ABSTRACT
BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.
Subject(s)
Lung Neoplasms , Neuroendocrine Tumors , Humans , Lung Neoplasms/pathology , Lung Neoplasms/classification , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/classification , Female , Ki-67 Antigen/metabolism , Male , Biomarkers, Tumor/metabolism , Middle Aged , World Health Organization , Histones/metabolism , Aged , Prognosis , Deep LearningABSTRACT
The tumor suppressor p53 protein is activated by genotoxic stress and regulates genes involved in senescence, apoptosis and cell-cycle arrest. Nine p53 isoforms have been described that may modulate suppressive functions of the canonical p53 protein. Among them, Delta133p53 lacks the 132 proximal residues and has been shown to modulate p53-induced apoptosis and cell-cycle arrest. Delta133p53 is expressed from a specific mRNA, p53I4, driven by an alternative promoter P2 located between intron 1 and exon 5 of TP53 gene. Here, we report that the P2 promoter is regulated in a p53-dependent manner. Delta133p53 expression is increased in response to DNA damage by doxorubicin in p53 wild-type cell lines, but not in p53-mutated cells. Chromatin immunoprecipitation and luciferase assays using P2 promoter deletion constructs indicate that p53 binds functional response elements located within the P2 promoter. We also show that Delta133p53 does not bind specifically to p53 consensus DNA sequence in vitro, but competes with wild-type p53 in specific DNA-binding assays. Finally, we report that Delta133p53 counteracts p53-dependent growth suppression in clonogenic assays. These observations indicate that Delta133p53 is a novel target of p53 that may participate in a negative feedback loop controlling p53 function.
Subject(s)
Genes, p53 , Promoter Regions, Genetic , Response Elements/physiology , Tumor Suppressor Protein p53/physiology , Cell Line, Tumor , DNA/metabolism , DNA Damage , Humans , Protein Isoforms , Transcription, Genetic , Transcriptional Activation , Tumor Suppressor Protein p53/analysisABSTRACT
El mercurio no tiene ninguna función fisiológica en el cuerpo humano y está ampliamente distribuido en la naturaleza. Puede ser tóxico por inhalación, ingestión o contacto. El timerosal es una sal orgánica de mercurio usada como antiséptico y antifúngico desde 1928. Desde finales de la década de 1990, el mercurio empezó a ser retirado de los medicamentos y materiales de uso clínico. Se ha hecho un esfuerzo para eliminar el timerosal de las vacunas siguiendo el principio de precaución, pues no hay evidencias científicas que avalen un daño cerebral atribuible al timerosal. No se ha encontrado ninguna asociación entre su uso y el riesgo de desarrollar autismo. Actualmente, en los países de nuestro entorno solo se usa en muy pocas vacunas en envases multidosis, y todas las incluidas en los calendarios oficiales españoles, así como las de uso común en niños fuera de ellos (neumocócicas y rotavirus), están libres de timerosal. No obstante, la OMS ha reiterado que las vacunas que contienen timerosal pueden seguir utilizándose, especialmente en el Tercer Mundo donde, por necesidades logísticas, se utilizan envases multidosis, pues el riesgo real de enfermedad y muerte por enfermedades vacunables en quienes no se vacunan es muy superior al riesgo hipotético derivado del su uso. Como con cualquier otro medicamento, pueden presentarse reacciones de hipersensibilidad al timerosal, generalmente locales. Los esfuerzos investigadores sobre determinados problemas neurológicos como el autismo deberían encaminarse a buscar sus verdaderas causas en lugar de a sembrar dudas sobre la seguridad de las vacunas (AU)
Mercury has no physiological function in the human body and is widely distributed in nature. It may be toxic by inhalation, ingestion or contact. Thimerosal is an organic salt of mercury used as an antiseptic and antifungal since 1928. Since the late 1990s, mercury began to be withdrawn from drugs and materials for clinical use. An effort has been made to remove thimerosal from vaccines as a precautionary principle, since there is no scientific evidence to substantiate that brain damage can be attributable to thimerosal. No connection has been found between its use and the risk of developing autism. In the Western World it is only currently used in very few vaccines in multidose containers, whereas all those included in Spanish Schedules, as well as in those commonly used for children outside them (pneumococcal and rotavirus), are free from thimerosal. However, the WHO has reiterated that vaccines containing thimerosal may still be used, especially in the Third World where, for logistical needs, multidose containers are used, as the real risk of illness and death by vaccianble diseases in those who do not get vaccinated is much higher than the hypothetical risk arising from their use. As with any medicine, there may be hypersensitivity reactions to thimerosal, usually local. Research efforts should be directed towards finding the real causes of neurological problems like autism instead of throwing doubts about the safety of vaccines (AU)
Subject(s)
Humans , Male , Female , Child , Thimerosal/adverse effects , Thimerosal/toxicity , Vaccines/administration & dosage , Vaccines/adverse effects , Mercury/adverse effects , Methylmercury Compounds/adverse effects , Methylmercury Compounds , Autistic Disorder/chemically induced , Autistic Disorder/complications , Thimerosal/immunology , Mercury/toxicity , Methylmercury Compounds/administration & dosage , Vaccines , Vaccines/toxicity , Neuropsychology/trendsABSTRACT
Se expone la trayectoria de la vacuna conjugada frente a Neisseria meningitidis serogrupo Cen España desde su introducción en el calendario, sus pautas de utilización y el seguimiento desu efectividad clínica. Se comenta la posibilidad de reducir el número de dosis en la pauta deprimovacunación en los lactantes, la conveniencia de una dosis de recuerdo en el segundo añode vida, en vista de la rápida disminución de la efectividad en los que recibieron la vacuna siendolactantes, las posibles actuaciones sobre la población adolescente y algunas estrategias devacunación futuras
Concise review regarding the evolution of the polysaccharide-protein conjugate vaccineagainst serogroup C Neisseria meningitidis since its introduction in the immunization schedulein Spain, its administration guidelines and the follow up of its clinical effectiveness. Theauthor considers the possibility of reducing the number of vaccine doses for infants, the advisabilityof a booster shot in the second year of life, due to its reduced effectiveness in thosevaccinated as infants, possible interventions in the adolescent population and some immunizationschedules for the future