Explore the vast range of titles available.

Immunotherapy is now the standard of care for advanced hepatocellular carcinoma (HCC), yet many patients fail to respond. A major unmet goal is the boosting of T-cells with both strong HCC reactivity and the protective advantages of tissue-resident memory T-cells (T RM ). Here, we show that higher intratumoural frequencies of γδ T-cells, which have potential for HLA-unrestricted tumour reactivity, associate with enhanced HCC patient survival. We demonstrate that γδ T-cells exhibit bona fide tissue-residency in human liver and HCC, with γδT RM showing no egress from hepatic vasculature, persistence for >10 years and superior anti-tumour cytokine production. The Vγ9Vδ2 T-cell subset is selectively depleted in HCC but can efficiently target HCC cell lines sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid. Aminobisphosphonate-based expansion of peripheral Vγ9Vδ2 T-cells recapitulates a T RM  phenotype and boosts cytotoxic potential. Thus, our data suggest more universally effective HCC immunotherapy may be achieved by combining aminobisphosphonates to induce Vγ9Vδ2T RM capable of replenishing the depleted pool, with additional intratumoural delivery to sensitise HCC to Vγ9Vδ2T RM -based targeting. Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.

A two-step process, in which circulating levels of amyloid P are reduced and then anti–serum amyloid P antibody is given to activate macrophage clearance mechanisms of tissue deposits, appears to reduce amyloid deposits in liver and some other organs. In systemic amyloidosis, the extracellular deposition of normally soluble plasma proteins as insoluble amyloid fibrils damages the structure and function of tissues and organs. 1 Current treatment consists of support or replacement of failing organs and measures to reduce the abundance of the amyloid fibril precursor protein. 1 , 2 A sufficient reduction of precursor supply arrests the accumulation of amyloid and can reduce morbidity and mortality. However, amyloid regression is very slow and often does not occur at all, in contrast to the usually swift clearance of other extracellular debris and efficient tissue remodeling — for example, after trauma. At least 65% . . .

Liver synthetic and metabolic function can only be optimised by the growth of cells within a supportive liver matrix. This can be achieved by the utilisation of decellularised human liver tissue. Here we demonstrate complete decellularization of whole human liver and lobes to form an extracellular matrix scaffold with a preserved architecture. Decellularized human liver cubic scaffolds were repopulated for up to 21 days using human cell lines hepatic stellate cells (LX2), hepatocellular carcinoma (Sk-Hep-1) and hepatoblastoma (HepG2), with excellent viability, motility and proliferation and remodelling of the extracellular matrix. Biocompatibility was demonstrated by either omental or subcutaneous xenotransplantation of liver scaffold cubes (5 × 5 × 5 mm) into immune competent mice resulting in absent foreign body responses. We demonstrate decellularization of human liver and repopulation with derived human liver cells. This is a key advance in bioartificial liver development.

[...]complexity has been introduced by the recent description of the entity termed 'acute on chronic liver failure' (ACLF) which refers to a very rapid progression of liver injury and multiorgan failure in cirrhotic patients at all stages following a defined or an undefined precipitating illness. 3 The aetiology of chronic liver disease has a profound impact on the pattern of fibrotic evolution and on the relative predominant mechanism It is increasingly clear that different CLDs are characterised by different predominant profibrogenic mechanisms and, while cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrosis development in different and even within the same CLD ( figure 1 ). For these and other reasons (sampling error, lack of adequate standards, etc), the value of liver biopsy as a gold standard slowly became questionable for clinicians and pathologists particularly when biopsy started to be used almost exclusively for the identification of 'disease stage', that is, the extent of tissue fibrosis and, accordingly, fibrosis and stage have been confused in histological staging systems. 75 A hyperdynamic circulation is a hallmark of advanced cirrhosis. 76 Norfloxacin partially reversed the hyperdynamic circulation in cirrhotic patients. 74 Similar observations were made with rifaximin, which resulted in an improvement in systemic haemodynamics in patients with alcoholic cirrhosis and ascites, 77 which also reduced portal pressure in animal models.

Objective Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive. Design Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays. Results In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib. Conclusions Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.

Background Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented. Methods The associations of nutritional status and sarcopenia with post‐transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital‐Global Assessment (RFH‐GA) tool and the L3‐psoas muscle index (L3‐PMI) on CT, respectively. Results A wide range of RFH‐SGA and L3‐PMI were observed within similar Model for End‐stage Liver Disease (MELD) sub‐categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post‐transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002–1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99–21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036–1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48–48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056–5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004–1.106), MELD (OR = 1.137, 95%CI = 1.057–1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57–35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004–4.419) and L3‐PMI (OR = 0.996, 95%CI = 0.994–0.999); 1 year mortality with L3‐PMI (OR = 0.996, 95%CI = 0.992–0.999). Patients at the lowest L3‐PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections. Conclusions Malnutrition and sarcopenia are associated with early post‐liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.

ObjectiveChromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown.DesignDNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors. Chk2 was also determined in two discrete cohorts of human HCC specimens. To assess the functional role of Chk2, gain on and loss-of-function, mutagenesis, karyotyping and immunofluorescence/live imaging were performed by using HCT116, Huh7 and human hepatocytes immortalised with hTERT gene (HuS).ResultsWe demonstrate that mitotic errors during HCC tumorigenesis cause lagging chromosomes/DNA damage and activation of Chk2. Overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to induce lagging chromosomes. Lagging chromosomes and mitotic activity are reversed by knockdown of Chk2. Furthermore, upregulated Chk2 maintains mitotic activity interacting with Aurora B kinase for chromosome condensation and cytokinesis. The forkhead-associated domain of Chk2 is required for Chk2 mislocalisation to mitotic structures. In addition, retinoblastoma protein phosphorylation contributes to defective mitoses. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC.ConclusionsThe study reveals a new mechanistic insight in the coinvolvement of Chk2 in HCC progression. These findings propose Chk2 as a putative biomarker to detect CIN in HCC providing a valuable support for clinical/therapeutical management of patients.

The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue. ALTCs were engineered with human parenchymal and non-parenchymal liver cell lines (HepG2 and LX2 cells, respectively), human umbilical vein endothelial cells (HUVEC), as well as primary human hepatocytes and hepatic stellate cells. Both parenchymal and non-parenchymal liver cells grown in ALTCs exhibited markedly different gene expression when compared to standard 2D cell cultures. Remarkably, HUVEC cells naturally migrated in the ECM scaffold and spontaneously repopulated the lining of decellularized vessels. The metabolic function and protein synthesis of engineered liver scaffolds with human primary hepatocytes reseeded under dynamic conditions were maintained. These results provide a solid basis for the establishment of effective protocols aimed at recreating human liver tissue in vitro .

The term “liver tissue engineering” summarizes one of the ultimate goals of modern biotechnology: the possibility of reproducing in total or in part the functions of the liver in order to treat acute or chronic liver disorders and, ultimately, create a fully functional organ to be transplanted or used as an extracorporeal device. All the technical approaches in the area of liver tissue engineering are based on allocating adult hepatocytes or stem cell‐derived hepatocyte‐like cells within a three‐dimensional structure able to ensure their survival and to maintain their functional phenotype. The hosting structure can be a construct in which hepatocytes are embedded in alginate and/or gelatin or are seeded in a pre‐arranged scaffold made with different types of biomaterials. According to a more advanced methodology termed three‐dimensional bioprinting, hepatocytes are mixed with a bio‐ink and the mixture is printed in different forms, such as tissue‐like layers or spheroids. In the last decade, efforts to engineer a cell microenvironment recapitulating the dynamic native extracellular matrix have become increasingly successful, leading to the hope of satisfying the clinical demand for tissue (or organ) repair and replacement within a reasonable timeframe. Indeed, the preclinical work performed in recent years has shown promising results, and the advancement in the biotechnology of bioreactors, ex vivo perfusion machines, and cell expansion systems associated with a better understanding of liver development and the extracellular matrix microenvironment will facilitate and expedite the translation to technical applications. (Hepatology Communications 2018;2:131–141) The term “liver tissue engineering” summarizes one of the ultimate goals of modern biotechnology: the possibility of reproducing in total or in part the functions of the liver in order to treat acute or chronic liver disorders and, ultimately, create a fully functional organ to be transplanted or used as extracorporeal device.