The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study

Background A hypercoagulable state is not associated with development of portal vein thrombosis in cirrhosis, as we previously demonstrated. However, some groups demonstrated elevated levels of inflammatory markers and activation of hemostasis in the portal vein (PV) compared to posthepatic veins, but because the liver is involved in clearance of these markers, we hypothesize that interpretation of these data is not straightforward. Aim To determine whether the PV has particular proinflammatory/hypercoagulable characteristics by comparing plasma sampled in the PV, hepatic vein (HV), and the systemic circulation. Methods Plasma samples from 51 cirrhotic patients with portal hypertension undergoing transjugular intrahepatic portosystemic shunt placement, were taken from the PV, HV, and jugular vein (JV). Markers of inflammation (lipopolysaccharide, tumor necrosis factor-alpha, interleukin-6, thiobarbituric acid-reactive substances), neutrophil-extracellular-traps (cfDNA, MPO-DNA), endothelial damage (von Willebrand factor [VWF]), and hemostasis were determined and compared among the three vascular beds. Results Markers of inflammation were slightly, but significantly higher in the PV than in the HV and systemic circulation. VWF and markers of hemostasis were modestly elevated in the PV. Levels of multiple markers were lower in the HV compared with the PV and systemic circulation. Higher model for end-stage liver disease score was associated with a more prothrombotic state in all three sample sites. Conclusion In contrast to published studies, we did not detect a clear proinflammatory or prothrombotic environment in the PV of cirrhotic patients. Many markers are lowest in the HV, indicating that the low levels of these markers in the HV, at least in part, reflect clearance of those markers in the liver

Phosphoproteomic analysis and protein-protein interaction of rat aorta GJA1 and rat heart FKBP1A after secoiridoids consumption from virgin olive oil: A functional proteomics approach

Protein functional interactions could explain the biological response of secoiridoids (SECs), main phenolic compounds in virgin olive oil (VOO). The aim was to assess protein¿protein interactions (PPIs) of the aorta gap junction alpha-1 (GJA1) and the heart peptidyl-prolyl cis-trans isomerase (FKBP1A), plus the phosphorylated heart proteome, to describe new molecular pathways in the cardiovascular system in rats using nanoliquid chromatography coupled with mass spectrometry. PPIs modified by SECs and associated with GJA1 in aorta rat tissue were calpain, TUBA1A, and HSPB1. Those associated with FKBP1A in rat heart tissue included SUCLG1, HSPE1, and TNNI3. In the heart, SECs modulated the phosphoproteome through the main canonical pathways PI3K/mTOR signaling (AKT1S1 and GAB2) and gap junction signaling (GAB2 and GJA1). PPIs associated with GJA1 and with FKBP1A, the phosphorylation of GAB2, and the dephosphorylation of GJA1 and AKT1S1 in rat tissues are promising protein targets promoting cardiovascular protection to explain the health benefits of VOO.The work summarized in this paper was supported in part by grants (grant nos. MEFOPC Project, AGL2012-40144-C03-02 and AGL2012-40144-C03-03, and AppleCOR Project, AGL2016-76943-C2-2-R) from the Ministerio de Economía, Industria y Competitividad, the Agencia Estatal de Investigación (AEI), and the European Regional Development Fund (ERDF). L.R. is supported by a Sara Borrell postdoctoral grant (CD14/00275; Spain), A.P. is supported by a postdoctoral grant (PTQ-15-08068; Spain), and Ú.C. is supported by a Pla Estratègic de Recerca i Innovació en Salut (PERIS) postdoctoral grant (SLT002/16/00239; Catalunya, Spain)

Chemokine C-C motif ligand 2 overexpression drives tissue-specific metabolic responses in the liver and muscle of mice

Chemokine (C-C motif) ligand 2 (CCL2) has been associated with chronic metabolic diseases. We aimed to investigate whether Ccl2 gene overexpression is involved in the regulation of signaling pathways in metabolic organs. Biochemical and histological analyses were used to explore tissue damage in cisgenic mice that overexpressed the Ccl2 gene. Metabolites from energy and one-carbon metabolism in liver and muscle extracts were measured by targeted metabolomics. Western blot analysis was used to explore the AMP-activated protein kinase (AMPK) and mammalian target of rapamycin pathways. Ccl2 overexpression resulted in steatosis, decreased AMPK activity and altered mitochondrial dynamics in the liver. These changes were associated with decreased oxidative phosphorylation and alterations in the citric acid cycle and transmethylation. In contrast, AMPK activity and its downstream mediators were increased in muscle, where we observed an increase in oxidative phosphorylation and increased concentrations of different metabolites associated with ATP synthesis. In conclusion, Ccl2 overexpression induces distinct metabolic alterations in the liver and muscle that affect mitochondrial dynamics and the regulation of energy sensors involved in cell homeostasis. These data suggest that CCL2 may be a therapeutic target in metabolic diseases

Congenital antithrombin deficiency in patients with splanchnic vein thrombosis

Splanchnic vein thromboses (SVT) are a rare condition that can be life-threatening. The most severe thrombophilia associated to SVT is antithrombin (AT) deficiency, usually caused by SERPINC1 mutations. Although transitory AT deficiencies and congenital disorders of the N-glycosylation pathways (CDG) have been recently reported as causes of AT deficiency, the current AT clinical screening still only includes anti-FXa activity. This study aims to 1) improve the detection of antithrombin deficiency in SVT and 2) characterize the features of antithrombin deficiency associated with SVT.The study was performed in 2 cohorts: 1) 89 SVT patients with different underlying etiologies but in whom AT deficiency had been ruled out by classical diagnostic methods; and 2) 271 unrelated patients with confirmed AT deficiency and venous thrombosis. Antithrombin was evaluated by functional (anti-FXa and anti-FIIa) and immunological methods (ELISA, crossed immunoelectrophoresis, western blot), and SERPINC1 sequencing was performed.In 4/89 patients (4.5%) additional alterations in AT were found (two had SERPINC1 mutations, one had a specific variant causing transient AT deficiency and one patient had CDG). In 11 of the 271 patients (4.1%) with AT deficiency and thrombosis, thrombosis was located at the splanchnic venous territory.AT deficiency may be underdiagnosed by current clinical screening techniques. Therefore, a comprehensive AT evaluation should be considered in cases of rethrombosis or doubtful interpretation of anti-FXa activity levels. SVT is a relatively common localization of the thrombotic event in patients with congenital AT deficiency.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis

Short-chain fatty acids (SCFAs) are gut microbiota-derived products that participate in maintaining the gut barrier integrity and host's immune response. We hypothesize that reduced SCFA levels are associated with systemic inflammation, endotoxemia, and more severe hemodynamic alterations in cirrhosis. Patients with cirrhosis referred for a hepatic venous pressure gradient (HVPG) measurement (n = 62) or a transjugular intrahepatic portosystemic shunt placement (n = 12) were included. SCFAs were measured in portal (when available), hepatic, and peripheral blood samples by GC-MS. Serum endotoxins, proinflammatory cytokines, and NO levels were quantified. SCFA levels were significantly higher in portal vs. hepatic and peripheral blood. There were inverse relationships between SCFAs and the severity of disease. SCFAs (mainly butyric acid) inversely correlated with the model for end-stage liver disease score and were further reduced in patients with history of ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis. There was an inverse relationship between butyric acid and HVPG values. SCFAs were directly related with systemic vascular resistance and inversely with cardiac index. Butyric acid inversely correlated with inflammatory markers and serum endotoxin. A global reduction in the blood levels of SCFA in patients with cirrhosis is associated with a more advanced liver disease, suggesting its contribution to disease progression.-Juanola, O., Ferrusquía-Acosta, J., García-Villalba, R., Zapater, P., Magaz, M., Marín, A., Olivas, P., Baiges, A., Bellot, P., Turon, F., Hernández-Gea, V., González-Navajas, J. M., Tomás-Barberán, F. A., García-Pagán, J. C., Francés, R. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis

Co-expression gene network analysis reveals novel regulatory pathways involved in porto-sinusoidal vascular disease

[Background & Aims] Porto-sinusoidal vascular disease (PSVD) is a rare vascular liver disease of unknown etiology that causes portal hypertension. It usually affects young individuals and shortens live expectancy. The deregulated pathways involved in PSVD development are unknown and therefore we lack curative treatments. The purpose of this study was to integrate transcriptomic and clinical data by comprehensive network-based modeling in order to uncover altered biological processes in patients with PSVD.[Methods] We obtained liver tissue samples from 20 consecutive patients with PSVD and 21 sex- and age-matched patients with cirrhosis and 13 histologically normal livers (HNL) (initial cohort) and performed transcriptomic analysis. Microarray data were analyzed using weighted gene correlation network analysis to identify clusters of highly correlated genes differently expressed in patients with PSVD. We next evaluated the molecular pathways enriched in patients with PSVD and the core-related genes from the most significantly enriched pathways in patients with PSVD. Our main findings were validated using RNA sequencing in a different cohort of PSVD, cirrhosis and HNL (n = 8 for each group).[Results] Patients with PSVD have a distinctive genetic profile enriched mainly in canonical pathways involving hemostasis and coagulation but also lipid metabolism and oxidative phosphorylation. Serpin family (SERPINC1), the apolipoproteins (APOA, APOB, APOC), ATP synthases (ATP5G1, ATP5B), fibrinogen genes (FGB, FGA) and alpha-2-macroglobulin were identified as highly connective genes that may have an important role in PSVD pathogenesis.[Conclusion] PSVD has a unique transcriptomic profile and we have identified deregulation of pathways involved in vascular homeostasis as the main pathogenic event of disease development. [Lay summary] Porto-sinusoidal vascular disease is a rare but life-shortening disease that affects mainly young people. Knowledge of the disrupted pathways involved in its development will help to identify novel therapeutic targets and new treatments. Using a systems biology approach, we identify that pathways regulating endothelial function and tone may act as drivers of porto-sinusoidal vascular disease.This study was supported by the Instituto de Salud Carlos III FIS PI17/00398, the Ministry of Education and Science, Spain (SAF-2016-75767-R); Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR-SGR2017-517) a grant from Generalitat de Catalunya, Fondo Europeo de Desarrollo Regional (FEDER) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), funded by Instituto de Salud Carlos III. Marta Magaz is a recipient of a Río Hortega grant from Instituto de Salud Carlos III. Pol Olivas has been funded by Contractes Clínic de Recerca ”Emili Letang-Josep Font’’ 2020, granted by Hospital Clínic de Barcelona.Peer reviewe

Baixem de les tarimes i connectem: recerca en història medieval i innovació docent

We would like to introduce our group of research, [CONTRA TAEDIUM], created by professionals from different fields, that have contributed in this article. Our purpose is to expose our reflections based on our own experiences, not only in research, but also in teaching. We propose new forms of writing history in order to understand the dairy life of the women and men of the past, from birth to death. We would like to point out that interacting all types of sources is essential to understand our history. But, what really makes sense is to bring our students in the historical methodology and involve them in their education. Moreover, it is necessary to design new teaching materials using the new technologies, although it requires team-work and a great, but satisfying, effor

Modification of BRCA1-associated breast cancer risk by HMMR overexpression

Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase BRCA1-associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to BRCA1-HMMR profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases Brca1-mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-kappa B signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of BRCA1-associated breast cancer. The effect of hyaluronan-mediated motility receptor (HMMR) expression in BRCA1-associated breast cancer risk remains unknown. Here, HMMR overexpression induces the activation of cGAS-STING and non-canonical NF-kappa B signalling, instigating an immune permissive environment for breast cancer development

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension

IntroductionMacrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients with and without cirrhosis.MethodsWe studied plasma sCD163 and sMR levels in patients with IPH (n = 26), non-cirrhotic PVT (n = 20), patients with cirrhosis without PVT (n = 31) and with PVT (n = 17), and healthy controls (n = 15).ResultsMedian sCD163 concentration was 1.51 (95% CI: 1.24–1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49–2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75–2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls (P < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16–7.73) in cirrhotics without PVT and 5.19 (95% CI: 4.18–6.46) with PVT (P < 0.01, all). Similar differences were observed for sMR.ConclusionSoluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension

Heterogeneity and Cancer-Related Features in Lymphangioleiomyomatosis Cells and Tissue

Lymphangioleiomyomatosis (LAM) is a rare, low-grade metastasizing disease characterized by cystic lung destruction. LAM can exhibit extensive heterogeneity at the molecular, cellular, and tissue levels. However, the molecular similarities and differences among LAM cells and tissue, and their connection to cancer features are not fully understood. By integrating complementary gene and protein LAM signatures, and single-cell and bulk tissue transcriptome profiles, we show sources of disease heterogeneity, and how they correspond to cancer molecular portraits. Subsets of LAM diseased cells differ with respect to gene expression profiles related to hormones, metabolism, proliferation, and stemness. Phenotypic diseased cell differences are identified by evaluating lumican (LUM) proteoglycan and YB1 transcription factor expression in LAM lung lesions. The RUNX1 and IRF1 transcription factors are predicted to regulate LAM cell signatures, and both regulators are expressed in LAM lung lesions, with differences between spindle-like and epithelioid LAM cells. The cancer single-cell transcriptome profiles most similar to those of LAM cells include a breast cancer mesenchymal cell model and lines derived from pleural mesotheliomas. Heterogeneity is also found in LAM lung tissue, where it is mainly determined by immune system factors. Variable expression of the multifunctional innate immunity protein LCN2 is linked to disease heterogeneity. This protein is found to be more abundant in blood plasma from LAM patients than from healthy women.This research was partially supported by AELAM (ICO-IDIBELL agreement, to M.A. Pujana), The LAM Foundation Seed Grant 2019, to M.A. Pujana, Carlos III Institute of Health grant PI18/01029, to M.A. Pujana and ICI19/00047 to M. Molina-Molina [co-funded by European Regional Development Fund (ERDF), a way to build Europe], Generalitat de Catalunya SGR grant 2017-449, to M.A. Pujana, the CERCA Program for IDIBELL institutional support, and ZonMW-TopZorg grant 842002003, to C.H.M. van Moorsel. M. Plass was supported by a “Ramón y Cajal” contract of the Spanish Ministry of Science and Innovation (RYC2018-024564-I) and J. Moss was supported by the Intramural Research Program of NIH/NHLBI