38 research outputs found
A Novel Noninvasive Method Based on Salivary Inflammatory Biomarkers for the Screening of Celiac Disease
This study was supported by a grant from theSpanish Ministry of Science, Universities andInnovation (SAF2017-91873-EXP), a grant fromthe Department of Health from the BasqueGovernment (EJ-2017111082), and a researchfellowship from the Asociación de Celiacos ySensibles al Gluten de Madrid (A.C.R.). Alsosupported by a predoctoral fellowship from theUniversity of the Basque Country (M.S.dlC.) andthe Basque Government (A.O.G.)
Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
Background and Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.Supported by the Spanish Carlos III Health Institute (ISCIII; J.M. Banales: FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129; M.J. Perugorria: PI14/00399, PI17/00022; J.J.G. Marin: FIS PI16/00598) cofinanced by "Fondo Europeo de Desarrollo Regional" (FEDER); CIBERehd (ISCIII): J.M. Banales, M.J. Perugorria, L. Bujanda, and J.J.G. Marin; Spanish Ministry of Economy and Competitiveness (M. J. Perugorria: Ramon y Cajal Program RYC-2015-17755); IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); " Diputacion Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundacion Cientifica de la Asociacion Espanola Contra el Cancer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). F.J. Caballero-Camino was funded by the Spanish Ministry of Science and Innovation (BES-2014-069148), A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). The Spanish Ministry of Science and Innovation supported F. P. Cossio: (CTQ2016-80375-P and CTQ2014-51912-REDC) as well as the Basque Government (F.P. Cossio: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center
TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms
[EN] Objective Hepatocellular carcinoma (HCC) is a prevalent
and aggressive cancer usually arising on a background
of chronic liver injury involving inflammatory and hepatic
regenerative processes. The triggering receptor expressed
on myeloid cells 2 (TREM-2) is predominantly expressed in
hepatic non-parenchymal
cells and inhibits Toll-like
receptor
signalling, protecting the liver from various hepatotoxic
injuries, yet its role in liver cancer is poorly defined. Here,
we investigated the impact of TREM-2 on liver regeneration
and hepatocarcinogenesis.
Design TREM-2 expression was analysed in liver tissues
of two independent cohorts of patients with HCC and
compared with control liver samples. Experimental HCC
and liver regeneration models in wild type and Trem-2-/-
mice, and in vitro studies with hepatic stellate cells (HSCs)
and HCC spheroids were conducted.
Results TREM-2 expression was upregulated in human
HCC tissue, in mouse models of liver regeneration and
HCC. Trem-2-/- mice developed more liver tumours
irrespective of size after diethylnitrosamine (DEN)
administration, displayed exacerbated liver damage,
inflammation, oxidative stress and hepatocyte proliferation.
Administering an antioxidant diet blocked DEN-induced
hepatocarcinogenesis in both genotypes. Similarly,
Trem-2-/- animals developed more and larger tumours in
fibrosis-associated
HCC models. Trem-2-/- livers showed
increased hepatocyte proliferation and inflammation after
partial hepatectomy. Conditioned media from human HSCs
overexpressing TREM-2 inhibited human HCC spheroid
growth in vitro through attenuated Wnt ligand secretion.
Conclusion TREM-2 plays a protective role in
hepatocarcinogenesis via different pleiotropic effects,
suggesting that TREM-2 agonism should be investigated
as it might beneficially impact HCC pathogenesis in a
multifactorial manner.Spanish Ministry of Economy and Competitiveness and ’Instituto de Salud
Carlos III’ grants (MJP (PI14/00399, PI17/00022 and Ramon y Cajal Programme
RYC-2015–17755); JMB (PI12/00380, PI15/01132, PI18/01075, Miguel Servet
Programme CON14/00129 and CPII19/00008) cofinanced by ’Fondo Europeo de
Desarrollo Regional’ (FEDER); CIBERehd: MJP, JMB and LB), Spain; IKERBASQUE,
Basque foundation for Science (MJP and JMB), Spain; ’Diputación Foral de Gipuzkoa’
(MJP: DFG18/114, DFG19/081; JMB: DFG15/010, DFG16/004); BIOEF (Basque
Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/
BD to JMB); Department of Health of the Basque Country (MJP: 2015111100 and
2019111024; JMB: 2017111010), Euskadi RIS3 (JMB: 2016222001, 2017222014,
2018222029, 2019222054, 2020333010) Department of Industry of the Basque
Country (JMB: Elkartek: KK-2020/00008) and AECC Scientific Foundation (JMB).
AE-B
was funded by the University of the Basque Country (UPV/EHU) (PIF2014/11)
and by the short-term
training fellowship Andrew K Burroughs (European
Association for the Study of the Liver, EASL). IL and AA-L
were funded by the
Department of Education, Language Policy and Culture of the Basque Government
(PRE_2016_1_0152 and PRE_2018_1_0184). OS and SK were funded by the
Austrian Science Fund (FWF25801-B22,
FWF-P35168
to OS and L-Mac:
F 6104-B21
to SK). FO and DAM were funded by a UK Medical Research Council programme
Grant MR/R023026/1. DAM was also funded by the CRUK programme grant
C18342/A23390, CRUK/AECC/AIRC Accelerator Award A26813 and the MRC MICA
programme grant MR/R023026/1. JBA is supported by the Danish Medical Research
Council, Danish Cancer Society, Nordisk Foundation, and APM Foundation. CJO’R
and PM-G
are supported by Marie Sklodowska-Curie
Programme and EASL Sheila
Sherlock postdoctoral fellowships
Utilidad de cinco tejidos para discriminar variantes somáticas y germinales en neoplasias mieloides
CO-091
Introducción: Los síndromes hereditarios están adquiriendo una gran importancia en el panorama de las hemopatías malignas. De hecho, la revisión de 2016 de la OMS ha incluido una sección sobre predisposición germinal a neoplasias mieloides (NM). Distinguir entre una neoplasia mieloide de predisposición hereditaria (NMPH) de una NM esporádica es crucial por su impacto en el seguimiento de estos pacientes, así como en el de sus familiares sanos. La generalización de técnicas como la NGS en el estudio inicial de pacientes con NM ha puesto de manifiesto que un porcentaje no desdeñable de pacientes podrían tener variantes de origen germinal. Sin embargo, para su diagnóstico, se precisa de la confirmación de la naturaleza de la variante en un tejido no hematopoyético, sin que exista un consenso sobre el tejido a utilizar.
Métodos: Nos propusimos evaluar cinco tejidos (fibroblastos de médula ósea, fibroblastos de piel, folículos pilosos, frotis bucal y células CD3+) en cuanto a su capacidad de discriminar si las variantes sospechosas eran de origen somático o germinal. El estudio se realizó en una cohorte de 299 pacientes a los que en algún momento del curso de la enfermedad se les hizo un panel de NGS Pan-Mieloide (PMP, 48 genes), que incluye 22 genes descritos en la literatura como relacionados con NMPH, incluyendo los recomendados por la OMS (ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1). De los 299 pacientes, 100 portaban variantes en algunos de esos 22 genes, que presentaban una frecuencia alélica (VAF) ~ 50%. Recolectamos un total de 21 muestras de tejidos ..
Integrated flow cytometry and sequencing to reconstruct evolutionary patterns from dysplasia to acute myeloid leukemia
Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n = 12 of 21), branching (n = 4 of 21), and clonal evolution (n = 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in ∼80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.This work was supported by grants from the Área de Oncología del Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red (CIBER-ONC) (CB16/12/00369, CB16/12/00233, CB16/12/00489, and CB16/12/00284), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS numbers PI16/01661, PI16/00517, and PI19/01518), and the Plan de Investigación de la Universidad de Navarra (PIUNA 2014-18). This work was supported internationally by the Cancer Research UK, FCAECC, and AIRC under the Accelerator Award Program (EDITOR)
Evaluation of appendicitis risk prediction models in adults with suspected appendicitis
Background
Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis.
Methods
A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis).
Results
Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent).
Conclusion
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified