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We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%). Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified \"Abx-free/Abx <10 days\" as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.

Aim To perform a systematic review and meta-analysis of the effectiveness and complications of BRTO for gastric varices. Materials and Methods A systematic review was performed to identify relevant articles. Inclusion criteria were applied to select studies with at least ten patients with acute bleeding or at-risk gastric varices treated with BRTO. Meta-analysis with random effects model was performed to calculate data for immediate technical success, clinical success, and complications. Results A total of 1,016 Patients from 24 studies met inclusion criteria. Technical success rate for BRTO was 96.4 % (95 % CI 93.7, 98.3 %; Q  = 3,269.26, p  < 0.01, I 2  = 99.39 %). Clinical success (defined as no recurrence or rebleed of gastric varices, or complete obliteration of varices on subsequent imaging) rate was 97.3 % (95 % CI 95.2, 98.8 %; Q  = 3,105.91, p  < 0.01, I 2  = 99.29 %). Major complication rate was 2.6 % (95 % CI 1.1, 4.6 %; Q  = 3,348.98, p  < 0.01, I 2  = 99.34 %). Esophageal variceal recurrence rate was 33.3 % (95 % CI 24.6, 42.6 %; Q  = 7,291.75, p  < 0.01, I 2  = 99.74 %). Conclusion BRTO is safe and efficacious for gastric varices, and current best evidence suggests that BRTO could be considered as therapy for patients with gastric varices.

Hepatic ischemia and reperfusion injury (IRI) is an inflammatory condition and a significant cause of morbidity and mortality after surgery. Matrix metalloproteinases (MMPs) have been widely implicated in the pathogenesis of inflammatory diseases. Among the different MMPs, gelatinases (MMP-2 and MMP-9) are within the most prominent MMPs detected during liver IRI. While the role of MMP-9 in liver damage has been fairly documented, direct evidence of the role for MMP-2 activity in hepatic IRI remains to be established. Due to the lack of suitable inhibitors to target individual MMPs in vivo, gene manipulation is as an essential tool to assess MMP direct contribution to liver injury. Hence, we used MMP-2-/- deficient mice and MMP-2+/+ wild-type littermates to examine the function of MMP-2 activity in hepatic IRI. MMP-2 expression was detected along the sinusoids of wild-type livers before and after surgery and in a small population of leukocytes post-IRI. Compared to MMP-2+/+ mice, MMP-2 null (MMP-2-/-) mice showed exacerbated liver damage at 6, 24, and 48 hours post-reperfusion, which was fatal in some cases. MMP-2 deficiency resulted in upregulation of MMP-9 activity, spontaneous leukocyte infiltration in naïve livers, and amplified MMP-9-dependent transmigration of leukocytes in vitro and after hepatic IRI. Moreover, complete loss of MMP-2 activity impaired the degradation of poly (ADP-ribose) polymerase (PARP-1) in extensively damaged livers post-reperfusion. However, the administration of a PARP-1 inhibitor to MMP-2 null mice restored liver preservation to almost comparable levels of MMP-2+/+ mice post-IRI. Deficient PARP-1 degradation in MMP-2-null sinusoidal endothelial cells correlated with their increased cytotoxicity, evaluated by the measurement of LDH efflux in the medium. In conclusion, our results show for the first time that MMP-2 gene deletion exacerbates liver IRI. Moreover, they offer new insights into the MMP-2 modulation of inflammatory responses, which could be relevant for the design of new pharmacological MMP-targeted agents to treat hepatic IRI.

BackgroundOvert hepatic encephalopathy (OHE) is a serious complication of liver dysfunction, which is associated with severe morbidity/mortality and healthcare resource utilization. OHE can be medically refractory due to spontaneous portosystemic shunts (SPSSs) and therefore a new treatment option for these SPSSs is critical.MethodsThis is a retrospective study of 43 patients with medically refractory OHE, who underwent CARTO (Coil-Assisted Retrograde Transvenous Obliteration) procedures between June 2012 and October 2016. The patient demographic characteristics, technical and clinical outcomes with an emphasis on HE improvement, and complications are reviewed and analyzed.ResultsThe overall clinical success rate was 91% with a significant HE improvement. Eighty-one percent of patients had clinically significant improvement from OHE and 67% of patients had complete resolution of their HE symptoms during our follow-up period of 893 ± 585 days (range 36–1881 days, median 755.0 days). The median WH score improved from 3 (range 2–4) pre-CARTO to 1 (range 0–4) post-CARTO (p < 0.001). The median ammonia level significantly decreased from 134.5 pre-CARTO to 70.0 post-CARTO (p < 0.001) in 3 days. The overall mean survival was 1465.5 days (95% CI of 1243.0 and 1688.0 days). Only three patients had recurrent HE symptoms. There were 39.6% minor complication rate including new or worsened ascites and esophageal varices, and only 2.3% major complication rate requiring additional treatment (one patient with bleeding esophageal varices requiring treatment). No procedure-related death is noted.ConclusionsCARTO appears to be a safe and effective treatment option for refractory overt hepatic encephalopathy (OHE) due to spontaneous portosystemic shunts. CARTO could be an excellent addition to currently available treatment options for these patients.

Hepatocellular carcinoma (HCC) is a leading cause of mortality. Checkpoint inhibitors of programmed cell death protein‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have shown great efficacy, but lack biomarkers that predict response. Circulating tumor cells (CTCs) have promise as a liquid‐biopsy biomarker; however, data on HCC CTCs expressing PD‐L1 have not been reported. We sought to detect PD‐L1‐expressing HCC‐CTCs and investigated their role as a prognostic and predictive biomarker. Using an antibody‐based platform, CTCs were enumerated/phenotyped from a prospective cohort of 87 patients with HCC (49 early‐stage, 22 locally advanced, and 16 metastatic), 7 patients with cirrhosis, and 8 healthy controls. Immunocytochemistry identified total HCC CTCs (4′,6‐diamidino‐2‐phenylindole–positive [DAPI+]/cytokeratin‐positive [CK+]/clusters of differentiation 45–negative [CD45−]) and a subpopulation expressing PD‐L1 (DAPI+/CK+/PD‐L1+/CD45−). PD‐L1+ CTCs were identified in 4 of 49 (8.2%) early‐stage patients, but 12 of 22 (54.5%) locally advanced and 15 of 16 (93.8%) metastatic patients, accurately discriminating early from locally advanced/metastatic HCC (sensitivity = 71.1%, specificity = 91.8%, area under the receiver operating characteristic curve = 0.807; P < 0.001). Compared to patients without PD‐L1+ CTCs, patients with PD‐L1+ CTCs had significantly inferior overall survival (OS) (median OS = 14.0 months vs. not reached, hazard ratio [HR] = 4.0, P = 0.001). PD‐L1+ CTCs remained an independent predictor of OS (HR = 3.22, P = 0.010) even after controlling for Model for End‐Stage Liver Disease score (HR = 1.14, P < 0.001), alpha‐fetoprotein (HR = 1.55, P < 0.001), and overall stage/tumor burden (beyond University of California, San Francisco, HR = 7.19, P < 0.001). In the subset of 10 patients with HCC receiving PD‐1 blockade, all 5 responders demonstrated PD‐L1+ CTCs at baseline, compared with only 1 of 5 nonresponders, all of whom progressed within 4 months of starting treatment. Conclusion: We report a CTC assay for the phenotypic profiling of HCC CTCs expressing PD‐L1. PD‐L1+ CTCs are predominantly found in advanced‐stage HCC, and independently prognosticate OS after controlling for Model for End‐Stage Liver Disease, alpha‐fetoprotein, and tumor stage. In patients with HCC receiving anti‐PD‐1 therapy, there was a strong association with the presence of PD‐L1+ CTCs and favorable treatment response. Prospective validation in a larger cohort will better define the utility of PD‐L1+ CTCs as a prognostic and predictive biomarker in HCC.

Guidelines to evaluate patients for coronary artery disease (CAD) during preoperative evaluation for orthotopic liver transplantation (OLT) are conflicting. Cardiac catheterization is not without risk in patients with end-stage liver disease. No study to date has looked at the utility of non–electrocardiogram-gated chest computed tomography (CT) in the preliver transplant population. Our hypothesis was that coronary artery calcium scores (CACSs) from chest CT scans ordered during the liver transplant workup can identify patients who would benefit from invasive angiography. Nine hundred and fifty-three patients who underwent coronary angiography as part of their OLT workup were considered. Charts were randomly selected and reviewed for the presence of a chest CT performed before coronary angiography during the OLT workup. Agatston and Weston scores were calculated. CACS results were compared with coronary angiography findings. Nine of 54 patients were found to have obstructive CAD by angiography. Receiver-operating characteristic analysis demonstrated that an Agatston score of 251 and a Weston score of 6 maximized sensitivity and specificity for detection of obstructive coronary disease. An Agatston score <4 or Weston score <2 excluded the presence of obstructive CAD; using these thresholds, 13 patients (24%) or 15 patients (28%), respectively, could have theoretically avoided catheterization without missing significant CAD. In conclusion, our data identify the strength of CACS in ruling out coronary disease in patients being evaluated for OLT. Calcium scoring from non–electrocardiogram-gated CT studies may be integrated into preoperative algorithms to rule out obstructive CAD and help avoid invasive angiography in this high-risk population.

Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution versus inflammation activation is unclear. In a murine liver, partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, it also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3β-KO mice. In CD11b-DTR mice, Gsk3β-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver-infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK-deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the proresolving function of liver-infiltrating macrophages in an MerTK-dependent manner.

Ischaemia–reperfusion injury (IRI) in the liver is a major complication of transplantation. This Review outlines our current understanding of the cellular and molecular mechanisms that underlie liver IRI and summarizes the latest progress in large animal models and clinical trials of liver IRI. Ischaemia–reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate–adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia–reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate–adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia–reperfusion inflammation and organ dysfunction. Key Points The cellular damage incurred by organ procurement and preservation affects transplantation outcomes, contributes to donor organ shortage and represents a major risk factor for acute and chronic liver graft rejection Liver ischaemia–reperfusion injury (IRI) is a local proinflammatory response that is mediated by the innate immune system Several pattern recognition receptors, including Toll-like receptor (TLR)4, TLR9 and the inflammasome, are involved in liver immune activation against ischaemia–reperfusion in distinct cell types at different stages of IRI development Different subsets of T cells participate in innate immune responses triggered by ischaemia–reperfusion via positive and negative co-stimulatory pathways Studies of regulated hepatic reperfusion in large animals might lead to successful clinical use of liver grafts procured from extended criteria donors and donation after cardiac death

Liver transplantation has progressed from an experimental procedure to routine operation since the first human liver transplantation in 1963. This Timeline article revisits the important milestones in the development of liver transplantation, discussing how the procedure has evolved over time and what challenges are still to overcome. The first human liver transplant operation was performed by Thomas Starzl in 1963. The next two decades were marked by difficulties with donor organ quality, recipient selection, operative and perioperative management, immunosuppression and infectious complications. Advances in each of these areas transformed liver transplantation from an experimental procedure to a standard treatment for end-stage liver disease and certain cancers. From the handful of pioneering programmes, liver transplantation has expanded to hundreds of programmes in >80 countries. 1-year patient survival rates have exceeded 80% and outcomes continue to improve. This success has created obstacles. Ongoing challenges of liver transplantation include those concerning donor organ shortages, recipients with more advanced disease at transplant, growing need for retransplantation, toxicities and adverse effects associated with long-term immunosuppression, obesity and NASH epidemics, HCV recurrence and the still inscrutable biology of hepatocellular carcinoma. This Perspectives summarizes this transformation over time and details some of the challenges ahead.