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.

BACKGROUND: Our understanding of the correlation between postdischarge cancer and mortality in patients with coronary artery disease (CAD) remains incomplete. The aim of this study was to investigate the relationships between postdischarge cancers and all-cause mortality and cardiovascular mortality in CAD patients. METHODS: In this retrospective cohort study, 25% of CAD patients without prior cancer history who underwent coronary artery angiography between January 1, 2011 and December 31, 2015, were randomly enrolled using SPSS 26.0. Patients were monitored for the incidence of postdischarge cancer, which was defined as cancer diagnosed after the index hospitalization, survival status and cause of death. Cox regression analysis was used to explore the association between postdischarge cancer and all-cause mortality and cardiovascular mortality in CAD patients. RESULTS: A total of 4085 patients were included in the final analysis. During a median follow-up period of 8 years, 174 patients (4.3%) developed postdischarge cancer, and 343 patients (8.4%) died. A total of 173 patients died from cardiovascular diseases. Postdischarge cancer was associated with increased all-cause mortality risk (HR = 2.653, 95% CI: 1.727-4.076, P < 0.001) and cardiovascular mortality risk (HR = 2.756, 95% CI: 1.470-5.167, P = 0.002). Postdischarge lung cancer (HR = 5.497, 95% CI: 2.922-10.343, P < 0.001) and gastrointestinal cancer (HR = 1.984, 95% CI: 1.049-3.750, P = 0.035) were associated with all-cause mortality in CAD patients. Postdischarge lung cancer was significantly associated with cardiovascular death in CAD patients (HR = 4.979, 95% CI: 2.114-11.728, P < 0.001), and cardiovascular death was not significantly correlated with gastrointestinal cancer or other types of cancer. CONCLUSIONS Postdischarge cancer was associated with all-cause mortality and cardiovascular mortality in CAD patients. Compared with other cancers, postdischarge lung cancer had a more significant effect on all-cause mortality and cardiovascular mortality in CAD patients.

Aim To explore the lipid-lowering effect of Dendrobium huoshanense C.Z.Tang et S.J.Cheng polysaccharides(DHP),on atherosclerotic mice and its regulatory effect on intestinal flora.Methods Twelve 8-week-old ApoE-/-mice were randomly di-vided into two groups:H-1 and H-2.Both groups were fed a high-fat diet(HFD).After eight weeks,the H-2 group received DHP(400 mg·kg-1·d-1)for six weeks,while the H-1 group received normal saline.Blood samples were collected at 0,4,8 and 14 weeks.Feces from the H-2 group were collected and labeled as B,E,F and D,and liver and kidney tissues were col-lected post-mortem at week 14.Blood indexes were de-tected using kits,and fecal flora was analyzed by met-agenomics.Results DHP significantly decreased blood lipid levels in mice(P＜0.05)without causing significant liver and kidney damage.Metagenomic a-nalysis showed that,compared with group B,the rela-tive abundance of Deferribacterota and Faecalibaculum increased in EF group,while the relative abundance of Bacteroidota,Prevotella and Lachnoclostridium de-creased(P＜0.05).Compared with EF group,the relative abundance of Bacteroidota,Prevotella and Lachnoclostridium increased in group D,while the rela-tive abundance of Deferribacterota,Bacillota,Oscilli-bacter and Faecalibaculum decreased(P＜0.05).Actinomycetota,Faecalibaculum rodentium and other bacteria increased with longer HFD feeding time(P＜0.05).Conversely,Parabacteroides and Lachnoclos-tridium decreased with increased HFD feeding time(P＜0.05).Conclusions The intestinal flora structure of mice changes significantly with the progression of atherosclerosis.DHP intervention shows a potential to improve microflora structure and lipid metabolism in mice.

Objective:To investigate the expression of complement C3 in serums and tissues of lung adenocarcinoma patients with brain metastases and the mechanism of complement C3 in inducing epithelial mesenchymal transition (EMT).Methods:The retrospective case-control study, cell experiments and animal experiments were conducted. The serum samples from 20 healthy examinees, 20 advanced lung adenocarcinoma patients without brain metastases and 20 advanced lung adenocarcinoma patients with brain metastases at the First People's Hospital of Yancheng from January 2021 to January 2023 were collected, and the expression of complement C3 in serum samples was detected by immunoturbidimetry. At the same time, lung tissue samples were collected from 10 lung adenocarcinoma patients without brain metastases, and lung tissue and brain tissue samples were collected from 10 lung adenocarcinoma patients with brain metastases in the First People's Hospital of Yancheng. Immunohistochemistry was used to detect the expression of complement C3, C3aR, Kruppel like factor 5 (KLF5), and N-cadherin (N-cad) in the tissue samples. Using lentivirus to construct a human lung adenocarcinoma with brain metastases cell line PC14-C3 with stable overexpression of complement C3, with cells infected with empty vector virus as the control group (PC14-Ctrl). Western blotting was used to detect the expression of complement C3, KLF5, N-cad, and E-cadherin (E-cad) in PC14-C3 and PC14-Ctrl cells, and scratch assay was used to assess cell migration ability. Using the random number table method, 12 BALB/c nude mice were evenly divided into PC14-C3 group and PC14-Ctrl group. PC14-C3 cells and PC14-Ctrl cells were subcutaneously inoculated on the ventral side, and the body mass and tumor volume of the nude mice were recorded. Real-time fluorescence quantitative polymerase chain reaction was used to detect the expression of KLF5, N-cad and E-cad mRNA in various tumor cells and tumor tissues of nude mice.Results:The serum complement C3 levels in healthy individuals, lung adenocarcinoma patients without brain metastases and lung adenocarcinoma patients with brain metastases were (1.14±0.17) g/L, (1.20±0.15) g/L and (1.61±0.21) g/L, respectively. The serum complement C3 level in lung adenocarcinoma patients with brain metastases was higher than that in lung adenocarcinoma patients without brain metastases and healthy individuals, and the differences were statistically significant (both P < 0.001). The results of immunohistochemical testing showed that the proportions of positive expression areas of complement C3, C3aR, KLF5, and N-cad proteins in the lung primary lesions of lung adenocarcinoma patients with brain metastases were higher than those of patients without brain metastases, and the differences were statistically significant (all P < 0.05). The mRNA ( P < 0.05) and protein expression levels of complement C3 in PC14-C3 cells were higher than those in PC14-Ctrl cells, indicating successful transfection. The scratch assay results showed that the migration rate of PC14-Ctrl cells was (37.5±4.1)%, and the migration rate of PC14-C3 cells was (60.4±2.9)%, and the difference was statistically significant ( t = 7.86, P < 0.01). The relative expressions of EMT promoting molecules KLF5 and N-cad mRNA in PC14-C3 cells were higher than those in PC14-Ctrl cells, while the relative expression of EMT inhibiting molecule E-Cad mRNA was lower than that in PC14-Ctrl cells, and the differences were statistically significant (all P < 0.05). On the 26th day of tumor loading, the tumor volume of nude mice in PC14-C3 group was (610±10) mm 3, while that of PC14-Ctrl group was (321±30) mm 3; the body mass of nude mice in PC14-C3 group was lower than that in PC14-Ctrl group [(21.6±0.6) g vs. (23.2±0.6) g], and the differences were statistically significant (both P < 0.05). At the end of the experiment, 5 nude mice died and 1 survived in the PC14-C3 group; 1 nude mouse died and 5 survived in the PC14-Ctrl group. The relative expressions of KLF5 and N-cad mRNA in the tumor tissues of nude mice in PC14-C3 group were higher than those in PC14-Ctrl group, while the relative expression of E-Cad mRNA was lower than that in PC14-Ctrl group, and the differences were statistically significant (all P < 0.05). Conclusions:Lung adenocarcinoma patients with brain metastases have high levels of complement C3 in their serums and primary lesions. Complement C3 may induce EMT and promote the occurrence of lung adenocarcinoma brain metastases by affecting the expressions of KLF5, N-cad and E-cad.

Objective To investigate the infiltration of peripheral monocyte in the hippocampal CA3 area in neuralgia mice at different time points and explore the effects of the infiltration on neuralgia and the neuralgia-induced anxiety-like behavior in mice.Methods The healthy male C57 mice were randomly divided into four groups:sham,sciatic nerve branch selective injury(SNI)model(SNI),CCR2 inhibitor RS102895(SNI+RS102895)and microglial inhibitor minocycline(MC)(SNI+MC)groups.Both the sham and SNI groups were further divided into 7 days,14 days and 18 days groups,and the SNI+RS102895 and SNI+MC groups were sampled on the 18th day.Neuralgia was induced by SNI,and mechanical hyperalgesia was assessed by paw withdrawal threshold(PWTs)at different time points.Elevated plus maze(EPM)and open field test(OFT)were performed respectively two days and one day before sacrifice.Immunofluorescence was used to observe the expressions of leukocyte differentiation antigen 45(CD45)and the co-expression with microglial markers ionized calcium binding adaptor molecule-1(IBA-1),transmembrane protein 119(TMEM119),astrocyte marker glial fibrillary acidic protein(GFAP),and neuronal marker neuronal nuclei(NeuN)in the hippocampal CA3.The percentage of monocytes in the whole brain of 14 days SNI mice was determined by flow cytometry.Minocycline at 90 mg/(kg·d),RS 102895 at 5 mg/(kg·d)and saline were administered orally on the 5th to 16th day in the corresponding 18 days groups,and the effects of blocking monocyte infiltration on neuralgia and anxiety-like behavior and the expressions of CD45 and 1BA-1 in CA3 region of hippocampus were observed.Results On the first day after SNI,the PWTs of mice in the 7 days and 14 days groups decreased and continued until before sacrifice(P＜0.01).The CD45 expression did little in the 7 days sham group.Compared with the sham group at the same time point,the CD45 expression did not increase in 7 days SNI mice((P＞0.05)and increased significantly in 14 days SNI mice(P＜0.01),only slightly co-expressed with IBA-1 and TMEM119 and no co-expression with GFAP and NeuN,the percentage of monocytes in the whole brain increased significantly in 14 days SNI mice(P＜0.01).Inhibition of microglial activation or CCR2 expression reduced the expression of CD45 in the CA3 in SNI mice(P＜0.01),increased the PWTs(P＜0.01)and alleviated anxiety-like behavior in SNI mice(P＜0.01).Conclusion There was an infiltration of peripheral monocytes in the hippocampal CA3 region after 14 days of SNI-induced neuralgia,which might be involved in the maintenance of neuralgia and the development of neuralgia-induced anxiety-like behaviors.

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.
Humans ; Tumor Necrosis Factor-alpha ; DNA-Binding Proteins/metabolism* ; Ubiquitin-Specific Peptidase 7 ; Cisplatin ; Temozolomide ; Transcription Factors ; Glioma ; Cell Proliferation ; Melanoma ; Cell Line, Tumor ; Apoptosis ; Nuclear Proteins/genetics*

The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.
Animals ; Mice ; Antiviral Agents/pharmacology* ; COVID-19 ; Hepatitis B virus ; Interferon Type I/metabolism* ; SARS-CoV-2/drug effects* ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/antagonists & inhibitors*

Objective:To investigate the clinical characteristics of influenza A and influenza B pneumonia and the risk factors of severe influenza pneumonia in children.Methods:The epidemiology, clinical characteristics, laboratory tests and pathogens of co-infection in children with pneumonia caused by influenza A virus and influenza B virus, and the risk factors of severe influenza pneumonia were retrospectively analyzed.Results:(1) The cases of influenza A infection accounted for 65.1% and those with influenza B infection accounted for 32.9% among the 711 children with influenza pneumonia.The dominant strain was Influenza B Victoria virus in spring and summer, influenza A(H 3N 2) virus in autumn, and influenza A(H1N1) virus in winter.The dominant strain was influenza A virus at the age of < 1 year and ~3 years, influenza A virus and influenza B virus at the age of ~6 years, and influenza B virus at the age of ≥6 years.(2) The gastrointestinal symptoms were more common in children with influenza B pneumonia compared with those with influenza A pneumonia(53.4% vs 44.7%, χ2=4.728, P=0.030), but crackles and wheezing were more common in children with influenza A pneumonia compared with those with influenza B pneumonia(80.1% vs 70.5%, 36.9% vs 25.6%, χ2=8.945, 8.093, all P<0.05). (3) The percentage of decreased lymphocyte count in children with influenza B pneumonia was higher than those with influenza A pneumonia(5.6% vs 1.9%, χ2=6.633, P=0.010). (4) Mixed Mycoplasma Pneumoniae was more common in children with influenza B pneumonia compared with those with influenza A pneumonia(23.9% vs 10.8%, χ2=20.789, P<0.001), and mixed virus and bacteria were more common in children with influenza A pneumonia compared with those with influenza B pneumonia(15.8% vs 8.1%, 50.1% vs 41.9%, χ2=7.934, 4.221, all P<0.05). (5) Multivariate logistic regression analysis showed that age <2 years( OR=1.886, 95% CI 1.149~3.096, P=0.012), increased LDH( OR=1.736, 95% CI 1.080~2.790, P=0.023), the percentage of lymphocyte decreased( OR=2.762, 95% CI 1.669~4.571, P<0.001) and the percentage of CD3 + decreased ( OR=6.019, 95% CI 3.993~9.331, P<0.001)were risk factors for severe influenza pneumonia. Conclusion:Among hospitalized children with influenza pneumonia, there were some differences in the age of infection, clinical characteristics, laboratory tests and pathogens of co-infection between the cases caused by influenza B and influenza A, and clinicians should remain vigilant for the occurrence of severe influenza pneumonia.