Grupos Investigadores

Miembros del Grupo

Investigadores
Maite
García Fernández de Barrena, (Co-coordinadora)
Iker
Uriarte Díaz-Varela
Colaboradores
Roberto Carlos
Barbero Lopez
Miriam
Belzunce Saldise

Líneas de Investigación

  • Colangiocarcinogénesis
  • Hepatocarcinogénesis
  • Porfirias: mecanismos patogénicos, carcinogénesis y terapias innovadoras

Palabras Clave

  • Biopsia líquida
  • Carcinoma hepatocelular
  • Colangiocarcinoma
  • Dianas epigenéticas
  • Enfermedad metabólica hepática
  • Hepatoblastoma
  • Inmunoterapia
  • Mecanismos moleculares
  • Metabolismo del hemo
  • Porfiria aguda intermitente
  • Terapias biológicas

Publicaciones Científicas desde 2018

  • Autores: Rodríguez-Agudo, R.; González-Recio, I.; Serrano-Maciá, M.; et al.
    Revista: JHEP REPORTS
    ISSN: 2589-5559 Vol.6 N° 1 2024 págs. 100918
    Resumen
    Background & Aims: Current therapies for the treatment of alcohol-related liver disease (ALD) have proven largely ineffective. Patients relapse and the disease progresses even after liver transplantation. Altered epigenetic mechanisms are characteristic of alcohol metabolism given excessive acetate and NAD depletion and play an important role in liver injury. In this regard, novel therapeutic approaches based on epigenetic modulators are increasingly proposed. MicroRNAs, epigenetic modulators acting at the post-transcriptional level, appear to be promising new targets for the treatment of ALD. Methods: MiR-873-5p levels were measured in 23 liver tissue from Patients with ALD, and GNMT levels during ALD were confirmed using expression databases (transcriptome n = 62, proteome n = 68). High-resolution proteomics and metabolomics in mice following the Gao-binge model were used to investigate miR-873-5p expression in ALD. Hepatocytes exposed to 50 mM alcohol for 12 h were used to study toxicity. The effect of anti-miR-873-5p in the treatment outcomes of ALD was investigated. Results: The analysis of human and preclinical ALD samples revealed increased expression of miR-873-5p in the liver. Interestingly, there was an inverse correlation with NNMT, suggesting a novel mechanism for NAD depletion and aberrant acetylation during ALD progression. High-resolution proteomics and metabolomics identified miR-873-5p as a key regulator of NAD metabolism and SIRT1 deacetylase activity. Anti-miR-873-5p reduced NNMT activity, fuelled the NAD salvage pathway, restored the acetylome, and modulated the levels of NF-KB and FXR, two known SIRT1 substrates, thereby protecting the liver from apoptotic and inflammatory processes, and improving bile acid homeostasis. Conclusions: These data indicate that targeting miR-873-5p, a repressor of GNMT previously associated with NAFLD and acetaminophen-induced liver failure. is a novel and attractive approach to treating alcohol-induced hepatoxicity. Impact and implications: The role of miR-873-5p has not been explicitly examined in the progression of ALD, a pathology with no therapeutic options. In this study, inhibiting miR-873-5p exerted hepatoprotective effects against ALD through rescued SIRT1 activity and consequently restored bile acid homeostasis and attenuated the inflammatory response. Targeting hepatic miR-873-5p may represent a novel therapeutic approach for the treatment of ALD. (c) 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Autores: Rimassa, L. (Autor de correspondencia); Finn, R. S.; Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.79 N° 2 2023 págs. 506 - 515
    Resumen
    Single-agent immune checkpoint inhibitors (ICIs) have been tested in patients with advanced hepatocellular carcinoma (HCC), leading to objective response rates of 15-20%, mostly without a significant overall survival (OS) benefit. Furthermore, approximately 30% of HCC exhibits intrinsic resistance to ICIs. In the absence of predictive biomarkers to identify patients likely to benefit most from immunotherapy, research has moved to exploring combinations with potential activity in broader patient populations. Basket trials, including cohorts of patients with HCC, and early phase studies tested the combination of ICIs with anti-angiogenic agents as well as the combination of two different ICIs. The promising results that were achieved provided the rationale for the following phase III trials, which tested the combination of anti-PD-1/PD-L1 antibodies with bevacizumab, or tyrosine kinase inhibitors, or anti-CTLA-4 antibodies. Positive results from the IMbrave150 trial led to the practice-changing approval of atezolizumab-bevacizumab, the first regimen to demonstrate improved survival in the front-line setting since the approval of sorafenib. More recently, the HIMALAYA trial demonstrated the superiority of durvalumab-tremelimumab (STRIDE regimen) over sorafenib, establishing a new first-line option. In contrast, inconsistent results have been achieved with combinations of ICIs and tyrosine kinase inhibitors, with only one phase III trial showing an OS benefit. The rapid evolution of the therapeutic landscape for patients with advanced HCC has left many unanswered questions that will need to be addressed by future research. These include the choice and sequencing of treatments, identification of biomarkers, combinations with locoregional therapies, and development of new immunotherapy agents. This review summarises the scientific rationale and available clinical data for combination immunotherapy in advanced HCC. & COPY; 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Autores: Berasain Lasarte, María del Carmen (Autor de correspondencia); Arechederra Calderon, Maria; Argemí Ballbé, José María; et al.
    Revista: JOURNAL OF HEPATOLOGY
    ISSN: 1600-0641 Vol.78 N° 2 2023 págs. 401 - 414
    Resumen
    Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.Adult hepatocytes' identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors (TFs), along with pre-mRNA splice regulators (SRs) define the transcriptome encoding the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can be part of the liver regenerative mechanisms triggered in acute injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core TFs and SRs that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, would be of high clinical relevance. In this context, here we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4alpha, which impairment mediate the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core TFs expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate the organ's histology. The possibility of correcting the phenotype of severely damaged and malfunctional livers may open new therapeutic opportunities for patients with cirrhosis and advanced liver disease.
  • Autores: Sangro del Alcazar, Paloma (Autor de correspondencia); de la Torre Aláez, Manuel Antonio (Autor de correspondencia); Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
    ISSN: 1138-7548 Vol.79 N° 4 2023 págs. 869 - 879
    Resumen
    Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.
  • Autores: Solares, I.; Jericó Asenjo, Daniel; Córdoba Quiñones, Karol Marcela; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.24 N° 1 2023 págs. 51
    Resumen
    Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking alpha-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.
  • Autores: Ducreux, M. (Autor de correspondencia); Abou-Alfa, G. K.; Bekaii-Saab, T.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.8 N° 3 2023 págs. 101567
    Resumen
    This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.
  • Autores: Appenzeller-Herzog, C. (Autor de correspondencia); Rosat, A.; Mathes, T.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN: 1478-3223 Vol.44 N° 1 2023 págs. 250 - 262
    Resumen
    Background & AimsSuccessful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term pre-withdrawal time. To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis.MethodsWe systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses.ResultsWe included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively).ConclusionsOur data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.
  • Autores: Martín Navarro, Loreto Giesela; De Andrea, Carlos Eduardo; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: JOURNAL OF HEPATOLOGY
    ISSN: 1600-0641 Vol.78 N° 1 2023 págs. e20 - e22
  • Autores: Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia); Argemí Ballbé, José María
    Revista: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
    ISSN: 1051-0443 Vol.34 N° 6 2023 págs. 976 - 977
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° 5 2023 págs. 885 - 888
  • Autores: Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
    Revista: GUT
    ISSN: 0017-5749 2023 págs. 329322
  • Autores: García Fernández de Barrena, Maite; Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
    Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
    ISSN: 1138-7548 Vol.79 N° 4 2023 págs. 811 - 813
  • Autores: Hernaez, R. (Autor de correspondencia); Ávila Zaragoza, Matías Antonio
    Revista: GUT
    ISSN: 0017-5749 Vol.72 N° 1 2023 págs. 7 - 9
  • Autores: Spoto, S.; Basili, S.; Cangemi, R.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.24 N° 24 2023 págs. 17429
    Resumen
    Sepsis causes immune dysregulation and endotheliitis, with an increase in mid-regional pro-adrenomedullin (MR-proADM). The aim of the study is to determine an MR-proADM value that, in addition to clinical diagnosis, can identify patients with localized infection or those with sepsis/septic shock, with specific organ damage or with the need for intensive care unit (ICU) transfer and prognosis. The secondary aim is to correlate the MR-proADM value with the length of stay (LOS). In total, 301 subjects with sepsis (124/301 with septic shock) and 126 with localized infection were retrospectively included. In sepsis, MR-proADM ¿ 3.39 ng/mL identified acute kidney injury (AKI); ¿2.99 ng/mL acute respiratory distress syndrome (ARDS); ¿2.28 ng/mL acute heart failure (AHF); ¿2.55 ng/mL Glascow Coma Scale (GCS) < 15; ¿3.38 multi-organ involvement; ¿3.33 need for ICU transfer; ¿2.0 Sequential Organ Failure Assessment (SOFA) score ¿ 2; and ¿3.15 ng/mL non-survivors. The multivariate analysis showed that MR-proADM ¿ 2 ng/mL correlates with AKI, anemia and SOFA score ¿ 2, and MR-proADM ¿ 3 ng/mL correlates with AKI, GCS < 15 and SOFA score ¿ 2. A correlation between mortality and AKI, GCS < 15, ICU transfer and cathecolamine administration was found. In localized infection, MR-proADM at admission ¿ 1.44 ng/mL identified patients with AKI; ¿1.0 ng/mL with AHF; and ¿1.44 ng/mL with anemia and SOFA score ¿ 2. In the multivariate analysis, MR-proADM ¿ 1.44 ng/mL correlated with AKI, anemia, SOFA score ¿ 2 and AHF. MR-proADM is a marker of oxidative stress due to an infection, reflecting severity proportionally to organ damage.
  • Autores: Carmona-Rodríguez, L.; Gajadhar, A. S.; Blázquez-García, I.; et al.
    Revista: BIOFACTORS
    ISSN: 0951-6433 Vol.49 N° 4 2023 págs. 912 - 927
    Resumen
    The liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR-FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14-3-3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow-up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.
  • Autores: Goikoetxea-Usandizaga, N.; Bravo, M.; Egia-Mendikute, L.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.78 N° 3 2023 págs. 878 - 895
    Resumen
    Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as anendogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/ NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.
  • Autores: Bakr, S.; Brennan, K.; Mukherjee, P.; et al.
    Revista: CELL REPORTS. METHODS
    ISSN: 2667-2375 Vol.3 N° 1 2023 págs. 100392
    Resumen
    Despite the abundance of multimodal data, suitable statistical models that can improve our understanding of diseases with genetic underpinnings are challenging to develop. Here, we present SparseGMM, a statistical approach for gene regulatory network discovery. SparseGMM uses latent variable modeling with sparsity constraints to learn Gaussian mixtures from multiomic data. By combining coexpression patterns with a Bayesian framework, SparseGMM quantitatively measures confidence in regulators and uncertainty in target gene assignment by computing gene entropy. We apply SparseGMM to liver cancer and normal liver tissue data and evaluate discovered gene modules in an independent single-cell RNA sequencing (scRNA-seq) dataset. SparseGMM identifies PROCR as a regulator of angiogenesis and PDCD1LG2 and HNF4A as regu-lators of immune response and blood coagulation in cancer. Furthermore, we show that more genes have significantly higher entropy in cancer compared with normal liver. Among high-entropy genes are key multifunctional components shared by critical pathways, including p53 and estrogen signaling.
  • Autores: Herranz, J. M.; López Pascual, Amaya; Clavería Cabello, Alex; et al.
    Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
    ISSN: 1138-7548 Vol.79 N° 4 2023 págs. 901 - 924
    Resumen
    Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes' expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.
  • Autores: Aguilar-Bravo, B.; Arino, S.; Blaya, D.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.79 N° 3 2023 págs. 728 - 740
    Resumen
    Background & aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results: Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Impact and implications: Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
  • Autores: Aliseda Jover, Daniel (Autor de correspondencia); Zozaya Larequi, Gabriel Nicolás; Marti-Cruchanga, P.; et al.
    Revista: BJS OPEN
    ISSN: 2474-9842 Vol.7 N° 2 2023 págs. zrad037
  • Autores: Longo, M.; Jericó Asenjo, Daniel; Córdoba Quiñones, Karol Marcela; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1661-6596 Vol.24 N° 15 2023 págs. 11938
    Resumen
    Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (similar to 1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.
  • Autores: Ruíz de Galarreta Martínez, Marina; Arriazu Ruiz, Elena; Pérez de Obanos Martell, María Pilar; et al.
    Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
    ISSN: 1138-7548 Vol.79 N° 4 2023 págs. 881 - 890
    Resumen
    Ocoxin is a nutritional supplement that has been shown to exert antioxidant and immunomodulatory responses in patients with chronic hepatitis C. The present work aimed to determine the effects of Ocoxin on activated hepatic stellate cells (HSC), the cell type mainly responsible for collagen deposition in the fibrotic liver. Ocoxin was found to reduce the survival of a cell line of immortalized non-tumoral rat HSC in a dose-response fashion and to diminish collagen type I levels. This latter effect was observed even at doses not affecting cell survival, pointing to an antifibrogenic action for the supplement. The decrease in viability exerted by Ocoxin on HSC correlated with an increase in histone-associated fragments in the cytoplasm and with increased activity of caspase-3, indicating the induction of apoptosis. To determine the molecular mechanisms mediating Ocoxin-induced apoptosis, the activation of members of the MAPK family was analyzed. Incubation of HSC with Ocoxin caused a transient and dramatic enhancement on ERK, JNK, and p38 MAPK phosphorylation levels. Using specific inhibitors for these enzymes, p38 MAPK was identified as a key mediator of the apoptotic effect of Ocoxin on HSC.
  • Autores: Morón-Ros, S.; Blasco-Roset, A.; Navarro-Gascon, A.; et al.
    Revista: JOURNAL OF PATHOLOGY
    ISSN: 0022-3417 Vol.261 N° 3 2023 págs. 335-348
    Resumen
    FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium.(c) 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
  • Autores: Maleux, G.; Albrecht, T.; Arnold, D.; et al.
    Revista: CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
    ISSN: 0174-1551 Vol.46 N° 7 2023 págs. 852 - 867
    Resumen
    BackgroundUsing data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours.MethodsWe analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS).ResultsAll-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade >= 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS.ConclusionOur study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.
  • Autores: Abou-Alfa, G. K. (Autor de correspondencia); Lau, G.; Kudo, M.; et al.
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.19 N° 38 2023 págs. 2505 - 2516
    Resumen
    What is this summary about?: This is a summary of results from a phase 3 clinical study called HIMALAYA. HIMALAYA looked at treatment with one dose of a medication called tremelimumab combined with multiple doses of a medication called durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone. These treatments were compared with a medication called sorafenib in participants with unresectable hepatocellular carcinoma (HCC). HCC is a type of liver cancer that is difficult to treat because it is often diagnosed when it is unresectable, meaning it can no longer be removed with surgery. Sorafenib has been the main treatment for unresectable HCC since 2007. However, people who take sorafenib may experience side effects that can reduce their quality of life, so alternative medicines are being trialed. Tremelimumab and durvalumab are types of drugs called immunotherapies, and they both work in different ways to help the body's immune system fight cancer. What were the results of the study?: Participants who took STRIDE lived longer than participants who took sorafenib, whilst participants who took durvalumab alone lived a similar length of time as participants who took sorafenib. Participants who took STRIDE or durvalumab had a lower relative risk of experiencing worsening in their quality of life than participants who took sorafenib. The side effects that participants who received STRIDE or durvalumab experienced were expected for these types of treatments and could mostly be managed. What do the results of the study mean?: Overall, STRIDE is more effective than sorafenib for people with unresectable HCC.
  • Autores: Surov, A. (Autor de correspondencia); Thormann, M.; Hinnerichs, M.; et al.
    Revista: HEPATOLOGY COMMUNICATIONS
    ISSN: 2471-254X Vol.7 N° 6 2023 págs. e0165
    Resumen
    Background:Body composition parameters have been reported to be prognostic factors in patients with oncologic diseases. However, the available data on patients with HCC are conflicting. The aim of this study was to assess the impact of body composition on survival in patients with HCC treated with sorafenib or selective internal radioembolization (SIRT) and sorafenib. Methods:This is an exploratory subanalysis of the prospective, randomized controlled SORAMIC trial. Within the palliative arm of the study, patients were selected if a baseline abdominal CT was available. A broad set of skeletal muscle and adipose tissue parameters were measured at the L3 level. Low skeletal muscle mass (LSMM) and density parameters were defined using published cutoffs. The parameters were correlated with overall survival. Results:Of 424 patients in the palliative study arm, 369 patients were included in the analysis. There were 192 patients in the combined sorafenib/SIRT and 177 patients in the sorafenib group. Median overall survival was 9.9 months for the entire cohort and 10.8 and 9.2 months for the SIRT/sorafenib and sorafenib groups, respectively. There was no relevant association of either body composition parameter with overall survival in either the overall cohort or in the SIRT/sorafenib or sorafenib subgroups. Conclusions:This subanalysis of the prospective SORAMIC trial does not suggest a relevant influence of body composition parameters of survival in patients with advanced HCC. Body composition parameters therefore do not serve in patient allocation in this palliative treatment cohort.
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Yau, T.; El- Khoueiry, A. B.; et al.
    Revista: CTS-CLINICAL AND TRANSLATIONAL SCIENCE
    ISSN: 1752-8054 Vol.16 N° 8 2023 págs. 1445 - 1457
    Resumen
    This analysis was conducted to inform dose selection of a combination of nivolumab plus ipilimumab for the treatment of sorafenib-experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open-label, multicohort, phase I/II trial in adults with advanced HCC that evaluated nivolumab monotherapy (0.1-10 mg/kg once every 2 weeks [q2w]) and the following three combinations of nivolumab plus ipilimumab: (1) nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks (q3w) for four doses, followed by nivolumab monotherapy 240 mg q2w (arm A); (2) nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w (arm B); and (3) nivolumab 3 mg/kg q2w plus ipilimumab 1 mg/kg every 6 weeks continuously (arm C). Exposure-response relationships (efficacy and safety) were characterized using nivolumab and ipilimumab concentrations after the first dose (Cavg1) as the exposure measure. Objective tumor response (OTR) and overall survival (OS) improvements were associated with increased ipilimumab exposure (OTR: odds ratio 1.45, 95% confidence interval [CI], 1.13-1.86; OS: hazard ratio 0.86, 95% CI 0.75-0.98), but not nivolumab exposure (OTR: odds ratio 0.99, 95% CI 0.97-1.02; OS: hazard ratio 1.08, 95% CI 0.89-1.32). Hepatic treatment-related and immune-mediated adverse events were more common in arm A than in arms B or C. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg q3w for four doses, followed by nivolumab monotherapy 240 mg q2w had the most favorable benefit:risk profile in patients with advanced HCC.
  • Autores: Salem, R. (Autor de correspondencia); Padia, S. A.; Lam, M.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.50 N° 2 2023 págs. 328 - 343
    Resumen
    Purpose In light of recently published clinical reports and trials, the TheraSphere Global Dosimetry Steering Committee (DSC) reconvened to review new data and to update previously published clinical and dosimetric recommendations for the treatment of hepatocellular carcinoma (HCC). Methods The TheraSphere Global DSC is comprised of health care providers across multiple disciplines involved in the treatment of HCC with yttrium-90 (Y-90) glass microsphere-based transarterial radioembolization (TARE). Literature published between January 2019 and September 2021 was reviewed, discussed, and adjudicated by the Delphi method. Recommendations included in this updated document incorporate both the results of the literature review and the expert opinion and experience of members of the committee. Results Committee discussion and consensus led to the expansion of recommendations to apply to five common clinical scenarios in patients with HCC to support more individualized efficacious treatment with Y-90 glass microspheres. Existing clinical scenarios were updated to reflect recent developments in dosimetry approaches and broader treatment paradigms evolving for patients presenting with HCC. Conclusion Updated consensus recommendations are provided to guide clinical and dosimetric approaches for the use of Y-90 glass microsphere TARE in HCC, accounting for disease presentation, tumor biology, and treatment intent.
  • Autores: Öcal, O.; Zech, C. J.; Fabritius, M. P.; et al.
    Revista: EUROPEAN RADIOLOGY
    ISSN: 0938-7994 Vol.33 N° 1 2023 págs. 493 - 500
    Resumen
    Objectives To identify clinical and imaging parameters associated with progression of non-hypervascular hepatobiliary phase hypointense lesions during follow-up in patients who received treatment for hepatocellular carcinoma. Methods A total of 67 patients with 106 lesions were identified after screening 538 patients who underwent gadoxetic acid-enhanced MRI within the SORAMIC trial. All patients were allocated to the trial treatment according to the trial scheme, and 61 of 67 patients received systemic treatment with sorafenib (either alone or combined with locoregional therapies) during the trial period. Follow-up images after treatment according to trial scheme were reviewed for subsequent hypervascularization or > 1 cm size increase. The correlation between progression and several imaging and clinical parameters was assessed using univariable and multivariable analyses. Results On a median 178 (range, 48-1072) days follow-up period, progression was encountered in 18 (16.9%) lesions in 12 (17.9%) patients. In univariable analysis size > 12.6 mm (p = 0.070), ECOG-PS (p = 0.025), hypointensity at T1-weighted imaging (p = 0.028), hyperintensity at T2-weighted imaging (p < 0.001), hyperintensity at DWI images (p = 0.007), and cirrhosis (p = 0.065) were correlated with progression during follow-up. Hyperintensity at T2 images (p = 0.011) was an independent risk factor for progression in multivariable analysis, as well as cirrhosis (p = 0.033) and ECOG-PS (p = 0.030). Conclusions Non-hypervascular hepatobiliary phase hypointense lesions are associated with subsequent progression after treatment in patients with HCC. T2 hyperintensity, diffusion restriction, cirrhosis, and higher ECOG-PS could identify lesions with increased risk. These factors should be considered for further diagnostic evaluation or treatment of such lesions.
  • Autores: Aliseda Jover, Daniel; Martí Cruchaga, Pablo; Zozaya Larequi, Gabriel Nicolás; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.15 N° 3 2023 págs. 733
    Resumen
    Simple Summary Radioembolization is a locoregional therapy used in primary liver malignancies with different applications depending on the treatment goal. The aim of this retrospective study was to evaluate postoperative and long-term survival outcomes of patients with unresectable or high biological risk HCC and ICC treated with RE that were finally rescued to liver surgery with curative intent. In a cohort of 34 patients, we assessed that liver resection and transplantation after RE seem safe and feasible with adequate short-term outcomes. Moreover, long-term outcomes after RE and LR were optimal, with a 10-year OS rate greater than 50% for HCC and ICC patients. On the other hand, the 10-year OS rates from RE were also greater than 50% for patients with HCC downstaged or bridged to LT. Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.
  • Autores: Clavería Cabello, Alex; Herranz, J. M.; Latasa Sada, María Ujué; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.79 N° 4 2023 págs. 989 - 1005
    Resumen
    Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models.Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed.Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of I3-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming.Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
  • Autores: Alvarado-Tapias, E.; Martí-Aguado, D.; Kennedy, K.; et al.
    Revista: OBESITY SURGERY
    ISSN: 0960-8923 Vol.33 N° 5 2023 págs. 1494 - 1505
    Resumen
    Background/Aims Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated.Methods A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching.Results The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD.Conclusions Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency.
  • Autores: Leineweber, C. G.; Rabehl, M.; Pietzner, A.; et al.
    Revista: FRONTIERS IN PHARMACOLOGY
    ISSN: 1663-9812 Vol.14 2023 págs. 1124214
    Resumen
    Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.
  • Autores: Zheng, K.; Hao, F.; Medrano-Garcia, S.; et al.
    Revista: CELL DEATH AND DISEASE
    ISSN: 2041-4889 Vol.14 N° 8 2023 págs. 514
    Resumen
    Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS(-/-)) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS(+/+)) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS(+/+) counterparts, N-RAS(-/-) mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS(-/-) livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.
  • Autores: Kolligs, F.; Arnold, D.; Golfieri, R.; et al.
    Revista: JHEP REPORTS
    ISSN: 2589-5559 Vol.5 N° 2 2023 págs. 100633
    Resumen
    Background & aims: Transarterial radioembolization (TARE) with Yttrium-90 resin microspheres is an established treatment option for patients with hepatocellular carcinoma (HCC). However, optimising treatment application and patient selection remains challenging. We report here on the effectiveness, safety and prognostic factors, including dosing methods, associated with TARE for HCC in the prospective observational CIRT study. Methods: We analysed 422 patients with HCC enrolled between Jan 2015 and Dec 2017, with follow-up visits every 3 months for up to 24 months after first TARE. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every 3-month follow-up visit. We used the multivariable Cox proportional hazard model and propensity score matching to identify independent prognostic factors for effectiveness outcomes. Results: The median OS was 16.5 months, the median PFS was 6.1 months, and the median hepatic PFS was 6.7 months. Partition model dosimetry resulted in improved OS compared to body surface area calculations on multivariable analysis (hazard ratio 0.65; 95% CI 0.46-0.92; p = 0.0144), which was confirmed in the exact matching propensity score analysis (hazard ratio 0.56; 95% CI 0.35-0.89; p = 0.0136). Other independent prognostic factors for OS were ECOG-performance status >0 (p = 0.0018), presence of ascites (p = 0.0152), right-sided tumours (p = 0.0002), the presence of portal vein thrombosis (p = 0.0378) and main portal vein thrombosis (p = 0.0028), ALBI grade 2 (p = 0.0043) and 3 (p = 0.0014). Adverse events were recorded in 36.7% of patients, with 9.7% of patients experiencing grade 3 or higher adverse events. Conclusions: This large prospective observational dataset shows that TARE is an effective and safe treatment in patients with HCC. Using partition model dosimetry was associated with a significant improvement in survival outcomes. Impact and implications: Transarterial radioembolization (TARE) is a form of localised radiation therapy and is a potential treatment option for primary liver cancer. We observed how TARE was used in real-life clinical practice in various European countries and if any factors predict how well the treatment performs. We found that when a more complex but personalised method to calculate the applied radiation activity was used, the patient responded better than when a more generic method was used. Furthermore, we identified that general patient health, ascites and liver function can predict outcomes after TARE. Clinical trial number: NCT02305459.
  • Autores: Yau, T. (Autor de correspondencia); Zagonel, V.; Santoro, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 9 2023 págs. 1747 - 1757
    Resumen
    Purpose: To investigate the safety and efficacy of nivolumab plus cabozantinib with or without ipilimumab in patients with advanced hepatocellular carcinoma. Methods: In cohort 6 of the multicohort, open-label, phase I/II CheckMate 040 study, patients who were treatment-naive, sorafenib-intolerant, or had progressed on sorafenib were randomly assigned 1:1 to nivolumab 240 mg once every 2 weeks plus cabozantinib 40 mg once daily (doublet arm); or nivolumab 3 mg/kg every 2 weeks plus cabozantinib 40 mg once daily with ipilimumab 1 mg/kg once every 6 weeks (triplet arm). Primary objectives were safety and tolerability, objective response rate, and duration of response by investigator assessment per RECIST v1.1. Secondary objectives included progression-free survival (by blinded independent central review) and overall survival. Results: Seventy-one patients were randomly assigned: 36 to the doublet arm and 35 to the triplet arm. After 32.0-month median follow-up, objective response rate (95% CI) was 17% (6 to 33) and 29% (15 to 46) in the doublet and triplet arms, respectively. Median (95% CI) duration of response was 8.3 (6.9 to not estimable) months in the doublet arm and not reached (0.0 to not estimable) in the triplet arm. Median progression-free survival was 5.1 and 4.3 months, and median overall survival was 20.2 and 22.1 months for the doublet and triplet arms, respectively. Grade 3-4 treatment-related adverse events occurred in 50% and 74% of patients and treatment-related adverse events leading to discontinuation were reported for 11% and 23% in the doublet and triplet arms, respectively. There were no treatment-related deaths in either arm. Conclusion: Nivolumab plus cabozantinib with or without ipilimumab showed encouraging preliminary antitumor activity and had consistent safety profiles with those established for the individual drugs in patients with advanced hepatocellular carcinoma. Trial registration: ClinicalTrials.gov NCT01658878.
  • Autores: Gregory, J. (Autor de correspondencia); Tselikas, L.; Allimant, C.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.50 N° 3 2023 págs. 921 - 928
    Resumen
    Background A textbook outcome (TO) is a composite indicator covering the entire intervention process in order to reflect the "ideal" intervention and be a surrogate for patient important outcomes. Selective internal radiation therapy (SIRT) is a complex multidisciplinary and multistep intervention facing the challenge of standardization. This expert opinion-based study aimed to define a TO for SIRT of hepatocellular carcinoma. Methods This study involved two steps: (1) the steering committee (4 interventional radiologists) first developed an extensive list of possible relevant items reflecting an optimal SIRT intervention based on a literature review and (2) then conducted an international and multidisciplinary survey which resulted in the final TO. This survey was online, from February to July 2021, and consisted three consecutive rounds with predefined settings. Experts were identified by contacting senior authors of randomized trials, large observational studies, or studies on quality improvement in SIRT. This study was strictly academic. Results A total of 50 items were included in the first round of the survey. A total of 29/40 experts (73%) responded, including 23 interventional radiologists (79%), three nuclear medicine physicians (10%), two hepatologists, and one oncologist, from 11 countries spanning three continents. The final TO consisted 11 parameters across six domains ("pre-intervention workup," "tumor targeting and dosimetry," "intervention," "post-Y-90 imaging," "length of hospital stay," and "complications"). Of these, all but one were applied in the institutions of > 80% of experts. Conclusions This multidimensional indicator is a comprehensive standardization tool, suitable for routine care, clinical round, and research.
  • Autores: Saalfeld, S. (Autor de correspondencia); Kreher, R.; Hille, G.; et al.
    Revista: JOURNAL OF CACHEXIA, SARCOPENIA AND MUSCLE
    ISSN: 2190-5991 Vol.14 N° 5 2023 págs. 2301 - 2309
    Resumen
    BackgroundParameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics-based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC). MethodsRadiomics features were extracted from a cohort of 297 HCC patients as post hoc sub-study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (n = 147) and (2) sorafenib and SIRT (n = 150). The main outcome was 1-year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups. ResultsWe used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376-0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930-0.9134). ConclusionsParameters of radiomics-based analysis of the skeletal musculature and adipose tissue predict 1-year survival in patients with advanced HCC. The prognostic value of radiomics-based parameters was higher in patients who were treated with SIRT and sorafenib.
  • Autores: Singal, A.; Fried, M.; Colombo, M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S1189
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Chan, S.; Kelley, R.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.34 N° Supl. 1 2023 págs. S168
  • Autores: Prenen, H.; Arnold, D.; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.34 N° Supl. 1 2023 págs. S47
  • Autores: Fernandez-Barrena, M. G.; Herranz, J. M.; Adan-Villaescusa, E.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S526
  • Autores: Hernandez-Tejero, M.; Clemente, A.; Melo, L.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S145
  • Autores: Weber, N. D.; Odriozola, L.; Ros-Ganán, I.; et al.
    Revista: MOLECULAR THERAPY
    ISSN: 1525-0016 Vol.31 N° 4 Supl. 1 2023 págs. 102
  • Autores: Tinahones, A.; Blazquez Vicens, J.; Cañas, J.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S560 - S561
  • Autores: Conde, I.; Martinez, S.; Bosca, A.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S133 - S134
  • Autores: Aguilera Sancho, V.; Romero Moreno, S.; Conde, I.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S470
  • Autores: de la Torre Aláez, Manuel Antonio; Matilla, A.; Varela, M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S573 - S574
  • Autores: Alvarado-Tapias, E.; Marti-Aguado, D.; Gómez, C.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S164 - S165
  • Autores: Blazquez Vicens, J.; Tinahones Ruano, A.; Cañas, J.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.78 N° Supl. 1 2023 págs. S326 - S327
  • Autores: Gallego-Durán, R.; Albillos, A.; Ampuero, J.; et al.
    Revista: Gastroenterologia y hepatologia
    ISSN: 0210-5705 Vol.45 N° 9 2022 págs. 724 - 734
    Resumen
    This is a meeting report of the 3rd Translational Hepatology Meeting held in Alicante, Spain, in October 2021. The meeting, which was organized by the Spanish Association for the Study of the Liver (AEEH), provided an update on the recent advances in the field of basic and translational hepatology, with a particular focus on the molecular and cellular mechanisms and therapeutic targets involved in metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage hepatocellular carcinoma (HCC).
  • Autores: Reig, M. (Autor de correspondencia); Forner, A.; Rimola, J.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.76 N° 3 2022 págs. 681 - 693
    Resumen
    There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management.
  • Autores: Karlsen, T. H. (Autor de correspondencia); Sheron, N.; Zelber-Sagi, S.; et al.
    Revista: LANCET
    ISSN: 0140-6736 Vol.399 N° 10319 2022 págs. 61 - 116
  • Autores: Allaire, M.; Bruix, J.; Korenjak, M.; et al.
    Revista: JHEP REPORTS
    ISSN: 2589-5559 Vol.4 N° 12 2022 págs. 100578
    Resumen
    Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the inci-dence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and manage-ment, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex -presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/ by/4.0/).
  • Autores: Braghini, M. R.; Lo Re, O.; Romito, I.; et al.
    Revista: JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH
    ISSN: 1756-9966 Vol.41 N° 1 2022 págs. 107
    Resumen
    Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death. As other heterogeneous solid tumours, HCC results from a unique synergistic combination of genetic alterations mixed with epigenetic modifications. In HCC the patterns and frequencies of somatic variations change depending on the nearby chromatin. On the other hand, epigenetic alterations often induce genomic instability prone to mutations. Epigenetics refers to heritable states of gene expression without alteration to the DNA sequence itself and, unlike genetic changes, the epigenetic modifications are reversible and affect gene expression more extensively than genetic changes. Thus, studies of epigenetic regulation and the involved molecular machinery are greatly contributing to the understanding of the mechanisms that underline HCC onset and heterogeneity. Moreover, this knowledge may help to identify biomarkers for HCC diagnosis and prognosis, as well as future new targets for more efficacious therapeutic approaches. In this comprehensive review we will discuss the state-of-the-art knowledge about the epigenetic landscape in hepatocarcinogenesis, including evidence on the diagnostic and prognostic role of non-coding RNAs, modifications occurring at the chromatin level, and their role in the era of precision medicine. Apart from other better-known risk factors that predispose to the development of HCC, characterization of the epigenetic remodelling that occurs during hepatocarcinogenesis could open the way to the identification of personalized biomarkers. It may also enable a more accurate diagnosis and stratification of patients, and the discovery of new targets for more efficient therapeutic approaches.
  • Autores: Argemí Ballbé, José María; Ponz Sarvisé, Mariano; Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
    Revista: ADVANCES IN CANCER RESEARCH
    ISSN: 2162-5557 Vol.156 2022 págs. 367 - 413
    Resumen
    Liver cancer including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) is the third leading cause of cancer-related deaths worldwide. HCC arises from hepatocyte or hepatic stem cells, while iCCA originates from biliary epithelial cells, and the respective biological context are very different. Despite screening programs, the diagnosis of liver cancer is in most cases made when curative treatments such as surgery or ablation are not possible. In 2020, after a decade of using only tyrosine kinase inhibitors (TKI), a combination of an immune-check point inhibitor (ICI) and a VEGF antagonist proved superior to a TKI as first line therapy of advanced HCC. In 2022, the addition of an ICI to standard chemotherapy demonstrated an improvement of patient survival in iCCA. Moreover, ICI offer an unprecedented rate of durable responses to HCC and iCCA patients. Nevertheless, still two thirds of patients do not respond to ICI-based combinations, and research efforts are focused on deciphering the mechanisms of immune evasion of these lethal cancers. Reliable predictive and prognostic biomarkers are still lacking, but the molecular phenotyping of the tumor microenvironment is currently providing potential candidates for patient stratification. In this review, we will summarize the current knowledge on the immune biology of the liver, the discovery of cell-intrinsic and immune cell-mediated mechanisms of immune evasion by means of high-resolution single cell data, the main targets of current immunotherapy approaches, and the recent milestones in immunotherapy of HCC and iCCA.
  • Autores: Córdoba Quiñones, Karol Marcela; Jericó Asenjo, Daniel; Sampedro Pascual, Ana; et al.
    Revista: International review of cell and molecular biology
    ISSN: 1937-6448 Vol.372 2022 págs. 55 - 96
    Resumen
    Inborn errors of metabolism (IEM) encompass a group of monogenic diseases affecting both pediatric and adult populations and currently lack effective treatments. Some IEM such as familial hypercholesterolemia or X-linked protoporphyria are caused by gain of function mutations, while others are characterized by an impaired protein function, causing a metabolic pathway blockage. Pathophysiology classification includes intoxication, storage and energy-related metabolic disorders. Factors specific to each disease trigger acute metabolic decompensations. IEM require prompt and effective care, since therapeutic delay has been associated with the development of fatal events including severe metabolic acidosis, hyperammonemia, cerebral edema, and death. Rapid expression of therapeutic proteins can be achieved hours after the administration of messenger RNAs (mRNA), representing an etiological solution for acute decompensations. mRNA-based therapy relies on modified RNAs with enhanced stability and translatability into therapeutic proteins. The proteins produced in the ribosomes can be targeted to specific intracellular compartments, the cell membrane, or be secreted. Non-immunogenic lipid nanoparticle formulations have been optimized to prevent RNA degradation and to allow safe repetitive administrations depending on the disease physiopathology and clinical status of the patients, thus, mRNA could be also an effective chronic treatment for IEM. Given that the liver plays a key role in most of metabolic pathways or can be used as bioreactor for excretable proteins, this review focuses on the preclinical and clinical evidence that supports the implementation of mRNA technology as a promising personalized strategy for liver metabolic disorders such as acute intermittent porphyria, ornithine transcarbamylase deficiency or glycogen storage disease.
  • Autores: Jericó Asenjo, Daniel; Córdoba Quiñones, Karol Marcela; Sampedro Pascual, Ana; et al.
    Revista: LIFE
    ISSN: 2075-1729 Vol.12 N° 11 2022 págs. 1858 - *
    Resumen
    Rare diseases, especially monogenic diseases, which usually affect a single target protein, have attracted growing interest in drug research by encouraging pharmaceutical companies to design and develop therapeutic products to be tested in the clinical arena. Acute intermittent porphyria (AIP) is one of these rare diseases. AIP is characterized by haploinsufficiency in the third enzyme of the heme biosynthesis pathway. Identification of the liver as the target organ and a detailed molecular characterization have enabled the development and approval of several therapies to manage this disease, such as glucose infusions, heme replenishment, and, more recently, an siRNA strategy that aims to down-regulate the key limiting enzyme of heme synthesis. Given the involvement of hepatic hemoproteins in essential metabolic functions, important questions regarding energy supply, antioxidant and detoxifying responses, and glucose homeostasis remain to be elucidated. This review reports recent insights into the pathogenesis of acute attacks and provides an update on emerging treatments aimed at increasing the activity of the deficient enzyme in the liver and restoring the physiological regulation of the pathway. While further studies are needed to optimize gene therapy vectors or large-scale production of liver-targeted PBGD proteins, effective protection of PBGD mRNA against the acute attacks has already been successfully confirmed in mice and large animals, and mRNA transfer technology is being tested in several clinical trials for metabolic diseases.
  • Autores: Macías, R. I. R.; Cardinale, V.; Kendall, T. J.; et al.
    Revista: GUT
    ISSN: 0017-5749 Vol.71 N° 8 2022 págs. 1669 - 1683
    Resumen
    Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.
  • Autores: Gárate Rascón, María; Recalde Domínguez de Vidaurreta, Miriam; Rojo González González, Carla; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 21 2022 págs. 13411
    Resumen
    SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3 ' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.
  • Autores: Morales-Arráez, D. (Autor de correspondencia); Ventura-Cots, M.; Altamirano, J.; et al.
    Revista: AMERICAN JOURNAL OF GASTROENTEROLOGY
    ISSN: 0002-9270 Vol.117 N° 5 2022 págs. 818 - 818
  • Autores: Vogel, A.; Cervantes, A.; Chau, I.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 6 2022 págs. 666
  • Autores: Clavería Cabello, Alex; Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
    Revista: CMGH
    ISSN: 2352-345X Vol.13 N° 2 2022 págs. 678 - 680
  • Autores: Arechederra Calderon, Maria (Autor de correspondencia); García Fernández de Barrena, Maite (Autor de correspondencia)
    Revista: Journal of hepatology
    ISSN: 1600-0641 Vol.77 N° 6 2022 págs. 1479 - 1481
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° 4 2022 págs. 899 - 902
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° 2 2022 págs. 273 - 276
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.76 N° 4 2022 págs. 959 - 974
  • Autores: Fontanellas Roma, Antonio (Autor de correspondencia); Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
    Revista: Journal of hepatology
    ISSN: 1600-0641 Vol.77 N° 4 2022 págs. 912 - 914
  • Autores: Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia); Argemí Ballbé, José María
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.76 N° 4 2022 págs. 906 - 908
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° 1 2022 págs. 1 - 4
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.76 N° 1 2022 págs. 1 - 4
  • Autores: Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° 3 2022 págs. 585 - 588
  • Autores: Morales-Arráez, D.; Ventura-Cots, M.; Altamirano, J.; et al.
    Revista: AMERICAN JOURNAL OF GASTROENTEROLOGY
    ISSN: 0002-9270 Vol.117 N° 2 2022 págs. 301 - 310
    Resumen
    INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.
  • Autores: Campanale, E. R. (Autor de correspondencia); Maragno, M.; Annese, G.; et al.
    Revista: EUROPEAN JOURNAL OF TRAUMA AND EMERGENCY SURGERY
    ISSN: 1863-9933 Vol.48 N° 5 2022 págs. 3831 - 3836
    Resumen
    Introduction Mass Casualty Incidents (MCI) may occur during Mass Gathering Events (MGE). A failure to prepare and train the health care system for potential MCI, can cause chaos and delays in the response, leading to an increased morbidity and mortality. Education and training of staff are crucial for preparedness. In Italy, hospital Emergency Plans for Massive Influx of Injured (in Italian designated with the acronym PEMAF) are mandatory since the '90's. However, when available, they are usually poorly known by the staff, rarely reviewed and validated. In 2014, Matera, a city in Southern Italy, was designated as the European Capital of Culture for 2019. As a result, we took this opportunity to revise the "Madonna delle Grazie" PEMAF and to start a program for increasing the awareness of the plan among the medical staff and provide specific training for MCI management. Material & methods The PEMAF was reviewed through simulations that involved the entire staff. A partnership with the International Association for Medical Response to Major Incidents & Disasters (MRMI) led to the support of experts and to the organization of residential courses based on the MAss Casualty SIMulation tool (MACSIM (R)). In total, six residential educational events of MACSIM-PEMAF were organized. Individual capacity was tested before and after the education through self-administered semi-quantitative questionnaires. Results All the available resources were mapped and the functional areas identified. Alert, coordination and command sequences were defined. The communication network was improved. Documentation and registration systems were developed. Standard operational procedures (action cards) were created for the key positions. The knowledge and capacity to function in active roles during a MCI was improved among the participants in the educational program. Conclusions MGE are great opportunities for the development of the hosting community but also represent an increased risk of MCI. Preparedness is mandatory for health care systems. The educational format MACSIM-PEMAF seems to be adequate to review and improve the existing plans and transfer specific skills to attendants.
  • Autores: Melderis, S.; Warkotsch, M. T.; Dang, J.; et al.
    Revista: JOURNAL OF AUTOIMMUNITY
    ISSN: 0896-8411 Vol.129 2022 págs. 102829
    Resumen
    Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immuno-pathogenesis. Lupus nephritis (LN) is a frequent and difficult to treat complication, which causes high morbidity and mortality. The multifunctional cytokine amphiregulin (AREG) has been implicated in SLE pathogenesis, but its function in LN currently remains unknown. We thus studied the model of pristane-induced LN and found increasing renal and systemic AREG expression during the course of disease. Importantly, renal injury was significantly aggravated in the absence of AREG, revealing a net anti-inflammatory role. Analyses of immune responses showed dual effects. On the one hand, AREG enhanced activation of pro-inflammatory myeloid cells, which however did not play a major role for the course of LN. More importantly, on the other hand, AREG strongly suppressed pathogenic cytokine production by T helper effector cells. This effect was more general in nature and could be reproduced in response to antigen immunization. Since AREG has been postulated to downregulate T cell responses via enhancing Treg suppressive capacity, we followed up on this aspect. Interestingly, however, in vitro studies revealed potential direct and Treg independent effects of AREG on T helper effector cells. In favor of this notion, we found significantly enhanced T cell responses and consecutive aggravation of LN, only if epidermal growth factor receptor (EGFR) signaling was abrogated in total T cells, but not if the EGFR was absent on Tregs alone. Finally, we also found enhanced AREG expression in plasma and renal biopsies of patients with LN, supporting the relevance of our findings for human disease. In summary, our data identify AREG as an anti-inflammatory mediator of LN via broad downregulation of pathogenic T cell immunity. These findings further highlight the AREG/EGFR axis as a potential therapeutic target.
  • Autores: Oecal, O.; Schuette, K.; Kupcinskas, J.; et al.
    Revista: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
    ISSN: 0171-5216 Vol.148 N° 2 2022 págs. 475 - 485
    Resumen
    Purpose To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Methods A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. Results Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). Conclusion IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.
  • Autores: Páramo Alfaro, María; Santa María Monasterio, Eva; Idoate Gastearena, Miguel Ángel; et al.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.12 N° 1 2022 págs. 1777
    Resumen
    Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy-hypertrophy complex after SIRT. Three groups of 5-8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of Y-90 resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity.
  • Autores: Colmenero, J.; Tabrizian, P.; Bhangui, P.; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.106 N° 1 2022 págs. e30 - e45
    Resumen
    De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.
  • Autores: Garcia Garcia, Jorge; de Miguel Vázquez, Carlos; Milagro Yoldi, Fermín Ignacio; et al.
    Revista: ANTIOXIDANTS
    ISSN: 2076-3921 Vol.11 N° 1 2022 págs. 30
    Resumen
    Obesity is a global health issue associated with the development of metabolic syndrome, which correlates with insulin resistance, altered lipid homeostasis, and other pathologies. One of the mechanisms involved in the development of these pathologies is the increased production of reactive oxygen species (ROS). One of the main producers of ROS is the family of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, among which NOX5 is the most recently discovered member. The aim of the present work is to describe the effect of endothelial NOX5 expression on neighboring adipose tissue in obesity conditions by using two systems. An in vivo model based on NOX5 conditional knock-in mice fed with a high-fat diet and an in vitro model developed with 3T3-L1 adipocytes cultured with conditioned media of endothelial NOX5-expressing bEnd.3 cells, previously treated with glucose and palmitic acid. Endothelial NOX5 expression promoted the expression and activation of specific markers of thermogenesis and lipolysis in the mesenteric and epididymal fat of those mice fed with a high-fat diet. Additionally, the activation of these processes was derived from an increase in IL-6 production as a result of NOX5 activity. Accordingly, 3T3-L1 adipocytes treated with conditioned media of endothelial NOX5-expressing cells, presented higher expression of thermogenic and lipolytic genes. Moreover, endothelial NOX5-expressing bEnd.3 cells previously treated with glucose and palmitic acid also showed interleukin (IL-6) production. Finally, it seems that the increase in IL-6 stimulated the activation of markers of thermogenesis and lipolysis through phosphorylation of STAT3 and AMPK, respectively. In conclusion, in response to obesogenic conditions, endothelial NOX5 activity could promote thermogenesis and lipolysis in the adipose tissue by regulating IL-6 production.
  • Autores: Schott, M.; Kappelmann-Fenzl, M.; Fischer, S.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
    ISSN: 1107-3756 Vol.49 N° 5 2022 págs. 66
    Resumen
    The tumor suppressive role of CYLD lysine 63 deubiquitinase (CYLD) is known in melanoma. To the best of our knowledge, however, the precise mechanism underlying the tumor suppressive function of CYLD has yet to be clarified. In the present study, a novel melanoma mouse model was generated, which revealed accelerated tumor growth in Cyld-knockout (Cyld(-/-)) compared with Cyld-wild-type (Cyld(+/+)) mice. To determine the underlying molecular mechanism, mutation analysis of primary tumor-derived cell lines from Cyld(+/+) and Cyld(-/-) mice was performed using RNA sequencing data. Variant calling revealed no common mutations in Cyld(-/-) compared with Cyld(+/+) cells. Thus, the epigenetic processes influencing development and progression of melanoma were investigated. Initial analysis of expression pattern of known hypermethylated genes in melanoma (suppressor of cytokine signalling, methylthioadenosine phosphorylase, cadherin 1) in the presence or absence of 5 '-Aza-deoxyctidine treatment revealed that CYLD does not play a key role in DNA methylation. Chromatin accessibility and histone H3 modification assay uncovered a role of CYLD in the formation of chromatin structure. Subsequent inhibitor experiments confirmed the effect of CYLD on H3K9me2 level associated with heterochromatin. Furthermore, enhanced H3K9 dimethylation in Cyld(-/-) melanoma cells was associated with upregulation of euchromatic histone lysine methyltransferase 2 (EHMT2). Moreover, the specific inhibitor of EHMT2, CM272, resulted in decreased proliferation and relaxation of compact chromatin in Cyld-deficient melanoma cells. These results reveal a novel role of CYLD in histone methylation and chromatin packaging.
  • Autores: Op den Winkel, M. (Autor de correspondencia); Nagel, D.; de la Torre Aláez, Manuel Antonio; et al.
    Revista: DIGESTIVE DISEASES
    ISSN: 0257-2753 Vol.40 N° 3 2022 págs. 322 - 334
    Resumen
    Introduction: Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. Methods: A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. Results: median overall survival was 13 months (95% confidence interval 9.9-21.9). AFP (p = 0.005; hazard ratio [HR] 2.38), albumin (p < 0.001; HR 5.87), and alkaline phosphatase (p < 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: p = 0.003, II vs. III: p < 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: p = 0.03; II vs. III: p = 0.007). Conclusion: Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.
  • Autores: Yau, T. (Autor de correspondencia); Park, J. W.; Finn, R. S.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.23 N° 1 2022 págs. 77 - 90
    Resumen
    Background Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15.2 months (IQR 5.7-28.0) for the nivolumab group and 13.4 months (5.7-25.9) in the sorafenib group. Median overall survival was 16.4 months (95% CI 13.9-18.4) with nivolumab and 14.7 months (11.9-17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72-1.02]; p=0.075; minimum follow-up 22.8 months); the protocol-defined significance level of p=0.0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.
  • Autores: Schaefer, N.; Groezinger, G.; Pech, M.; et al.
    Revista: CLINICAL COLORECTAL CANCER
    ISSN: 1533-0028 Vol.21 N° 4 2022 págs. 285 - 296
    Resumen
    This study explored factors that can predict effectiveness outcomes after transarterial radioembolization in colorectal liver metastases in the liver. In a cohort of 237 patients, among other factors, we found that an Aspartate transaminase to Platelet Ratio Index (APRI) value of > 0.40 was a particularly strong independent predictor of worse overall survival, progression-free survival and hepatic progression-free survival outcomes. Background: Transarterial radioembolisation (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with metastatic colorectal cancer in the liver (mCRC). A better understanding of the prognostic factors and treat-ment application can improve survival outcomes. Methods: We analysed the safety and effectiveness of 237 mCRC patients included in the prospective observational study CIRSE Registry for SIR-Spheres Therapy (CIRT) for indepen-dent prognostic factors for overall survival (OS), progression-free survival (PFS) and hepatic progression-free survival (hPFS) using the Cox proportional-hazard model. Results: The median OS was 9.8 months, median PFS was 3.4 months and median hPFS was 4.2 months. Independent prognostic factors for an improved overall survival were the absence of extra-hepatic disease ( P = .0391), prior locoregional procedures ( P = .0037), an Aspartate transaminase to Platelet Ratio Index (APRI) value of <= 0.40 ( P < .0001) and Inter national Nor malized Ratio (INR) <= 1 ( P = .0078). Partition model dosimetry resulted in improved OS outcomes compared to the body surface area model ( P = .0120). Independent predictors for PFS were APRI > 0.40 ( P = .0416) and prior ablation ( P = .0323), and for hPFS these were 2 to 5 tumor nodules ( P = .0148), Albumin-bilirubin (ALBI) grade 3 ( P = .0075) and APRI > 0.40 ( P = .0207). During the study, 95 of 237 (40.1%) patients experienced 197 adverse events, with 28 of 237 (11.8%) patients having a grade 3 or higher adverse events. Conclusion: Including easy-to-acquire laboratory markers INR, APRI, ALBI and using partition model dosimetry can identify mCRC patients that may benefit from TARE.
  • Autores: Hu, K.; Pérez-Matos, M. C.; Argemí Ballbé, José María; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.75 N° 4 2022 págs. 968 - 982
    Resumen
    Background and Aims Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. Approach and Results We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index <= 0.6 and a decline of Z-index by >= 0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. Conclusions Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index <= 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
  • Autores: Loi, E.; Zavattari, C.; Tommasi, A.; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN: 0007-0920 Vol.126 N° 12 2022 págs. 1783 - 1794
    Resumen
    Background Biliary tract cancers (BTC) are rare but highly aggressive tumours with poor prognosis, usually detected at advanced stages. Herein, we aimed at identifying BTC-specific DNA methylation alterations. Methods Study design included statistical power and sample size estimation. A genome-wide methylation study of an explorative cohort (50 BTC and ten matched non-tumoral tissue samples) has been performed. BTC-specific altered CpG islands were validated in over 180 samples (174 BTCs and 13 non-tumoral controls). The final biomarkers, selected by a machine-learning approach, were validated in independent tissue (18 BTCs, 14 matched non-tumoral samples) and bile (24 BTCs, five non-tumoral samples) replication series, using droplet digital PCR. Results We identified and successfully validated BTC-specific DNA methylation alterations in over 200 BTC samples. The two-biomarker panel, selected by an in-house algorithm, showed an AUC > 0.97. The best-performing biomarker (chr2:176993479-176995557), associated with HOXD8, a pivotal gene in cancer-related pathways, achieved 100% sensitivity and specificity in a new series of tissue and bile samples. Conclusions We identified a novel fully efficient BTC biomarker, associated with HOXD8 gene, detectable both in tissue and bile by a standardised assay ready-to-use in clinical trials also including samples from non-invasive matrices.
  • Autores: Rodríguez-Perálvarez, M. (Autor de correspondencia); Colmenero, J.; González, A.; et al.
    Revista: AMERICAN JOURNAL OF TRANSPLANTATION
    ISSN: 1600-6135 Vol.22 N° 6 2022 págs. 1671 - 1682
    Resumen
    Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.
  • Autores: Serrano Alonso, María; Martín Moreno, Paloma Leticia; Rabago Juan Aracil, Gregorio; et al.
    Revista: MEDICINA CLINICA
    ISSN: 0025-7753 Vol.158 N° 11 2022 págs. 543 - 546
    Resumen
    Background and objective: We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation. Materials and methods: Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R-) (2007-2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared. Results: CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05). Conclusions: Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity.
  • Autores: Loffler, M. W.; Gori, S.; Izzo, F.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.28 N° 12 2022 págs. 2555 - 2566
    Resumen
    Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. Patients and Methods: A total of 82 patients with very early-to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against >= 1 vaccinated HLA class I tumor-associated peptide (TAA) and >= 1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. Conclusions: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
  • Autores: Argemí Ballbé, José María; Kedia, K.; Gritsenko, M. A.; et al.
    Revista: AMERICAN JOURNAL OF PATHOLOGY
    ISSN: 0002-9440 Vol.192 N° 12 2022 págs. 1658 - 1669
    Resumen
    Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent studies have shown that defective function of hepatocyte nuclear factor 4 alpha (HNF4a) and systemic inflammation are major disease drivers of AH. Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein, an integrative analysis of hepatic RNA sequencing and liquid chromatographyetandem mass spectrometry was performed to identify plasma protein signatures for patients with mild and severe AH. Alcohol-related liver disease cirrhosis, nonalcoholic fatty liver disease, and healthy subjects were used as comparator groups. Levels of identified proteins primarily involved in hepatocellular function were decreased in patients with AH, which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators. A protein signature of AH disease severity was identified, including thrombin, hepatocyte growth factor alpha, clusterin, human serum factor H-related protein, and kallistatin, which exhibited large abundance shifts between severe and nonsevere AH. The combination of thrombin and hepatocyte growth factor alpha discriminated between severe and nonsevere AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions. This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.
  • Autores: Ocal, O.; Schutte, K. ; Zech, C. J.; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.49 N° 13 2022 págs. 4716 - 4726
    Resumen
    Purpose To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE). Methods Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC. Results The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS. Conclusion In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.
  • Autores: Cervantes-Álvarez, E.; Limón-de la Rosa, N.; Vilatoba, M.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN: 1478-3223 Vol.42 N° 10 2022 págs. 2260 - 2273
    Resumen
    Background & Aims Patients with advanced cirrhosis often have immune dysfunction and are more susceptible to infections. Galectin-3 is a beta-galactoside-binding lectin implicated in inflammation, immune regulation and liver fibrosis. We aim to investigate galectin-3 expression in advanced cirrhosis and its ability to predict post-transplant infectious complications. Methods We collected sera and liver samples from 129 cirrhotic patients at the time of liver transplantation and from an external cohort of 37 patients with alcoholic liver disease including alcoholic hepatitis (AH) at the time of diagnosis. Galectin-3 was assessed by ELISA, real-time PCR, immunohistochemistry and RNA-seq. Receiver operating characteristic curves and Cox proportional-hazards regression analysis were performed to assess the predictive power of galectin-3 for disease severity and post-transplant infections. Results Increased galectin-3 levels were found in advanced cirrhosis. Galectin-3 significantly correlated with disease severity parameters and inflammatory markers. Galectin-3 had significant discriminating power for compensated and advanced cirrhosis (AUC = 0.78/0.84, circulating/liver galectin-3; p < .01), and was even higher to discriminate severe AH (AUC = 0.95, p < .0001). Cox Proportional-hazard model showed that galectin-3, MELD-Na and the presence of SIRS predict the development of post-transplant infectious complications. Patients with circulating galectin-3 (>16.58 ng/ml) were at 2.19-fold 95% CI (1.12-4.29) increased risk, but when combined with MELD-Na > 20.0 and SIRS, the risk to develop post-transplant infectious complications, increased to 4.60, 95% CI (2.38-8.90). Conclusion Galectin-3 is a novel biological marker of active inflammation and disease severity that could be clinically useful alone or in combination with other scores to discriminate advanced cirrhosis and predict post-transplant infectious complications.
  • Autores: Marín, J. J. G. (Autor de correspondencia); Reviejo, M.; Soto, M.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 1 2022 págs. 18
    Resumen
    Simple Summary Among the top ten deadly solid tumors are the two most frequent liver cancers, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, whose development and malignancy are favored by multifactorial conditions, which include aberrant maturation of pre-mRNA due to abnormalities in either the machinery involved in the splicing, i.e., the spliceosome and associated factors, or the nucleotide sequences of essential sites for the exon recognition process. As a consequence of cancer-associated aberrant splicing in hepatocytes- and cholangiocytes-derived cancer cells, abnormal proteins are synthesized. They contribute to the dysregulated proliferation and eventually transformation of these cells to phenotypes with enhanced invasiveness, migration, and multidrug resistance, which contributes to the poor prognosis that characterizes these liver cancers. The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.
  • Autores: Córdoba Quiñones, Karol Marcela; Serrano Mendioroz, Irantzu; Jericó Asenjo, Daniel; et al.
    Revista: SCIENCE TRANSLATIONAL MEDICINE
    ISSN: 1946-6234 Vol.14 N° 627 2022 págs. eabc0700
    Resumen
    Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria ( AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.
  • Autores: Chen, C. B.; Wu, H. H.; Ye, H.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 1 2022 págs. 78
    Resumen
    Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development.
  • Autores: Recalde, M.; Gárate Rascón, María; Herranz, J. M.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 9 2022 págs. 2048
    Resumen
    Simple Summary Hepatocarcinogenesis is a long process which implies the loss of hepatic functions. Our effort is to understand the mechanisms implicated in this pathological process in order to contribute to the development of new diagnostic markers and therapeutic targets. In this study we have identified a set of lncRNAs significantly downregulated in hepatocellular carcinoma (HCC) in correlation with the grade of tumor dedifferentiation and patients' worse prognosis. Mechanistically, our results show that they are related with hepatic differentiation and at least a subset of those lncRNAs are essential to ensure the expression of other hepato-specific genes required for liver function. Moreover, we demonstrate that the expression of these lncRNAs in HCC is silenced by DNA methylation. All in all, we uncover connected epigenetic alterations involved in the progression of liver cancer and identify potential new biomarkers. Background: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. Methods and Results: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Conclusions: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.
  • Autores: Spoto, S. (Autor de correspondencia); Markley, J. D.; Valeriani, E.; et al.
    Revista: FRONTIERS IN MICROBIOLOGY
    ISSN: 1664-302X Vol.13 2022 págs. 797932
    Resumen
    ObjectiveThe prevalence of colonization with multidrug-resistant organisms (MDRO) has increased over the last decade, reaching levels as high as 23% in certain patient populations. Active surveillance cultures (ASC) represent a valuable tool to identify patients colonized with MDRO to apply preventive measures, reduce transmission, and guide empiric antimicrobial therapy. There is a paucity of data evaluating the impact of admission ASCs to predict future infection. The aim of this study was to evaluate the concordance between ASCs results and the development of clinical infection by the same microorganism identified in the surveillance swab (swab-related infection), in hospitalized septic patients, and to evaluate the presence of specific risk factors associated with the development of a swab-related infection. MethodsAll adults admitted to the Diagnostic and Therapeutic Medicine Department of the University Hospital Campus Bio-Medico of Rome with a diagnosis of infection or any other medical reason with admission surveillance swabs (rectal or nasal) between January 2018 and February 2021 were included in the study. A retrospective chart review was conducted to identify patients that developed infections with concordant MDROs identified on ASC, and the risk factors for swab-related infection. Secondary outcomes were need of intensive care unit transfer, length of stay, sepsis or septic shock development, and all-cause mortality. ResultsA total of 528 patients were included in the study, of which 97 (18.3%) had a positive surveillance swab. Among patients with positive surveillance swabs, 18 (18.5%) developed an infection with the same microorganism recovered from the swab, 57 (58.8%) developed an infection with a different microorganism than that recovered from the surveillance swab, and 22 (22.7%) did not develop an infection during hospitalization. The number of colonized sites, an interventional procedure within the previous 3 months, a Systemic Inflammatory Response Syndrome (SIRS) score >= 2, and a quick Sequential Organ Failure Assessment (q-SOFA) score >= 2 were associated with a significantly higher risk of developing a swab-related infection. SIRS and q-SOFA scores >= 2 and procalcitonin >= 0.43 ng/ml help for identifying patients with a swab-related infection. ConclusionPatients with positive surveillance swabs were at increased risk for development of infections by the same MDRO identified in surveillance swabs (swab-related infection). This study is the first to show that the positivity of surveillance swabs, in combination with anamnestic data, PCT values, and SIRS or q-SOFA scores, serves as a valuable tool to help clinicians predict patients at higher risk for swab-related infection development and guide the administration of appropriate empiric antimicrobial therapy in septic patients.
  • Autores: Olaizola, P.; Lee-Law, P. Y.; García Fernández de Barrena, Maite; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° 1 2022 págs. 177 - 190
    Resumen
    Background & Aims: Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors associated with dismal prognosis. Alterations in post-translational modifications (PTMs), including NEDDylation, result in abnormal protein dynamics, cell disturbances and disease. Herein, we investigate the role of NEDDylation in CCA development and progression. Methods: Levels and functions of NEDDylation, together with response to pevonedistat (NEDDylation inhibitor) or CRISPR/Cas9 against NAE1 were evaluated in vitro, in vivo and/or in patients with CCA. The development of preneoplastic lesions in Nae1(+/-) mice was investigated using an oncogene-driven CCA model. The impact of NEDDylation in CCA cells on tumor-stroma crosstalk was assessed using CCA-derived cancer-associated fibroblasts (CAFs). Proteomic analyses were carried out by mass-spectrometry. Results: The NEDDylation machinery was found overexpressed and overactivated in human CCA cells and tumors. Most NEDDylated proteins found upregulated in CCA cells, after NEDD8-immunoprecipitation and further proteomics, participate in the cell cycle, proliferation or survival. Genetic (CRISPR/Cas9-NAE1) and pharmacological (pevonedistat) inhibition of NEDDylation reduced CCA cell proliferation and impeded colony formation in vitro. NEDDylation depletion (pevonedistat or Nae1(+/)(-) mice) halted tumorigenesis in subcutaneous, orthotopic, and oncogenedriven models of CCA in vivo. Moreover, pevonedistat potentiated chemotherapy-induced cell death in CCA cells in vitro. Mechanistically, impaired NEDDylation triggered the accumulation of both cullin RING ligase and NEDD8 substrates, inducing DNA damage and cell cycle arrest. Furthermore, impaired NEDDylation in CCA cells reduced the secretion of proteins involved in fibroblast activation, angiogenesis, and oncogenic pathways, ultimately hampering CAF proliferation and migration. Conclusion: Aberrant protein NEDDylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, NEDDylation impacts the CCA-stroma crosstalk. Inhibition of NEDDylation with pevonedistat may represent a potential therapeutic strategy for patients with CCA.
  • Autores: Ye, H.; Chen, C.; Wu, H.; et al.
    Revista: CELL DEATH AND DISEASE
    ISSN: 2041-4889 Vol.13 N° 2 2022 págs. 143
    Resumen
    Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1(f/f)) and hepatocyte-specific knockout Xbp1 mice (Xbp1( increment hepa)) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1( increment hepa) livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1( increment hepa) animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury.
  • Autores: Aliseda Jover, Daniel; Martí Cruchaga, Pablo; Zozaya Larequi, Gabriel Nicolás; et al.
    Revista: LANGENBECKS ARCHIVES OF SURGERY
    ISSN: 1435-2443 Vol.407 N° 3 2022 págs. 1099 - 1111
    Resumen
    Background Liver surgery after radioembolization (RE) entails highly demanding and challenging procedures due to the frequent combination of large tumors, severe RE-related adhesions, and the necessity of conducting major hepatectomies. Laparoscopic liver resection (LLR) and its associated advantages could provide benefits, as yet unreported, to these patients. The current study evaluated feasibility, morbidity, mortality, and survival outcomes for major laparoscopic liver resection after radioembolization. Material and methods In this retrospective, single-center study patients diagnosed with hepatocellular carcinoma, intrahepatic cholangiocarcinoma or metastases from colorectal cancer undergoing major laparoscopic hepatectomy after RE were identified from institutional databases. They were matched (1:2) on several pre-operative characteristics to a group of patients that underwent major LLR for the same malignancies during the same period but without previous RE. Results From March 2011 to November 2020, 9 patients underwent a major LLR after RE. No differences were observed in intraoperative blood loss (50 vs. 150 ml; p = 0.621), operative time (478 vs. 407 min; p = 0.135) or pedicle clamping time (90.5 vs 74 min; p = 0.133) between the post-RE LLR and the matched group. Similarly, no differences were observed on hospital stay ( median 3 vs. 4 days; p = 0.300), Clavien-Dindo = III complications (2 vs. 1 cases; p = 0.250), specific liver morbidity (1 vs. 1 case p = 1.000), or 90 day mortality (0 vs. 0; p = 1.000). Conclusion The laparoscopic approach for post radioembolization patients may be a feasible and safe procedure with excellent surgical and oncological outcomes and meets the current standards for laparoscopic liver resections. Further studies with larger series are needed to confirm the results herein presented.
  • Autores: de la Torre Aláez, Manuel Antonio; Matilla, A.; Varela, M.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 11 2022 págs. e005457 -*
    Resumen
    Purpose To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization.Patients and methods NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naive to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS).Results 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1).Conclusions The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.
  • Autores: Ciordia, S.; Álvarez-Sola, G.; Rullan, M.; et al.
    Revista: METHODS IN MOLECULAR BIOLOGY
    ISSN: 1940-6029 Vol.2420 2022 págs. 44835 - *
    Resumen
    One of the critical issues to warrant the success of a proteome-wide analysis is sample preparation. Efficient protein extraction in the absence of interferent material is mandatory to achieve an ample proteome coverage by mass spectrometry. The study of biological fluids is always challenging due to their specific biochemical composition. However, there is increasing interest in their characterization as it will provide proteins that may advice disease setting, state, and progression. In particular, bile is proximal to liver and pancreas, and its study is especially attractive since it might provide valuable information for the clinical management of severe diseases afflicting these organs, which are at an urgent need of new biomarkers. Though previous efforts have been made to optimize protocols to analyze bile proteome, only partial descriptions were achieved due to its complex composition, where proteins represent less than 5% of the organic components. Here we describe a new method that significantly increases the bile proteome coverage while reducing by a factor of six the amount of sample required for the proteomic analysis.
  • Autores: Arechederra Calderon, Maria; Rullán, M.; Amat, I.; et al.
    Revista: GUT
    ISSN: 0017-5749 Vol.71 N° 6 2022 págs. 1141 - 1151
    Resumen
    Objective Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). Design A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. Results An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. Conclusion Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.
  • Autores: Vera Yunca, Diego; Córdoba Quiñones, Karol Marcela; Parra Guillén, Zinnia Patricia; et al.
    Revista: BRITISH JOURNAL OF PHARMACOLOGY
    ISSN: 0007-1188 Vol.179 N° 14 2022 págs. 3815 - 3830
    Resumen
    Background and Purpose Acute intermittent porphyria (AIP) is a rare disease caused by a genetic mutation in the hepatic activity of the porphobilinogen-deaminase. We aimed to develop a mechanistic model of the enzymatic restoration effects of a novel therapy based on the administration of different formulations of recombinant human-PBGD (rhPBGD) linked to the ApoAI lipoprotein. This fusion protein circulates in blood, incorporating into HDL and penetrating hepatocytes. Experimental Approach Single i.v. dose of different formulations of rhPBGD linked to ApoAI were administered to AIP mice in which a porphyric attack was triggered by i.p. phenobarbital. Data consist on 24 h urine excreted amounts of heme precursors, 5-aminolevulinic acid (ALA), PBG and total porphyrins that were analysed using non-linear mixed-effects analysis. Key Results The mechanistic model successfully characterized over time the amounts excreted in urine of the three heme precursors for different formulations of rhPBGD and unravelled several mechanisms in the heme pathway, such as the regulation in ALA synthesis by heme. Treatment with rhPBGD formulations restored PBGD activity, increasing up to 51 times the value of the rate of tPOR formation estimated from baseline. Model-based simulations showed that several formulation prototypes provided efficient protective effects when administered up to 1 week prior to the occurrence of the AIP attack. Conclusion and Implications The model developed had excellent performance over a range of doses and formulation type. This mechanistic model warrants use beyond ApoAI-conjugates and represents a useful tool towards more efficient drug treatments of other enzymopenias as well as for acute intermittent porphyria.
  • Autores: Lertxundi, U. (Autor de correspondencia); Aramburu Montenegro, Jorge; Antón Remírez, Raúl; et al.
    Revista: EKAIA
    ISSN: 0214-9001 Vol.42 2022 págs. 339 - 348
    Resumen
    Erradioenbolizazioa (RE) gibeleko minbizia tratatzeko metodoetako bat da. Bertan, mikrokateter bidez gibeleko arterian mikroesfera erradioaktiboak injektatzen dira, hauek tumoreak enbolizazio eta erradiazio bidez erasotzeko. Mikroesferen ibilbidea ordenagailu bidezko fluido dinamika simulazioekin (CFD) aztertu daiteke. Kalkulu hauen iraupen luzea arazo bat da medikuntzaren egunerokotasunean simulazioak erabili ahal izateko. Kalkuluak azkartzeko asmoz, odolaren biskositatearen izaera ez¿newtondarra izaera newtondarrera sinplifikatu da. Emaitzek erakutsi dute mikroesferen banaketan eta odolaren hemodinamikan biskositate aldakorraren eragina mespretxagarria dela, odola fluido newtondar bezala aztertzearen sinplifikazioa ontzat emanez.
  • Autores: Ocal, O.; Rossler, D.; Gasbarrini, A.; et al.
    Revista: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
    ISSN: 0171-5216 Vol.148 N° 9 2022 págs. 2487 - 2496
    Resumen
    Purpose Gadoxetic acid uptake on hepatobiliary phase MRI has been shown to correlate with ss-catenin mutation in patients with HCC, which is associated with resistance to certain therapies. This study aimed to evaluate the prognostic value of gadoxetic acid uptake on hepatobiliary phase MRI in patients with advanced HCC receiving sorafenib. Methods 312 patients with available baseline hepatobiliary phase MRI images received sorafenib alone or following selective internal radiation therapy (SIRT) within SORAMIC trial. The signal intensity of index tumor and normal liver parenchyma were measured on the native and hepatobiliary phase MRI images, and relative tumor enhancement higher than relative liver enhancement were accepted as high gadoxetic acid uptake, and its prognostic value was assessed using univariate and multivariate Cox proportional hazard models. Results The median OS of the study population was 13.4 (11.8-14.5) months. High gadoxetic acid uptake was seen in 51 (16.3%) patients, and none of the baseline characteristics was associated with high uptake. In univariate analysis, high gadoxetic acid uptake was significantly associated with shorter overall survival (10.7 vs. 14.0 months, p = 0.005). Multivariate analysis confirmed independent prognostic value of high gadoxetic acid uptake (HR, 1.7 [1.21-2.3], p = 0.002), as well as Child-Pugh class (p = 0.033), tumor diameter (p = 0.002), and ALBI grade (p = 0.015). Conclusion In advanced HCC patients receiving sorafenib (alone or combined with SIRT), high gadoxetic acid uptake of the tumor on pretreatment MRI, a surrogate of ss-catenin mutation, correlates with shorter survival. Gadoxetic acid uptake status might serve in treatment decision-making process.
  • Autores: González-Recio, I.; Simón, J.; Goikoetxea-Usandizaga, N.; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.13 N° 1 2022 págs. 6816 -*
    Resumen
    Drug induced liver injury (DILI) is an important cause acute liver failure. Here the authors report that serum Mg2+ serum levels decrease in patients with DILI as well as in preclinical animal models treated with acetaminophen overdose, and that early intervention targeting the Mg2+ transporter Cyclin M4 may be beneficial for acetaminophen overdose in preclinical models. Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.
  • Autores: Ventura-Cots, M.; Argemí Ballbé, José María; Jones, P. D.; et al.
    Revista: GUT
    ISSN: 0017-5749 Vol.71 N° 9 2022 págs. 1856 - 1866
    Resumen
    Objective Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. Design Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. Results Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. Conclusions Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.
  • Autores: Guerrero, L.; Sangro Gómez-Acebo, Bruno Carlos; Ambao, V.; et al.
    Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
    ISSN: 1138-7548 Vol.78 N° 1 2022 págs. 229 - 243
    Resumen
    Precision medicine promises to overcome the constraints of the traditional one-for-all healthcare approach through a clear understanding of the molecular features of a disease, allowing for innovative and tailored treatments. State-of-the-art proteomics has the potential to accurately explore the human proteome to identify, quantify, and characterize proteins associated with disease progression. There is a pressing need for informative biomarkers to diagnose liver disease early in its course to prevent severe disease for which no efficient treatment is yet available. Here, we propose the concept of a cellular pathway as a functional biomarker, whose monitorization may inform normal and pathological status. We have developed a standardized targeted selected-reaction monitoring assay to detect and quantify 13 enzymes of one-carbon metabolism (1CM). The assay is compliant with Clinical Proteomics Tumor Analysis Consortium (CPTAC) guidelines and has been included in the protein quantification assays that can be accessed through the assay portal at the CPTAC web page. To test the feasibility of the assay, we conducted a retrospective, proof-of-concept study on a collection of liver samples from healthy controls and from patients with cirrhosis or hepatocellular carcinoma (HCC). Our results indicate a significant reconfiguration of 1CM upon HCC development resulting from a process that can already be identified in cirrhosis. Our findings indicate that the systematic and integrated quantification of 1CM enzymes is a promising cell function-based biomarker for patient stratification, although further experiments with larger cohorts are needed to confirm these findings.
  • Autores: Ocal, O.; Schinner, R.; Schutte, K.; et al.
    Revista: CANCER IMAGING
    ISSN: 1740-5025 Vol.22 N° 1 2022 págs. 1
    Resumen
    Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; >= 20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22-0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS >= 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.
  • Autores: Alonso-Pena, M.; Espinosa-Escudero, R.; Hermanns, H. M.; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.11 N° 24 2022 págs. 3983
    Resumen
    Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4 alpha (HNF4 alpha) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7 alpha-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4 alpha levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile.
  • Autores: Zhu, A. X. (Autor de correspondencia); Dayyani, F. ; Yen, C. J. ; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.28 N° 16 2022 págs. 3537 - 3545
    Resumen
    Purpose: Atezolizumab + bevacizumab is the new standard of care for systemic treatmentna? euro ve, unresectable hepatocellular car-cinoma (HCC). This exploratory study investigated on-treatment alpha-fetoprotein (AFP) response as a potential surrogate biomark-er of prognosis for the combination therapy. Experimental Design: Data from Group A of the phase Ib GO30140 study were used to identify the optimal time for AFP measurement and AFP cutoffs to differentiate patients by their best confirmed response per independent review facility-assessed RECIST (IRF-RECIST) version 1.1: responders from nonresponders and patients with disease control from primary progressors. We applied these cutoffs to independent data from the atezolizumab + bevacizumab arm of the phase III IMbrave150 trial to distinguish patients based on (i) overall survival (OS) and progression-free survival (PFS) per IRF-RECIST 1.1 and (ii) best confirmed response per IRF-RECIST 1.1. Results: We derived AFP cutoffs of >= 75% decrease and <= 10% increase from baseline at 6 weeks to identify responders and those who had disease control, respectively. These cutoffs had high sensitivity and specificity in GO30140. In IMbrave150 patients, sensitivity was 0.59 and specificity was 0.86 for the >= 75% decrease AFP cutoff; the sensitivity was 0.77 and specificity was 0.44 for the <= 10% increase AFP cutoff. Both AFP cutoffs were associated with longer OS and PFS, particularly in patients with hepatitis B virus etiology (HR < 0.5; P < 0.01). Conclusions: AFP response at 6 weeks after initiating treatment is a potential surrogate biomarker of prognosis for patients with HCC receiving atezolizumab + bevacizumab. See related commentary by Cappuyns and Llovet, p. 3405
  • Autores: Iñarrairaegui Bastarrica, Mercedes; Fernández Ros, Nerea; Lucena Ramírez, Juan Felipe; et al.
    Revista: BMC MEDICAL EDUCATION
    ISSN: 1472-6920 Vol.22 N° 1 2022 págs. 779
    Resumen
    Background One of the most important challenges in medical education is the preparation of multiple-choice questions able to discriminate between students with different academic level. Average questions may be very easy for students with good performance, reducing their discriminant power in this group of students. The aim of this study was to analyze if the discriminative power of multiple-choice questions is different according to the students' academic performance. Methods We retrospectively analyzed the difficulty and discrimination indices of 257 multiple-choice questions used for the end of course examination of pathophysiology and analyzed whether the discrimination indices were lower in students with good academic performance (group 1) than in students with moderate/poor academic performance (group 2). We also evaluated whether case-based questions maintained their discriminant power better than factual questions in both groups of students or not. Comparison of the difficulty and discrimination indices between both groups was based on the Wilcoxon test. Results Difficulty index was significantly higher in group 1 (median: 0.78 versus 0.56; P < 0.001) and discrimination index was significantly higher in group 2 (median: 0.21 versus 0.28; P < 0.001). Factual questions had higher discriminative indices in group 2 than in group 1 (median: 0.28 versus 0.20; P < 0.001), but discriminative indices of case-based questions did not differ significantly between groups (median: 0.30 versus 0.24; P = 0.296). Conclusions Multiple-choice question exams have lower discriminative power in the group of students with high scores. The use of clinical vignettes may allow to maintain the discriminative power of multiple-choice questions.
  • Autores: Shuen, T. W. H.; Alunni-Fabbroni, M.; Ocal, E.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.28 N° 17 2022 págs. 3890 - 3901
    Resumen
    Purpose: SORAMIC is a randomized controlled trial in patients with advanced hepatocellular carcinoma (HCC) undergoing sorafenib +/- selective internal radiation therapy (SIRT). We investigated the value of extracellular vesicle (EV)-based proteomics for treatment response prediction. Experimental Design: The analysis population comprised 25 patients receiving SIRT+sorafenib and 20 patients receiving sorafenib alone. Patients were classified as responders or nonresponders based on changes in AFP and imaging or overall survival. Proteomic analysis was performed on plasma EVs by LC/MS, followed by bioinformatics analysis. Clinical relevance of candidate EV proteins was validated by survival and receiver-operating characteristic analysis with bootstrap internal sampling validation. Origin of circulating EV was explored by IHC staining of liver and tumor tissues and transcriptomics of blood cells. Results: Proteomic analysis identified 56 and 27 EV proteins that were differentially expressed in plasma EVs between responders and nonresponders receiving SIRT+sorafenib and sorafenib alone, respectively. High EV-GPX3/ACTR3 and low EV-ARHGAP 1 were identified as candidate biomarkers at base-line from the 13 responders to SIRT+sorafenib with statistically significant AUC = 1 for all and bootstrap P values 2.23 x 10(-5), 2.22 x 10(-5), and 2.23 x 10(-5), respectively. These patients showed reduced abundance of EV-VPS13A and EV-KALRN 6 to 9 weeks after combined treatment with significant AUC and bootstrap P values. In reverse, low GPX3 and high ARHGAP1 demonstrated better response to sorafenib monotherapy with AUC = 0.9697 and 0.9192 as well as bootstrap P values 8.34 x 10(-5) and 7.98 x 10(-4), respectively. HCC tumor was the likely origin of circulating EVs. Conclusions: In this exploratory study, EV-based proteomics predicted response to SIRT+sorafenib and sorafenib-only treatment in patients with advanced HCC of metabolic origin.
  • Autores: Ginès, P. (Autor de correspondencia); Buti, M.; Lazarus, J. V.; et al.
    Revista: MEDICINA CLINICA
    ISSN: 0025-7753 Vol.159 N° 12 2022 págs. 598 - 603
  • Autores: Chan, S. L.; Kudo, M.; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.38 N° 9 2022 págs. S1465 - S1466
  • Autores: Chan, S. L.; Kudo, M.; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 9 2022 págs. S1456 - S1456
  • Autores: Martínez-Arenas, L.; Carvalho-Gomes, A.; Díaz-Fontenla, F.; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.106 N° 8S 2022 págs. 99
  • Autores: Serrano, T.; Sabroso, S.; Esteban, L. M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S792 - S793
  • Autores: Martínez-Arenas, L.; Carvalho-Gomes, A.; Bhat, V.; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.106 N° 8S 2022 págs. 32 - 33
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Galle, P. R.; Kelley, R. K.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
  • Autores: Abou-Alfa, G. K.; Chan, S. L.; Kudo, M.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 4 2022
  • Autores: Taieb, J.; Arnold, D.; Prenen, H.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° Supl. 4 2022 págs. S252
  • Autores: Bastidas Tamayo, Juan Fernando; Cabrera Villegas, Antonio; Bronte Viedma, Angela; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.49 N° SUPPL 1 2022 págs. S303 - S304
  • Autores: Gil-Pitarch, C.; Bertran, E.; Uriarte Díaz-Varela, Iker; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Suppl. 1 2022 págs. S48 - S48
  • Autores: Cervantes-Álvarez, E.; Vilatoba, M.; Argemí Ballbé, José María; et al.
    Revista: AMERICAN JOURNAL OF TRANSPLANTATION
    ISSN: 1600-6135 Vol.22 N° Supl. 3 2022 págs. 1033 - 1034
  • Autores: Sarode, G.; Argemí Ballbé, José María; Bataller, R.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.76 N° Supl. 1 2022 págs. S106 - S107
  • Autores: Martínez-Arenas, L.; Carvalho-Gomes, A.; Vidal, E.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.76 N° SUPPL 1 2022 págs. S837 - S838
  • Autores: Pujols, P.; Caballeros Lam, Fanny Meylin; Iñarrairaegui Bastarrica, Mercedes; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S802 - S803
  • Autores: Gárate Rascón, María; Recalde, M.; Bilbao Del Olmo, Idoia; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S500
  • Autores: Herranz, J. M.; Clavería Cabello, Alex; Colyn, L.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S112
  • Autores: Conde, I.; Aguilera Sancho, V.; Martínez, S.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S406 - S407
  • Autores: Recalde-Domínguez de Vidaurreta, M.; Gárate Rascón, María; Herranz-Alzueta, J. M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S644 - S645
  • Autores: Neely, J.; Yao, J.; Kudo, M.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Martínez-Arenas, L.; Carvalho-Gomes, A.; Díaz Fontela, F.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S150
  • Autores: Colyn, L.; Álvarez-Sola, G.; Latasa Sada, María Ujué; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S643
  • Autores: Olaizola, P.; Lee-Law, P. Y.; García Fernández de Barrena, Maite; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Suppl. 1 2022 págs. S46 - S46
  • Autores: Conde, I.; Aguilera, V.; Martínez, S.; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.106 N° 8S 2022 págs. 100
  • Autores: Chan, L. S.; Kudo, M.; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S869 - S870
  • Autores: Rotellar Sastre, Fernando; Zozaya Larequi, Gabriel Nicolás; Martí Cruchaga, Pablo; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.106 N° 8S 2022 págs. 53
  • Autores: Finnemore, A.; Herranz, J. M.; Barace Jiménez, Sergio; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.77 N° Supl. 1 2022 págs. S697
  • Autores: Solares, I.; Heredia-Mena, C.; Castelbón, F. J.; et al.
    Revista: DIAGNOSTICS
    ISSN: 2075-4418 Vol.11 N° 11 2021 págs. 2148
    Resumen
    Inborn errors of metabolism (IEM) constitute an important group of conditions characterized by an altered metabolic pathway. There are numerous guidelines for the diagnosis and management of IEMs in the pediatric population but not for adults. Given the increasing frequency of this group of conditions in adulthood, other clinicians in addition to pediatricians should be aware of them and learn to identify their characteristic manifestations. Early recognition and implementation of an appropriate therapeutic approach would improve the clinical outcome of many of these patients. This review presents when and how to investigate a metabolic disorder with the aim of encouraging physicians not to overlook a treatable disorder.
  • Autores: Clavería Cabello, Alex; Arechederra Calderon, Maria; Berasain Lasarte, María del Carmen; et al.
    Revista: HEPATOMA RESEARCH
    ISSN: 2394-5079 Vol.7 2021 págs. 65
    Resumen
    Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of non-coding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.
  • Autores: Wu, H.; Chen, C.; Ziani, S.; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.10 N° 5 2021 págs. 1107
    Resumen
    Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
  • Autores: Iraburu Elizalde, María; Garner, T.; Montiel-Duarte, C. (Autor de correspondencia)
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.22 N° 13 2021 págs. 6978
    Resumen
    The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.
  • Autores: Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia); Sarobe Ugarriza, Pablo; Hervas Stubbs, Sandra; et al.
    Revista: NATURE REVIEWS GASTROENTEROLOGY AND HEPATOLOGY
    ISSN: 1759-5053 Vol.18 N° 8 2021 págs. 525 - 543
    Resumen
    Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
  • Autores: Arechederra Calderon, Maria; Recalde, M.; Gárate Rascón, María; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 6 2021 págs. 1265
    Resumen
    Simple Summary Cellular identity and function depends on the correct and specific expression of genetic information. Different epigenetic mechanisms including DNA methylation, modifications of histones, and expression of non-coding RNAs control chromatin structure and DNA accessibility to the transcriptional machinery. Alterations of these mechanisms are associated with the development of multiple diseases. The incidence of chronic liver diseases, including hepatocellular carcinoma (HCC), is increasing worldwide. However, the management of those patients is poor due to the late diagnosis of the disease and the absence of effective therapies. Here, we review the epigenetic alterations described in the process of hepatocarcinogenesis, and we discuss the applicability of epigenetic markers as therapeutic targets and liquid biopsy biomarkers for diagnosis. Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.
  • Autores: Sogbe Diaz, Miguel Eduardo (Autor de correspondencia); López-Guerra, D.; Blanco-Fernández, G.; et al.
    Revista: TRANSPLANTATION
    ISSN: 0041-1337 Vol.105 N° 12 2021 págs. e398 - e400
  • Autores: Fontanellas Roma, Antonio (Autor de correspondencia); Ávila Zaragoza, Matías Antonio; Arranz, E.; et al.
    Revista: JOURNAL OF INHERITED METABOLIC DISEASE
    ISSN: 0141-8955 Vol.44 N° 4 2021 págs. 790 - 791
  • Autores: Marino, Z.; Darnell, A.; Lens, S.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.74 N° 2 2021 págs. 491
  • Autores: Iñarrairaegui Bastarrica, Mercedes; Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° 5 2021 págs. 2333 - 2335
  • Autores: Berasain Lasarte, María del Carmen; Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
    Revista: CMGH
    ISSN: 2352-345X Vol.11 N° 1 2021 págs. 291 - 293
  • Autores: Yu, A. T.; Berasain Lasarte, María del Carmen; Bhatia, S.; et al.
    Revista: ELIFE
    ISSN: 2050-084X Vol.10 2021 págs. e68263
    Resumen
    Hepatocellular carcinoma, the most common type of liver malignancy, is one of the most lethal forms of cancer. We identified a long non-coding RNA, Gm19705, that is overexpressed in hepatocellular carcinoma and mouse embryonic stem cells. We named this RNA Pluripotency and Hepatocyte Associated RNA Overexpressed in HCC, or PHAROH. Depletion of PHAROH impacts cell proliferation and migration, which can be rescued by ectopic expression of PHAROH. RNA-seq analysis of PHAROH knockouts revealed that a large number of genes with decreased expression contain a Myc motif in their promoter. MYC is decreased in knockout cells at the protein level, but not the mRNA level. RNA-antisense pulldown identified nucleolysin TIAR, a translational repressor, to bind to a 71-nt hairpin within PHAROH, sequestration of which increases MYC translation. In summary, our data suggest that PHAROH regulates MYC translation by sequestering TIAR and as such represents a potentially exciting diagnostic or therapeutic target in hepatocellular carcinoma.
  • Autores: Serrano-Macia, M.; Simón, J.; González-Rellán, M. J.; et al.
    Revista: MOLECULAR METABOLISM
    ISSN: 2212-8778 Vol.53 2021 págs. 101275
    Resumen
    Objective: Neddylation is a druggable and reversible ubiquitin-like post-translational modification upregulated in many diseases, including liver fibrosis, hepatocellular carcinoma, and more recently, non-alcoholic fatty liver disease (NAFLD). Herein, we propose to address the effects of neddylation inhibition and the underlying mechanisms in pre-clinical models of NAFLD. Methods: Hepatic neddylation measured by immunohistochemical analysis and NEDD8 serum levels measured by ELISA assay were evaluated in NAFLD clinical and pre-clinical samples. The effects of neddylation inhibition by using a pharmacological small inhibitor, MLN4924, or molecular approaches were assessed in isolated mouse hepatocytes and pre-clinical mouse models of diet-induced NAFLD, male adult C57BL/6 mice, and the AlfpCre transgenic mice infected with AAV-DIO-shNedd8. Results: Neddylation inhibition reduced lipid accumulation in oleic acid-stimulated mouse primary hepatocytes and ameliorated liver steatosis, preventing lipid peroxidation and inflammation in the mouse models of diet-induced NAFLD. Under these conditions, increased Deptor levels and the concomitant repression of mTOR signaling were associated with augmented fatty acid oxidation and reduced lipid content. Moreover, Deptor silencing in isolated mouse hepatocytes abolished the anti-steatotic effects mediated by neddylation inhibition. Finally, serum NEDD8 levels correlated with hepatic neddylation during the disease progression in the clinical and pre-clinical models Conclusions: Overall, the upregulation of Deptor, driven by neddylation inhibition, is proposed as a novel effective target and therapeutic approach to tackle NAFLD.
  • Autores: Mirra, S.; Gavalda Navarro, A.; Manso, Y.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 5 2021 págs. 1110
    Resumen
    Simple Summary An excess fat in the liver enhances the susceptibility to hepatic cancer. We found that Armcx3, a protein only known to date to play a role in neural development, is strongly increased in mouse liver in response to lipid availability and proliferation-inducing insults. In patients, the levels of hepatic Armcx3 are also increased in conditions of high exposure of the liver to fat. We wanted to determine the role of Armcx3 in the hepatocarcinogenesis favored by a high-fat diet. We generated mice with genetically driven suppression of Armcx3, and we found that they were protected against experimentally induced hepatic cancer, especially in conditions of a high-fat diet. Armcx3 was also found to promote hepatic cell proliferation through the interaction with Sox9, a known proliferation factor in hepatocellular carcinoma. Armcx3 is identified as a novel factor in meditating propensity to liver cancer in conditions of high hepatic lipid insults. ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
  • Autores: Fernández Ros, Nerea; Lucena Ramírez, Juan Felipe; Iñarrairaegui Bastarrica, Mercedes; et al.
    Revista: BMC MEDICAL EDUCATION
    ISSN: 1472-6920 Vol.21 N° 1 2021 págs. 249
    Resumen
    Background: Active learning strategies such as formative assessment through clinical cases may help to get a deeper learning. We have studied the effect of this kind of online formative assessment in pathophysiology teaching. Methods: Seven brief clinical cases were used to give formative assessment in the first semester of a pathophysiology course. To evaluate its effect on learning, we analyzed the proportion of students that passed the end of semester exam with a score above 60 over 100. We also analyzed the effect of the intervention according to the students' previous academic performance. Results: Ninety-six students participated in the study and sat the exam. Sixty-five of them passed it. Students that passed the exam had a higher previous academic performance and had done a higher number of exercises of formative assessment, both in univariate and multivariate analysis. The participants were divided in three groups, according to their previous academic performance. In the intermediate group, the number of cases done by the students who passed the exam was significantly higher than in those who did not pass it (median: 4 versus 0; P = 0.009). Conclusion: Formative assessment through web-based clinical cases was followed by an improvement of the academic results in pathophysiology, mainly in students with intermediate performance.
  • Autores: Ocal, O.; Kupcinskas, J.; Morkunas, E.; et al.
    Revista: EJNMMI RESEARCH
    ISSN: 2191-219X Vol.11 N° 1 2021 págs. 51
    Resumen
    Background To confirm the prognostic value of previously published baseline interleukin 6 (IL6) and IL8 cutoff values in survival and liver dysfunction in patients with advanced HCC undergoing Y-90 radioembolization. Methods A total of 83 patients (77 male) represented a subset of HCC patients undergoing Y-90 radioembolization combined with sorafenib as part of the prospective multicenter phase II trial SORAMIC. IL6 and IL8 levels were determined in serum samples collected at baseline. In this post hoc analysis, we sought to confirm the prognostic value of baseline cutoff values of 6.53 pg/mL and 60.8 pg/mL for IL6 and IL8, respectively, in overall survival (OS) or liver dysfunction (grade 2 bilirubin increase) after treatment. Results Median OS was 12.0 months. While low baseline albumin and high bilirubin values were associated with high IL6, liver cirrhosis, alcoholic liver disease, and portal vein infiltration were associated with high IL8. In univariate analysis, high baseline IL6 and IL8 were associated with significantly shorter overall survival (7.8 vs. 19.0 months for IL6 and 8.4 vs. 16.0 months for IL8). In addition to IL values, liver cirrhosis, Child-Pugh grade, baseline albumin (< 36 g/dL), and total bilirubin (>= 17 mu mol/L), and higher mALBI grade (2b &3) values were associated with OS. At multivariate analysis, high baseline IL6 was the only independent prognostic factor for OS (HR 2.35 [1.35-4.1], p = 0.002). Risk factors for liver dysfunction were high baseline IL6, albumin, and total bilirubin, and mALBI grade as found in univariate analysis. High baseline IL6 (HR 2.67 [1.21-5.94], p = 0.016) and total bilirubin >= 17 mu mol/L (HR 3.73 [1.72-8.06], p < 0.001) were independently associated with liver dysfunction. Conclusion In advanced HCC patients receiving Y-90 radioembolization combined with sorafenib, baseline IL6 values proved to be prognostic, confirming previous findings in patients undergoing (90)Yradioembolization. IL6 might be useful for patient selection or stratification in future trials.
  • Autores: Bruix, J.; Chan, S. L.; Galle, P. R.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° 4 2021 págs. 960 - 974
    Resumen
    The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multityrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Autores: Kelley, R. K.; Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia); Harris, W.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 27 2021 págs. 2991 - 3001
    Resumen
    PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade >= 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
  • Autores: Muñoz-Martínez, S.; Sapena, V.; Forner, A.; et al.
    Revista: JHEP REPORTS
    ISSN: 2589-5559 Vol.3 N° 3 2021 págs. 100260
    Resumen
    Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%,17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. Lay summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).
  • Autores: Pereira, P. L. ; Iezzi, R.; Manfredi, R.; et al.
    Revista: CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
    ISSN: 0174-1551 Vol.44 N° 1 2021 págs. 50 - 62
    Resumen
    Purpose Transarterial chemoembolisation (TACE) using irinotecan-eluting beads is an additional treatment option for colorectal cancer liver metastases (CRLM) patients that are not eligible for curative treatment approaches. This interim analysis focuses on feasibility of the planned statistical analysis regarding data distribution and completeness, treatment intention, safety and health-related quality of life (HRQOL) of the first 50 patients prospectively enrolled in the CIrse REgistry for LifePearl (TM) microspheres (CIREL), an observational multicentre study conducted across Europe. Methods In total, 50 patients >= 18 years diagnosed with CRLM and decided to be treated with irinotecan-eluting LifePearl (TM) microspheres TACE (LP-irinotecan TACE) by a multidisciplinary tumour board. There were no further inclusion or exclusion criteria. The primary endpoint is the categorisation of treatment intention, and secondary endpoints presented in this interim analysis are safety, treatment considerations and HRQOL. Results LP-irinotecan TACE was conducted in 42% of patients as salvage therapy, 20% as an intensification treatment, 16% as a first-line treatment, 14% a consolidation treatment and 8% combination treatment with ablation with curative intent. Grade 3 and 4 adverse events were reported by 4% of patients during procedure and by 10% within 30 days. While 38% reported a worse, 62% reported a stable or better global health score, and 54% of patients with worse global health score were treated as salvage therapy patients. Conclusion This interim analysis confirms in a prospective analysis the feasibility of the study, with an acceptable toxicity profile. More patients reported a stable or improved HRQOL than deterioration. Deterioration of HRQOL was seen especially in salvage therapy patients.
  • Autores: Colyn, L.; Bárcena Varela, Marina; Álvarez-Sola, G.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.73 N° 6 2021 págs. 2380 - 2396
    Resumen
    Background and Aims Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. Approach and Results Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (Jnk(Delta hepa) + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk(Delta hepa) + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.
  • Autores: Bárcena Varela, Marina; Paish, H.; Álvarez Asiain, Laura; et al.
    Revista: GUT
    ISSN: 0017-5749 Vol.70 N° 2 2021 págs. 388 - 400
    Resumen
    Objective Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis. Design G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. G9a and DNMT1 expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-beta 1 (TGF beta 1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl4 administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology. Results G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGF beta 1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGF beta 1 fibrogenic responses in hHSC. TGF beta 1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity. Conclusions Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis.
  • Autores: Ricke, J. (Autor de correspondencia); Schinner, R.; Seidensticker, M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° 6 2021 págs. 1387 - 1396
    Resumen
    Background & Aims: SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. Methods: The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. >= 65 years-old, Child Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol-vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. Results: ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age >= 65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). Conclusion: SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. Clinical trial number: EudraCT 2009-012576-27, NCT01126645 Lay summary: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.(C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Autores: Moron Ros, S.; Uriarte, I.; Berasain Lasarte, María del Carmen; et al.
    Revista: MOLECULAR METABOLISM
    ISSN: 2212-8778 Vol.43 2021 págs. 101113
    Resumen
    Objective: To determine the role of enterokine FGF15/19 in adipose tissue thermogenic adaptations. Methods: Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from obese human patients. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses spanned metabolic profiling, tissue characterization, histology, gene expression, and immunoblot assays. Results: In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases in FGF15 or FGF19 induced white fat browning in mice as demonstrated by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization. Conclusions: Enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations. (C) 2020 The Authors. Published by Elsevier GmbH.
  • Autores: Onorato, A. M.; Fiore, E.; Bayo, J.; et al.
    Revista: LIVER INTERNATIONAL
    ISSN: 1478-3223 Vol.41 N° 7 2021 págs. 1677 - 1693
    Resumen
    Background and aims Non-alcoholic fatty liver (NAFLD) and its more serious form non-alcoholic steatohepatitis increase risk of hepatocellular carcinoma (HCC). Lipid metabolic alterations and its role in HCC development remain unclear. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is involved in lipid metabolism, NAFLD and diabetes, but the effects on hepatic lipid metabolism and HCC development is unknown. The aim of this study was to evaluate the role of SPARC in HCC development in the context of NAFLD. Methods Primary hepatocyte cultures from knockout (SPARC(-/-)) or wild-type (SPARC(+/+)) mice, and HepG2 cells were used to assess the effects of free fatty acids on lipid accumulation, expression of lipogenic genes and de novo triglyceride (TG) synthesis. A NAFLD-HCC model was stabilized on SPARC(-/-) or SPARC(+/+) mice. Correlations among SPARC, lipid metabolism-related gene expression patterns and clinical prognosis were studied using HCC gene expression dataset. Results SPARC(-/-) mice increases hepatic lipid deposits over time. Hepatocytes from SPARC(-/-) mice or inhibition of SPARC by an antisense adenovirus in HepG2 cells resulted in increased TG deposit, expression of lipid-related genes and nuclear translocation of SREBP1c. Human HCC database analysis revealed that SPARC negatively correlated with genes involved in lipid metabolism, and with poor survival. In NAFLD-HCC murine model, the absence of SPARC accelerates HCC development. RNA-seq study revealed that pathways related to lipid metabolism, cellular detoxification and proliferation were upregulated in SPARC(-/-) tumour-bearing mice. Conclusions The absence of SPARC is associated with an altered hepatic lipid metabolism, and an accelerated NAFLD-related HCC development.
  • Autores: Ciordia, S.; Alvarez Sola, G.; Rullan, M.; et al.
    Revista: JOURNAL OF PROTEOMICS
    ISSN: 1874-3919 Vol.230 2021 págs. 103984
    Resumen
    The analysis of biological fluids to identify proteins that may indicate a disease setting, state and progression, is an increasingly explored field. Despite the expectatives created, there are several hurdles that must be solved to reach an extensive proteome coverage using mass spectrometry, mainly due to the complex composition of the matrices. In this regard, bile is specially challenging and yet, very attractive, as a proximal fluid that might provide valuable information for the management of liver and pancreas associated diseases. Proteins account for less than 5% of bile organic components and, although optimized protocols for protein extraction have been developed, only partial descriptions of bile proteome have been achieved. In this manuscript a new procedure is described that significantly improves protein recovery from rat bile, which reduces by a factor of six the sample amount required for a typical proteomics analysis. Moreover, the number of proteins reliably identified in a single nanoLC-MS/MS run from 1 mu g protein was increased by three-fold. This procedure provides a valuable resource to dig deeper into the molecular composition of bile and open new avenues to identify new hallmarks of disease such as cholangiocarcinoma, hepatocellular carcinoma and pancreatic cancer for their better clinical management.
  • Autores: Recalde, M.; Gárate Rascón, María; Elizalde Pérez, Arlette María; et al.
    Revista: NUCLEIC ACIDS RESEARCH
    ISSN: 0305-1048 Vol.49 N° 15 2021 págs. 8592 - 8609
    Resumen
    Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.
  • Autores: Maestro Galilea, Sheila; Córdoba Quiñones, Karol Marcela; Olague Micheltorena, María Cristina; et al.
    Revista: BIOMEDICINE AND PHARMACOTHERAPY
    ISSN: 0753-3322 Vol.137 2021 págs. 111384
    Resumen
    Antiviral agents with different mechanisms of action could induce synergistic effects against SARS-CoV-2 infection. Some reports suggest the therapeutic potential of the heme oxygenase-1 (HO-1) enzyme against virus infection. Given that hemin is a natural inducer of the HO-1 gene, the aim of this study was to develop an in vitro assay to analyze the antiviral potency of hemin against SARS-CoV-2 infection. A SARS-CoV-2 infectivity assay was conducted in Vero-E6 and Calu-3 epithelial cell lines. The antiviral effect of hemin, and chloroquine as a control, against SARS-CoV-2 virus infection was quantified by RT-qPCR using specific oligonucleotides for the N gene. Chloroquine induced a marked reduction of viral genome copies in kidney epithelial Vero-E6 cells but not in lung cancer Calu-3 cells. Hemin administration to the culture medium induced a high induction in the expression of the HO-1 gene that was stronger in Vero-E6 macaque-derived cells than in the human Calu-3 cell line. However, hemin treatment did not modify SARS-CoV-2 replication, as measured by viral genome quantification 48 h post-infection for Vero-E6 and 72 h post-infection for the Calu-3 lineages. In conclusion, although exposure to hemin induced strong HO-1 up-regulation, this effect was unable to inhibit or delay the progression of SARS-CoV-2 infection in two epithelial cell lines susceptible to infection. Antiviral agents with different mechanisms of action could induce synergistic effects against SARS-CoV-2 infection. Some reports suggest the therapeutic potential of the heme oxygenase-1 (HO-1) enzyme against virus infection. Given that hemin is a natural inducer of the HO-1 gene, the aim of this study was to develop an in vitro assay to analyze the antiviral potency of hemin against SARS-CoV-2 infection. A SARS-CoV-2 infectivity assay was conducted in Vero-E6 and Calu-3 epithelial cell lines. The antiviral effect of hemin, and chloroquine as a control, against SARS-CoV-2 virus infection was quantified by RT-qPCR using specific oligonucleotides for the N gene. Chloroquine induced a marked reduction of viral genome copies in kidney epithelial Vero-E6 cells but not in lung cancer Calu-3 cells. Hemin administration to the culture medium induced a high induction in the expression of the HO-1 gene that was stronger in Vero-E6 macaque-derived cells than in the human Calu-3 cell line. However, hemin treatment did not modify SARS-CoV-2 replication, as measured by viral genome quantification 48 h post-infection for Vero-E6 and 72 h post-infection for the Calu-3 lineages. In conclusion, although exposure to hemin induced strong HO-1 up-regulation, this effect was unable to inhibit or delay the progression of SARS-CoV-2 infection in two epithelial cell lines susceptible to infection.
  • Autores: Benede Ubieto, R.; Estevez Vazquez, O.; Guo, F.; et al.
    Revista: HEPATOLOGY COMMUNICATIONS
    ISSN: 2471-254X Vol.5 N° 6 2021 págs. 1051 - 1068
    Resumen
    Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.
  • Autores: Benede Ubieto, R.; Estevez Vazquez, O.; Flores Perojo, V.; et al.
    Revista: JOURNAL OF CLINICAL MEDICINE
    ISSN: 2077-0383 Vol.10 N° 5 2021 págs. 1039
    Resumen
    The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.
  • Autores: Loffroy, R.; Ronot, M. ; Greget, M.; et al.
    Revista: CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
    ISSN: 0174-1551 Vol.44 N° 1 2021 págs. 36 - 49
    Resumen
    Purpose Radioembolization has emerged as a treatment modality for patients with primary and secondary liver tumours. This observational study CIRT-FR (CIRSE Registry for SIR-Spheres Therapy in France) aims to evaluate real-life clinical practice on all patients treated with transarterial radioembolization (TARE) using SIR-Spheres yttrium-90 resin microspheres in France. In this interim analysis, safety and quality of life data are presented. Final results of the study, including secondary effectiveness outcomes, will be published later. Overall, CIRT-FR is aiming to support French authorities in the decision making on reimbursement considerations for this treatment. Methods Data on patients enrolled in CIRT-FR from August 2017 to October 2019 were analysed. The interim analysis describes clinical practice, baseline characteristics, safety (adverse events according to CTCTAE 4.03) and quality of life (according to EORTC QLQ C30 and HCC module) aspects after TARE. Results This cohort included 200 patients with hepatocellular carcinoma (114), metastatic colorectal cancer (mCRC; 38) and intrahepatic cholangiocarcinoma (33) amongst others (15). TARE was predominantly assigned as a palliative treatment (79%). 12% of patients experienced at least one adverse event in the 30 days following treatment; 30-day mortality was 1%. Overall, global health score remained stable between baseline (66.7%), treatment (62.5%) and the first follow-up (66.7%). Conclusion This interim analysis demonstrates that data regarding safety and quality of life generated by randomised-controlled trials is reflected when assessing the real-world application of TARE.
  • Autores: Jericó Asenjo, Daniel; Córdoba Quiñones, Karol Marcela; Jiang, L.; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN: 2162-2531 Vol.25 2021 págs. 207 - 219
    Resumen
    Variegate porphyria (VP) results from haploinsufficiency of pro-toporphyrinogen oxidase (PPDX), the seventh enzyme in the heme synthesis pathway. There is no VP model that recapitulates the clinical manifestations of acute attacks. Combined administrations of 2-allyl-2-isopropylacetamide and rifampicin in rabbits halved hepatic PP OX activity, resulting in increased accumulation of a potentially neurotoxic heme precursor, lipid peroxidation, inflammation, and hepatocyte cytoplasmic stress. Rabbits also showed hypertension, motor impairment, reduced activity of critical mitochondrial hemoprotein functions, and altered glucose homeostasis. Hemin treatment only resulted in a slight drop in heme precursor accumulation but further increased hepatic heme catabolism, inflammation, and cytoplasmic stress. Hemin replenishment did protect against hypertension, but it failed to restore action potentials in the sciatic nerve or glucose homeostasis. Systemic porphobilinogen deaminase (PBGD) mRNA administration increased hepatic PBGD activity, the third enzyme of the pathway, and rapidly normalized serum and urine porphyrin precursor levels. All features studied were improved, including those related to critical hemoprotein functions. In conclusion, the VP model recapitulates the biochemical characteristics and some clinical manifestations associated with severe acute attacks in humans.
  • Autores: Guldiken, N.; Argemí Ballbé, José María; Gurbuz, B.; et al.
    Revista: BMC MEDICINE
    ISSN: 1741-7015 Vol.19 N° 1 2021 págs. 39
    Resumen
    Background Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4 alpha activity. Methods Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. Results In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4 alpha and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4 alpha signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGF beta 1), tumor necrosis factor alpha (TNF alpha), interleukin 1 beta (IL-1 beta), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGF beta 1 or the HNF4 alpha inhibitor BI6015 suppressed transferrin production, while exposure to TNF alpha, IL-1 beta, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. Conclusions Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4 alpha signaling and liver failure.
  • Autores: Kudo, M. (Autor de correspondencia); Matilla, A.; Santoro, A.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° 3 2021 págs. 600 - 609
    Resumen
    Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was similar to 3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
  • Autores: Rimola, J.; Fonseca, L. G. ; Sapena, V.; et al.
    Revista: EUROPEAN JOURNAL OF RADIOLOGY
    ISSN: 0720-048X Vol.135 2021 págs. 109484
    Resumen
    Background and aims: Immune-checkpoint inhibitors are effective in many advanced tumors. However, there is scarce information regarding the radiological response to these agents in hepatocellular carcinoma outside clinical trials. We aimed to describe the radiological response in a retrospective cohort of hepatocellular carcinoma patients treated with nivolumab and to analyze the radiological evolution according to tumor response at first post-treatment radiological assessment. Methods: We reviewed pre-treatment and post-treatment images (CT or MRI) obtained at different time-points in patients with hepatocellular carcinoma treated with nivolumab outside clinical trials at seven Spanish centers, assessing the response according to RECIST 1.1 and iRECIST and registering atypical responses. We also analyzed the imaging findings on subsequent assessments according to tumor status on the first posttreatment imaging assessment. Results: From the 118 patients with hepatocellular carcinoma treated with nivolumab, we finally analyzed data from 31 patients (71 % Child-Pugh A; 74 % BCLC-C). Median follow-up was 8.39 months [IQR 5.00-10.92]; median overall survival was 12.82 months (95 %CI 10.92-34.79). According to RECIST 1.1, the objective response rate was 16 % and according to iRECIST, the objective response rate was 22.6 %. Findings at the first post-treatment assessment varied, showing stable disease in 44.8 % of patients; findings during follow-up also varied widely, including 4 hyperprogressions and 3 pseudoprogressions. Conclusion: Imaging findings during nivolumab treatment are heterogeneous between and within patients. Progression of disease does not always signify treatment failure, and surrogate end-points may not reflect survival outcomes, making the management of hepatocellular carcinoma patients under immunotherapy challenging.
  • Autores: Massey, V.; Parrish, A.; Argemí Ballbé, José María; et al.
    Revista: GASTROENTEROLOGY
    ISSN: 0016-5085 Vol.160 N° 5 2021 págs. 1725 - 1740
    Resumen
    BACKGROUND & AIMS: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism. METHODS: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. RESULTS: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes. CONCLUSIONS: Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.
  • Autores: Duan, Y.; Chu, H.; Brandl, K.; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.12 N° 1 2021 págs. 7172
    Resumen
    CRIg is expressed on liver macrophages and binds Gram-positive bacteria to mediate phagocytosis, but it is not clear how its phagocytic functions contribute to liver homeostasis or disease. Here the authors report that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of alcoholic liver disease. Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.
  • Autores: Helmberger, T.; Golfieri, R.; Pech, M.; et al.
    Revista: CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
    ISSN: 0174-1551 2021
    Resumen
    Purpose To address the lack of prospective data on the real-life clinical application of trans-arterial radioembolization (TARE) in Europe, the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) initiated the prospective observational studyCIRSE Registry for SIR-Spheres (R) Therapy (CIRT). Materials and Methods Patients were enrolled from 1 January 2015 till 31 December 2017. Eligible patients were adult patients treated with TARE with Y90 resin microspheres for primary or metastatic liver tumours. Patients were followed up for 24 months after treatment, whereas data on the clinical context of TARE, overall survival (OS) and safety were collected. Results Totally, 1027 patients were analysed. 68.2% of the intention of treatment was palliative. Up to half of the patients received systemic therapy and/or locoregional treatments prior to TARE (53.1%; 38.3%). Median overall survival (OS) was reported per cohort and was 16.5 months (95% confidence interval (CI) 14.2-19.3) for hepatocellular carcinoma, 14.6 months (95% CI 10.9-17.9) for intrahepatic cholangiocarcinoma. For liver metastases, median OS for colorectal cancer was 9.8 months (95% CI 8.3-12.9), 5.6 months for pancreatic cancer (95% CI 4.1-6.6), 10.6 months (95% CI 7.3-14.4) for breast cancer, 14.6 months (95% CI 7.3-21.4) for melanoma and 33.1 months (95% CI 22.1-nr) for neuroendocrine tumours. Statistically significant prognostic factors in terms of OS include the presence of ascites, cirrhosis, extra-hepatic disease, patient performance status (Eastern Cooperative Oncology Group), number of chemotherapy lines prior to TARE and tumour burden. Thirty-day mortality rate was 1.0%. 2.5% experienced adverse events grade 3 or 4 within 30 days after TARE. Conclusion In the real-life clinical setting, TARE is largely considered to be a part of a palliative treatment strategy across indications and provides an excellent safety profile.
  • Autores: Blaya, D.; Rubio-Tomás, T.; Rodrigo-Torres, D.; et al.
    Revista: HEPATOLOGY INTERNATIONAL
    ISSN: 1936-0533 Vol.15 N° 4 2021 págs. 106 - 1017
    Resumen
    Objectives Alcoholic hepatitis (AH) is a severe condition characterized by a marked inflammatory response and high short-term mortality. Endothelial dysfunction (ED) is an early event in vascular and inflammatory disorders. The aim of this study is to evaluate ED in AH patients. Methods Prognostic value of ED biomarkers was evaluated in patients with severe AH (n = 67), compensated alcoholic cirrhosis (n = 15), heavy drinkers without liver disease (n = 15) and controls (n = 9), and in a validation cohort of 50 patients with AH. Gene expression of ED markers was analyzed in liver tissue. Results Plasma levels of ED markers such as vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin and von Willebrand factor (vWF) increased along alcohol-related liver disease (ALD) progression. Intergroup analysis showed a significant increase of these markers in AH patients. In addition, VCAM-1 showed a positive correlation with Maddrey, MELD and ABIC scores and inflammation parameters (i.e. C-reactive protein and LPS levels). Importantly, levels of VCAM-1 were higher in patients with increased mortality and were independently associated with short-term survival (90-day) when adjusted by ABIC score. These results were confirmed in an independent cohort of AH patients. In addition, severe AH patients showed altered hepatic expression of ED markers. Conclusions In this study we show that advanced ALD and particularly severe AH is associated with an increase of ED biomarkers, which correlate with patient outcomes. These results suggest that ED may be a pathogenic event in AH and highlight endothelial factors as potential biomarkers in AH.
  • Autores: Lewinska, M.; Santos-Laso, A.; Arretxe, E.; et al.
    Revista: EBIOMEDICINE
    ISSN: 2352-3964 Vol.73 2021
    Resumen
    Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC. Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score. Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients' metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum. Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients. (C) 2021 The Author(s). Published by Elsevier B.V.
  • Autores: Herrero Santos, José Ignacio (Autor de correspondencia); Quinones, M.; Perez, X.; et al.
    Revista: CLINICAL TRANSPLANTATION
    ISSN: 0902-0063 Vol.35 N° 1 2021 págs. e14154
    Resumen
    Background Liver transplant recipients have an increased incidence of malignancies, but it is unclear whether they have a higher risk of colorectal cancer. Aim To investigate whether liver transplant recipients have an increased risk of developing colorectal adenomas (a surrogate marker of colorectal cancer risk). Patients and methods One hundred thirty-nine liver transplant recipients (excluding primary sclerosing cholangitis) who underwent a colonoscopy and polypectomy before and after transplantation, and 367 nontransplanted patients who underwent a colonoscopy for colorectal cancer screening and a second colonoscopy later were retrospectively studied. The risks of incident colorectal adenomas and high-risk adenomas (advanced or multiple adenomas or carcinomas) were compared between both cohorts. Results Incident colorectal adenomas were found in 40.3% of the transplanted patients and 30.0% of the nontransplanted patients (15.1% and 5.5%, respectively, had high-risk adenomas). After adjusting for age, sex, presence of adenomas in the baseline endoscopy, and interval between colonoscopies, transplant recipients showed a higher risk of developing colorectal adenomas (OR: 1.61; 95% CI: 1.05-2.47; p = .03) and high-risk adenomas (OR: 2.87; 95% CI: 1.46-5.65; p = .002). Conclusions Our results suggest that liver transplant recipients have an increased risk of developing colorectal adenomas and lesions with high risk of colorectal cancer.
  • Autores: Gárate Rascón, María; Recalde, M.; Jiménez Andrés, Maddalen; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° 5 2021 págs. 2791 - 2807
    Resumen
    Background and Aims Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4 alpha, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7(+/-)) mice undergoing chronic (CCl4) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4-injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4 alpha P1 to P2 usage. This response was reproduced in Slu7(+/-) mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4 alpha 1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
  • Autores: Reig, M.; Forner, A.; Ávila Zaragoza, Matías Antonio; et al.
    Revista: MEDICINA CLINICA
    ISSN: 0025-7753 Vol.156 N° 9 2021 págs. 463.e1 - 463.e30
    Resumen
    El carcinoma hepatocelular (CHC) es la neoplasia primaria de hígado más frecuente y una de las causas de muerte más común en los pacientes afectos de cirrosis hepática. Simultáneamente al reconocimiento de la relevancia clínica de esta neoplasia, en los últimos años han aparecido novedades importantes en el diagnóstico, evaluación pronóstica y, especialmente, en el tratamiento del CHC. Por tal motivo, desde la Asociación Española para el Estudio del Hígado (AEEH) se ha impulsado la necesidad de actualizar las guías de práctica clínica, invitando de nuevo a todas las sociedades involucradas en el diagnóstico y tratamiento de esta enfermedad a participar en la redacción y aprobación del documento: Sociedad Española de Trasplante Hepático (SETH), Sociedad Española de Radiología Médica (SERAM), Sociedad Española de Radiología Vascular e Intervencionista (SERVEI), Asociación Española de Cirujanos (AEC) y Sociedad Española de Oncología Médica (SEOM). Se han tomado como documentos de referencia las guías de práctica clínica publicadas en 2016, aceptadas como Guía de Práctica Clínica del Sistema Nacional de Salud, incorporando los avances más importantes que se han obtenido en los últimos años. La evidencia científica y la fuerza de la recomendación se basa en el sistema GRADE. © 2020 Publicado por Elsevier España, S.L.U. Este es un artículo Open Access bajo la licencia CC
  • Autores: Carotti, S.; Zingariello, M.; Francesconi, M.; et al.
    Revista: ONCOGENE
    ISSN: 0950-9232 Vol.40 N° 23 2021 págs. 4033 - 4049
    Resumen
    Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic biliary tract with a very poor prognosis. Although some clinicopathological parameters can be prognostic factors for iCCA, the molecular prognostic markers and potential mechanisms of iCCA have not been well investigated. Here, we report that the Fragile X mental retardation protein (FMRP), a RNA binding protein functionally absent in patients with the Fragile X syndrome (FXS) and also involved in several types of cancers, is overexpressed in human iCCA and its expression is significantly increased in iCCA metastatic tissues. The silencing of FMRP in metastatic iCCA cell lines affects cell migration and invasion, suggesting a role of FMRP in iCCA progression. Moreover, we show evidence that FMRP is localized at the invasive front of human iCCA neoplastic nests and in pseudopodia and invadopodia protrusions of migrating and invading iCCA cancer cells. Here FMRP binds several mRNAs encoding key proteins involved in the formation and/or function of these protrusions. In particular, we find that FMRP binds to and regulates the expression of Cortactin, a critical regulator of invadopodia formation. Altogether, our findings suggest that FMRP could promote cell invasiveness modulating membrane plasticity and invadopodia formation at the leading edges of invading iCCA cells.
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Numata, K.; Huang, Y.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 3 2021 págs. S117
  • Autores: Bataller, R.; Fernández-Carrillo, C.; Alvarado-Tapias, E.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° Supl. 1 2021 págs. 211A - 212A
  • Autores: Serrano-Macia, M.; Espinosa, J. S.; González-Rellan, M. J.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° Supl. 1 2021 págs. 1146A - 1147A
  • Autores: Kim, T. Y.; Santoro, A.; Kang, Y. K.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 3 Supl. 2021 págs. 269 - 269
  • Autores: Matilla, A.; Sangro Gómez-Acebo, Bruno Carlos; El-Khoureiry, A.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S243 - S244
  • Autores: Rodríguez Fraile, María Macarena; Cabrera Villegas, Antonio; Rosales Castillo, Juan Jose; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.48 N° Supl. 1 2021 págs. S287
  • Autores: Kolligs, F.; Arnold, D.; Helmberger, T.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S244 - S245
  • Autores: Goikoetxea-Usandizaga, N.; Egia-Mendikute, L.; Serrano-Macia, M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S243 - S243
  • Autores: González-Recio, I.; Espinosa, J. S.; Goikoetxea-Usandizaga, N.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S301 - S302
  • Autores: Rodríguez Agudo, R.; Goikoetxea, N.; Serrano-Macia, M.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S320 - S321
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Harding, J. J.; Johnson, M.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 3 Supl. 2021 págs. TPS349 - TPS349
  • Autores: Solís-Muñoz, P.; De La Flor-Robledo, M.; Monsalve-Alonso, S.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° Suppl. 1 2021 págs. 233A - 234A
  • Autores: Serrano-Macia, M.; Espinosa, J. S.; González Rellán, M. J.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S624 - S624
  • Autores: Schaefer, N.; Sangro Gómez-Acebo, Bruno Carlos; Kolligs, F.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 3 2021 págs. S143
  • Autores: Loeffler, M.; Izzo, F.; Gori, S.; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN: 0168-8278 Vol.75 N° Supl. 2 2021 págs. S246 - S246
  • Autores: Rodríguez Agudo, R.; Goikoetxea-Usandizaga, N.; Serrano-Macia, M.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 N° Supl. 1 2021 págs. 261A - 261A
  • Autores: Goikoetxea-Usandizaga, N.; Egia-Mendikute, L.; Serrano-Macia, M.; et al.
    Revista: HEPATOLOGY
    ISSN: 0270-9139 Vol.74 2021 págs. 701A - 702A
  • Autores: Helmberger, T.; Arnold, D.; Balli, T.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 3 2021 págs. 308 - 308
  • Autores: Navarro Corcuera, Amaia; Ansorena Artieda, Eduardo; Montiel Duarte, Cristina; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.21 N° 4 2020 págs. 1400
    Resumen
    AGAP2 (Arf GAP with GTP-binding protein-like domain, Ankyrin repeat and PH domain 2) isoform 2 is a protein that belongs to the Arf GAP (GTPase activating protein) protein family. These proteins act as GTPase switches for Arfs, which are Ras superfamily members, being therefore involved in signaling regulation. Arf GAP proteins have been shown to participate in several cellular functions including membrane trafficking and actin cytoskeleton remodeling. AGAP2 is a multi-tasking Arf GAP that also presents GTPase activity and is involved in several signaling pathways related with apoptosis, cell survival, migration, and receptor trafficking. The increase of AGAP2 levels is associated with pathologies as cancer and fibrosis. Transforming growth factor beta-1 (TGF-beta 1) is the most potent pro-fibrotic cytokine identified to date, currently accepted as the principal mediator of the fibrotic response in liver, lung, and kidney. Recent literature has described that the expression of AGAP2 modulates some of the pro-fibrotic effects described for TGF-beta 1 in the liver. The present review is focused on the interrelated molecular effects between AGAP2 and TGF beta 1 expression, presenting AGAP2 as a new player in the signaling of this pro-fibrotic cytokine, thereby contributing to the progression of hepatic fibrosis.
  • Autores: Sangro Gómez-Acebo, Bruno Carlos; Chan, S. L.; Meyer, T.; et al.
    Revista: JOURNAL OF HEPATOLOGY
    ISSN: 1600-0641 Vol.72 N° 2 2020 págs. 320 - 341
  • Autores: Solares, I.; Tejedor, M.; Jericó Asenjo, Daniel; et al.
    Revista: ANNALS OF TRANSLATIONAL MEDICINE
    ISSN: 2305-5839 Vol.8 N° 17 2020 págs. 1098
    Resumen
    Hyponatremia is a common feature during the neurovisceral acute attacks which characterize hepatic porphyrias, as well as a sign of its severity. Therapeutic options for first-line acute attacks are intravenous administration of glucose and/or exogenous heme. The former treatment can aggravate hyponatremia by dilution and cause seizures; thus, the correction of hyponatremia must be carried out with extreme caution. This review summarizes recommendations for the management of hyponatremia during acute episodes of porphyria. Hyponatremia should be corrected slowly and seizures treated with medications in order to not exacerbate motor and sensory axonal neuropathy. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is considered a frequent cause of hyponatremia in acute porphyrias and must be identified as a symptom of an acute porphyria attack. Tolvaptan produces aquaresis and is considered a safe drug in porphyria. However, its use has only been reported in isolated cases during a porphyria attack. The convenience and usefulness of this drug in acute porphyria are discussed.
  • Autores: Clavería Cabello, Alex; Colyn, L.; Arechederra Calderon, Maria; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.9 N° 10 2020
    Resumen
    Chronic liver diseases (CLD) represent a worldwide health problem. While CLDs may have diverse etiologies, a common pathogenic denominator is the presence of liver fibrosis. Cirrhosis, the end-stage of CLD, is characterized by extensive fibrosis and is markedly associated with the development of hepatocellular carcinoma. The most important event in hepatic fibrogenesis is the activation of hepatic stellate cells (HSC) following liver injury. Activated HSCs acquire a myofibroblast-like phenotype becoming proliferative, fibrogenic, and contractile cells. While transient activation of HSCs is part of the physiological mechanisms of tissue repair, protracted activation of a wound healing reaction leads to organ fibrosis. The phenotypic changes of activated HSCs involve epigenetic mechanisms mediated by non-coding RNAs (ncRNA) as well as by changes in DNA methylation and histone modifications. During CLD these epigenetic mechanisms become deregulated, with alterations in the expression and activity of epigenetic modulators. Here we provide an overview of the epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. We also discuss recent studies supporting the promising therapeutic potential of histone deacetylase inhibitors in liver fibrosis.
  • Autores: Argemí Ballbé, José María (Autor de correspondencia); Ventura-Cots, M.; Rachakonda, V.; et al.
    Revista: REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
    ISSN: 1130-0108 Vol.112 N° 11 2020 págs. 869 - 878
    Resumen
    Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms of AH, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. ...
  • Autores: Arechederra Calderon, Maria; Berasain Lasarte, María del Carmen (Autor de correspondencia); Ávila Zaragoza, Matías Antonio (Autor de correspondencia); et al.
    Revista: SEMINARS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN: 1084-9521 Vol.97 2020 págs. 38 - 46
    Resumen
    Liver regeneration is the most important reaction of the liver to an injury. Indeed, the liver possesses an extraordinary regenerative capacity orchestrated by a highly coordinated response of all the different cell types in order to recover the tissue lost, while maintaining homeostasis and all the hepatic functions. To achieve this impressive physiological accomplishment, the liver experiences a transient but precisely controlled transcriptional reprogramming that allows the simultaneous activation and silencing of multiple genes at different stages of the regeneration process. Epigenetic events play a fundamental role in the organization of chromatin architecture and hence in the tight control of gene transcription. In this review, we will summarize the most relevant epigenetic modifications associated with the critical changes in gene expression and cellular behavior occurring during liver regeneration. We will discuss the relevance of DNA methylation, histone modifications, and chromatin remodelers, and the interplay between these epigenetic events, during the regeneration process, mainly after partial hepatectomy or after chemical injury.
  • Autores: Marin, J. J. G. ; Prete, M. G.; Lamarca, A. ; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN: 0007-0920 Vol.123 N° 7 2020 págs. 1047-1059
    Resumen
    Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such asIDHmutations andFGFRfusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.