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Interplay between cancer cells, fibroblasts, immune cells, and resistance to PD-1/PD-L1 inhibition in breast cancer
No full textAlthough the dual anti-HER2 blockade with trastuzumab and pertuzumab monoclonal antibodies has improved the outcome of patients with HER2+ breast cancer, a significant number of patients relapse. Additional strategies for improving its clinical efficacy are needed. Combination of anti-HER2 treatment and anti-PD-1/PD-L1 immunotherapy has been tested, but with poor results. We hypothesized that IFN--driven resistance to immune responses and/or the inefficient access of NK and T cells to the tumor site could
promote anti-HER2 and anti-PD-1/PD-L1 therapy resistance. We observed that IFN- could potentiate the effects of anti-HER2 agents in some HER2+ cancer models, whereas other models were resistant to IFN--induced apoptosis, suggesting that some breast cancers may be intrinsically resistant to PD-(L)1 inhibitors.
On the other hand, the inhibition of SDF-1/CXCR4 axis in a syngeneic mouse model of triple negative breast cancer modulates the immune cell profile in the tumor microenvironment, allowing the cytotoxic immune cells to infiltrate the tumor. Given SDF-1 expression in HER2+ breast cancer fibroblasts, it is reasonable to expect that neutralizing this axis to optimize the immune effects of anti-HER2/anti-PD-(L)1 therapy
in HER2+ breast cancer may be worth investigating. Taking all the data together, it is reasonable to suggest the need for a more individualized approach toward combining PD-(L)1/anti-HER2 therapy, as the mechanism of resistance may reside in the tumor cell itself or in the tumor microenvironment, depending on the
ecology of each tumor.Aunque el bloqueo dual anti-HER2 con los anticuerpos monoclonales trastuzumab y pertuzumab ha mejorado el pronóstico de las pacientes con cáncer de mama HER2+, un número significativo de pacientes recae. Se necesitan estrategias adicionales para mejorar la eficacia clínica de esta terapia. La combinación del tratamiento anti-HER2 con la inmunoterapia anti-PD-1/PD-L1 ha sido probada, aunque ha tenido unos resultados pobres. Nuestra hipótesis es que la resistencia a las respuestas inmunitarias impulsada por el IFN- y/o el acceso ineficaz de las células NK y T a la zona tumoral podrían promover la resistencia a la combinación de la terapia anti-HER2 y anti-PD-1/PD-L1. Hemos visto que el IFN- puede potenciar los efectos de los agentes anti-HER2 en algunos modelos de cáncer HER2+, mientras que otros modelos son resistentes a la apoptosis inducida por el IFN-, lo que sugiere que algunos cánceres de mama puedan ser intrínsecamente resistentes a los inhibidores de PD-(L)1. Por otro lado, la inhibición del eje SDF-1/CXCR4 en un modelo de ratón singénico de
cáncer de mama triple negativo modula el perfil de células inmunitarias en el microambiente tumoral, permitiendo que las células inmunitarias citotóxicas se infiltren en el tumor. Dada la expresión de SDF-1 en fibroblastos de cáncer de mama HER2+, es razonable pensar que merece la pena investigar la neutralización de este eje para optimizar los efectos inmunitarios de la terapia anti-HER2/anti-PD-(L)1 en el cáncer de mama HER2+. Teniendo en cuenta todos los resultados, es razonable sugerir la necesidad de un enfoque más individualizado hacia la combinación de la terapia PD-(L)1/anti-HER2, ya que el mecanismo de resistencia puede residir en la propia célula tumoral o en el microambiente tumoral, dependiendo de la ecología de cada tumor.Programa de doctorat en Biomedicin
Blame shifting in autocracies following large-scale disasters: evidence from Turkey
No full textData de publicació electrònica: 08-09-2025Large-scale disasters, particularly when handled poorly, often spark popular outrage and threaten an autocrat's hold on power. Autocrats frequently employ blame-shifting strategies to redirect public anger and weather these storms. We examine whether blame shifting after a large-scale disaster helps or hurts an autocrat's popularity through a mixed-methods research design in the electoral autocracy of Turkey in April-July 2023, following the February 2023 earthquakes. An online survey experiment (n = 3,839) identifies the effects of blaming the aftermath of the earthquakes on the opposition, a force majeure, private construction companies, or a government minister, while focus groups explore the mechanisms behind these effects. We find that blaming the opposition or a force majeure leads to a backlash, especially among those more able to critically evaluate information. Focus groups reveal that these backlash effects are driven by voters' dismay at electoral opportunism and the incumbent's polarizing language following a large-scale disaster
OccRF-Health study: occupational exposure of workers to RF-EMF
No full textRadiofrequency electromagnetic fields (RF-EMF) exposure,
ubiquitous in our environment due to the rise in mobile phones and
wireless technology, has grown significantly in the last 30 years. This
exposure is generally low in everyday environments, but certain
occupations, like those in the medical sector or telecommunications,
involve high-intensity RF-EMF exposure scenarios. Although
studies on RF-EMF's health effects, particularly its link to brain
tumors, are inconclusive, the International Agency of Research on
Cancer (IARC) classifies it as possibly carcinogenic (Group 2B). The
current limitations in exposure assessment might contribute to these
inconclusive findings. This thesis aims to i) perform full-shift
personal RF-EMF measurements in various occupations, ii) compare
measurements performed to the exposure estimates in the previously
developed INTEROCC RF-JEM iii) explore the link between
occupational RF-EMF exposure and brain tumors in the INTEROCC
study using the RF-JEM.
Personal RF-EMF measurements were carried out on 333 workers
across 46 ISCO88 occupations using body-worn exposimeters. These
measurements revealed that exposures exceeding 1% of the
International Commission on Non-Ionizing Radiation Protection
(ICNIRP) 1998 occupational standards were uncommon and
typically of short duration, with exposure levels surpassing ICNIRP
standards being confined to specific occupations and generally
lasting only a few seconds. This data was used to conduct a
comparison of estimated exposure profiles with the INTEROCC RF-
JEM. Results showed poor agreement overall, likely due to the
different exposure assessment methods used to create the exposure
estimates. In the context of the INTEROCC case-control study, the
use of the RF-JEM did not find clear positive associations overall
across the range of exposure metrics and time periods evaluated.
Only marginally increased Odds Ratios (ORs) for gliomas in both
electric (E) and magnetic (H) fields, particularly in the 1 to 4 years
exposure period prior to diagnosis were found.
The findings of this thesis suggest that accurately depicting personal
occupational exposure to RF-EMF in various occupations is complex
and challenging, and still limited by several factors. Further personal
measurements of occupational RF-EMF exposure are necessary,
particularly in highly-exposed occupations. This would enhance our
understanding of the reliability of these exposure assessments and
their implications for epidemiological findings related to brain tumor
risks.La exposición a los campos electromagnéticos de radiofrecuencia
(RF-EMF), ubicua en nuestro entorno debido al aumento de los
teléfonos móviles y la tecnología inalámbrica, ha crecido
significativamente en los últimos 30 años. Esta exposición es
generalmente baja en entornos cotidianos, pero ciertas ocupaciones,
como las del sector médico o las telecomunicaciones, implican
escenarios de exposición a RF-EMF de alta intensidad. Aunque los
estudios sobre los efectos en la salud de los RF-EMF, particularmente
su vínculo con los tumores cerebrales, son inconclusos, la Agencia
Internacional de Investigación sobre el Cáncer (IARC) lo clasifica
como posiblemente carcinogénico (Grupo 2B). Las limitaciones
actuales en la evaluación de la exposición podrían contribuir a estos
hallazgos inconclusos. Esta tesis tiene como objetivo i) realizar
mediciones personales de RF-EMF durante toda la jornada laboral en
varias ocupaciones, ii) comparar las mediciones realizadas con las
estimaciones de exposición en el INTEROCC RF-JEM previamente
desarrollado, iii) explorar el vínculo entre la exposición ocupacional
a RF-EMF y los tumores cerebrales en el estudio INTEROCC
utilizando el RF-JEM.
Las mediciones personales de RF-EMF se llevaron a cabo en 333
trabajadores en 46 ocupaciones ISCO88 usando exposímetros
portátiles. Estas mediciones revelaron que las exposiciones que
superan el 1% de los estándares ocupacionales de la Comisión
Internacional de Protección contra la Radiación No Ionizante
(ICNIRP) de 1998 eran poco comunes y típicamente de corta
duración, con niveles de exposición que superaban los estándares de
la ICNIRP limitados a ocupaciones específicas y que generalmente
duraban solo unos segundos. Estos datos se utilizaron para realizar
una comparación de los perfiles de exposición estimados con el
INTEROCC RF-JEM. Los resultados mostraron un acuerdo
generalmente pobre, probablemente debido a los diferentes métodos
de evaluación de la exposición utilizados para crear las estimaciones
de exposición. En el contexto del estudio de caso-control
INTEROCC, el uso del RF-JEM no encontró asociaciones positivas
claras en general en toda la gama de métricas de exposición y
períodos de tiempo evaluados. Solo se encontraron Odds Ratios (OR)
marginalmente aumentados para gliomas en campos eléctricos (E) y
magnéticos (H), particularmente en el período de exposición de 1 a 4
años antes del diagnóstico.
Los hallazgos de esta tesis sugieren que representar con precisión la
exposición ocupacional personal a RF-EMF en varias ocupaciones es
complejo y desafiante, y todavía está limitado por varios factores. Se
necesitan más mediciones personales de la exposición ocupacional a
RF-EMF, particularmente en ocupaciones altamente expuestas. Esto
mejoraría nuestra comprensión de la fiabilidad de estas evaluaciones
de exposición y sus implicaciones para los hallazgos epidemiológicos
relacionados con los riesgos de tumores cerebrales.Programa de Doctorat en Biomedicin
Archaea methanogens are associated with cognitive performance through the shaping of gut microbiota, butyrate and histidine metabolism
No full textThe relationship between bacteria, cognitive function and obesity is well established, yet the role of archaeal species remains underexplored. We used shotgun metagenomics and neuropsychological tests to identify microbial species associated with cognition in a discovery cohort (IRONMET, n = 125). Interestingly, methanogen archaeas exhibited the strongest positive associations with cognition, particularly Methanobrevibacter smithii (M. smithii). Stratifying individuals by median-centered log ratios (CLR) of M. smithii (low and high M. smithii groups: LMs and HMs) revealed that HMs exhibited better cognition and distinct gut bacterial profiles (PERMANOVA p = 0.001), characterized by increased levels of Verrucomicrobia, Synergistetes and Lentisphaerae species and reduced levels of Bacteroidetes and Proteobacteria. Several of these species were linked to the cognitive test scores. These findings were replicated in a large-scale validation cohort (Aging Imageomics, n = 942). Functional analyses revealed an enrichment of energy, butyrate, and bile acid metabolism in HMs in both cohorts. Global plasma metabolomics by CIL LC-MS in IRONMET identified an enrichment of methylhistidine, phenylacetate, alpha-linolenic and linoleic acid, and secondary bile acid metabolism associated with increased levels of 3-methylhistidine, phenylacetylgluamine, adrenic acid, and isolithocholic acid in the HMs group. Phenylacetate and linoleic acid metabolism also emerged in the Aging Imageomics cohort performing untargeted HPLC-ESI-MS/MS metabolic profiling, while a targeted bile acid profiling identified again isolithocholic acid as one of the most significant bile acid increased in the HMs. 3-Methylhistidine levels were also associated with intense physical activity in a second validation cohort (IRONMET-CGM, n = 116). Finally, FMT from HMs donors improved cognitive flexibility, reduced weight, and altered SCFAs, histidine-, linoleic acid- and phenylalanine-related metabolites in the dorsal striatum of recipient mice. M. smithii seems to interact with the bacterial ecosystem affecting butyrate, histidine, phenylalanine, and linoleic acid metabolism with a positive impact on cognition, constituting a promising therapeutic target to enhance cognitive performance, especially in subjects with obesity.(ISCIII, Madrid, Spain) through the projects PI15/01934, PI18/01022 and PI21/01361 to J.M.F-R and the project PI20/01090 and PI23/00575 (co-funded by the European Union under the European Regional Development Fund (FEDER) “A way to make Europe”) to J.M-P, the project CNS2023-144218 funded by MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR to J.M-P, and (2021 SGR 01263). This work has also been co-financed by the Spanish Ministry of Science, Innovation and Universities with funds from the European Union NextGenerationEU, from the Recovery, Transformation and Resilience Plan (PRTR-C17.I1) and from the Autonomous Community of Catalonia within the framework of the Biotechnology Plan Applied to Health through the project PPCC-ADGUT to J.M.-P. J.M-P and A.C.N are funded by (Madrid, Spain) through the Miguel Servet Program CP18/00009 and CP24/00033 (co-funded by the European Union under the European Social Fund “Investing in your future”), respectively. A.F. is funded by Girona Biomedical Research Institute (Girona, Spain) through the Horizon 2020 Framework Programme of the European Union under the Marie Skłodowska-Curie Innovative Training Network grant agreement No 859890. This study was conducted using samples/data from the Aging Imageomics Study, supported by the through the Strategic Plan for Health Research and Innovation (PERIS) 2016–2020 (SLT002/16/00250). We want to particularly acknowledge the participants, to the IDIBGI Horizontal Aging Program and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), integrated in the Platform ISCIII Biomodels and Biobanks, for their collaboration. JRS is supported by the NIHR Southampton Biomedical Research Centre, and the Biotechnology and Biological Sciences Research Council (BB/W00139X/1)
The incorporation of international human rights norms into the Spanish constitutional system: the apertus clause of article 10.2 of the Spanish constitution
No full textTreball de Fi de Grau en Dret. Curs 2024-2025Tutor: Jorge Ernesto Roa RoaArticle 10.2 of the Spanish Constitution is the key instrument for the incorporation of fundamental rights and freedoms into the Spanish constitutional system in accordance with the Universal Declaration of Human Rights and the international treaties and agreements ratified by Spain. Through the aforementioned apertus clause, the Spanish Constitutional Court carries out its jurisprudential interpretation in line with the international human rights system, guaranteeing legal certainty and the protection of rights and freedoms. In this context, the objective of this paper is to determine and examine the implications of the apertus clause, complemented by the research into the most recent jurisprudence of the Constitutional Court on the matter. Therefore, it is sought to determine how constitutional jurisprudence has interpreted and applied Art. 10.2 of the Constitution. To do so, first , the theoretical scheme will delve into the concept, role and field of application of Art.10.2. Subsequently, in a practical framework it will carry out an analysis of the most recent , and relevant jurisprudence of the Constitutional Court focusing on the jurisprudential debates on the incorporated rights and the definition of the article limits. Finally, it will be studied the incorporation of the jurisprudence in human rights issues, of the European Court of Human Rights and the Court of Justice of the European Union.L’article 10.2 de la Constitució espanyola és l’instrument clau per la incorporació dels drets i llibertats fonamentals en el sistema constitucional espanyol de conformitat amb la Declaració Universal de Drets Humans i amb els tractats internacionals i acords ratificats per Espanya. Per mitjà de la citada clàusula apertus, el Tribunal Constitucional en realitza la interpretació jurisprudencial en línia amb el sistema internacional de drets humans garantint -ne la seguretat jurídica i la protecció dels drets i llibertats. En aquest context, l’objectiu del present treball és determinar i examinar les implicacions que té la clàusula apertus, complementant -ho amb la recerca de la jurisprudència més recent del Tribunal Constitucional en la matèria. Es busca , per tant, determinar de quina forma la jurisprudència constitucional ha interpretat i aplicat l’art. 10.2 de la Constitució. Per fer -ho, primerament s’ha realitzat un estudi teòric al voltant del concepte, rol i àmbit d’aplicació de l’art. 10.2 de la Constitució. Seguidament, en un marc pràctic s’ha analitzat la jurisprudència més recent i rellevant del Tribunal Constitucional centrant -nos en els dos principals debats jurisprudencials que són els drets incorporats i la definició dels límits de l’art. 10.2. Finalment, s’estudia la incorporació de la jurisprudència en assumptes de drets humans del Tribunal Europeu de Drets Humans i del Tribunal de Justícia de la Unió Europea
The impact of amino acid insertions and deletions on protein stability and function
No full textAmino acid insertions and deletions (indels) are common mutational
events but there is limited information about their effects on protein
stability and function. Whereas substitutions alter amino acid side
chains, indels are ‘backbone mutations’ that modify protein length
with potentially severe and difficult-to-predict outcomes. To address
the sparsity of data, we quantified indel effects on the in vivo
abundance of diverse protein domains using a deep-sequencing-
based protein fragment complementation assay. We use this data,
together with an existing large-scale indel mutagenesis dataset on
in vitro protein stability, to examine indel tolerance across protein
domains and secondary structures, comparing how patterns of indel
tolerance differ from those of substitutions. Additionally, our analysis
shows that current computational methods poorly predict indel
effects. To address this, we present INDELi, a series of models that
integrate experimental or predicted substitution effects with
secondary structure information to provide better predictions of indel
effects on both protein stability and pathogenicity. Lastly, we explore
the impact of indels on protein-protein interactions, showing that
while frequently detrimental to protein binding, 1aa insertions can
also act as an important class of gain-of-function variants. Using
abundance and binding data, we further quantify allosteric
communication across three protein-protein interactions, revealing
that insertions and deletions can have long-range and allosteric
effects on binding affinity. In summary, our results provide insights
into the impact of indels on protein stability and function, as well as
a method to predict indel tolerance genome-wide.Les insercions i deleccions (indels) són mutacions comunes.
Tanmateix, els seus efectes en l’estabilitat i funció de les proteïnes
estan poc caracteritzats. Mentre que les substitutions alteren les
cadenes laterals dels aminoàcids, els indels afecten directament
l’esquelet proteic modificant la seua longitud, amb conseqüències
severes i difícils de predir per la proteïna. En aquesta tesi doctoral
hem quantificat els efectes dels indels en l’abundància de diversos
dominis de proteïna in vivo, mitjançant assajos de complementació
de fragments de proteïna i seqüenciació massiva. Amb aquestes
dades, juntament amb dades existents dels efectes dels indels en
l’estabilitat de plegament de dominis de proteïna in vitro, hem
analitzat els patrons de tolerància als indels en diverses proteïnes i
elements d’estructura secundària, en comparació amb les
substitucions. Els nostres resultats demostren que els métodes
computacionals actuals de predicció dels efectes de mutacions en
proteïnes tenen un rendiment baix en la predicció d’indels. Per a
resoldre aquest problema, hem desenvolupat INDELi, una sèrie de
models per a la predicció la patogenicitat dels indels i els seus
efectes en l’estabilitat de les proteïnes, a partir de dades d’estructura
secundària i els efectes de les substitucions (mesurats
experimentalment o predits). Finalment, explorem l’impacte dels
indels en interaccions proteïna-proteïna. Malgrat que la majoria
d’indels tenen efectes deleteris, les nostres dades indiquen que les
insercions poden actuar com a variants de guany de funció (gain-of-
function), mitjançant increments d’afinitat. D’una altra banda,
demostrem que els indels poden actuar al·lostèricament, és a dir,
modular l’afinitat de les interaccions proteïna-proteïna a llargues
distàncies. En resum, en aquesta tesi descrivim patrons
fonamentals dels efectes dels indels en l’estabilitat i funció de les
proteïnes, i proporcionem un nou mètode general per a la predicció
de la tolerància als indels al llarg del genoma.Programa de Doctorat en Biomedicin
Testing autonomous vehicles and AI: perspectives and challenges from cybersecurity, transparency, robustness and fairness
No full textThis study aims to comprehensively explore the complexities of integrating Artificial Intelligence (AI) into Autonomous Vehicles (AVs), examining the challenges introduced by AI components and their impact on testing procedures. The research focuses on essential requirements for trustworthy AI, including cybersecurity, transparency, robustness, and fairness. We first analyse the role of AI at the most relevant operational layers of AVs, and discuss the implications of the EU’s AI Act on AVs, highlighting the importance of the concept of a safety component. Using an expert opinion-based methodology, involving an interdisciplinary workshop with 21 academics and a subsequent in-depth analysis by a smaller group of experts, this study provides a state-of-the-art overview of the current landscape of vehicle regulation and standards, including ex-ante, post-hoc, and accident investigation processes, highlighting the need for new testing methodologies for both Advanced Driver Assistance Systems (ADAS) and Automated Driving Systems (ADS). The study also provides a detailed analysis of cybersecurity audits, explainability in AI decision-making processes and protocols for assessing the robustness and ethical behaviour of predictive systems in AVs. The analysis highlights significant challenges and suggests future directions for research and development of AI in AV technology, emphasising the need for multidisciplinary expertise. The study’s conclusions have relevant implications for the development of trustworthy AI systems, vehicle regulations, and the safe deployment of AVs
The midline catheter within the context of home intravenous antibiotic treatment
No full textHome intravenous antibiotic treatment (HIAT) consists of the administration of intravenous antibiotic therapy in the home of the patient. Short peripheral intravenous catheters have long been the first option for antimicrobial therapies. However, these devices are known for their short durability. At present, the midline catheter is one of the median duration devices most commonly used and recommended within the context of HIAT. The objective of this study was to evaluate the occurrence of complications related to midline catheters implanted by a vascular access team in patients undergoing HIAT within the context of home hospitalization. This was a prospective observational study, which consecutively included 77 patients. A total of 92 midline catheters were analyzed. The complications observed were device obstruction (8.7%), infiltration (3.3%), dislodgement (2.2%), and thrombosis (1.1%). Bivariate analysis showed that the pH of the drug and ertapenem administration were associated with catheter obstruction. The authors found a low prevalence of midline catheter-associated complications in patients undergoing HIAT. The use of antireflux needleless connectors should be considered to reduce obstructions. In addition, algorithms that include the variable of type of daily life activity should be developed for deciding the most appropriate catheter for home hospitalized patients receiving HIAT
A single composite index of semantic behavior tracks symptoms of psychosis over time
No full textSemantic variables automatically extracted from spontaneous speech characterize anomalous semantic associations generated by groups with schizophrenia spectrum disorders (SSD). However, with the use of different language models and numerous aspects of semantic associations that could be tracked, the semantic space has become very high-dimensional, challenging both theoretical understanding and practical applications. This study aimed to summarize this space into a single composite semantic index and to test whether it can track diagnosis and symptom profiles over time at an individual level. The index was derived from a principal component analysis (PCA) yielding a linear combination of 117 semantic variables. It was tested in discourse samples of English speakers performing a picture description task, involving a total of 103 individuals with SSD and 36 healthy controls (HC) compared across four time points. Results showed that the index distinguished between SSD and HC groups, identified transitions from acute psychosis to remission and stabilization, predicted the sum of scores of the Thought, Language and Communication (TLC) index as well as subscores, capturing 65 % of the variance in the sum of TLC scores. These findings show that a single indicator meaningfully summarizes a shift in semantic associations in psychosis and tracks symptoms over time, while also pointing to variance unexplained, which is likely covered by other semantic and non-semantic factors.This work was supported by the European Union (GA 101080251 - TRUSTING). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union or the Agency. Neither the European Union nor the granting authority can be held responsible for them. Data collection for the LPoP sample was provided by Winterlight Labs, Inc. SXT is supported by the Brain and Behavior Research Foundation Young Investigator Grant and NIH K23 MH130750
Derecho y humor: cuestiones iusfilosóficas sobre la limitación del humor en España
No full textTreball de Fi de Grau en Dret. Curs 2024-2025Tutor: Josep Joan MoresoEl humor es una expresión humana particular, en ocasiones ambigua y sustentada en aspectos polémicos, y pudiéndose manifestar en expresiones ofensivas o que generen cierto rechazo. Este tipo de expresión, no siempre ha sido tenida en cuenta en las disciplinas jurídicas ni en la aplicación del Derecho. Así pues, en ocasiones se ha usado el Derecho para limitar expresiones humorísticas en el Estado Español, incluso mediante la imposición de penas de prisión en algunos casos. Este trabajo pretende arrojar cierta luz sobre las características del humorismo, los debates en torno a la limitación de la ofensa, proponer algunos enfoques deónticos ante casos difíciles enmarcados en el conflicto de la libertad de expresión, en su vertiente humorística, con otros derechos y analizar críticamente algunos casos recientes, todo desde una perspectiva eclética, combinando aspectos descriptivos y normativos, así como distintas fuentes filosóficas y jurídicas, en defensa de la conveniencia del humor dentro del derecho a la libertad de expresión.Humour constitutes a distinct form of human expression, often marked by ambiguity and rooted in controversial elements, that may it manifest through expressions that can be perceived as offensive or that generate some rejection. This kind of expression have not always been not consistently addressed within legal scholarship or considered in the application of the law. In the Spanish State, Law have, at times, been used to restrict humorous expression, including the imposition of prison penalties in certain cases. This paper seeks to elucidate the defining features of humour, to examine the debates concerning the limitations of the offense, to propose deontic approaches applied to hard cases in which free speech, in its humorous manifestation, conflicts with other rights and to offer a critical analysis of some recent cases from an eclectic perspective that integrates both descriptive and normative dimensions, drawing on diverse philosophical and legal sources, to advocate for the recognition of humour as a legitimate and protected dimension of the right to free speech