9 research outputs found
FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted
[EN] Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of
the biliary tract driven by genetic, epigenetic and transcriptional
mechanisms. Herein, we investigated the role of the transcription
factor FOSL1, as well as its downstream transcriptional effectors,
in the development and progression of CCA.
Methods: FOSL1 was investigated in human CCA clinical samples.
Genetic inhibition of FOSL1 in human and mouse CCA cell
lines was performed in in vitro and in vivo models using
constitutive and inducible short-hairpin RNAs. Conditional
FOSL1 ablation was done using a genetically engineered mouse
(GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup
RNA and chromatin immunoprecipitation (ChIP) sequencing
analyses were carried out and downstream targets were validated
using genetic and pharmacological inhibition.
Results: An inter-species analysis of FOSL1 in CCA was conducted.
First, FOSL1 was found to be highly upregulated in human
and mouse CCA, and associated with poor patient survival.
Pharmacological inhibition of different signalling pathways in
CCA cells converged on the regulation of FOSL1 expression.
Functional experiments showed that FOSL1 is required for cell
proliferation and cell cycle progression in vitro, and for tumour
growth and tumour maintenance in both orthotopic and subcutaneous
xenograft models. Likewise, FOSL1 genetic abrogation
in a GEM model of CCA extended mouse survival by decreasing
the oncogenic potential of transformed cholangiocytes. RNA and
ChIP sequencing studies identified direct and indirect transcriptional
effectors such as HMGCS1 and AURKA, whose genetic
and pharmacological inhibition phenocopied FOSL1 loss.
Conclusions: Our data illustrate the functional and clinical
relevance of FOSL1 in CCA and unveil potential targets amenable
to pharmacological inhibition that could enable the implementation
of novel therapeutic strategies.
Lay summary: Understanding the molecular mechanisms
involved in cholangiocarcinoma (bile duct cancer) development
and progression stands as a critical step for the development of
novel therapies. Through an inter-species approach, this study
provides evidence of the clinical and functional role of the
transcription factor FOSL1 in cholangiocarcinoma. Moreover, we
report that downstream effectors of FOSL1 are susceptible to
pharmacological inhibition, thus providing new opportunities
for therapeutic intervention.A.V. was supported by ADA of the University of Navarra, Spain,
O.E. by FSE; MINECO; FJCI-2017-34233, Spain, R.E. by a donation
from Mauge Burgos de la Iglesia’s family, Spain, and P. Olaizola by
the Basque Government (PRE_2016_1_0269), Basque Country,
Spain. M.J.P. was funded by ISCIII [FIS PI14; 00399, PI17; 00022]
cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER),
Spain; Spanish Ministry of Economy and Competitiveness
(MINECO: “Ramón y Cajal” Program RYC-2015-17755), Spain.
M.A.A was funded by La Caixa Foundation, HEPACARE project,
Spain, ISCIII FIS PI16/01126 cofinanced by “Fondo Europeo de
Desarrollo Regional” (FEDER), Spain, and “Fundación Científica de
la Asociación Española Contra el Cáncer’’ (AECC Scientific Foundation)
Rare Cancers 2017, Spain. J.M.B. was funded by the
Spanish Carlos III Health Institute (ISCIII) (FIS PI15; 01132, PI18;
01075 and Miguel Servet Program CON14; 00129 and CPII19;
00008), Spain, co-financed by “Fondo Europeo de Desarrollo
Regional” (FEDER), Spain; “Euskadi RIS3” (2019222054) and
BIOEF (Basque Foundation for Innovation and Health Research:
EiTB Maratoia BIO15; CA; 016; BD), Basque Country, Spain;
“Fundación Científica de la Asociación Española Contra el Cáncer”
(AECC Scientific Foundation) Rare Cancers 2017, Spain. S.V. was
supported by FEDER; MINECO (SAF2017-89944-R), Spain, by the
Government of Navarra-Health Research Department (58; 2018),
Navarra, Spain, by La Caixa and Caja Navarra Foundation-CIMA
agreement, Spain. None of the funding sources were involved
in the decision to submit the article for publication. This article is
based upon work from COST Action CA18122 European Cholangiocarcinoma
Network, supported by COST (European Cooperation
in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and
innovation networks (www.cost.eu)
Benefit of double-reading cytology smears as a triage strategy among high-risk human papillomavirus-positive women in Mexico
Opuntia in México: Identifying Priority Areas for Conserving Biodiversity in a Multi-Use Landscape
BACKGROUND: México is one of the world's centers of species diversity (richness) for Opuntia cacti. Yet, in spite of their economic and ecological importance, Opuntia species remain poorly studied and protected in México. Many of the species are sparsely but widely distributed across the landscape and are subject to a variety of human uses, so devising implementable conservation plans for them presents formidable difficulties. Multi-criteria analysis can be used to design a spatially coherent conservation area network while permitting sustainable human usage. METHODS AND FINDINGS: Species distribution models were created for 60 Opuntia species using MaxEnt. Targets of representation within conservation area networks were assigned at 100% for the geographically rarest species and 10% for the most common ones. Three different conservation plans were developed to represent the species within these networks using total area, shape, and connectivity as relevant criteria. Multi-criteria analysis and a metaheuristic adaptive tabu search algorithm were used to search for optimal solutions. The plans were built on the existing protected areas of México and prioritized additional areas for management for the persistence of Opuntia species. All plans required around one-third of México's total area to be prioritized for attention for Opuntia conservation, underscoring the implausibility of Opuntia conservation through traditional land reservation. Tabu search turned out to be both computationally tractable and easily implementable for search problems of this kind. CONCLUSIONS: Opuntia conservation in México require the management of large areas of land for multiple uses. The multi-criteria analyses identified priority areas and organized them in large contiguous blocks that can be effectively managed. A high level of connectivity was established among the prioritized areas resulting in the enhancement of possible modes of plant dispersal as well as only a small number of blocks that would be recommended for conservation management
Un Modelo de Prácticas para analizar el Proceso Social de Institucionalización Escolar del Conocimiento Matemático
El proceso de transición de un saber matemático desde que es concebido y desarrollado en el ámbito científico hasta su difusión en las aulas ha sido estudiado por diversos autores y desde diferentes perspectivas de la Matemática Educativa. En este artículo se describe un marco teórico-metodológico que permite analizar ese proceso, que hemos denominado proceso social de institucionalización, poniendo el foco de atención en las prácticas de los actores involucrados en cada uno de sus momentos. El modelo se desarrolla bajo la perspectiva socioepistemológica y se apoya en la teoría del análisis del discurso como acción social para estudiar el discurso matemático escolar.En particular, se desarrolla la manera en que se ha empleado el marco teórico-metodológico para analizar el proceso social de institucionalización del concepto de límite en el contexto educativo uruguayo. Se explora, a su vez, su posible extensión al proceso de institucionalización que atraviesan otros saberes matemáticos, en otros contextos socioculturales
Construcción social del concepto de derivada de una función en un punto: una mirada socioepistemológica
Discovery and validation of candidate SNP markers associated to heat stress response in pregnant ewes managed inside a climate-controlled chamber
Contribution of Ion Binding Affinity to Ion Selectivity and Permeation in KcsA, a Model Potassium Channel
Further exploring the "sting of the scorpion": hydride migration and subsequent rearrangement of norbornadiene to nortricyclyl on rhodium(i)
A new boron-based flexible scorpionate ligand based upon 7-azaindole, Li[Ph(H)B(azaindolyl)2] (Li[phBai]), has been prepared. This ligand, together with the previously reported ligand K[HB(azaindolyl) 3] (K[Tai]), have been used to prepare a range of monovalent group 9 transition-metal complexes. The complexes [M(COD){K3N,N,H-Ph(H) B(azaindolyl)2}] (where M = rhodium, iridium and COD = 1,5-cyclooctadiene) and [Rh(NBD){K3N,N,H-HB(R)(azaindolyl) 2}] (where NBD = 2,5-norbornadiene and R = Ph, azaindolyl) have been prepared. Structural characterization of [M(COD){K3NNH-Ph(H) B(azaindolyl)2}] (where M = rhodium, iridium) and [Rh(NBD){k 3N, N, H-HB(azaindolyl)3}] reveal strong interactions of the B-H functional group with the metal centers, particularly in the case of [Ir(COD){K3N,N,H-Ph(H)B(azaindolyl)2}]. The complex [Rh(NBD){K3N,N,H-HB(azaindolyl)3}] undergoes a further reaction, resulting from hydride migration from boron to the norbornadiene group. Subsequent rearrangement results in the formation of the rhodium-nortricyclyl complex [Rh(nortricyclyl){k4 N,N,-B,N-B(azaindolyl)3}], providing the first nitrogen-based metallaboratrane complex to contain the tetradentate (K4N,N,B,N) coordination mode