DSpace Collection:https://hdl.handle.net/10171/122052024-03-29T14:47:39Z2024-03-29T14:47:39ZFGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacyhttps://hdl.handle.net/10171/662762023-05-22T05:12:15Z2020-01-01T00:00:00ZTitle: FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their coexpression may predict FGFR-targeted therapy efficacy
Abstract: Background: Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis
in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types
of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with
limited success.
Methods: In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in
patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to
determine the prognostic potential of the genes under study.
Findings: We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of
the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression
alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin
inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and
patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high
FGFR1/4 and N-cadherin expression.
Interpretation: Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.2020-01-01T00:00:00ZStereological estimates of glutamatergic, GABAergic, and cholinergic neurons in the pedunculopontine and laterodorsa tegmental nuclei in the rathttps://hdl.handle.net/10171/655992023-03-06T06:16:04Z2018-01-01T00:00:00ZTitle: Stereological estimates of glutamatergic, GABAergic, and cholinergic neurons in the pedunculopontine and laterodorsa tegmental nuclei in the rat
Abstract: The pedunculopontine tegmental nucleus (PPN) and laterodorsal tegmental nucleus (LDT) are functionally associated brainstem structures implicated in behavioral state control and sensorimotor integration. The PPN is also involved in gait and posture, while the LDT plays a role in reward. Both nuclei comprise characteristic cholinergic neurons intermingled with glutamatergic and GABAergic cells whose absolute numbers in the rat have been only partly established. Here we sought to determine the complete phenotypical profile of each nucleus to investigate potential differences between them. Counts were obtained using stereological methods after the simultaneous visualization of cholinergic and either glutamatergic or GABAergic cells. The two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67, were separately analyzed. Dual in situ hybridization revealed coexpression of GAD65 and GAD67 mRNAs in ∼90% of GAD-positive cells in both nuclei; thus, the estimated mean numbers of (1) cholinergic, (2) glutamatergic, and (3) GABAergic cells in PPN and LDT, respectively, were (1) 3,360 and 3,650; (2) 5,910 and 5,190; and (3) 4,439 and 7,599. These data reveal significant differences between PPN and LDT in their relative phenotypical composition, which may underlie some of the functional differences observed between them. The estimation of glutamatergic cells was significantly higher in the caudal PPN, supporting the reported functional rostrocaudal segregation in this nucleus. Finally, a small subset of cholinergic neurons (8% in PPN and 5% in LDT) also expressed the glutamatergic marker Vglut2, providing anatomical evidence for a potential corelease of transmitters at specific target areas.2018-01-01T00:00:00ZTwo cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinomahttps://hdl.handle.net/10171/649962023-01-24T13:12:47Z2022-01-01T00:00:00ZTitle: Two cell line models to study multiorganic metastasis and immunotherapy in lung squamous cell carcinoma
Abstract: There is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e. UN-SCC679 and UN-SCC680, derived from A/J mice that had been chemically induced with N-nitroso-tris-chloroethylurea (NTCU). Furthermore, we genetically characterized and compared both LUSC cell lines by performing whole-exome and RNA sequencing. These experiments revealed similar genetic and transcriptomic patterns that may correspond to the classic LUSC human subtype. In addition, we compared the immune landscape generated by both tumor cells lines in vivo and assessed their response to immune checkpoint inhibition. The differences between the two cell lines are a good model for the remarkable heterogeneity of human squamous cell carcinoma. Study of the metastatic potential of these models revealed that both cell lines represent the organotropism of LUSC in humans, i.e. affinity to the brain, bones, liver and adrenal glands. In summary, we have generated valuable cell line tools for LUSC research, which recapitulates the complexity of the human disease.2022-01-01T00:00:00ZEl núcleo tegmental pedunculopontino. Anatomía, consideraciones funcionales e implicaciones fisiopatológicashttps://hdl.handle.net/10171/645962023-01-31T13:06:51Z1999-01-01T00:00:00ZTitle: El núcleo tegmental pedunculopontino. Anatomía, consideraciones funcionales e implicaciones fisiopatológicas
Abstract: El núcleo tegmental pedúnculopontino está constituido por un conjunto de neuronas colinérgicas y no colinérgicas, localizadas en el tegmento pontomesencefálico caudal, rodeando al pedúnculo cerebeloso superior. Es un núcleo considerado parte integral de la formación reticular del tronco del encéfalo, con extensas conexiones anatómicas y funciones muy variadas. Mediante las proyecciones ascendentes que envía al tálamo, interviene en la regulación del ciclo vigilia-sueño. Además, constituye el núcleo más caudal del neuroeje que recibe conexiones de los ganglios basales, por lo que ha atraído el interés de aquellos investigadores que se ocupan del estudio de estas estructuras. Gracias a sus conexiones recíprocas con los ganglios basales, así como a sus proyecciones descendentes a diversas estructuras de la protuberancia, bulbo y médula espinal, se ha relacionado al núcleo tegmental pedúnculopontino con el control de la locomoción. Recientemente, se le ha considerado un posible centro de integración de la información motora que le aporta el estriado dorsal con la información motivacional o límbica proveniente del estriado ventral, para permitir su acceso directo a centros motores bulbares o medulares. En este trabajo vamos a revisar sus características anatómicas y funcionales así como su implicación en algunas enfermedades del sistema nervioso como la narcolepsia, la parálisis supranuclear progresiva, la esquizofrenia y la enfermedad de Parkinson.; Pedunculopontine tegmental nucleus is formed by an ensemble of cholinergic and non-cholinergic neurons located in the caudal pontomesencephalic tegmentum, surrounding the superior cerebellar peduncle. It is an integral part of the reticulate formation of the brain stem, with extensive anatomical connections and highly varied functions. By means of ascendant projections that it sends to the thalamus, it intervenes in the waking-sleep cycle. Besides, it constitutes the most caudal nucleus of the neuroaxis, receiving connections from the basal ganglia, for which reason it has attracted the interest of those researchers concerned with the study of these structures. Thanks to its reciprocal connections with the basal ganglia, as well as to its descending projections to different structures of the pons, medulla and spinal cord; it has been related to the control of locomotion. Recently, it has also been considered as a possible centre for the integration of the motor information provided by the dorsal striatum with the motivational or limbic information proceeding from the ventral striatum, to permit its direct access to bulbar or spinal motor centres. In this work we will review its anatomical and functional characteristics, as well as its implication in some diseases of the nervous system such as narcolepsy, progressive supranuclear paralysis, schizophrenia and Parkinson's disease.1999-01-01T00:00:00Z