A randomized trial of normothermic preservation in liver transplantation.

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing.

Expression of Fibrogenic Markers in Tumor and Tumor-Surrounding Tissue at Time of Transplantation Correlates with Recurrence of Hepatocellular Carcinoma in Patients Undergoing Liver Transplantation.

BACKGROUND Liver transplantation (LT) remains the only curative treatment option for patients with defined stages of hepatocellular carcinoma (HCC). Up to 25% of patients show a tumor recurrence following transplantation. The correlation of fibrogenic markers prior to LT with HCC recurrence has not been characterized.

Reconditioning by end-ischemic hypothermic in-house machine perfusion: A promising strategy to improve outcome in expanded criteria donors kidney transplantation.

This clinical study evaluates end-ischemic hypothermic machine perfusion (eHMP) in expanded criteria donors (ECD) kidneys. eHMP was initiated upon arrival of the kidney in our center and continued until transplantation. Between 11/2011 and 8/2014 eHMP was performed in 66 ECD kidneys for 369 (98-912) minutes after 863 (364-1567) minutes of cold storage (CS).

A -1573T>C SNP within the human TRAIL promoter determines TRAIL expression and HCC tumor progression.

The cytokine tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in liver cancer cells but not in normal liver cells. Therefore, TRAIL got credited to play a role in hepatocellular carcinoma (HCC) development and progression. Impaired expression of TRAIL in HCC cells and sequence variations in the TRAIL promoter may facilitate development, growth, and spread .

Morbidity and Mortality Rounds in Liver Transplantation.

Background: Morbidity and mortality conferences (MMCs) provide powerful opportunities for learning, reflection, and improvement. The current literature gives examples of how MMCs can be designed; however, no systematic review of cases and no original data related to liver transplantation are available. Liver transplantation requires a multidisciplinary approach to case identification, presentation, and analysis.

Past, Present, and Future of Dynamic Kidney and Liver Preservation and Resuscitation.

The increased demand for organs has led to the increased usage of "higher risk" kidney and liver grafts. These grafts from donation after circulatory death or expanded criteria donors are more susceptible to preservation injury and have a higher risk of unfavorable outcomes. Dynamic, instead of static, preservation could allow for organ optimization, offering a platform for viability assessment, active organ repair and resuscitation.

Hypothermic machine perfusion in kidney transplantation.

Purpose Of Review: This article summarizes novel developments in hypothermic machine perfusion (HMP) as an organ preservation modality for kidneys recovered from deceased donors.

Recent Findings: HMP has undergone a renaissance in recent years. This renewed interest has arisen parallel to a shift in paradigms; not only optimal preservation of an often marginal quality graft is required, but also improved graft function and tools to predict the latter are expected from HMP.

Immunohistochemical Markers Distinguishing Cholangiocellular Carcinoma (CCC) from Pancreatic Ductal Adenocarcinoma (PDAC) Discovered by Proteomic Analysis of Microdissected Cells.

Cholangiocellular carcinoma (CCC) and pancreatic ductal adenocarcinoma (PDAC) are two highly aggressive cancer types that arise from epithelial cells of the pancreatobiliary system. Owing to their histological and morphological similarity, differential diagnosis between CCC and metastasis of PDAC located in the liver frequently proves an unsolvable issue for pathologists. The detection of biomarkers with high specificity and sensitivity for the differentiation of these tumor types would therefore be a valuable tool.

Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice.

Background & Aims: Hepatic stellate cells (HSCs) activate during injury to orchestrate the liver's inflammatory and fibrogenic responses. A critical feature of HSC activation is the rapid induction of beta platelet-derived growth factor (β-PDGFR), which drives cellular fibrogenesis and proliferation; in contrast, normal liver has minimal β-PDGFR expression. While the role of β-PDGFR is well established in liver injury, its expression and contribution during liver regeneration are unknown.

β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.

Background & Aims: Rapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis.

Methods: The impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation.

Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils.

Neutrophils are the most abundant cell type in the immune system and play an important role in the innate immune response. Using a diverse range of mouse models with either defective dendritic cell (DC) development or conditional DC depletion, we provide in vivo evidence indicating that conventional DCs play an important role in the regulation of neutrophil homeostasis. Flk2, Flt3L, and Batf3 knockout mice, which have defects in DC development, have increased numbers of liver neutrophils in the steady state.

Post-transcriptional activation of PPAR alpha by KLF6 in hepatic steatosis.

Background & Aims: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling.

Methods: Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks.

Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis.

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD.

Cellular basis of hepatic fibrosis and its role in inflammation and cancer.

Multiple etiologies of liver injury can lead to fibrosis, which results from an imbalance between production and resorption of extracellular matrix. Hepatic stellate cells (HSCs), resident vitamin A storing cells, play a vital role in the response to injury. Upon activation, HSCs orchestrate the responsiveness of the liver to different types of injury, leading to deposition of excessive scar matrix into the interstitium as a wound-healing response.

GSK3β phosphorylation of the KLF6 tumor suppressor promotes its transactivation of p21.

KLF6, a ubiquitously expressed Krüppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several cancer-derived KLF6 mutants lead to the loss of p21-mediated growth suppression through an unknown mechanism.

Enhanced hepatocarcinogenesis in mouse models and human hepatocellular carcinoma by coordinate KLF6 depletion and increased messenger RNA splicing.

Unlabelled: KLF6-SV1 (SV1), the major splice variant of KLF6, antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis and to elucidate its mechanism of action.

A polymorphism that delays fibrosis in hepatitis C promotes alternative splicing of AZIN1, reducing fibrogenesis.

Unlabelled: Among several single-nucleotide polymorphisms (SNPs) that correlate with fibrosis progression in chronic HCV, an SNP in the antizyme inhibitor (AzI) gene is most strongly associated with slow fibrosis progression. Our aim was to identify the mechanism(s) underlying this observation by exploring the impact of the AzI SNP on hepatic stellate cell (HSC) activity. Seven novel AZIN1 splice variants ("SV2-8") were cloned by polymerase chain reaction from the LX2 human HSC line.

Does long-term ventilation with PEEP > or = 10mbar influence graft-function in patients following liver transplantation?

Background/aims: Long-term positive end-expiratory pressure (PEEP) ventilation, particular with PEEP up to 15 mbar may impair graft-function in liver transplant (LT) patients. The aim of our study was to evaluate the impact of long-term high PEEP (at least 48 hours) on liver graft function. We retrospectively reviewed the records of 50 patients, who required artificial ventilation for at least 1 week with a PEEP level > or = 10mbar due to pulmonary complication caused mainly by sepsis (n = 19), pneumonia (n = 7) and lung edema associated with reperfusion syndrome or primary non-function of the graft (n = 13).

Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury.

Background & Aims: Predicting the probability of patients with acute liver failure (ALF) to recover spontaneously is of major clinical importance. As apoptotic and necrotic cell death are crucial in the pathogenesis of ALF, we determined whether selected cell-death markers predict outcome of patients with ALF and/or discriminate between etiologies.

Methods: In a prospective study (11/2006-06/2009), 68 ALF patients were recruited consecutively.

Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis.

Unlabelled: Stress-induced soluble major histocompatibility complex class I-related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity.