-
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.
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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
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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.
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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.
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Autores:
Aramburu Montenegro, Jorge (Autor de correspondencia);
Antón Remírez, Raúl;
Rodríguez Fraile, María Macarena;
et al.
Revista:
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN: 1051-0443
Vol.34
N° 1
2023
págs. 21 - 22
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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
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Autores:
Vogel, A.;
Cervantes, A.;
Chau, I.;
et al.
Revista:
ANNALS OF ONCOLOGY
ISSN: 0923-7534
Vol.33
N° 6
2022
págs. 666
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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
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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
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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
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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:
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
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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:
Hernaez, R. (Autor de correspondencia);
Ávila Zaragoza, Matías Antonio
Revista:
GUT
ISSN: 0017-5749
Vol.72
N° 1
2022
págs. 7 - 9
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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:
Clavería Cabello, Alex;
Ávila Zaragoza, Matías Antonio (Autor de correspondencia)
Revista:
CMGH
ISSN: 2352-345X
Vol.13
N° 2
2022
págs. 678 - 680
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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:
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
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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
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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
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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
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Autores:
Martínez-Arenas, L.;
Carvalho-Gomes, A.;
Díaz-Fontenla, F.;
et al.
Revista:
TRANSPLANTATION
ISSN: 0041-1337
Vol.106
N° 8S
2022
págs. 99
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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:
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 Fontela, F.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.77
N° Supl. 1
2022
págs. S150
-
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:
Conde, I.;
Aguilera, V.;
Martínez, S.;
et al.
Revista:
TRANSPLANTATION
ISSN: 0041-1337
Vol.106
N° 8S
2022
págs. 100
-
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
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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:
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:
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:
Martínez-Arenas, L.;
Carvalho-Gomes, A.;
Bhat, V.;
et al.
Revista:
TRANSPLANTATION
ISSN: 0041-1337
Vol.106
N° 8S
2022
págs. 32 - 33
-
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:
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:
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:
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:
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:
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:
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:
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.
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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.
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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.
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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.
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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.
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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.
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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:
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:
Marino, Z.;
Darnell, A.;
Lens, S.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.74
N° 2
2021
págs. 491
-
Autores:
Burra, P. (Autor de correspondencia);
Tacke, F.;
Ratziu, V.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.75
N° 2
2021
págs. 257 - 260
-
Autores:
Burra, P. (Autor de correspondencia);
Tacke, F.;
Ratziu, V.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.74
N° 2
2021
págs. 265 - 268
-
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:
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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Autores:
Goikoetxea-Usandizaga, N.;
Egia-Mendikute, L.;
Serrano-Macia, M.;
et al.
Revista:
HEPATOLOGY
ISSN: 0270-9139
Vol.74
2021
págs. 701A - 702A
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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
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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
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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
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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
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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
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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
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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
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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
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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 Agudo, R.;
Goikoetxea-Usandizaga, N.;
Serrano-Macia, M.;
et al.
Revista:
HEPATOLOGY
ISSN: 0270-9139
Vol.74
N° Supl. 1
2021
págs. 261A - 261A
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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
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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:
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
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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:
Helmberger, T.;
Arnold, D.;
Balli, T.;
et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN: 0732-183X
Vol.39
N° 3
2021
págs. 308 - 308
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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
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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
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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.
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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. ...
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Autores:
Canale, M. ;
Casadei-Gardini, A. (Autor de correspondencia);
Ulivi, P.;
et al.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 1422-0067
Vol.21
N° 15
2020
Resumen
Gastric cancer (GC) is one of the deadliest malignancies worldwide. Complex disease heterogeneity, late diagnosis, and suboptimal therapies result in the poor prognosis of patients. Besides genetic alterations and environmental factors, it has been demonstrated that alterations of the epigenetic machinery guide cancer onset and progression, representing a hallmark of gastric malignancies. Moreover, epigenetic mechanisms undergo an intricate crosstalk, and distinct epigenomic profiles can be shaped under different microenvironmental contexts. In this scenario, targeting epigenetic mechanisms could be an interesting therapeutic strategy to overcome gastric cancer heterogeneity, and the efforts conducted to date are delivering promising results. In this review, we summarize the key epigenetic events involved in gastric cancer development. We conclude with a discussion of new promising epigenetic strategies for gastric cancer treatment.
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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.
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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
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Autores:
Berenguer, M. (Autor de correspondencia);
Burra, P.;
Ghobrial, M.;
et al.
Revista:
TRANSPLANTATION
ISSN: 0041-1337
Vol.104
N° 6
2020
págs. 1143 - 1149
Resumen
Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.
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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.
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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.
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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.
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Autores:
Ricke, J.;
Sangro Gómez-Acebo, Bruno Carlos;
Malfertheiner, P.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.73
N° 3
2020
págs. 735 - 736
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Autores:
Martinez-Chantar, M. L. (Autor de correspondencia);
Ávila Zaragoza, Matías Antonio (Autor de correspondencia);
Lu, S. C. (Autor de correspondencia)
Revista:
CANCERS
ISSN: 2072-6694
Vol.12
N° 10
2020
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Autores:
Herrero Santos, José Ignacio (Autor de correspondencia);
Ampuero, J.;
Fernández, C.
Revista:
REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
ISSN: 1130-0108
Vol.112
N° 7
2020
págs. 513 - 514
Resumen
Hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma, as well as the primary indication for liver transplant in Europe. The highly effective direct-acting antivirals currently available make it possible to achieve the hepatitis C elimination targets set by the World Health Organization. For this, population screening and reflect testing are fundamental strategies.
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Autores:
de la Torre Aláez, Manuel Antonio;
Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN: 0174-1551
Vol.43
N° 8
2020
págs. 1182 - 1183
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Autores:
Urman, J. M. ;
Herranz, J. M. ;
Uriarte Díaz-Varela, Iker;
et al.
Revista:
CANCERS
ISSN: 2072-6694
Vol.12
N° 6
2020
págs. 1644
Resumen
Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n= 36) and malignant conditions, CCA (n= 36) or PDAC (n= 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (H-1-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n= 10) and proteins (n= 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.
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Autores:
de la Torre Aláez, Manuel Antonio (Autor de correspondencia);
Jordán Iborra, Carlota;
Casadei-Gardini, A.;
et al.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN: 0174-1551
Vol.43
N° 8
2020
págs. 1165 - 1172
Resumen
Purpose In patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib, post-progression survival (PPS) is marked by the pattern of progression. Our aim was to assess the influence of the pattern of progression to selective internal radiotherapy (SIRT) in PPS among patients with HCC. Methods A retrospective analysis of patients treated with SIRT between 2003 and 2015 was conducted, excluding those with a single nodule < 5 cm or with metastases. Four patterns of progression to SIRT were defined: target tumour growth, non-target tumour growth, new intrahepatic disease, and new extrahepatic disease. PPS was calculated from the time of progression based on RECIST 1.1 criteria. Results Out of the 102 patients who met the selection criteria, 76 progressed after a median follow-up of 15 months. Median PPS was 6.5 months (95% CI 3.8-9.3 months). Patients who progressed at pre-existing lesions had a better PPS (median 12.5 months) than those who progressed with new lesions inside or outside the liver (median 4.2 months) (p = 0.02). In a Cox model adjusted by liver function and systemic inflammation, the pattern of progression had a hazard ratio of 1.64 (95% CI 0.92-2.93;p = 0.093). Conclusion In a cohort of HCC patients treated with SIRT, the pattern of progression associated with worst survival was the development of new intrahepatic lesions or extrahepatic metastases.
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Autores:
Clavería Cabello, Alex;
Colyn, L. ;
Uriarte Díaz-Varela, Iker;
et al.
Revista:
CANCERS
ISSN: 2072-6694
Vol.12
N° 12
2020
págs. 3748
Resumen
Simple Summary Chronic liver injury and inflammation leads to excessive deposition of extracellular matrix, known as liver fibrosis, and the distortion of the hepatic parenchyma. Liver fibrosis may progress to cirrhosis, a condition in which hepatic function is impaired and most cases of liver tumors occur. Currently, there are no effective therapies to inhibit and reverse the progression of liver fibrosis, and therefore, chronic liver disease remains a global health problem. In this study we have tested the efficacy of a new class of molecules that simultaneously target two molecular pathways known to be involved in the pathogenesis of hepatic fibrosis. In a clinically relevant mouse model of liver injury and inflammation we show that the combined inhibition of histones deacetylases and the cyclic guanosine monophosphate (cGMP) phosphodiesterase phosphodiesterase 5 (PDE5) results in potent anti-inflammatory and anti-fibrotic effects. Our findings open new avenues for the treatment of liver fibrosis and therefore, the prevention of hepatic carcinogenesis. Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor beta (TGF beta). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
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Autores:
Martínez-Urbistondo, D. (Autor de correspondencia);
Argemí Ballbé, José María;
Martínez Hernández, Alfredo
Revista:
CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS
ISSN: 0214-9168
Vol.32
N° 5
2020
págs. 206 - 208
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Autores:
Helmberger, T. ;
Arnold, D.;
Bilbao Jaureguizar, José Ignacio;
et al.
Revista:
JMIR RESEARCH PROTOCOLS
ISSN: 1929-0748
Vol.9
N° 4
2020
págs. e16296
Resumen
Background: Radioembolization, also known as transarterial radioembolization or selective internal radiation therapy with yttrium-90 (90Y) resin microspheres, is an established treatment modality for patients with primary and secondary liver tumors. However, large-scale prospective observational data on the application of this treatment in a real-life clinical setting is lacking. Objective: The main objective is to collect data on the clinical application of radioembolization with 90Y resin microspheres to improve the understanding of the impact of this treatment modality in its routine practice setting. Methods: Eligible patients are 18 years or older and receiving radioembolization for primary and secondary liver tumors as part of routine practice, as well as have signed informed consent. Data is collected at baseline, directly after treatment, and at every 3-month follow-up until 24 months or study exit. The primary objective of the Cardiovascular and Interventional Radiological Society of Europe Registry for SIR-Spheres Therapy (CIRT) is to observe the clinical application of radioembolization. Secondary objectives include safety, effectiveness in terms of overall survival, progression-free survival (PFS), liver-specific PFS, imaging response, and change in quality of life. Results: Between January 2015 and December 2017, 1047 patients were included in the study. The 24-month follow-up period ended in December 2019. The first results are expected in the third quarter of 2020. Conclusions: The CIRT is the largest observational study on radioembolization to date and will provide valuable insights to the clinical application of this treatment modality and its real-life outcomes.
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Autores:
Goñi Esarte, S. (Autor de correspondencia);
Juanbeltz, R.;
Zozaya, J. M.;
et al.
Revista:
GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN: 0210-5705
Vol.43
N° 5
2020
págs. 248 - 255
Resumen
Introduction: There is little information on whether direct-acting antiviral (DAA) treatment can improve liver fibrosis or change glucose and lipid profile in patients with chronic hepatitis C (CHC). We aimed to evaluate the impact of sustained virologic response (SVR) on liver stiffness, glucose and lipid levels.
Methods: 445 monoinfected CHC patients started treatment with interferon-free DAA therapy from January 2015 to February 2017. Transient elastography (TE), fibrosis scores, glucose and lipid levels were analyzed at baseline and 48 weeks post-treatment (SVR48).
Results: The SVR rate was 97.7%. Finally, we evaluated 369 patients who achieved SVR and had reliable TE measurements. Median liver stiffness significantly decreased from 9.3 (IQR 7.3-14.3)kPa at baseline to 6.4 (IQR 4.9-8.9) at SVR48 (p<0.0001). 54.7% of the cohort presented fibrosis regression. Median FIB4 score regressed from 2.0 (IQR 1.1-3.3) to 1.3 (IQR 0.9-2.0) (p<0.0001). Median APRI and Forns values significantly decreased from 0.9 (IQR 0.5-1.7) to 0.3 (IQR 0.2-0.4) and from 6.2 (5.0-7.5) to 4.9 (IQR 3.8-5.9) (p<0.001), respectively. Mean levels of total cholesterol and LDL-C increased from 172mg/dL and 101.5mg/dL to 191mg/dL and 117.5mg/dL (p<0.0001), respectively. In the sub-group of patients with pre-diabetes or diabetes, mean glucose levels decreased from 142.7mg/dL at baseline to 127.2mg/dL at SVR48 (p<0.001).
Discussion: SVR reduces liver stiffness based on TE and fibrosis scores, in patients treated with DAA. Our results show elevated total cholesterol and LDL-C and decreased glucose levels at SVR48.
Keywords: Antivirales de acción directa; Direct acting antiviral; Elastografía; Fibrosis scores; Glucosa; Glucose; Hepatitis C virus; Lipid profile; Marcadores serológicos; Perfil lipídico; Transient elastography; Virus de la hepatitis C.
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Autores:
Jericó Asenjo, Daniel;
Luis García, Elkin Oswaldo;
Cusso, L.;
et al.
Revista:
HUMAN MOLECULAR GENETICS
ISSN: 0964-6906
Vol.29
N° 19
2020
págs. 3211 - 3223
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Autores:
Tolosa, E. J. ;
García Fernández de Barrena, Maite;
Iguchi, E. ;
et al.
Revista:
BIOCHEMICAL JOURNAL
ISSN: 0264-6021
Vol.477
N° 17
2020
págs. 3131 - 3145
Resumen
The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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Autores:
Han, G. H.;
Berhane, S.;
Toyoda, H.;
et al.
Revista:
HEPATOLOGY
ISSN: 0270-9139
Vol.72
N° 1
2020
págs. 198 - 212
Resumen
Background and Aims The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Approach and Results Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusions A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.
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Autores:
Pereira, P. L.;
Arnold, D.;
de Baere, T.;
et al.
Revista:
DIGESTIVE AND LIVER DISEASE
ISSN: 1878-3562
Vol.52
N° 8
2020
págs. 857 - 861
Resumen
Background: About 70-80% of patients with colorectal liver metastases appear as ineligible for a curative treatment approach. Transarterial chemoembolisation (TACE) using irinotecan-eluting beads has emerged as a promising treatment option in cases with irresectable liver metastases. Despite being in clinical practice for years, little is known about the treatment characteristics and outcomes when used as per routine hospital practice.
Methods: Patients with hepatic metastases from colorectal cancer origin, admitted to contributing centres to receive TACE with drug-eluting LifePearl® Microspheres loaded with irinotecan, as part of their standard care, will be consecutively added to the registry. Data will be collected until the end of study, loss to follow-up or death. Primary endpoint is the characterisation of the treatment usage at the selected sites in Europe. Secondary endpoints include outcome parameters, safety and toxicity, as well as quality of life.
Conclusion and aims: This multicentre, international, prospective observational study conducted in European centres plans to collect real-life data. This data will form an evidence-base from which conclusions can be drawn on how to improve patient selection and optimise treatment protocols when treating with TACE using irinotecan-eluting microspheres. Trial registration NCT03086096.
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Autores:
Kilanczyk, E. ;
Banales, J. M. ;
Wunsch, E.;
et al.
Revista:
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN: 0925-4439
Vol.1866
N° 11
2020
Resumen
S-adenosyl-L-methionine is an endogenous molecule with hepato-protective properties linked to redox regulation and methylation. Here, the potential therapeutic value of SAMe was tested in 17 patients with PBC, a cholestatic disease with autoimmune phenomena targeting small bile ducts. Nine patients responded to SAMe (SAMe responders) with increased serum protein S-glutathionylation. That posttranslational protein modification was associated with reduction of serum anti-mitochondrial autoantibodies (AMA-M2) titers and improvement of liver biochemistry. Clinically, SAMe responders were younger at diagnosis, had longer duration of the disease and lower level of serum S-glutathionylated proteins at entry. SAMe treatment was associated with negative correlation between protein S-glutathionylation and TNF alpha. Furthermore, AMA-M2 titers correlated positively with INF gamma and FGF-19 while negatively with TGF beta. Additionally, cirrhotic PBC livers showed reduced levels of glutathionylated proteins, glutaredoxine-1 (Grx-1) and GSH synthase (GS). The effect of SAMe was also analyzed in vitro. In human cholangiocytes overexpressing miR-506, which induces PBC-like features, SAMe increased total protein S-glutathionylation and the level of gamma-glutamylcysteine ligase (GCLC), whereas reduced Grx-1 level. Moreover, SAMe protected primary human cholangiocytes against mitochondrial oxidative stress induced by tBHQ (tert-Butylhydroquinone) via raising the level of Nrf2 and HO-1. Finally, SAMe reduced apoptosis (cleaved-caspase3) and PDC-E2 (antigen responsible of the AMA-M2) induced experimentally by glycochenodeoxycholic acid (GCDC). These data suggest that SAMe may inhibit autoimmune events in patients with PBC via its antioxidant and S-glutathionylation properties. These findings provide new insights into the molecular events promoting progression of PBC and suggest potential therapeutic application of SAMe in PBC.
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Autores:
Yau, T. (Autor de correspondencia);
Kang, Y. K.;
Kim, T. Y.;
et al.
Revista:
JAMA ONCOLOGY
ISSN: 2374-2437
Vol.6
N° 11
2020
págs. e204564
Resumen
IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.
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Autores:
Cubero, F. J. (Autor de correspondencia);
Mohamed, M. R. ;
Woitok, M. M.;
et al.
Revista:
HEPATOLOGY COMMUNICATIONS
ISSN: 2471-254X
Vol.4
N° 6
2020
págs. 834 - 851
Resumen
Targeted inhibition of the c-Jun N-terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)(hepatocyte-specific knockout (Delta hepa)) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO Delta hepa/JNK1(Delta hepa) mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO Delta hepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO Delta hepa (NEMO Delta hepa/JNK(Delta hepa)) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO Delta hepa/JNK1(Delta hepa) mice recapitulated the phenotype of NEMO Delta hepa/JNK(Delta hepa) mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO Delta hepa mice. We found that NEMO Delta hepa/JNK(Delta hepa) livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMO Delta hepa/JNK(Delta hepa) mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
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Autores:
Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia);
Melero Bermejo, Ignacio;
Wadhawan, S.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.73
N° 6
2020
págs. 1460 - 1469
Resumen
Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
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Autores:
Gholizadeh, M.;
Szelag-Pieniek, S.;
Post, M.;
et al.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 1422-0067
Vol.21
N° 19
2020
págs. 7368
Resumen
Liver diseases are important causes of morbidity and mortality worldwide. The aim of this study was to identify differentially expressed microRNAs (miRNAs), target genes, and key pathways as innovative diagnostic biomarkers in liver patients with different pathology and functional state. We determined, using RT-qPCR, the expression of 472 miRNAs in 125 explanted livers from subjects with six different liver pathologies and from control livers. ANOVA was employed to obtain differentially expressed miRNAs (DEMs), and miRDB (MicroRNA target prediction database) was used to predict target genes. A miRNA-gene differential regulatory (MGDR) network was constructed for each condition. Key miRNAs were detected using topological analysis. Enrichment analysis for DEMs was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We identified important DEMs common and specific to the different patient groups and disease progression stages. hsa-miR-1275 was universally downregulated regardless the disease etiology and stage, while hsa-let-7a*, hsa-miR-195, hsa-miR-374, and hsa-miR-378 were deregulated. The most significantly enriched pathways of target genes controlled by these miRNAs comprise p53 tumor suppressor protein (TP53)-regulated metabolic genes, and those involved in regulation of methyl-CpG-binding protein 2 (MECP2) expression, phosphatase and tensin homolog (PTEN) messenger RNA (mRNA) translation and copper homeostasis. Our findings show a novel panel of deregulated miRNAs in the liver tissue from patients with different liver pathologies. These miRNAs hold potential as biomarkers for diagnosis and staging of liver diseases.
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Autores:
Santos-Laso, A.;
Izquierdo-Sanchez, L.;
Rodrigues, P. M.;
et al.
Revista:
LIVER INTERNATIONAL
ISSN: 1478-3223
Vol.40
N° 7
2020
págs. 1670 - 1685
Resumen
Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. We hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. Methods ER stress was analysed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy, TEM) and functional (proteasome activity) levels in different PLD models. The effect of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or activators [tunicamycin (TM)] was tested in polycystic (PCK) rats and cystic cholangiocytes in vitro. Results The expression levels of unfolded protein response (UPR) components were upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (ie synthesis, folding, trafficking and degradation of proteins), marked enlargement of the ER lumen (by TEM) and hyperactivation of the proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline conditions or after TM administration compared to controls. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized proteomic profiles related to protein synthesis, folding, trafficking and degradation and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusions Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel therapeutic strategy.
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Autores:
Macias, R. I. R. (Autor de correspondencia);
Munoz-Bellvis, L. ;
Sanchez-Martin, A. ;
et al.
Revista:
CANCERS
ISSN: 2072-6694
Vol.12
N° 6
2020
Resumen
The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers with potential usefulness in the differential diagnosis of these tumors, we have determined serum metabolomic profiles in healthy controls and patients with dCCA, PDAC or benign pancreatic diseases (BPD). Ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis was performed in serum samples from dCCA (n= 34), PDAC (n= 38), BPD (n= 42) and control (n= 25) individuals, divided into discovery and validation cohorts. This approach permitted 484 metabolites to be determined, mainly lipids and amino acids. The analysis of the results led to the proposal of a logistic regression model able to discriminate patients with dCCA and PDAC (AUC value of 0.888) based on the combination of serum levels of nine metabolites (acylcarnitine AC(16:0), ceramide Cer(d18:1/24:0), phosphatidylcholines PC(20:0/0:0) and PC(O-16:0/20:3), lysophosphatidylcholines PC(20:0/0:0) and PC(0:0/20:0), lysophosphatidylethanolamine PE(P-18:2/0:0), and sphingomyelins SM(d18:2/22:0) and SM(d18:2/23:0)) and CA 19-9. In conclusion, we propose a novel specific panel of serum metabolites that can help in the differential diagnosis of dCCA and PDAC. Further validation of their clinical usefulness in prospective studies is required.
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Autores:
Ezponda Casajús, Ana (Autor de correspondencia);
Rodríguez Fraile, María Macarena;
Morales Lozano, María Isabel;
et al.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN: 0174-1551
Vol.43
N° 7
2020
págs. 987 - 995
Resumen
Purpose To assess the feasibility of performing same-day vascular flow redistribution and Yttrium-90 radioembolization (90Y-RE) for hepatic malignancies. Materials and Methods From November 2015 to February 2019, patients undergoing same-day hepatic flow redistribution during work-up angiography,(99m)Technetium-labeled macroaggregated albumin (Tc-99m-MAA) SPECT/CT and 90Y microsphere-RE, were recruited. Within 18 h following the delivery of 90Y resin microspheres, an 90Y-PET/CT study was performed. According to patients' vascular anatomy, flow redistribution was performed by microcoil embolization of extrahepatic branches (group A), intrahepatic non-tumoral vessels (group B) and intrahepatic tumoral arteries (group C). The accumulation of(99m)Tc-MAA particles and microspheres in the redistributed areas was qualitatively evaluated using a 5-point visual scale (grade 1 = < 25% accumulation; grade 5 = 100% accumulation). Differences in the distribution of microspheres among groups were assessed with Mann-WhitneyUtest. Results Twenty-two patients were treated for primary (n = 17) and secondary (n = 5) hepatic malignancies. The MAA-SPECT/CT showed uptake in all the redistributed areas. Regarding the accumulation of microspheres within the redistributed segments in all the groups, perfusion patterns were classified as 2 in 1 case, 4 in 6 cases and 5 in 15 cases. No statistically significant differences were observed between groups A and B-C (Uvalue = 34,p = 0.32) and between groups B and C (Uvalue = 26,p = 0.7). Mean predicted absorbed doses by the tumoral and normal hepatic tissues were 163.5 +/- 131.2 Gy and 60.4 +/- 69.3 Gy, respectively. Mean total procedure time (from work-up angiography to 90Y delivery) was 401 +/- 0.055 min. Conclusion Performing same-day redistribution of the arterial hepatic flow to the target and 90Y-microsphere delivery is feasible in the treatment of liver tumors. Clinical Trials RegistryNCT03380130.
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Autores:
Xiang, J. Y.;
Zhang, N.;
Sun, H. ;
et al.
Revista:
GASTROENTEROLOGY
ISSN: 0016-5085
Vol.158
N° 3
2020
págs. 664 - 678.e24
Resumen
BACKGROUND & AIMS: Immune checkpoint inhibitors have some efficacy in the treatment of hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1), expressed on some cancer cells, binds to the receptor programmed cell death 1 (PDCD1, also called PD1) on T cells to prevent their proliferation and reduce the antigen-tumor immune response. Immune cells that infiltrate some types of HCCs secrete interferon gamma (IFNG). Some HCC cells express myocyte enhancer factor 2D (MEF2D), which has been associated with shorter survival times of patients. We studied whether HCC cell expression of MEF2D regulates expression of PD-L1 in response to IFNG. METHODS: We analyzed immune cells from 20 fresh HCC tissues by flow cytometry. We analyzed 225 fixed HCC tissues (from 2 cohorts) from patients in China by immunohistochemistry and obtained survival data. We created mice with liver-specific knockout of MEF2D (MEF2D(LPC-KO) mice). We knocked out or knocked down MEF2D, E1A binding protein p300 (p300), or sirtuin 7 (SIRT7) in SMMC-7721, Huh7, H22, and Hepa1-6 HCC cell lines, some incubated with IFNG. We analyzed liver tissues from mice and cell lines by RNA sequencing, immunoblot, dual luciferase reporter, and chromatin precipitation assays. MEF2D protein acetylation and proteins that interact with MEF2D were identified by coimmunoprecipitation and pull-down assays. H22 cells, with MEF2D knockout or without (controls), were transplanted into BALB/c mice, and some mice were given antibodies to deplete T cells. Mice bearing orthotopic tumors grown from HCC cells, with or without knockout of SIRT7, were given injections of an antibody against PD1. Growth of tumors was measured, and tumors were analyzed by immunohistochemistry and flow cytometry. RESULTS: In human HCC specimens, we found an inverse correlation between level of MEF2D and numbers of CD4(+) and CD8(+) T cells; level of MEF2D correlated with percentages of PD1-positive or TIM3-positive CD8(+) T cells. Knockout of MEF2D from H22 cells reduced their growth as allograft tumors in immune-competent mice but not in immune-deficient mice or mice with depletion of CD8(+) T cells. When MEF2D-knockout cells were injected into immune- competent mice, they formed smaller tumors that had increased infiltration and activation of T cells compared with control HCC cells. In human and mouse HCC cells, MEF2D knockdown or knockout reduced expression of PD-L1. MEF2D bound the promoter region of the CD274 gene (encodes PD-L1) and activated its transcription. Overexpression of p300 in HCC cells, or knockout of SIRT7, promoted acetylation of MEF2D and increased its binding, along with acetylated histones, to the promoter region of CD274. Exposure of HCC cells to IFNG induced expression of p300 and its binding MEF2D, which reduced the interaction between MEF2D and SIRT7. MEF2D-induced expression of PD-L1 upon IFNG exposure was independent of interferon-regulatory factors 1 or 9. In HCC cells not exposed to IFNG, SIRT7 formed a complex with MEF2D that attenuated expression of PD-L1. Knockout of SIRT7 reduced proliferation of HCC cells and growth of tumors in immune-deficient mice. Compared with allograft tumors grown from control HCC cells, in immune-competent mice, tumors grown from SIRT7-knockout HCC cells expressed higher levels of PD-L1 and had reduced infiltration and activation of T cells. In immune-competent mice given antibodies to PD1, allograft tumors grew more slowly from SIRT7-knockout HCC cells than from control HCC cells. CONCLUSIONS: Expression of MEF2D by HCC cells increases their expression of PD-L1, which prevents CD8(+) T-cell-mediated antitumor immunity. When HCC cells are exposed to IFNG, p300 acetylates MEF2D, causing it to bind the CD274 gene promoter and up-regulate PD-L1 expression. In addition to promoting HCC cell proliferation, SIRT7 reduced acetylation of MEF2D and expression of PD-L1 in HCC cells not exposed to IFNG. Strategies to manipulate this pathway might increase the efficacy of immune therapies for HCC.
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Autores:
Melderis, S. ;
Hagenstein, J. ;
Warkotsch, M. T.;
et al.
Revista:
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN: 1046-6673
Vol.31
N° 9
2020
págs. 1996 - 2012
Resumen
Background Recent studies have identified the EGF receptor (EGFR) ligand amphiregulin (AREG) as an important mediator of inflammatory diseases. Both pro- and anti-inflammatory functions have been described, but the role of AREG in GN remains unknown. Methods The nephrotoxic nephritis model of GN was studied in AREG(-/-) mice after bone marrow transplantation, and in mice with myeloid cell-specific EGFR deficiency. Therapeutic utility of AREG neutralization was assessed. Furthermore, AREG's effects on renal cells and monocytes/macrophages (M/M) were analyzed. Finally, we evaluated AREG expression in human renal biopsies. Results Renal AREG mRNA was strongly upregulated in murine GN. Renal resident cells were the most functionally relevant source of AREG. Importantly, the observation that knockout mice showed significant amelioration of disease indicates that AREG is pathogenic in GN. AREG enhanced myeloid cell responses via inducing chemokine and colony stimulating factor 2 (CSF2) expression in kidney resident cells. Furthermore, AREG directly skewed M/M to a proinflammatory M1 phenotype and protected them from apoptosis. Consequently, anti-AREG antibody treatment dose-dependently ameliorated GN. Notably, selective abrogation of EGFR signaling in myeloid cells was sufficient to protect against nephritis. Finally, strong upregulation of AREG expression was also detected in kidneys of patients with two forms of crescentic GN. Conclusions AREG is a proinflammatory mediator of GN via (1) enhancing renal pathogenic myeloid cell infiltration and (2) direct effects on M/M polarization, proliferation, and cytokine secretion. The AREG/EGFR axis is a potential therapeutic target for acute GN.
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Autores:
Herrero Santos, José Ignacio (Autor de correspondencia);
Quiroga Vila, Jorge
Revista:
ADVANCES IN PHYSIOLOGY EDUCATION
ISSN: 1043-4046
Vol.44
N° 3
2020
págs. 370 - 375
Resumen
The flipped classroom has become increasingly popular in health professions education. The aim of this study was to analyze its effect on learning in a pathophysiology course. Flipped classroom was introduced to teach respiratory pathophysiology in 2018. We compared the exam results in respiratory pathophysiology in 2017 and 2018 and the exam results in blood pathophysiology from both years (taught by the same teacher, in a traditional way). Groups were compared with Student's t test. Students answered a survey after finishing the term. Two hundred and one students were examined in 2018 (and 229 in 2017). Gender distribution and the qualifications obtained in general pathology (in the previous year) were comparable in both years. Results in respiratory pathophysiology were significantly better in 2018 than in 2017 (mean: 48 vs. 42 out of 100; P = 0.004), but the results in blood pathophysiology remained similar. The improvement was significant only in students who scored below the median (mean: 40 vs. 33; P = 0.009) and was more evident in male than in female students (mean: 52 vs. 44; P = 0.01) and in those who did not have an academic delay (mean 51 vs. 44; P = 0.002). Most students considered that flipped classroom was more attractive and helped them to learn more and with less effort. Flipped classroom increased medical students' knowledge acquisitions in pathophysiology. It was more beneficial to male students and those with lower qualifications with no academic delay.
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Autores:
Ávila Zaragoza, Matías Antonio (Autor de correspondencia);
Dufour, J. F. ;
Gerbes, A. L.;
et al.
Revista:
GUT
ISSN: 0017-5749
Vol.69
N° 4
2020
págs. 764 - 780
Resumen
Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area. In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
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Autores:
Diaz-Gonzalez, A.;
Sanduzzi-Zamparelli, M.;
Fonseca, L. G.;
et al.
Revista:
LIVER INTERNATIONAL
ISSN: 1478-3231
Vol.40
N° 6
2020
págs. 1467 - 1476
Resumen
Background & Aims Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population.
Methods We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded.
Results As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE.
Conclusions The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.
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Autores:
Ancín, M.;
Sanz-Barrio, R.;
Santa María Monasterio, Eva;
et al.
Revista:
PLANTS
ISSN: 2223-7747
Vol.9
N° 2
2020
págs. 183
Resumen
Human cardiotrophin 1 (CT1), a cytokine with excellent therapeutic potential, was previously expressed in tobacco chloroplasts. However, the growth conditions required to reach the highest expression levels resulted in an impairment of its bioactivity. In the present study, we have examined new strategies to modulate the expression of this recombinant protein in chloroplasts so as to enhance its production and bioactivity. In particular, we assessed the effect of both the fusion and co-expression of Trx m with CT1 on the production of a functional CT1 by using plastid transformation. Our data revealed that the Trx m fusion strategy was useful to increase the expression levels of CT1 inside the chloroplasts, although CT1 bioactivity was significantly impaired, and this was likely due to steric hindrance between both proteins. By contrast, the expression of functional CT1 was increased when co-expressed with Trx m, because we demonstrated that recombinant CT1 was functionally active during an in vitro signaling assay. While Trx m/CT1 co-expression did not increase the amount of CT1 in young leaves, our results revealed an increase in CT1 protein stability as the leaves aged in this genotype, which also improved the recombinant protein's overall production. This strategy might be useful to produce other functional biopharmaceuticals in chloroplasts.
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Autores:
He, A. R. ;
Yau, T.;
Hsu, C. ;
et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN: 0732-183X
Vol.38
N° 4
2020
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Autores:
Kelley, R.K.;
Sangro Gómez-Acebo, Bruno Carlos;
Harris, W.P.;
et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN: 0732-183X
Vol.38
N° 15
2020
-
Autores:
Sangro Gómez-Acebo, Bruno Carlos;
Park, J.;
Finn, R.;
et al.
Revista:
ANNALS OF ONCOLOGY
ISSN: 0923-7534
Vol.31
N° Supl. 3
2020
págs. S241 - S242
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Autores:
Kelley, R. ;
Kudo, M. ;
Harris, W.;
et al.
Revista:
ANNALS OF ONCOLOGY
ISSN: 0923-7534
Vol.31
N° Supl. 3
2020
págs. S233 - S234
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Autores:
Edeline, J.;
Yau, T. ;
Park, J. W.;
et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN: 0732-183X
Vol.38
N° 4
2020
-
Autores:
Yau, T.;
Zagonel, V. ;
Santoro, A. ;
et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN: 0732-183X
Vol.38
N° 4
2020
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Autores:
Tolosa, E. J. ;
García Fernández de Barrena, Maite;
Iguchi, E. ;
et al.
Revista:
PANCREAS
ISSN: 0885-3177
Vol.49
N° 10
2020
págs. 1433 - 1433
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Autores:
Sangro Gómez-Acebo, Bruno Carlos;
Kudo, M. ;
Qin, S.;
et al.
Revista:
ANNALS OF ONCOLOGY
ISSN: 0923-7534
Vol.31
N° Supl. 3
2020
págs. S202 - S203
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Autores:
Buonaguro, L. ;
Mayer, A. ;
Loeffler, M. ;
et al.
Revista:
CANCER RESEARCH
ISSN: 0008-5472
Vol.80
N° 16
2020
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Autores:
Levillain, H.;
Bagni, O. ;
Deroose, C. M. ;
et al.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN: 1619-7070
Vol.47
N° Supl. 1
2020
págs. S107 - S108
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Autores:
Adeva, J. (Autor de correspondencia);
Sangro Gómez-Acebo, Bruno Carlos;
Salati, M.;
et al.
Revista:
LIVER INTERNATIONAL
ISSN: 1478-3223
Vol.39
N° Supl. 1
2019
págs. 123 - 142
Resumen
Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
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Autores:
Barcena-Varela, M.;
Colyn, L.;
García Fernández de Barrena, Maite (Autor de correspondencia)
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN: 1422-0067
Vol.20
N° 10
2019
págs. 2507
Resumen
Liver fibrosis is an essential component of chronic liver disease (CLD) and hepatocarcinogenesis. The fibrotic stroma is a consequence of sustained liver damage combined with exacerbated extracellular matrix (ECM) accumulation. In this context, activation of hepatic stellate cells (HSCs) plays a key role in both initiation and perpetuation of fibrogenesis. These cells suffer profound remodeling of gene expression in this process. This review is focused on the epigenetic alterations participating in the transdifferentiation of HSCs from the quiescent to activated state. Recent advances in the field of DNA methylation and post-translational modifications (PTM) of histones (acetylation and methylation) patterns are discussed here, together with altered expression and activity of epigenetic remodelers. We also consider recent advances in translational approaches, including the use of epigenetic marks as biomarkers and the promising antifibrotic properties of epigenetic drugs that are currently being used in patients.
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Autores:
Fontanellas Roma, Antonio (Autor de correspondencia);
Ávila Zaragoza, Matías Antonio;
Anderson, K. E.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.71
N° 2
2019
págs. 422 - 433
Resumen
Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Autores:
D'Avola, Delia;
Bilbao Jaureguizar, José Ignacio;
Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN: 0174-1551
Vol.42
N° 9
2019
págs. 1262 - 1270
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Autores:
Chen, C. B.;
Nelson, L. J.;
Ávila Zaragoza, Matías Antonio;
et al.
Revista:
CELLS
ISSN: 2073-4409
Vol.8
N° 10
2019
Resumen
In recent years, the incidence of both liver and biliary tract cancer has increased. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common types of hepatic malignancies. Whereas HCC is the fifth most common malignant tumor in Western countries, the prevalence of CCA has taken an alarming increase from 0.3 to 2.1 cases per 100,000 people. The lack of specific biomarkers makes diagnosis very difficult in the early stages of this fatal cancer. Thus, the prognosis of CCA is dismal and surgery is the only effective treatment, whilst recurrence after resection is common. Even though chemotherapy and radiotherapy may prolong survival in patients with CCA, the 5-year survival rate is still very low-a significant global problem in clinical diagnosis and therapy. The mitogen-activated protein kinase (MAPK) pathway plays an important role in signal transduction by converting extracellular stimuli into a wide range of cellular responses including inflammatory response, stress response, differentiation, survival, and tumorigenesis. Dysregulation of the MAPK cascade involves key signaling components and phosphorylation events that play an important role in tumorigenesis. In this review, we discuss the pathophysiological role of MAPK, current therapeutic options, and the current situation of MAPK-targeted therapies in CCA.
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Autores:
Herrero Santos, José Ignacio (Autor de correspondencia);
Lucena Ramírez, Juan Felipe;
Quiroga Vila, Jorge
Revista:
BMC MEDICAL EDUCATION
ISSN: 1472-6920
Vol.19
2019
págs. 72
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Autores:
Ávila Zaragoza, Matías Antonio (Autor de correspondencia);
Berasain Lasarte, María del Carmen (Autor de correspondencia)
Revista:
CMGH
ISSN: 2352-345X
Vol.7
N° 2
2019
págs. 293 - 294
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Autores:
Furuya, S.;
Cichocki, J. A.;
Konganti, K.;
et al.
Revista:
TOXICOLOGICAL SCIENCES : AN OFFICIAL JOURNAL OF THE SOCIETY OF TOXICOLOGY
ISSN: 1096-0929
Vol.170
N° 2
2019
págs. 427 - 437
Resumen
Human alcoholic hepatitis (AH) carries a high mortality rate. AH is an acute-on-chronic form of liver injury characterized by hepatic steatosis, ballooned hepatocytes, neutrophil infiltration, and pericellular fibrosis. We aimed to study the pathogenesis of AH in an animal model which combines chronic hepatic fibrosis with intragastric alcohol administration. Adult male C57BL6/J mice were treated with CCl4 (0.2 ml/kg, 2×weekly by intraperitoneal injections for 6 weeks) to induce chronic liver fibrosis. Then, ethyl alcohol (up to 25 g/kg/day for 3 weeks) was administered continuously to mice via a gastric feeding tube, with or without one-half dose of CCl4. Liver and serum markers and liver transcriptome were evaluated to characterize acute-on-chronic-alcoholic liver disease in our model. CCl4 or alcohol treatment alone induced liver fibrosis or steatohepatitis, respectively, findings that were consistent with expected pathology. Combined treatment resulted in a marked exacerbation of liver injury, as evident by the development of inflammation, steatosis, and pericellular fibrosis, pathological features of human AH. E. coli and Candida were also detected in livers of mice cotreated with CCl4 and alcohol, indicating pathogen translocation from gut to liver, similar to human AH. Importantly, liver transcriptomic changes specific to combined treatment group demonstrated close concordance with pathways perturbed in patients with severe AH. ...
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Autores:
Loffler, M. W. (Autor de correspondencia);
Mohr, C.;
Bichmann, L. ;
et al.
Revista:
GENOME MEDICINE
ISSN: 1756-994X
Vol.11
2019
Resumen
Background: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. Methods: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. Results: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somaticmutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignantmelanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. Conclusions: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignantmelanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
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Autores:
Grueso, E.;
Sánchez-Martínez, C.;
Calvo-López, T.;
et al.
Revista:
JOURNAL OF VIROLOGY
ISSN: 0022-538X
Vol.93
N° 19
2019
págs. e00798 - e00819
Resumen
As many tumor cells synthetize vascular endothelial growth factors (VEGF) that promote neo-vascularization and metastasis, frontline cancer therapies often administer anti-VEGF (alpha-VEGF) antibodies. To target the oncolytic parvovirus minute virus of mice (MVM) to the tumor vasculature, we studied the functional tolerance, evasion of neutralization, and induction of alpha-VEGF antibodies of chimeric viruses in which the footprint of a neutralizing monoclonal antibody within the 3-fold capsid spike was replaced by VEGF-blocking peptides: P6L (PQPRPL) and A7R (ATWLPPR). Both peptides allowed viral genome replication and nuclear translocation of chimeric capsid subunits. MVM-P6L efficiently propagated in culture, exposing the heterologous peptide on the capsid surface, and evaded neutralization by the anti-spike monoclonal antibody. In contrast, MVM-A7R yielded low infectious titers and was poorly recognized by an alpha-A7R monoclonal antibody. MVM-A7R showed a deficient assembly pattern, suggesting that A7R impaired a transitional configuration that the subunits must undergo in the 3-fold axis to close up the capsid shell. The MVM-A7R chimeric virus consistently evolved in culture into a mutant carrying the P6Q amino acid substitution within the A7R sequence, which restored normal capsid assembly and infectivity. Consistent with this finding, anti-native VEGF antibodies were induced in mice by a single injection of MVM-A7R empty capsids, but not by MVM-A7R virions. This fundamental study provides insights to endow an infectious parvovirus with immune antineovascularization and evasion capacities by replacing an antibody footprint in the capsid 3-fold axis with VEGF-blocking peptides, and it also illustrates the evolutionary capacity of single-stranded DNA (ssDNA) viruses to overcome engineered capsid structural restrictions. IMPORTANCE Targeting the VEGF signaling required for neovascularization by vaccination with chimeric capsids of oncolytic viruses may boost therapy for solid tumors. VEGF-blocking peptides (VEbp) engineered in the capsid 3-fold axis endowed the infectious parvovirus MVM with the ability to induce alpha-VEGF antibodies without adjuvant and to evade neutralization by MVM-specific antibodies. However, these properties may be compromised by structural restraints that the capsid imposes on the peptide configuration and by misassembly caused by the heterologous peptides. Significantly, chimeric MVM-VEbp resolved the structural restrictions by selecting mutations within the engineered peptides that restored efficient capsid assembly. These data show the promise of antineovascularization vaccines using chimeric VEbp-icosahedral capsids of oncolytic viruses but also raise safety concerns regarding the genetic stability of manipulated infectious parvoviruses in cancer and gene therapies.
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Autores:
Vera Yunca, Diego;
Serrano-Mendioroz, I.;
Sampedro Pascual, Ana;
et al.
Revista:
MOLECULAR GENETICS AND METABOLISM
ISSN: 1096-7192
Vol.128
N° 3
2019
págs. 367 - 375
Resumen
Introduction. Acute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acute attacks based on experimental pharmacodynamics data and support the development of new therapeutic strategies. Methods: Male AIP mice received recurrent phenobarbital challenge starting on days 1, 9, 16 and 30. 24-h urine excretion of ALA, porphobilinogen (PBG) and porphyrins from challenges Dl, D9 and D30 constituted the training data set to build the mechanistic model using the population approach. In a second study, porphyrin and porphyrin precursor excretion from challenge D16 were used as a validation data set. Results: The computational model presented the following features: (i) urinary excretion of ALA, PBG and porphyrins was governed by unmeasured circulating heme precursor amounts, (ii) the circulating amounts of ALA and PBG were the precursors of circulating amounts of PBG and porphyrins, respectively, and (iii) the phenobarbital effect linearly increased the synthesis of circulating ALA and PBG levels. The model displayed good parameter precision (coefficient of variation below 32% in all parameters), and adequately described the experimental data. Finally, a theoretical hemin effect was implemented to illustrate the applicability of the model to dosage optimization in drug therapies. Conclusions: A semi-mechanistic disease model was successfully developed to describe the temporal evolution of urinary heme precursor excretion during recurrent biochemical-induced acute attacks in AIP mice. This model represents the first computational approach to explore and optimize current and new therapies.
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Autores:
Berraondo López, Pedro;
Martini, P. G. V.;
Ávila Zaragoza, Matías Antonio (Autor de correspondencia);
et al.
Revista:
GUT
ISSN: 0017-5749
Vol.68
N° 7
2019
págs. 1323 - 1330
Resumen
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ' protein replacement therapy' could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
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Autores:
Herrero Santos, José Ignacio (Autor de correspondencia);
Lucena Ramírez, Juan Felipe;
Quiroga Vila, Jorge
Revista:
BMC MEDICAL EDUCATION
ISSN: 1472-6920
Vol.19
N° 1
2019
págs. 42
Resumen
Background: Writing multiple choice questions may be a valuable tool for medical education. We asked medical students to generate multiple choice questions and studied its effect on their exams. We hypothesized that students generating questions would improve their learning.
Methods: We randomized students in their second and third years at the School of Medicine to write four multiple choice questions on two different sections of General Pathology (Immunopathology and Electrolyte and acid-base status; second year) and Pathophysiology (Blood and Respiratory system; third year). We analyzed whether students writing questions on a section had better results in the exam test in that section than the rest of the students.
Results: Seventy-five (38.2%) students wrote questions for General Pathology and 109 (47.6%) for Pathophysiology. Students that wrote questions obtained significantly better results in the exam than those who did not. In General Pathology, students who wrote questions about Immunopathology obtained better results in that section than those who wrote questions about the other section (5.13 versus 3.86 over 10; P¿=¿0.03). In Pathophysiology, the differences between both groups were not significant, but students who wrote good questions about Respiratory system obtained better results in that section than those who wrote good questions about Blood (6.07 versus 4.28 over 10; P¿=¿0.015). Male students wrote good questions in Pathophysiology more frequently than female students (28.1% versus 10.4%; P¿=¿0.02).
Conclusions: The writing of multiple choice questions by medical students may improve their learning. A gender effect may also influence this intervention. Future investigations should refine its potential role in teaching.
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Autores:
Marin-Alejandre, B. A. ;
Abete Goñi, Itziar;
Cantero González, Irene;
et al.
Revista:
NUTRIENTS
ISSN: 2072-6643
Vol.11
N° 10
2019
págs. 2543
Resumen
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. NAFLD management is mainly focused on weight loss, but the optimal characteristics of the diet demand further investigation. This study aims to evaluate the effects of two personalized energy-restricted diets on the liver status in overweight or obese subjects with NAFLD after a 6 months follow-up. Ninety-eight individuals from the Fatty Liver in Obesity (FLiO) study were randomized into two groups and followed different energy-restricted diets. Subjects were evaluated at baseline and after 6 months. Diet, anthropometry, body composition, and biochemical parameters were evaluated. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, and determination of transaminases. Both dietary groups significantly improved their metabolic and hepatic markers after the intervention, with no significant differences between them. Multivariate regression models evidenced a relationship between weight loss, adherence to the Mediterranean Diet (MedDiet), and a decrease in liver fat content, predicting up to 40.9% of its variability after 6 months. Moreover, the antioxidant capacity of the diet was inversely associated with liver fat content. Participants in the group with a higher adherence to the MedDiet showed a greater reduction in body weight, total fat mass, and hepatic fat. These results support the benefit of energy-restricted diets, high adherence to the MedDiet, and high antioxidant capacity of the diet for the management of NAFLD in individuals with overweight or obesity.
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Autores:
Argemí Ballbé, José María;
Latasa Sada, María Ujué;
Atkinson, S. R.;
et al.
Revista:
NATURE COMMUNICATIONS
ISSN: 2041-1723
Vol.10
N° 3126
2019
Resumen
Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGF beta 1 is a key upstream transcriptome regulator in AH and induces the use of HNF4 alpha P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4 alpha are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4 alpha-dependent gene expression. We conclude that targeting TGF beta 1 and epigenetic drivers that modulate HNF4 alpha-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
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Autores:
Yuste Ara, José Ramón (Autor de correspondencia);
Serrano Alonso, María;
Carmona de la Torre, Francisco de Asís;
et al.
Revista:
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
ISSN: 0305-7453
Vol.74
N° 9
2019
págs. 2817 - 2819
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Autores:
Fan, Y.;
Bazai, S. K;
Daian, F.;
et al.
Revista:
JOURNAL OF HEPATOLOGY
ISSN: 1600-0641
Vol.70
N° 3
2019
págs. 470 - 482
Resumen
BACKGROUND & AIMS:
The variety of alterations found in hepatocellular carcinoma (HCC) makes the identification of functionally relevant genes and their combinatorial actions in tumorigenesis challenging. Deregulation of receptor tyrosine kinases (RTKs) is frequent in HCC, yet little is known about the molecular events that cooperate with RTKs and whether these cooperative events play an active role at the root of liver tumorigenesis.
METHODS:
A forward genetic screen was performed using Sleeping Beauty transposon insertional mutagenesis to accelerate liver tumour formation in a genetic context in which subtly increased MET RTK levels predispose mice to tumorigenesis. Systematic sequencing of tumours identified common transposon insertion sites, thus uncovering putative RTK cooperators for liver cancer. Bioinformatic analyses were applied to transposon outcomes and human HCC datasets. In vitro and in vivo (through xenografts) functional screens were performed to assess the relevance of distinct cooperative modes to the tumorigenic properties conferred by RTKs.
RESULTS:
We identified 275 genes, most of which are altered in patients with HCC. Unexpectedly, these genes are not restricted to a small set of pathway/cellular processes, but cover a large spectrum of cellular functions, including signalling, metabolism, chromatin remodelling, mRNA degradation, proteasome, ubiquitination, cell cycle regulation, and chromatid segregation. We validated 15 tumour suppressor candidates, as shRNA-mediated targeting confers tumorigenicity to RTK-sensitized cells, but not to cells with basal RTK levels. This demonstrates that the context of enhanced RTK levels is essential for their action in tumour initiation.
CONCLUSION:
Our study identifies unanticipated genetic interactions underlying gene cooperativity with RTKs in HCC. Moreover, these results show how subtly increased levels of wild-type RTKs provide a tumour permissive cellular environment allowing a large spectrum of deregulated mechanisms to initiate liver cancer.
LAY SUMMARY:
Receptor tyrosine kinases (RTKs) are among signals frequently deregulated in patients with hepatocellular carcinoma and their deregulation confers essential biological properties to cancer cells. We have applied a genetic method to randomly mutate large numbers of genes in the context of a mouse model with increased RTK levels, predisposed to develop liver cancer. We identified mechanisms that accelerate tumour formation in cooperation with enhanced RTK levels. The wide array of cellular functions among these cooperators illustrates an extraordinary capability of RTKs to render the liver more vulnerable to additional alterations, by priming cells for tumour initiation.
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Autores:
Navarro Corcuera, Amaia;
López Zabalza, María Jesús;
Martínez Irujo, Juan José;
et al.
Revista:
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
ISSN: 0167-4889
Vol.1866
N° 4
2019
págs. 673 - 685
Resumen
Liver damage induces hepatic stellate cells (HSC) activation, characterised by a fibrogenic, proliferative and migratory phenotype. Activated HSC are mainly regulated by transforming growth factor ß 1 (TGFß1), which increases the production of extracellular matrix proteins (e.g. collagen-I) promoting the progression of hepatic fibrosis. AGAP2 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2) is a GTPase/GTP-activating protein involved in the actin remodelling system and receptor recycling. In the present work the role of AGAP2 in human HSC in response to TGFß1 was investigated. LX-2 HSC were transfected with AGAP2 siRNA and treated with TGFß1. AGAP2 knockdown prevented to some extent the proliferative and migratory TGFß1-induced capacities of LX-2 cells. An array focused on human fibrosis revealed that AGAP2 knockdown partially prevented TGFß1-mediated gene expression of the fibrogenic genes ACTA2, COL1A2, EDN1, INHBE, LOX, PDGFB, TGF¿12, while favored the expression of CXCR4, IL1A, MMP1, MMP3 and MMP9 genes. Furthermore, TGFß1 induced AGAP2 promoter activation and its protein expression in LX-2. Moreover, AGAP2 protein levels were significantly increased in liver samples from rats with thioacetamide-induced fibrosis. In addition, AGAP2 silencing affected TGFß1-receptor 2 (TGFR2) trafficking in U2OS cells, blocking its effective recycling to the membrane. AGAP2 silencing in LX-2 cells prevented the TGFß1-induced increase of collagen-I protein levels, while its overexpression enhanced collagen-I protein expression in the presence or absence of the cytokine. AGAP2 overexpression also increased focal adhesion kinase (FAK) phosphorylated levels in LX-2 cells. FAK and MEK1 inhibitors prevented the increase of collagen-I expression caused by TGFß1 in LX-2 overexpressing AGAP2. In summary, the present work shows for the first time, that AGAP2 is a potential new target involved in TGFß1 signalling, contributing to the progression of hepatic fibrosis.
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Autores:
Santa María Monasterio, Eva;
Rodríguez Ortigosa, Carlos Manuel;
Uriarte Díaz-Varela, Iker;
et al.
Revista:
HEPATOLOGY
ISSN: 0270-9139
Vol.69
N° 4
2019
págs. 1632 - 1647
Resumen
Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg(-/-) mice showed aggravated liver injury after BDL and ANIT administration compared to Areg(+/+) mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg(-/-) mice displayed high hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg(-/-) mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr(-/-) mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
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Autores:
Ricke, J. (Autor de correspondencia);
Klumpen, H. J.;
Amthauer, H.;
et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN: 0168-8278
Vol.71
N° 6
2019
págs. 1164 - 1174
Resumen
Background & Aims: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 ( Y-90) resin microspheres - to sorafenib alone in patients with advanced HCC. Methods: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. Results: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients 65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. Conclusion: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. Lay summary: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with m yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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Autores:
Jiménez Andrés, Maddalen;
Urtasun, R.;
Elizalde, M.;
et al.
Revista:
NUCLEIC ACIDS RESEARCH
ISSN: 0305-1048
Vol.47
N° 7
2019
págs. 3450 - 3466
Resumen
Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
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Autores:
Shah, N. D.;
Ventura-Cots, M. ;
Abraldes, J. G.;
et al.
Revista:
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
ISSN: 1542-3565
Vol.17
N° 11
2019
págs. 2320 - 2329
Resumen
BACKGROUND & AIMS: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies. METHODS: We performed a cross-sectional study of 3453 consecutive patients with either early or adva
