Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis.

Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.

Small Transjugular Intrahepatic Portosystemic Shunt Plus Variceal Embolization for Gastric Varices: A Multicenter Cohort Study.

BACKGROUND & AIMS: The effect of transjugular intrahepatic portosystemic shunt (TIPS) plus variceal embolization for treating gastric varices (GVs) remains controversial. This nationwide multicenter cohort study aimed to evaluate whether adding variceal embolization to a small diameter (8-mm) TIPS could reduce the rebleeding incidence in patients with different types of GVs. METHODS: This retrospective cohort study involved 629 patients who underwent 8-mm TIPS for gastric varices at 7 medical centers. The primary endpoint was all-cause rebleeding, and the secondary endpoints included overt hepatic encephalopathy (OHE) and all-cause mortality. RESULTS: A total of 629 patients were included. Among them, 429 (68.2%) had gastroesophageal varices type 1 (GOV1), 145 (23.1%) had gastroesophageal varices type 2 (GOV2), and 55 (8.7%) had isolated gastric varices type 1 (IGV1). In the entire cohort, adjunctive embolization reduced rebleeding (6.2% vs 13.6%; P = .005) and OHE (31.0% vs 39.4%; P = .02) compared with TIPS alone. However, no significant differences were found in mortality (12.0% vs 9.7%; P = .42). In patients with GOV2 and IGV1, TIPS plus variceal embolization reduced both rebleeding (GOV2: 7.8% vs 25.1%; P = .01; IGV1: 5.6% vs 30.8%; P = .03) and OHE (GOV2: 31.8% vs 51.5%; P = .008; IGV1: 11.6% vs 38.5%; P = .04). However, in patients with GOV1, adjunctive embolization did not reduce rebleeding (5.9% vs 8.7%; P = .37) or OHE (33.1% vs 35.3%; P = .60). CONCLUSIONS: Compared with TIPS alone, 8-mm TIPS plus variceal embolization reduced rebleeding and OHE in patients with GOV2 and IGV1. These findings suggest that patients with GOV2 and IGV1, rather than GOV1, could benefit from embolization with TIPS.

Preventing variceal rebleeding in cirrhotic patients with portal vein thrombosis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Preventing rebleeding is crucial, but the best prevention technique for patients with cirrhosis and portal vein thrombosis (PVT) remains debatable. Therefore, this systematic review and meta-analysis compared a transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic therapy (ET) plus nonselective beta-blockers (NSBBs) for preventing variceal rebleeding in this patient population. METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from their inception until May 18, 2023. The studies were screened using predetermined criteria, relevant data were extracted, and pooled analyses were performed using the Reviewer Manager 5.4.1 software. RESULTS: We retrieved 1032 studies, of which 5 studies comprising a total of 272 patients were included. The postoperative variceal rebleeding rate was significantly lower in the TIPS group than in the ET + NSBBs group (odds ratio [OR] = 0.19, 95% confidence interval [CI] = 0.11-0.35, P < 0.05, I2 = 0%), but the portal vein recanalization rate was higher (OR = 7.92, 95% CI = 3.04-20.67, P < 0.05, I2 = 0%). The rates of hepatic encephalopathy (HE) and mortality did not differ between the groups. CONCLUSIONS: Our results suggest that TIPS prevents variceal rebleeding without increasing the hepatic encephalopathy risk more effectively than ET plus NSBBs, but this benefit did not translate into improved survival. Thus, it may be preferable to ET plus NSBBs for preventing variceal rebleeding in patients with cirrhosis and PVT. However, more large-scale and multicenter randomized controlled trials involving other patient populations are required to verify the clinical efficacy of both these treatments and ensure generalizability.

CPEB4 promotes cell migration and invasion via upregulating Vimentin expression in breast cancer.

Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a member of CPEB family which is overexpressed in variety of cancers. However, the biological role and regulatory mechanism of CPEB4 in cancers remain unknown. Here, we first investigate the role of CPEB4 in breast cancer progression and metastasis. The expression of CPEB4 is elevated in breast cancer tissues compared with adjacent normal tissues. Furthermore, high expression levels of CPEB4 is associated with tumor metastasis in breast cancer patients. Ectopic expression of CPEB4 dramatically promotes EMT, migration and invasion of breast cancer cells, while silencing CPEB4 expression significantly reduces these events. Mechanically, overexpression of CPEB4 upregulates Vimentin expression and silencing Vimentin expression blocks CPEB4-induced migration and invasion of breast cancer cells. These results implicate the potential role of CPEB4 and Vimentin in breast cancer metastasis, which is further confirmed by the finding that there is a physical interaction between the two proteins. Altogether, our results provide a novel insight into CPEB4 in regulating breast cancer progression and metastasis.

Efficacy of TIPS plus extrahepatic collateral embolisation in real-world data: a validation study.

OBJECTIVES: The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) plus extrahepatic collateral embolisation (TIPS+E) in reducing rebleeding and hepatic encephalopathy (HE) post-TIPS was recently reported in a meta-analysis, but further validation is essential. This study aims to confirm the effectiveness of TIPS+E using real-world data. METHODS: The multicentre retrospective cohort included 2077 patients with cirrhosis who underwent TIPS±E (TIPS: 631, TIPS+E: 1446) between January 2010 and December 2022. Regression and propensity score matching (PSM) were used to adjust for baseline characteristic differences. After PSM, clinical outcomes, including rebleeding, HE, survival and further decompensation (FDC), were analysed. Baseline data from all patients contributed to the construction of prognostic models. RESULTS: After PSM, 1136 matched patients (TIPS+E: TIPS=568:568) were included. TIPS+E demonstrated a significant reduction in rebleeding (HR 0.77; 95% CI 0.59 to 0.99; p=0.04), HE (HR 0.82; 95% CI 0.68 to 0.99; p=0.04) and FDC (HR 0.85; 95% CI 0.73 to 0.99; p=0.04), comparing to TIPS. Significantly, TIPS+E also reduced rebleeding, HE and FDC in subgroup of using 8 mm diameter stents and embolising of gastric varices+spontaneous portosystemic shunts (GV+SPSS). However, there were no differences in overall or subgroup survival analysis. Additionally, the random forest models showed higher accuracy and AUROC comparing to other models. Controlling post-TIPS portal pressure gradient (pPPG) within 7 mm Hg

Ice-Inspired Polymeric Slippery Surface with Excellent Smoothness, Stability, and Antifouling Properties.

Ice is omnipresent in our daily life and possesses intrinsic slipperiness as a result of the formation of a quasi-liquid layer. Thus, the functional surfaces inspired by ice show great prospects in widespread fields from surface lubrication to antifouling coatings. Herein, we report an ice-inspired polymeric slippery surface (II-PSS) constructed by a self-lubricating liquid layer and a densely surface-grafted polymer brush. The polymer brush layer could act as a homogeneous matrix to capture lubricant molecules via strong and dynamic dipole-dipole interactions to form a stable quasi-liquid layer that resembles the ice surface. The II-PSS can be easily fabricated on various solid substrates (e.g., silicon, glass, aluminum oxide, plastics, etc.) with excellent smoothness (roughness of ∼0.4 nm), optical transmittance (∼94.5%), as well as repellence toward diverse liquids with different surface tensions (22.3-72.8 mN m-1), pH values (1-14), salinity, and organic pollutants. Further investigation shows that the II-PSS exhibits extremely low attachment for proteins and marine organisms (e.g., algae and mussels) for over one month. These results demonstrate a robust and promising strategy for high-performance antifouling coatings.

Individualized portal pressure gradient threshold based on liver function categories in preventing rebleeding after TIPS.

BACKGROUND: The evidence in Portal pressure gradient (PPG) < 12 mmHg after transjugular intrahepatic portosystemic shunt (TIPS) for preventing rebleeding mostly comes from observations in uncovered stents era. Moreover, association between Child-Pugh classes and post-TIPS hepatic encephalopathy (HE) has indicated that tolerance of PPG reduction depends on liver function. This study aimed to investigate the optimal PPG for covered TIPS and explore the optimal threshold tailored to the Child-Pugh classes to find individualized PPG to balance rebleeding and overt HE. METHODS: This multicenter retrospective study analyzed rebleeding, OHE, and mortality of patients associated with post-TIPS PPGs (8, 10, 12, and 14 mmHg) in the entire cohort and among different Child-Pugh classes. Propensity score matching (PSM) and competing risk analyses were performed for sensitivity analyses. RESULTS: We included 2100 consecutively screened patients undergoing TIPS. In all patients, PPG < 12 mmHg reduced rebleeding after TIPS (p = 0.022). In Child-Pugh class A, none of the PPG thresholds were discriminative of clinical outcomes. In Child-Pugh class B, 12 mmHg (p = 0.022) and 14 mmHg (p = 0.037) discriminated rebleeding, but 12 mmHg showed a higher net benefit. In Child-Pugh class C, PPG < 14 mmHg had a lower rebleeding incidence (p = 0.017), and exhibited more net benefit than 12 mmHg. CONCLUSION: Different PPG standards may be required for patients with different liver function categories. A PPG threshold < 12 mmHg might be suitable for patients in Child-Pugh class B, while < 14 mmHg might be optimal for patients in Child-Pugh class C.