Summary
Donation after cardiac death (DCD) liver transplantation is increasingly common but concerns exist over the development of biliary complications and ischemic cholangiopathy (IC). This study ...aimed to compare outcomes between DCD and donation after brain death (DBD) liver grafts. Studies reporting on post‐transplantation outcomes after Maastricht category III DCD liver transplantation were screened for inclusion. Odds ratios (OR) with 95% confidence intervals were produced using random‐effects models for the incidence of biliary complications, IC, graft and recipient survival. Meta‐regression was undertaken to identify between‐study predictors of effect size for biliary complications and IC. PROSPERO Record: CRD42012002113. Twenty‐five studies with 62 184 liver transplant recipients (DCD = 2478 and DBD = 59 706) were included. In comparison with DBD, there was a significant increase in biliary complications OR = 2.4 (1.9, 3.1); P < 0.00001 and IC OR = 10.5 (5.7, 19.5); P < 0.00001 following DCD liver transplantation. In comparison with DBD, at 1 year OR = 0.7 (0.5, 0.8); P = 0.0002 and 3 years OR = 0.6 (0.5, 0.8); P = 0.001, there was a significant decrease in graft survival following DCD liver transplantation. At 1 year, there was also a nonsignificant decrease OR = 0.8 (0.6, 1.0); P = 0.08 and by 3 years a significant decrease OR = 0.7 (0.5, 1.0); P = 0.04 found in recipient survival following DCD liver transplantation. Eleven factors were entered into meta‐regression models, but none explained the variability in effect size between studies. DCD liver transplantation is associated with an increase in biliary complications, IC, graft loss and mortality. Significant unexplained differences in effect size exist between centers.
Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological ...matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.
Display omitted
•scRNA-seq reveals spatial zonation of hepatic stellate cells (HSCs)•HSCs partition into topographically diametric lobule regions•Functional zonation of HSCs during centrilobular injury-induced fibrosis is uncovered•LPAR1 is a therapeutic target on pathological central vein-associated HSC
Dobie et al. use scRNA-seq to reveal spatial and functional zonation of hepatic stellate cells (HSCs) across the hepatic lobule, identifying central vein-associated HSCs as the dominant pathogenic collagen-producing cells during centrilobular injury-induced fibrosis. This illustrates the power of scRNA-seq to resolve the key collagen-producing cells driving liver fibrosis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gallstone disease (GD) is one of the most common presentations to surgical units worldwide and shares several risk factors with cardiovascular disease (CVD). CVD remains the most common cause of ...death worldwide and results in considerable economic burden. Recent observational studies have demonstrated an association between GD and CVD with some studies demonstrating a stronger association with cholecystectomy. We present the findings of a meta-analysis assessing the relationship between GD and CVD. A total of fourteen cohort studies with over 1.2 million participants were included. The pooled hazard ratio (HR, 95% confidence interval CI) for association with GD from a random-effects model is 1.23 (95%CI: 1.16-1.30) for fatal and non-fatal CVD events. The association was present in females and males. Three studies report the relationship between cholecystectomy and CVD with a pooled HR of 1.41 (95%CI: 1.21-1.64) which compares to a HR of 1.30 (95%CI: 1.07-1.58) when cholecystectomy is excluded although confounding may influence this result. Our meta-analysis demonstrates a significant relationship between GD and CVD events which is present in both sexes. Further research is needed to assess the influence of cholecystectomy on this association.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
Atypical haemolytic uraemic syndrome (aHUS) is associated with a poor prognosis with regard to survival at presentation, recovery of renal function and transplantation. It is now established ...that aHUS is a disease of complement dysregulation with mutations in the genes encoding both complement regulators and activators, and autoantibodies against the complement regulator factor H. Identification of the underlying molecular abnormality in an individual patient can now help to guide their future management. In these guidelines we make recommendations for the investigation and management of aHUS patients both at presentation and in the long‐term. We particularly address the role of renal transplantation alone and combined liver‐kidney transplantation.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The prognosis of cholangiocarcinoma (CC) is dismal. Notch has been identified as a potential driver; forced exogenous overexpression of Notch1 in hepatocytes results in the formation of biliary ...tumors. In human disease, however, it is unknown which components of the endogenously signaling pathway are required for tumorigenesis, how these orchestrate cancer, and how they can be targeted for therapy. Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide. We find that across species, the atypical receptor NOTCH3 is differentially overexpressed; it is progressively up-regulated with disease development and promotes tumor cell survival via activation of PI3k-Akt. We use genetic KO studies to show that tumor growth significantly attenuates after Notch3 deletion and demonstrate signaling occurs via a noncanonical pathway independent of the mediator of classical Notch, Recombinant Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). These data present an opportunity in this aggressive cancer to selectively target Notch, bypassing toxicities known to be RBPJ dependent.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has ...been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.
Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides ...polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3
Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host.
Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of ...neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.
PDF
