Development and characterization of an immunotherapeutic platform based on oncolytic Herpes simplex virus and aCTLA-4 antibodies

In the last decade, immunotherapy has emerged as a promising approach to treat cancer. Although encouraging results have been obtained with monotherapy treatments, a large percentage of patients still do not respond, opening therapeutic options to combination of immunotherapeutics (i.e., oncolytic viruses and mAbs targeting immune checkpoints). Unfortunately, despite combination therapies emerged as a valid option thanks to synergistic efficacy, the occurrence of systemic immune-related adverse events (irAEs) often leads to treatment interruption. The purpose of my thesis was to implement a platform of immunotherapeutics based on oncolytic HSV (oHSV) encoding vectored immunomodulators for local cancer treatment. Interleukin-12 and αCTLA-4 antibody were identified as promising payloads, to be encoded within oHSV genome. The efficacy of these oHSVs was evaluated in in vivo mouse model showing significant improvement in antitumor efficacy compared to oncolytics devoid of the selected immunotherapeutic cargoes. As viral vectored αCTLA-4 antibody resulted in significant improvement of antitumor efficacy, to facilitate preclinical to clinical translation, I isolated human/murine cross-reactive αCTLA-4 antibodies through a high throughput screening of a phage display library of scFvs by Next Generation Sequencing. Additional work will explore the potential ability of the THV_CTLA4 to reduce irAEs occurrence thanks to the antibody confined expression within the TME

Slow food na Itália e no Brasil : história, projetos e processos de valorização dos recursos locais

Tese (doutorado)—Universidade de Brasília, Centro de Desenvolvimento Sustentável, 2016.O movimento SlowFood, após mais de 25 anos do surgimento, atua hoje em nível internacional, promovendo sistemas de produção e comercialização de alimentos que visam a sustentabilidade ambiental e social, em prol de produtos típicos e de pequenos produtores. No Brasil, o SlowFood vivencia uma história peculiar e alcança uma difusão notável. Este trabalho tem por objetivos (1) a reconstrução e interpretação históricas do surgimento e da difusão do movimento SlowFood na Itália e no Brasil; (2) o estudo da aplicação prática dos princípios pregados pelo movimento, seu papel e sua contribuição em projetos de valorização de produções alimentícias visando o desenvolvimento local (projetos Fortaleza); (3) a identificação e análise dos fatores socioculturais, institucionais e históricos que favorecem ou obstam a evolução exitosa de projetos de desenvolvimento embasados na valorização de recursos e do capital social territoriais. A pesquisa histórica sobre origem e evolução do movimento nos dois países está baseada em fontes bibliográficas e em fontes orais primárias, por meio de entrevistas com testemunhas-chave. A análise dos projetos foi realizada a partir da seleção de oito estudos de caso (quatro projetos na Itália, quatro no Brasil), por meio de visitas em campo, entrevistas, material fotográfico e fontes escritas. Isto foi alcançado por meio de levantamento de dados quantitativos e qualitativos sobre a história e o andamento dos projetos e de histórias de vida dos atores envolvidos. Entre os resultados principais, destaca-se que: (a) a conscientização e a preocupação com os aspectos sociais, políticos e ambientais relativos ao alimento, a seus processos produtivos e à sua procedência, por parte do público consumidor no Brasil e na Itália, refletem a conjuntura histórica e econômica peculiar que cada um dos dois países atravessa, mas, apesar de diferenças estruturais e culturais substanciais, existem sinais de aproximação; (b) no Brasil, desde o princípio, a atuação do movimento SlowFood toma o caminho da parceria governamental oficial e da gestão vertical, com consequências específicas sobre a configuração e atuação do movimento; (c) no âmbito dos projetos locais, o SlowFood funciona como agente e catalisador de percursos de desenvolvimento territorial apenas em contextos onde sua intervenção é acessória e integradora, quando as redes e as atitudes socioculturais idôneas à valorização dos recursos locais preexistem e independem da atuação do SlowFood; (d) existem conjuntos de fatores de diversas naturezas que propiciam ou dificultam o bom andamento dos projetos, os quais estão estritamente ligados à presença/ausência de capacitação e cultura cívica. Com base nisso, foi possível concluir que o SlowFood, no Brasil, achou âmbitos de atuação apropriados, dando vida a formas autóctones do movimento; que existem alguns tópicos socioculturais transversais interligando o desdobramento dos projetos realizados na Itália e no Brasil e em suas diferentes regiões; que, em relação a isso, não existe pré-determinação de tipo cultural ou institucional, mas sim existem variáveis históricas influentes e, ao mesmo tempo, espaço para a mudança. E, ainda, que os maiores e mais ricos repositórios de capital social primordial são representados por relações da mesma tipologia daquelas que constituem os obstáculos principais para a realização de boas práticas e da comunidade cívica.The Slow Food movement, since its creation more than 25 years ago, currently operates internationally, by promoting social and environmental sustainable systems of food production and food marketing and by promoting typical products and small producers. In Brazil, the Slow Food movement experiences a peculiar history and achieves a remarkable diffusion. This work aims to: (1) make a historical interpretation of the origin and diffusion of the Slow Food movement in Italy and Brazil; (2) study the implementation of the principles stated by the movement, its role and contribution in the enhancement of the projects of food production for the local development (Presidia projects); (3) identify and analyse the socio-cultural, institutional and historical factors that might support or hinder the successful evolution of the local resource appreciation and of the territorial capital based on developing projects. The historical research on the origin and the evolution of the movement in the two countries is based on literature sources and primary oral sources, by interviewing key witnesses. The analysis of the project was achieved through the selection of eight case studies (four projects in Italy and four in Brazil), through field work, interviews, photographic material and written sources. This was achieved by collecting qualitative and quantitative data on the project history and progress, also through the collection of the life stories of those involved. Among the main findings, it is possible to emphasize: (a) that awareness and concern of the Italian and Brazilian consuming public for the social, political and environmental aspects related to food production processes and food origins reflect the distinctive historical and economic conditions that each of the two countries goes through; but in despite of the substantial structural and cultural differences, there are approximation signals; (b) that in Brazil, from the beginning, the role of the Slow Food movement takes the peculiar way of official government partnership and vertical management, with specific consequences on the configuration of the movement and the movement action; (c) that within the framework of the local projects, Slow Food movement works as an agent and catalysis of territorial development paths merely in contexts where its intervention is subsidiary and integrating, where suitable networks and socio-cultural attitudes for the enhancement of the local resources pre-exist, without relying on the performance of Slow Food; (d) that there are sets of different factors that promote or hinder the smooth progress of projects, which are closely linked to the presence / absence of empowerment and civic culture. On that basis, it was concluded that the Slow Food movement in Brazil finds suitable areas of activity, giving rise to autochthonous forms of the movement. There are some cross socio-cultural topics linking the unfolding of the projects carried out in Italy and in Brazil, and among Brazilian and Italian different regions; in this respect, institutional or cultural pre-determination does not exist, but there are influential historical variables and, at the same time, there is space for change. Also, we can conclude that the best and richest primary social capital repositories are represented by relations of the same type from those that are the main obstacles to good practices and civic community realization

Metodo del gradiente coniugato per problemi ai minimi quadrati non lineari

In questo elaborato vengono prese in considerazione tre versioni del metodo del gradiente coniugato proposte per l'ottimizzazione di funzioni non quadratiche con l'obiettivo di analizzare il loro utilizzo come metodi di regolarizzazione per problemi ai minimi quadrati non lineari mal condizionati. In particolare le tre versioni prese in esame sono: il metodo di Fletcher-Reeves, il metodo di Polak-Polyak-Ribiére e una versione ibrida dei due. Dai risultati numerici è stato possibile osservare che i metodi in questione sono metodi di regolarizzazione iterativi e producono risultati competitivi con i metodi di solito utilizzati in questo contesto (Lavenberg-Marquard, Gauss-Newton)

Coopercuc: percursos de valorização dos recursos locais e de convivência com o Semiárido

The history and evolution of the experience of the Cooperativa Agropecuária Familiar de Canudos, Uauá and Curaçá - Coopercuc, located in the state of Bahia, (Northeastern Brazil), exemplify the successful assertion of events and socio-cultural processes that can reverse the effects of some of the historical and sociopolitical factors associated with the main weaknesses of the Brazilian semiarid region. This article presents the context of this region and its critical issues. It seeks to show the sense of coexistence with the semiarid climate resulting from participation in the cooperative and in agroecological practices. It examines in an exploratory mode the history of Coopercuc, through field work, semi-structured interviews and qualitative data collection. Findings point to processes, agents and results that build a local development experience, which can be considered virtuous because of the sustainable and local social relations that foster integrated pathways of change and benefits.Dentro del contexto de apropiación discursiva de la convivencia con la región semiárida brasileña, la historia y la evolución de la experiencia de la Cooperativa Agropecuaria Familiar de Canudos, Uauá y Curaçá (Coopercuc), Bahía, ejemplifican la afirmación exitosa de los acontecimientos y procesos sociales y culturales capaces de revertir los efectos de algunos de los factores históricos y sociopolíticos asociados a las principales fragilidades de la región. Considerando esto, este estudio tiene como objetivo examinar el significado de la convivencia con la región semiárida a partir del análisis de esta experiencia de agricultura familiar y de la práctica del desarrollo rural en la región semiárida. Para lograr este objetivo, se realizó una investigación exploratoria a través de visitas de campo, entrevistas semiestructuradas y recolección de datos cualitativos, orientados a la reconstrucción de la historia de la cooperativa y a la evaluación de sus efectos. Las conclusiones apuntan a procesos, agentes y resultados que construyen una experiencia situada de desarrollo que, por generar posibles vías de cambios y beneficios duraderos integrados con el tejido social local, puede ser considerada virtuosa.Dentro do contexto de apropriação discursiva da convivência com o semiárido brasileiro, a história e a evolução da experiência da Cooperativa Agropecuária Familiar de Canudos, Uauá e Curaçá (Coopercuc), BA, exemplificam a afirmação exitosa de eventos e processos sociais e culturais aptos para reverter os efeitos de alguns dos fatores históricos e sociopolíticos associados às principais fragilidades dessa região. Diante disso, este estudo tem o objetivo de examinar o sentido de convivência com o semiárido a partir da análise dessa experiência de agricultura familiar e prática de desenvolvimento rural no semiárido. Para atingir o objetivo, foi realizada uma pesquisa exploratória por meio de visitas de campo, entrevistas semiestruturadas e coleta de dados qualitativos, visando à reconstrução da história da cooperativa e à avaliação de seus efeitos. As conclusões apontam para processos, agentes e resultados que constroem uma experiência situada de desenvolvimento que, por gerar caminhos possíveis de mudança e benefícios duradouros integrados com o tecido social local, pode ser considerada virtuosa

I fragili confini del territorio: a proposito dell’efficacia extraterritoriale dei diritti

Il contributo analizza i casi giurisdizionali di maggiore rilievo in tema di efficacia extraterritoriale dei diritti, soffermandosi sugli aspetti più critici e sottolineandone i profili di maggiore interesse. Copiosa è la giurisprudenza delle Corti Supreme degli Stati Uniti e del Canada, le quali hanno affrontato il problema con particolare riferimento al privilegio dell’habeas corpus e al giusto processo. Alcune recenti pronunce della Corte di giustizia UE e della Corte europea dei diritti dell’uomo mostrano invece come le attività di sorveglianza elettronica e di intelligence sharing pongano in una nuova luce la questione dell’efficacia territoriale delle Carte dei diritti. Un’ultima riflessione la impone una recente sentenza del Tribunale costituzionale federale tedesco, sempre in materia di sorveglianza elettronica, con cui è stato affermato – per la prima volta – che le autorità pubbliche sono vincolate al rispetto dei diritti sanciti in Costituzione anche quando agiscono all’estero.The contribution analyses the most important jurisdictional cases on the extraterritorial effectiveness of rights, focusing on the most critical aspects and highlighting the most interesting profiles. The case law of the Supreme Courts of the United States and Canada is substantial, and they have addressed the issue with particular reference to the habeas corpus privilege and due process. On the other hand, some recent rulings of the EU Court of Justice and the European Court of Human Rights show how electronic supervision and intelligence sharing activities shed new light on the question of the territorial effectiveness of the Charters of Rights. A last reflection is required by a recent ruling of the German Federal Constitutional Court, also on the subject of electronic supervision, which affirmed - for the first time - that public authorities are bound to respect the rights enshrined in the Constitution even when they act abroad

Frequent detection of high human papillomavirus DNA loads in oral potentially malignant disorders

Human papillomavirus (HPV) is estimated to be the cause of 40-80% of the squamous cell carcinoma of the oropharynx but only of a small fraction of the oral cavity cancers. The prevalence of oral HPV infection has significantly increased in the last decade, raising concerns about the HPV role in progression of oral potentially malignant disorders (OPMD) toward squamous cell carcinomas. We sought to study HPV infection in patients with oral lesions, and in control individuals, using non-invasive and site-specific oral brushing and sensitive molecular methods. HPV DNA positivity and viral loads were evaluated in relation to patient data and clinical diagnosis. We enrolled 116 individuals attending Dental Clinics: 62 patients with benign oral lesions (e.g. fibromas, papillomatosis, ulcers) or OPMD (e.g. lichen, leukoplakia) and 54 controls. Oral cells were collected with Cytobrush and HPV-DNA detected with quantitative real-time PCR (qPCR) for the more common high-risk (HR) and low-risk (LR) genotypes. HPV detection rate, percentage of HR HPVs and HPV-DNA loads (namely HPV16 and in particular, HPV18) were significantly higher in patients than in controls. Lichen planus cases had the highest HPV positive rate (75.0%), hairy leukoplakia the lowest (33.3%). This study detected unexpectedly high rates of HPV infection in cells of the oral mucosa. The elevated HR HPV loads found in OPMD suggest the effectiveness of qPCR in testing oral lesions. Prospective studies are needed to establish whether elevated viral loads represent a clinically useful marker of the risk of malignant progression

The use of IM in research: the IM-SA study

Dati di Modena della multicentrica europe

Management of newly diagnosed patients with type 2 diabetes: What are the attitudes of physicians? A SUBITO!AMD survey on the early diabetes treatment in Italy

Early intensive therapy in type 2 diabetes can prevent complications. Nevertheless, metabolic control is often sub-optimal in newly diagnosed patients. This webbased survey aimed to evaluate opinions of physicians about treatment, priorities, and barriers in the care of patients first referred to diabetes clinics. Data on physician attitudes toward therapeutic preferences for two clinical case models (same clinical profile, except HbA1c levels of 8.6 and 7.3% at the first access, respectively) were collected. Participants were asked to rank from 1 (most important) to 6 (least important) a list of priorities and barriers associated with the care of new patients. Overall, 593 physicians participated. In both case models, metformin and education were primary options, although their combination with other classes of drugs varied substantially. Main priorities were ‘‘to teach the patient how to cope with the disease’’ and ‘‘to achieve HbA1c target’’; main barriers were ‘‘lack of time’’ and ‘‘long waiting list’’. At multivariate analyses, physicians from the South of Italy had a twofold higher likelihood to attribute a rank 1–2 to organizational barriers than those operating in the North (South vs. North: OR: 2.4; 95% CI 1.4–4.1; Center vs. North: OR: 2.4; 95% CI 0.9–3.2). In the absence of a widely accepted evidence-based therapeutic algorithm driving the therapeutic choices according to the patient characteristics, prescriptions vary according to physician preferences. Education is perceived as a key-strategy, but organizational barriers and geographic disparities are an obstacle. These findings can drive new strategies to reduce clinical inertia, attitudes variability, and geographic disparities

Unraveling the Electrochemical Mechanism in Tin Oxide/MXene Nanocomposites as Highly Reversible Negative Electrodes for Lithium‐Ion Batteries

Lithium-ion batteries are constantly developing as the demands for power and energy storage increase. One promising approach to designing high-performance lithium-ion batteries is using conversion/alloying materials, such as SnO$_{2}$. This class of materials does, in fact, present excellent performance and ease of preparation; however, it suffers from mechanical instabilities during cycling that impair its use. One way to overcome these problems is to prepare composites with bi-dimensional materials that stabilize them. Thus, over the past 10 years, two-dimensional materials with excellent transport properties (graphene, MXenes) have been developed that can be used synergistically with conversion materials to exploit both advantages. In this work, a 50/50 (by mass) SnO$_{2}$/Ti$_{3}$C$_{2}$T$_{z}$ nanocomposite is prepared and optimized as a negative electrode for lithium-ion batteries. The nanocomposite delivers over 500 mAh g$^{–1}$ for 700 cycles at 0.1 A g$^{–1}$ and demonstrates excellent rate capability, with 340 mAh g$^{–1}$ at 8 A g$^{–1}$. These results are due to the synergistic behavior of the two components of the nanocomposite, as demonstrated by ex situ chemical, structural, and morphological analyses. This knowledge allows, for the first time, to formulate a reaction mechanism with lithium-ions that provides partial reversibility of the conversion reaction with the formation of SnO

Novità editoriali di diritto costituzionale (luglio-dicembre 2022)

Il contributo contiene le novità editoriali di diritto costituzionale per il periodo di riferiment