Cellular and immune mechanisms involved in cetuximab activities and effects. (A) Cetuximab mechanism of action. Schematic model of the main mechanisms of cetuximab efficacy, including immune cells ...contributing to its therapeutic effect. (B) Cetuximab-induced adverse events. Possible cetuximab effects on healthy tissues responsible for skin toxicity (C) Acquired resistance to cetuximab. Main changes induced in the tumor microenvironment associated to acquired resistance to cetuximab. (D) Combined treatment with ICI. Possible synergy between cetuximab and immune checkpoint-inhibitors targeting molecules expressed by tumor cells or by inhibited immune effectors laying in the tumor microenvironment.
EGFR, epidermal growth factor receptor. ADCC, antibody-dependent cell cytotoxicity. S. aureus, Staphylococcus aureus. MDSC, myeloid-derived suppressor cells. Treg, regulatory T cells. RT, radiotherapy.
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•The current use of cetuximab in LA-HNSCC is limited to cisplatin-unfit patients.•Cetuximab-induced rash toxicity has been associated with efficacy in LA-HNSCC.•Cetuximab use in LA-HNSCC could reach better results in a selected population.•Immune activity involved in cetuximab efficacy supports its use with immunotherapy.
Since its introduction, the use of cetuximab in the treatment of head and neck squamous cell carcinoma (HNSCC) has experienced an evolution. Currently, cetuximab associated with radiotherapy is limited to the treatment of patients affected by a locally advanced malignancy and unfit for cisplatin. However, reliable biomarkers of cetuximab efficacy in this cancer setting are still lacking. This review focuses on the mechanisms of action of cetuximab, highlighting, in particular, the consequences of the binding to EGFR, and the pathways involved in the development of adverse events or acquired resistance. Indeed, adverse events, such as skin rash, have been associated with cetuximab efficacy in HNSCC several times. Acquired resistance is associated with microenvironment plasticity, which is, in turn, characterized by an increased immune infiltrate. The better definition of patients eligible for this kind of therapy could improve HNSCC management, possibly proposing a combined treatment with radiotherapy, cetuximab and immune checkpoint inhibitors as recently investigated.
Crowdfunding and micro-donations for funding political campaigns have been extensively studied, especially in the US. However, digital participatory financing in Europe, with a different regulatory ...context and relevant public funding, has been investigated less. This article analyses the effects of an innovative and digital-native electoral campaign financing tool: the microcredit. Microcredits consist of small "civil loans" that a political party requests from sympathizers to finance the party's electoral campaign. Based on the case study of the Spanish party Podemos - the first one to implement it - for the period of 2015-2021, we use official data and party documents to explore the consequences of microcredit. We argue, first, that microcredits (and party financing) should be considered another way to differentiate challenger parties from traditional ones. Second, there is a link between the number and amount of microcredits and the political context, not limited to good electoral expectations but also to the polarized political context. Third, microcredits change the structure of campaign funding. Finally, we point out a regulation problem that may deter other parties from adopting this mechanism and present different legal problems (monitoring, data protection, or potential corruption), showing the regulatory issues for adapting to the digitalization of politics.
Consistent climate data and reliable sizing methods are fundamental for designing Technical Building Systems. This paper addresses both these aspects with reference to the Italian context analyzing ...108 different locations. Regarding the climate data, a quality analysis through the application of rules and filters was performed on the locations. The results showed good data quality, with most sites having high percentages of usable material, although highlighting recursive criticalities in the detection of humidity and wind speed parameters. Regarding the sizing methods, a sensitivity analysis was carried on for the European standard EN ISO 15927-2 to evaluate its performances in selecting the Cooling Design Days in the 108 locations. The analysis highlighted great differences in terms of chosen Design Days when using different climatic parameters, showing at the same time a negligible influence of the wind speed on the selection process. Furthermore, a sizing process for a test building applied to the 108 locations was carried on by using the Cooling Design Days. The results highlighted that the Design Days obtained through the EN ISO method often give counterintuitive sizing outputs, even obtaining higher required powers for lower risk levels, the opposite of how it should be. This implies that a designer should be very careful in evaluating which parameters to use in the Design Day selection and if the output sizing powers obtained through them are reliable for its particular sizing process.
In the Standard Model the electroweak coupling of the gauge bosons to leptons is independent of the lepton flavour. Semileptonic and rare decays of b quarks provide an ideal laboratory to test this ...property. Any violation of Lepton Flavour Universality would be a clear sign of physics beyond the Standard Model. In this work a review of the Lepton Flavour Universality tests performed using data collected by the LHCb experiment in 2011 and 2012 at a centre of mass energy of 7 and 8 TeV is presented.
Durante la última legislatura europea se han multiplicado los debates sobre el futuro de Europa, intensificados por las policrisis experimentadas por la UE. Este artículo compara las propuestas de ...las dos principales instituciones europeas, Comisión y Parlamento (PE), y las posiciones de los veinte jefes de Estado y/o Gobierno que participaron en los debates sobre el futuro de Europa organizados por el PE en el período 2017-2019. Este análisis del contenido permite observar cuáles son las diversas posiciones, similitudes, diferencias y el potencial de politización de la integración europea. Se destaca la importancia de centrarse tanto en el régimen de políticas como el modelo de gobernanza y su relación. Los resultados muestran profundas diferencias sobre cómo se concibe el futuro de Europa y cómo existen prioridades más centradas en la legitimidad de input mientras que otras enfatizan la legitimidad de output. Las diversas posiciones muestran la relevancia de ciertos debates —Europa de varias velocidades, diferenciación, homogeneidad, unificación política, la lógica instrumental— y su relación con diversas teorías e hipótesis sobre el futuro de la integración. Adicionalmente, este análisis permite comprender cómo puede desarrollarse la Conferencia sobre el Futuro de Europa que la nueva Comisión está organizando durante el período 2020-2022.
Entre los diferentes cambios que han tenido lugar en el sistema de partidos español el presente artículo se centra en el cese de la hegemonía de un único partido en el ámbito de la derecha. Se ...necesita de un análisis detenido de la aparición de un nuevo bloque de derecha tripartito que conforman un partido histórico (PP) y dos nuevos partidos (Ciudadanos y Vox) siendo este último de derecha radical.
Mediante diversas fuentes de evidencia empírica que incluyen datos de opinión pública, de expertos y análisis de programas electorales se aborda la orientación, perfil ideológico y posiciones en materia territorial de los tres partidos de derecha que cuentan con proyección en toda España.
El trabajo pone de manifiesto la existencia de espacios de proximidad entre los tres partidos que los contraponen con las orientaciones de partidos de otros bloques. A la vez, el análisis pone de relieve los matices en las posiciones entre PP, VOX y Ciudadanos que permiten la existencia de competición en el interior del bloque de derecha por conquistar espacios y conseguir electores.
This paper investigates the influence of a stochastic variation of both energy and economic parameters in an optimization loop applied to a refurbished social housing building. Usually, energy and ...economic optimization procedures rely on the results of an underlying numerical deterministic model which influences both energy gains and economic figures. However, an analyst must always face the random variation of input and parameter data. The unknown data can represent poor initial information or data that can change in a long time; this is the case of fuel cost and economic indexes in particular. This paper deals with both problems for building refurbishment optimization, the former related to the initial state of a building, and the latter to the energy cost variability. Reliability analysis considers a stochastic variation of parameters looking for solutions that incorporate a risk level; in this case, it deals with optimization objectives related to different impacts on economic, environmental and health aspects. The considered building represents a social house, and the energy reduction measures involve the application of internal insulation layers to the walls and the replacement of existing windows with more efficient ones.
Persistent infection with high-risk Human Papilloma Virus (HPV) leads to the development of several tumors, including cervical, oropharyngeal, and anogenital squamous cell carcinoma. In the last ...years, the use of high-throughput sequencing technologies has revealed a number of non-coding RNA (ncRNAs), distinct from micro RNAs (miRNAs), that are deregulated in HPV-driven cancers, thus suggesting that HPV infection may affect their expression. However, since the knowledge of ncRNAs is still limited, a better understanding of ncRNAs biology, biogenesis, and function may be challenging for improving the diagnosis of HPV infection or progression, and for monitoring the response to therapy of patients affected by HPV-driven tumors. In addition, to establish a ncRNAs expression profile may be instrumental for developing more effective therapeutic strategies for the treatment of HPV-associated lesions and cancers. Therefore, this review will address novel classes of ncRNAs that have recently started to draw increasing attention in HPV-driven tumors, with a particular focus on ncRNAs that have been identified as a direct target of HPV oncoproteins.
Medical schools are developing global health programmes, and medical students are requesting global health training and creating opportunities when these are not provided by medical schools. This ...article described the Wolisso Project (WP), a medical experience on clinical electives in Sub-Saharan Africa, driven by a collaboration between a student organisation and a Nongovernmental Organization (NGO). Preclinical medical students spent 4 weeks as part of a multidisciplinary medical team in Africa. Post-elective questionnaires were administered to all subjects who participated in the project. Of all, 141 students responded to the questionnaire. The participants came from 30 Italian universities. The main difficulties reported are due to the lack of resources for the exercise of the medical activity, and difficulties related to language and communication. The African experience had a positive impact on the progress of the studies upon return, with an increase in determination and motivation. The experience had also positive influences on the future professional choices and carriers. The experience seems to contribute not only to the professional growth, but also to the personal development. A key factor in the positive outcomes of this experience is it being implemented by an NGO with long-term working relationships with the African populations. Another is that the project is carried out in health facilities where NGO staff have been working for a long time. These factors reduce the potential risks connected with this type of experience. They ensure a satisfactory level of supervision, the lack of which has been a serious problem in many similar experiences. A well-structured, mentored experience in international health can have a positive impact on preclinical students’ attitudes, including their compassion, volunteerism, and interest in serving underserved populations. Only a small number of Italian universities facilitate pre-graduate medical elective experiences in LMICs. The WP seems to be attempting to compensate for the lack of international experience in LMICs offered by universities. Italian medical schools should incorporate changes in their curricula to train socially responsible physicians.
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