PCDHGC3 hypermethylation as a potential biomarker of intestinal neuroendocrine carcinomas.

Neuroendocrine neoplasms (NENs) encompass tumors arising from neuroendocrine cells in various organs, including the gastrointestinal tract, pancreas, adrenal gland, and paraganglia. Despite advancements, accurately predicting the aggressiveness of gastroenteropancreatic (GEP) NENs based solely on pathological data remains challenging, thereby limiting optimal clinical management. Our previous research unveiled a crucial link between hypermethylation of the protocadherin PCDHGC3 gene and neuroendocrine tumors originating from the paraganglia and adrenal medulla. This epigenetic alteration was associated with increased metastatic potential and succinate dehydrogenase complex (SDH) dysfunction. Expanding upon this discovery, the current study explored PCDHGC3 gene methylation within the context of GEP-NENs in a cohort comprising 34 cases. We uncovered promoter hypermethylation of PCDHGC3 in 29% of GEP-NENs, with a significantly higher prevalence in gastrointestinal (GI) neuroendocrine carcinomas (NECs) compared with both pancreatic (Pan) NECs and neuroendocrine tumors (NETs) of GI and Pan origin. Importantly, these findings were validated in one of the largest multi-center GEP-NEN cohorts. Mechanistic analysis revealed that PCDHGC3 hypermethylation was not associated with SDH mutations or protein loss, indicating an SDH-independent epigenetic mechanism. Clinically, PCDHGC3 hypermethylation emerged as a significant prognostic factor, correlating with reduced overall survival rates in both patient cohorts. Significantly, whereas PCDHGC3 hypermethylation exhibited a strong correlation with TP53 somatic mutations, a hallmark of NEC, its predictive value surpassed that of TP53 mutations, with an area under the curve (AUC) of 0.95 (95% CI 0.83-1.0) for discriminating GI-NECs from GI-NETs, highlighting its superior predictive performance. In conclusion, our findings position PCDHGC3 methylation status as a promising molecular biomarker for effectively stratifying patients with GI-NENs. This discovery has the potential to advance patient care by enabling more precise risk assessments and tailored treatment strategies. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Binding of Pseudomonas aeruginosa to Cystic Fibrosis Bronchial Epithelial Model Cells Alters the Composition of the Exosomes They Produce Compared to Healthy Control Cells.

Cystic fibrosis (CF) is a genetic disease that causes dehydration of the surface of the airways, increasing lung infections, most frequently caused by Pseudomonas aeruginosa. Exosomes are nanovesicles released by cells that play an essential role in intercellular communication, although their role during bacterial infections is not well understood. In this article, we analyze the alterations in exosomes produced by healthy bronchial epithelial and cystic fibrosis cell lines caused by the interaction with P. aeruginosa. The proteomic study detected alterations in 30% of the species analyzed. In healthy cells, they mainly involve proteins related to the extracellular matrix, cytoskeleton, and various catabolic enzymes. In CF, proteins related to the cytoskeleton and matrix, in addition to the proteasome. These differences could be related to the inflammatory response. A study of miRNAs detected alterations in 18% of the species analyzed. The prediction of their potential biological targets identified 7149 genes, regulated by up to 7 different miRNAs. The identification of their functions showed that they preferentially affected molecules involved in binding and catalytic activities, although with differences between cell types. In conclusion, this study shows differences in exosomes between CF and healthy cells that could be involved in the response to infection.

Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

BET inhibitor nanotherapy halts kidney damage and reduces chronic kidney disease progression after ischemia-reperfusion injury.

Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney-an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.

Utilización de la aplicación Socrative en la asignatura de anatomía patológica del Grado en Medicina / Use of Socrative in the subject of Anatomic Pathology in the Degree of Medicine

INTRODUCCIÓN: Los cambios tecnológicos que se han producido y se están produciendo en estas últimas décadas afectan también al método educativo en el ámbito sanitario. Socrative es un gestor de la participación de los estudiantes en el aula en tiempo real. Permite realizar tests, evaluaciones, actividades, etc., y manejar los datos por el docente. Sujetos y métodos. Se ha utilizado esta aplicación en cinco temas diferentes de la asignatura de anatomía patológica del tercer curso del Grado en Medicina, con una participación de 44 alumnos. Se realizó un análisis estadístico básico y una encuesta de satisfacción del método. RESULTADOS: La encuesta de satisfacción mostró que los alumnos son muy receptivos a este tipo de modalidad docente. La valoración global media sobre la experiencia final en el uso de Socrative fue de 8,6 puntos sobre 10. La mayor parte de los alumnos no tenían experiencia previa con este tipo de plataformas de innovación. No obstante, una gran mayoría se mostraron muy receptivos a usarlas como material complementario a las clases. Con respecto al test, la media del porcentaje de aciertos global fue del 79,63%. El tema con más porcentaje de aciertos fue la patología genital masculina (93,17%), y con menor porcentaje de aciertos, patología hepática, biliar y pancreática (66,87%). CONCLUSIÓN: El uso de Socrative fomenta la atención y la asimilación de los conceptos y está muy bien valorada por los alumnos

INTRODUCTION: Technological changes during the last decades has also affected the educational method in the health field. Socrative is a manager of real-time student participation in classrooms. It allows tests, evaluations, activities, etc. and handle the data by the teacher. SUBJECTS AND METHODS: This application has been used in five different themes in the Academic Pathology subject in the third year of Medicine Degree, involving 44 students. A satisfaction survey of the method was done. A basic statistical analysis was performed. RESULTS: Satisfaction survey pointed out that students are very keen to this type of teaching modality. The average overall assessment of the final experience in the use of Socrative was 8.6 points out of 10. Most students have no previous experience with this type of innovation. However, a large majority will be very receptive to using them as complementary material to the classes. With respect to the test, the average of the percentage of global successes was 79.63%. The topic with the highest percentage of successes was male genital pathology (93.17%), while the topic with the lowest percentage of successes was liver, biliary and pancreatic pathology (66.87%). CONCLUSION: The use of Socrative encourages attention, assimilation of concepts and is highly valued by students

Neuronews Universal: el periódico online creado por estudiantes de la asignatura de neuropatología / Neuronews Universal: the online newspaper created by the students of neuropathology's subject

INTRODUCCIÓN: Un periódico es un elemento integrador de la comunicación y, como tal, puede utilizarse en las aulas de todos los niveles educativos. Sujetos y métodos. Con la herramienta en línea paper.li (http://paper.li/) hemos creado un periódico de forma automatizada con contenidos específicos relacionados con la neuropatología y ayudados de las redes sociales, especialmente de Twitter. Todos los alumnos han realizado una encuesta de satisfacción. RESULTADOS: Todos los alumnos de la asignatura de neuropatología de cuarto curso del Grado en Medicina han participa-do en la elaboración del periódico Neuronews Universal y han editado siete números. Los resultados de la encuesta han sido muy satisfactorios, con una valoración global del proyecto por parte de los estudiantes de 8,4 (IC 95%: 7,5-9,3). La parte peor valorada fue la relacionada con la búsqueda y gestión de los artículos a publicar (7,1 puntos sobre 10 posibles), y el ítem con mejor puntuación, el relacionado con la implementación de este tipo de iniciativas en innovación docente para complementar los aspectos teórico-prácticos en otras asignaturas (9,1 puntos sobre 10). CONCLUSIONES: Se ha fomentado la proactividad del estudiante orientado a la creación, por ellos mismos, de un periódico online, Neuronews Universal, con siete números editados y publicados en el curso 2018-2019. Es una experiencia única en el mundo de la docencia de anatomía patológica en general y de neuropatología en particular

INTRODUCTION: A newspaper is an integrating element of communication that can be used in classrooms at all educational levels. Subjects and methods. With paper.li (http://paper.li/) we have created a newspaper in an automated way with specifi c contents related to the neuropathology, using social networks, especially Twitter. All students have completed a satisfaction survey. RESULTS: All the students of the neuropathology subject of the fourth year of Degree in Medicine have edited seven issues of the Neuronews Universal newspaper. The results of the survey have been very satisfactory, with an overall assessment of 8.4 (95% CI: 7.5-9.3). The worst valued part was the relationship with the search and curation of the articles to be published (7.1 points out of 10) and the item with the best score was for the one related to the implementation of this type of initiatives in teaching innovation in other subjects (9.1 points out of 10). CONCLUSIONS: It has been fostered the proactivity of the student oriented to the creation by themselves an online newspaper such as Neuronews Universal, with seven issues edited and published in the 2018-2019 academic year. This fact is an unique experience in the teaching world of pathology in general, but particularly in neuropathogy

Adenomatosis hepática: una causa infrecuente de trasplante hepático / Hepatic adenomatosis: a rare cause of liver transplant

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Estudio de la evolución en la actividad en un Departamento de Anatomía Patológica de un hospital de tercer nivel en la última década (2007-2016) / Study of the evolution in the activity of a Department of Pathology from a third level hospital in the last decade (2007-2016)

Objetivo: Estudiar la evolución de variables de interés de un Departamento de Anatomía Patológica de un hospital de tercer nivel durante la última década. Valorar el impacto del traslado hospitalario en la actividad (año 2014). Material y método: Estudio retrospectivo observacional en el que se analizaron las muestras registradas (biopsias, citologías, PAAF, autopsias, intraoperatorias) así como las técnicas complementarias (IHQ, histoquímica, IF y FISH) y la cartera de servicios, durante la década 2007-2016. Para el análisis estadístico se compararon los quinquenios 2007-2011 y 2012-2016. Resultados: Las siguientes variables han sido estadísticamente significativas: citologías (34055,8±1994,0 vs. 26590,4±2938,3; p=0,002), autopsias (156,2±27,3 vs. 122,0±14,78; p=0,039), inmunohistoquímica (17855,4±3424,2 vs. 28559,2±4734,7; p=0,003), histoquímica (11117,8±2300,9 vs. 6225,0±1330,5; p=0,003) e inmunofluorescencia (610,2±185,3 vs. 1205,4±154,0; p=0,001). Se han identificado correlaciones estadísticas de interés entre las variables. En el año 2014 se observó que las variables de mayor peso específico (biopsias, citologías, IHQ e histoquímica) en la carga asistencial del Departamento mostraron un descenso medio del 12,5%. Se ha identificado un incremento generalizado en el catálogo de muestras disponibles. El número de anticuerpos (78,7%), la histoquímica (38,7%) y FISH (400%) fueron los que mayor aumento mostraron. Conclusión: Se han identificado variaciones relevantes del volumen de actividad, así como en la cartera de servicios, especialmente en las técnicas orientadas a mejorar la precisión diagnóstica (IHQ e IF); y un descenso importante en el número de citologías, autopsias e histoquímica. En el año 2014 se ha observado un descenso de más del 12% en las principales variables del estudio

Objective: To study the evolution of variables of interest in a department of pathology from a third level hospital during the last decade and to evaluate the impact on these of the hospital relocation in 2014. Material and method: Retrospective observational study in which the recorded samples (biopsies, cytology specimens, FNA, autopsies, intraoperative) as well as the complementary techniques (IHC, Histochemistry, IF and FISH) and portfolio of services were analyzed during the years 2007-2016 inclusive. For the statistical analysis, the five-year periods 2007-2011 and 2012-2016 were compared. Results: The following variables were statistically significant: cytology (34055.8±1994.0 vs 26590.4±2938.3, p=0.002), autopsies (156.2±27.3 vs 122.0±14.78, p=0.039), immunohistochemistry (17855.4±3424.2 vs 28559.2±4734.7, p=0.003), histochemistry (11117.8±2300.9 vs 6225.0±1330.5, p=0.003) and immunofluorescence (610.2±185.3 vs. 1205.4±154.0, p=0.001). Statistical correlations of interest among variables have been identified. In 2014, it was observed that the variables of greater specific weight (biopsies, cytology, IHQ and histochemistry) in the work load of the Department showed an average decrease of 12.5%. A generalized increase in the panel of available samples has been identified, the largest increase being seen in the number of antibodies (78.7%), histochemistry (38.7%) and FISH (400%). Conclusion: Relevant variations in work volume, as well as the service portfolio, have been identified, especially in the techniques aimed at improving diagnostic accuracy (IHQ and FI), and a significant decrease in the number of cytology specimens, autopsies and histochemistry. In the year 2014 a decrease of more than 12% in the main variables of the study was observed

La demencia del rey Fernando VI y el año sin rey (II) / The dementia of King Ferdinand VI and the year with no king II

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