Ultraestructura de las lesiones producidas por antibióticos aminoglucósidos (kalamicina y gentamicina) en el coclea de cobaya

Tesis Univ. Complutense.Depto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEProQuestpu

Ultraestructura de las lesiones producidas por antibióticos aminoglucósidos (kalamicina y gentamicina) en el coclea de cobaya

Tesis Univ. Complutense.Depto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEProQuestpu

Microscopía digital como herramienta para la docencia práctica en Anatomía Patológica

Memoria ID2022-185 Ayudas de la Universidad de Salamanca para la innovación docente, curso 2022-2023

Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer

Article number: 78 (2021)[EN]Despite advances in its treatment, lung cancer still represents the most common and lethal tumor. Because of that, efforts to decipher the pathophysiological actors that may promote lung tumor generation/progression are being made, with the final aim of establishing new therapeutic options. Using a transgenic mouse model, we formerly demonstrated that the sole activation of the MEK5/ERK5 MAPK route had a pathophysiological role in the onset of lung adenocarcinomas. Given the prevalence of that disease and its frequent dismal prognosis, our findings opened the possibility of targeting the MEK5/ERK5 route with therapeutic purposes. Here we have explored such possibility. We found that increased levels of MEK5/ERK5 correlated with poor patient prognosis in lung cancer. Moreover, using genetic as well as pharmacological tools, we show that targeting the MEK5/ERK5 route is therapeutically effective in lung cancer. Not only genetic disruption of ERK5 by CRISPR/Cas9 caused a relevant inhibition of tumor growth in vitro and in vivo; such ERK5 deficit augmented the antitumoral effect of agents normally used in the lung cancer clinic. The clinical correlation studies together with the pharmacological and genetic results establish the basis for considering the targeting of the MEK5/ERK5 route in the therapy for lung cancer.Cancer Center Network Program from the ISCIII (RD12/0036/0003

How to improve the precision of Bethesda System diagnostic categories I and III

Fine-needle aspiration (FNA) has a primary role in the diagnosis of thyroid nodules. FNA allows us to differentiate benign lesions from malignant ones in most of the cases. However, management of Bethesda System diagnostic categories I (Nondiagnostic or Unsatisfactory) and III (Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance) are a clinical challenge./nThe aim of this work is to expose the options we have to improve the diagnosis of those categories using a multidisciplinary approach, an active follow-up, repeating FNA, applying immunohistochemical and/or molecular technics or even perform a core needle biopsy./nSome or all of these choices are especially useful to identify category III, but active follow-up or additional FNA are preferred to detect category I.Introducción y objetivo: La punción aspiración con aguja fina es el método de elección para el diagnóstico del nódulo tiroideo, permitiendo discriminar entre lesiones malignas y benignas en un alto porcentaje de pacientes. Sin embargo, las categorías diagnósticas I (No diagnóstico o insatisfactorio) y III (Atipia o Lesión folicular de Significado Incierto) del Sistema Bethesda suponen un reto en el manejo de los nódulos tiroideos. El objetivo del presente trabajo es exponer las opciones de que se disponen en el momento actual para intentar incrementar la rentabilidad de estos diagnósticos. Síntesis: En primer lugar, el abordaje multidisciplinar de los casos, la posibilidad de seguimiento, la repetición de la punción aspiración, la complementación del diagnóstico incorporando técnicas inmunohistoquímicas o moleculares, y finalmente la posibilidad de realizar una biopsiacilindro. Conclusiones: Estas alternativas son especialmente útiles en la categoría diagnóstica III, mientras que se prefiere la opción de seguimiento o repetición de PAAF en la categoría diagnóstica I

MEK5 promotes lung adenocarcinoma

[EN]Lung cancer represents the leading cause of cancer death worldwide [1]. Because of that, intense efforts are being devoted to the development of novel therapeutic strategies to fight the disease [2]. In this respect, identification of new oncogenic drivers offers therapeutic opportunities in tumours in which those molecules or other cooperating elements play a pathophysiological role. Here, we show that the MEK5 mitogen-activated protein kinase kinase has a pivotal role in lung cancer. Originally, this study was initiated with the purpose of evaluating the potential oncogenic role of the MEK5 pathway. In fact, while the MEK5 pathway has been found to be deregulated in several neoplasias [3–6], whether exclusive activation of that pathway promotes tumorigenesis has not previously been addressed. To explore that possibility, we generated transgenic mice engineered to express a constitutively active form of MEK5 by site-directed mutagenesis of the MEK5 Ser311 and Thr315 residues to aspartic acid (MEK5DD) (figure 1a). These acidic amino acid changes result in a MEK5 form in which the aspartic acid substitutions function as phosphomimetic residues [7, 8]. As a consequence, MEK5DD acts as a constitutively active kinase that is able to phosphorylate its downstream target, the ERK5 mitogen-activated protein kinase. Phosphorylation of ERK5 by constitutively active MEK5DD results in sustained activation of ERK5. Such ERK5 phosphorylation ( pERK5) provokes a change in its electrophoretic mobility with respect to unphosphorylated ERK5, a characteristic that can be used to differentiate ERK5 from pERK5 by Western blotting [9]. The MEK5DD cDNA was subcloned into the pCEFL mammalian expression vector, which contains an N-terminal Flag tag sequence that serves to differentiate MEK5DD from endogenous MEK5. Increasing amounts of the cDNA coding for Flag-tagged MEK5DD were transfected in HeLa cells and its expression was analysed by Western blotting with an anti-Flag antibody. As shown in figure 1b, expression of Flag-MEK5DD caused the appearance of pERK5, indicative of pathway activationGrants from the Instituto de Salud Carlos III (ISCIII) (PS09/00868 and PI15/01180) and by the Scientific Foundation of the Spanish Association Against Cancer (AECC)

Acercamiento a la anatomía patológica mediante la utilización de metodología innovadora para la docencia teórico-práctica

Trabajo realizado en el departamento de Biología Celular y Psicopatología de la Facultad de Medicina de la Universidad de Salamanca por seis profesores del área de Anatomía Patológica. Los objetivos son por una parte, poner a disposición del alumnado los materiales que se han ido seleccionando, a lo largo de los años, por los diferentes profesores que imparten la asignatura de anatomía patológica: esquema del tema así como diapositivas macroscópicas y microscópicas representativas; y por otro incluir dentro de las prácticas microscópicas preparaciones con técnicas de inmunomatoquímica e hibridación in situ. Todo ello en un soporte cd-rom que facilite la utilización por parte de los alumnos del material diseñado para la enseñanza teórica y práctica. Los materiales elaborados son una colección de preparaciones histológicas que incluyen técnicas inmunomatoquímicas e hibridación in situ. El material producido es un cd-rom que incluye 597 diapositivas con dibujos, esquemas y 178 fotos.Junta de Castilla y León. Consejería de Educación y CulturaCastilla y LeónES

Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis

Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system’s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade ≥ 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669–61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments

The Impact of Liquid Biopsies Positive for <em>EGFR</em> Mutations on Overall Survival in Non-Small Cell Lung Cancer Patients

In recent years, non-small cell lung cancer treatment has been revolutionized. EGFR tyrosine kinase inhibitors and our improved understanding of its alterations have driven new diagnostic strategies. Liquid biopsies have emerged as a useful tool in these contexts, showing potential utility in early diagnosis combined with low-dose CT scans, as well as potential in monitoring treatment response and predicting the development of patients. We studied the circulating tumor DNA (ctDNA) of 38 EGFR-mutated non-small cell lung cancer patients at diagnosis in different moments of their disease by liquid biopsy techniques. Our results show that mean overall survival was significantly lower when a liquid biopsy was positive for the detection of EGFR mutations compared with wild-type patients in their liquid biopsy in both univariate (29 ± 4 vs. 104 ± 19 months; p = 0.004) and multivariate analysis (p = 0.008). Taking this into consideration, liquid biopsies could be key to improving the control of this disease

Immunohistochemical Assessment of the P53 Protein as a Predictor of Non-Small Cell Lung Cancer Response to Immunotherapy.

Determining predictive biomarkers for immune checkpoint inhibitors (ICIs) is a current challenge in oncology. Previous studies on non-small cell lung cancer (NSCLC) have shown how TP53 gene mutations are correlated with different responses to ICIs. Strong and diffuse immuno-expression of p53 by immunohistochemistry (IHC) is interpreted as a likely indicator of a TP53 gene mutation. We aimed to assess the p53 protein expression via IHC in NSCLC as a predictive biomarker of the response to ICIs. This was a retrospective hospital-based study of patients with NSCLC treated with Nivolumab in the University Hospital of Salamanca. All diagnostic biopsies were studied via IHC (measuring p53 protein expression, peroxidase anti-peroxidase immunohistochemistry technique using Leica BOND Polymer development kits). Survival analysis was performed by subgroups of expression of p53 and other factors using the Kaplan-Meier estimator and Cox proportional-hazards model. Seventy-three patients were included (59 men and 14 women). The median age was 68 (44-84) years. Thirty-six biopsies were adenocarcinoma, 34 were squamous, and three were undifferentiated. In 41 biopsies (56.2%), the cellular expression of p53 was A trend toward a greater response to ICIs was observed in the PFS and OS of patients with high expression of p53 by IHC (TP53 mutation), especially in the PD-L1 negative adenocarcinoma subgroup. These results will make it possible to make future modifications to the clinical guidelines of NSCLC according to the expression of p53