neoadjuvant therapy, perioperative management, adjuvant therapy, postoperative psychological rehabilitation, prognosis assessment, and follow-up protocol of NSCLC. It standardizes perioperative multimodality treatment and provides guidance for clinical practice among thoracic surgeons, medical oncologists, and radiotherapists, aiming to reduce postoperative recurrence, improve patient survival, accelerate recovery, and minimize postoperative complications such as atelectasis.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; Lung Neoplasms/therapy* ; Combined Modality Therapy ; Perioperative Care

OBJECTIVES: To investigate the mechanism by which transforming growth factor‑β (TGF‑β) regulates major histocompatibility complex class I (MHC-I) expression in hepatocellular carcinoma (HCC) cells and its role in immune evasion of HCC. METHODS: HCC cells treated with TGF‑β alone or in combination with SB-431542 (a TGF-β type I receptor inhibitor) were examined for changes in MHC-I expression using RT-qPCR and Western blotting. A RNA interference experiment was used to explore the role of miR-23a-3p/IRF1 signaling in TGF‑β‑mediated regulation of MHC-I. HCC cells with different treatments were co-cultured with human peripheral blood mononuclear cells (PBMCs), and the changes in HCC cell proliferation was assessed using CCK-8 and colony formation assays. T-cell cytotoxicity in the co-culture systems was assessed with lactate dehydrogenase (LDH) release and JC-1 mitochondrial membrane potential assays, and T-cell activation was evaluated by flow cytometric analysis of CD69 cells and ELISA for TNF-α secretion. RESULTS: TGF‑β treatment significantly suppressed MHC-I expression in HCC cells and reduced T-cell activation, leading to increased tumor cell proliferation and decreased HCC cell death in the co-culture systems. Mechanistically, TGF-β upregulated miR-23a-3p, which directly targeted IRF1 to inhibit MHC-I transcription. Overexpression of miR-23a-3p phenocopied TGF‑β‑induced suppression of IRF1 and MHC-I. CONCLUSIONS We reveal a novel immune escape mechanism of HCC, in which TGF‑β attenuates T cell-mediated antitumor immunity by suppressing MHC-I expression through the miR-23a-3p/IRF1 signaling axis.
Humans ; MicroRNAs/genetics* ; Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Interferon Regulatory Factor-1/metabolism* ; Transforming Growth Factor beta/metabolism* ; Signal Transduction ; Histocompatibility Antigens Class I/metabolism* ; Cell Line, Tumor ; Tumor Escape ; Coculture Techniques

Liver fibrosis is a significant health burden,marked by the consistent deposition of collagen.Unfortunately,the currently available treatment approaches for this condition are far from optimal.Lysyl oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver fibrosis.Mesenchymal stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver disorders.Previous studies have found that MSC-sEV can be used for microRNA delivery into target cells or tissues.It is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC activation.Additionally,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver fibrosis.This study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis development.The results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in HSC.Moreover,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in vitro.MSC-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse model.MSC-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 cells.In conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.

Objective To explore the effects of image registration using various regions of interest(ROI)on the setup error for nasopharyngeal carcinoma(NPC)patients who were immobilized individually.Methods Forty-three NPC patients who required radiotherapy were enrolled.The patients were immobilized with customized plastic foam and thermoplastic mask,and CBCT verification was performed once a week.In CBCT images,ROI was divided into the whole ROI(ROIPTV)and 7 local ROI containing different cervical structures(ROIsphenoid sinus,ROIatlantoaxial,ROIneck3,ROIneck4,ROIneck5,ROIneck6,and ROIneck7),which were then used for registrations with localized CT image.The setup errors in superior-inferior(SI),left-right(LR),anterior-posterior(AP),Pitch,Roll,and Yaw directions were recorded.Results In SI direction,the setup errors within 0.3 cm accounted for 89.74%for ROIneck7,and more than 90%for the other ROI.The proportion of setup errors within 0.3 cm gradually increased with the neck upward in LR direction,and they were 76.78%,81.70%,85.26%,and above 90%for ROIneck7,ROIneck6,ROIneck5,and the other ROI,respectively.In AP direction,the proportions of setup errors within 0.3 cm were less than 90%,except for ROIatlantoaxial and ROIneck3.The setup errors of ROIsphenoid sinus,ROIatlantoaxial,ROIneck3,and ROIneck4 were significantly positively correlated with ROIPTV in SI direction,and the correlation coefficients(R)were 0.94,0.95,0.90,and 0.83,respectively.In LR direction,there were positive correlations between the setup errors of ROIatlantoaxial and ROIsphenoid sinus(R=0.95),ROIneck3 and ROIsphenoid sinus(R=0.91),ROIPTV and ROIneck3(R=0.91).The setup errors of ROIPTV in AP direction were positively correlated with ROIatlantoaxial vertebrae and ROIneck3(R=0.88,0.90).The margins of all ROIs ranged from 0.38 cm to 1.01 cm.The extension of ROIneck6 and ROIneck7 in AP direction exceeded 0.9 cm,and the extension of ROIneck7 reached 0.95 cm in SI direction.Conclusion ROIPTV and ROIsphenoid sinus,ROIatlantoaxial,ROIneck3 are significantly correlated in SI,LR,and AP directions.The setup error of nasopharyngeal carcinoma patients gradually increases with the neck down.The nasopharyngeal and cervical regions need to be expanded in segments when patients are immobilized individually.

Objective To examine the regulation of malignant progression of colorectal cancer by LINC00626 via the JAK1/STAT3/KHSRP signaling axis and its molecular mechanism.Methods 96 individuals diagnosed with colorectal cancer at our hospital during June 11,2021 and June 11,2023 were chosen as research subjects,and their cancerous tissue and nearby normal tissue were collected.Cultivate colorectal cancer cell lines(SW620,HCT116,HT29,DLD-1,LOVO,Caco-2)and normal colorectal cells(NCM460)in vitro,and detect the expression of LINC00626 and KHSRP in colorectal cancer tissue and cell lines using qRT-PCR.Screening out cell lines infected with lentivirus,SW620 and HCT116 cell lines were transfected with knockdown lentivirus and its control,while HT29 and DLD-1 cell lines were transfected with overexpressing lentivirus and its control,respectively.Select stable transfected cell lines for cell function experiments to detect proliferation,migration,and invasion abilities.Detection of the effect of LINC00626 on the growth and migration of colorectal cancer tumors in live mouse experiments.The expression level of KHSRP protein in stable labeled cells was determined using a western blot analysis.Rescue experimental research on the regulatory relationship between LINC00626 and KHSRP.Results qRT-PCR showed low expression of LINC00626 and high expression of KHSRP in colorectal cancer tissues and cell lines.Cell function experiments showed that compared with the sh-NC group,the sh-LINC00626 group promoted cell proliferation,migration,and invasion in SW620 and HCT116 cells,while the overexpression group showed the opposite.Cell rescue experiments showed that,LINC00626+KHSRP significantly reversed the promotion effects of knocking down LINC00626 on cell proliferation,migration,and invasion.In the nude mouse experiment,com-pared with the sh-NC group,the sh-LINC00626 group showed a significant increase in tumor volume and weight,cell proliferation rate,and the number of lung metastases from colorectal cancer in the nude mice;Overexpression results in the opposite.The signal pathway experiment revealed that relative to the sh-NC group,the expression levels of JAK1 and STAT3 mRNA in the sh-LINC00626 group were significantly increased,whereas the results in the overexpression group were the opposite.Conclusion LINC00626 suppression the malignant progression of colorec-tal cancer metastasis through the JAK1/STAT3/KHSRP signaling axis.

Objective To explore the role of transcription factor EB(TFEB)induced by aerobic exer-cise in improving insulin resistance(IR)of skeletal muscles in high-fat diet mice.Method Eighteen male SPF C57BL/6 mice aged 6 weeks were randomly divided into a common diet group(CON),a high-fat diet group(HFD),and a high-fat diet exercise group(HFDE),each of 6.Both high-fat groups were on high-fat diet for 12 weeks.Then the HFDE group underwent daily 60-minute tread-mill exercise with the slope of 0°,at a speed of 12 m/min,5 times per week for 12 weeks.Finally,the glucose tolerance and insulin sensitivity were detected using the intraperitoneal injection glucose tol-erance test(IPGTT)and intraperitoneal injection insulin tolerance test(IPITT).The fasting blood glu-cose and insulin contents were measured by biochemical method,and the IR level was calculated by using the homeostatic model assessment of insulin resistance(HOMA-IR).Moreover,Western blotting was employed to detect the expression of phosphorylated transcription factor EB(pTFEB)and TFEB in skeletal muscle,glucose transporter 4(GLUT4)in cytoplasm and membrane,phosphorylated insulin re-ceptor substrates1(pIRS1),phosphorylated protein kinase B(pAKT),phosphoinositide 3-kinase(PI3K),and phosphorylated akt substrate of 160 kD(pTBC1D4)in skeletal muscle.The correlation of pTFEB and TFEB to insulin signaling pathway-related proteins was analyzed.Results(1)Compared with the CON group,there was a significant increase in the average body weight,IPGTT,blood glucose at each time point of IPGTT,area under curve(AUC),serum insulin,HOMA-IR,protein expressions of pTFEB,total-TFEB and GLUT4 in cytoplasm of the HFD group(P<0.01),but a significant decrease in the average protein expressions of pIRS1,pAKT,PI3K,pTBC1D4 and GLUT4 in cell membrane of skeletal muscles(P<0.01).However,no significant differences were found between the two groups in the average expression of pTFEB and T-TFEB proteins.(2)Compared to the HFD group,a signifi-cant increase was found in the average body weight,blood glucose at each time point of IPGTT,blood glucose of IPITT at 0 min,30 min and 60 min and AUC,serum insulin,HOMA-IR,expres-sions of pTFEB,T-TFEB and GLUT4 in cytoplasm of HFDE group(P<0.05 or P<0.01),with a signifi-cant decrease in the average protein expressions of pIRS1,pAKT,PI3K,pTBC1D4 and GLUT4 in cell membrane and T-TFEB in nucleus(P<0.01).(3)TFEB was negatively correlated with the expres-sion of pIRS1,PI3K,pAKT,and pTBC1D4 proteins(r=-0.8642,r=-0.7789,r=-0.8946,r=-0.8040)but positively correlated with cytoplasmic GLUT4(r=0.8532,P<0.01).Moreover,TFEB in the nucleus was of positive correlation with GLUT4 in the cell membrane(r=0.7744,P<0.01).Conclusions High-fat diet can decrease the expression of insulin signaling pathway related proteins in skeletal mus-cles of mice and weaken their insulin action,leading to the disorder of glucose and lipid metabolism.However,aerobic exercise can significantly increase the expression of such proteins to promote insulin function and sensitivity,and relieve disorders in glucose and lipid metabolism.This effect may be achieved through the promotion of skeletal muscle TFEB nuclear translocation,which activates IRS1/PI3K/AKT/TBC1D4/GLUT4 signaling pathway and facilitates GLUT4 membrane translocation,ultimately enhancing glucose uptake in skeletal muscle cells.The authors speculate that the TFEB-mediated insu-lin signaling pathway may be an important molecular pathway for aerobic exercise to improve insulin re-sistance.