Adenoviral Gene Therapy for Advanced Head and Neck Cancer

Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.Pitkälle levinneisiin pään ja kaulan alueen syöpiin sekä eturauhassyöpään ei ole olemassa tehokkaita parantavia hoitomuotoja. Onkolyyttisten virusten käyttö yhdessä perinteisten hoitojen kanssa on lupaava kokeellinen hoitomuoto ja sen turvallisuus on osoitettu useissa kliinisissä kokeissa. Kasvainta tuhoavaa vaikutusta pitää kuitenkin tehostaa riittävän hoitovasteen saavuttamiseksi. Tässä työssä kehitettiin pään ja kaulan alueen syövän eläinmalli, jonka avulla tutkittiin onkolyyttisten virusten, solunsalpaajien ja monoklonaalisen vasta-aineen (Setuksimab) kasvainta tuhoavaa yhteisvaikutusta. Tämä malli jäljittelee kliinistä tilannetta hyvin, sillä alun perin setuksimabille herkät syöpäsolut kehittivät nopeasti hoitoresistenssin. Kuten viimeaikaiset tutkimukset koskien solunsalpaajia ja sädehoitoa ovat osoittaneet, erityisesti syöpäsolut jotka ilmentävät syövän kantasoluille tyypillisiä pintaproteiineja olivat resistenttejä setuksimabille. Multimodaalihoito käyttäen onkolyyttisiä viruksia, solunsalpaajia ja monoklonaalista vasta-ainetta paransi hoidon kasvainta tuhoavaa vaikutusta, pienensi tarvittavia hoitoannoksia ja johti jopa kasvainten häviämiseen. Onkolyyttisten virusten kykyä herkistää syöpäsolut sädehoidolle tutkittiin eläinmallissa siirtämällä syöpäsoluihin ei-replikoituvien virusten avulla useita sädehoidolle herkistäviä viruksen proteiinejä. Tulokset osoittivat, että onkolyyttiset adenovirukset herkistävät syöpäsolut sädehoidolle viivyttämällä DNA:n kaksoiskierteeseen syntyvien katkosten korjausta. Tässä työssä kehitettiin kaksi syöpäsoluihin kohdennettua onkolyyttistä adenovirusta joista toinen oli aseistettu FCU1 itsemurhageenillä ja toinen ihmisen sytotoksiseen T lymfosyyttiin liittyvän antigeeni 4:n (CTLA-4) monoklonaalisella vasta-aineella. FCU1 koodaa proteiiniä joka katalysoi ei-myrkyllisen 5-fluorosytosiinin (5-FC) muuntumista myrkyllisiksi metaboliiteiksi, 5-fluorourasiiliksi ja 5-fluori uridiini monofosfaatiksi. CTLA-4:n monoklonaalinen vasta-aine edistää syopäsolujen apoptoottista kuolemista ja aktivoi elimistön immuunijärjestelmän kasvainta tuhoavaa vaikutusta. Molemmilla viruksilla osoitettiin olevan parempi kasvainta tuhoava vaikutus verrattuna muokkaamattomiin viruksiin. Onkolyyttisten virusten avulla siirtogeenin ilmentyminen voidaan kohdentaa syöpäsoluihin. Kasvaimessa todettiin suuri pitoisuus proteiinia, kun taas proteiinin pitoisuus veressä pysyi alhaisena. Tämän lisäksi, Ad5/3-24aCTLA4 viruksella infektoitujen solujen kasvatusliuoksella, joka sisälsi CTLA4:n monoklonaalista vasta-ainettta, pystyttiin aktivoimaan edennyttä syöpää sairastavien potilaiden verestä eristettyjä mononukleaarisia valkosoluja (PBMC). Yhteenvetona, tulokset osoittavat että geneettisesti muokattuja adenoviruksia voidaan käyttää edenneiden pään ja kaulan alueiden syöpien sekä eturauhassyövän hoidossa

Eco(il)logical Knowledge: on Different Ways of Relating with the Known

In this article, I narrate an ethnographic storyline that involves forest inhabitants, local politicians, development professionals, and scientific researchers in both representational and nonrepresentational worlds of knowing. I discuss how and why, in Angola, making forest knowledge through relations of distance to the forests is crucial for attaining institutional legitimacy over the forests. This way of acquiring authority and influence is championed by a broad epistemological tendency to address only the absent, which is then made present by accredited representers. Yet this technique disempowers local forest dwellers in their everyday territories and disallows the capacity that the ecological knowns have to reveal themselves. Knowing Angolan forests through absence and distance is not just a potent contemporary form of knowledge that qualifies as a way of ruling the forests, but is also integral to widespread (neo)colonial processes of distinction and separation: the knower and the known, the representer and the represented, the “cosmopolitan intellectual” and the “rustic bestial” Other. Finally, I discuss different forms of ecological knowledge in light of ethical stances toward knowing, relationality, and, ultimately, being.info:eu-repo/semantics/publishedVersio

Improved vehicle-to-home (iV2H) operation mode: experimental analysis of the electric vehicle as off-line UPS

This paper presents experimental results of electric vehicle (EV) operation as an off-line uninterruptible power supply (UPS). Besides the traditional grid-to-vehicle and vehicle-to-grid modes, this paper presents an improved vehicle-to-home operation mode. This new operation mode consists of the detection of a power outage in the power grid and the change of the EV battery charger control to operate as an off-line UPS. When the power grid voltage is restored, the voltage produced by the on-board EV battery charger is slowly synchronized with the power grid voltage before a complete transition to the normal mode. This paper presents results of two algorithms to detect a power outage: the root mean square (rms) calculation method based on half-cycle of the power grid voltage, and the rms estimation based on a Kalman filter. The experimental results were obtained in steady and transient state considering two cases with the EV plugged in at home:when charging the batteries and without charging the batteries. This paper describes the EV battery charger, the power outage detection methods, and the voltage and current control strategies.- This work was supported by the Fundacao para a Ciencia e Tecnologia (FCT) in the scope of the projects under Grant PEst-UID/CEC/00319/2013. The work of V. Monteiro was supported by the Doctoral Scholarship through the Portuguese FCT Agency under Grant SFRH/BD/80155/2011. The work of B. Exposto was supported by the Doctoral Scholarship through the Portuguese FCT Agency under Grant SFRH/BD/87999/2012.info:eu-repo/semantics/publishedVersio

Development of an IoT system with smart charging current control for electric vehicles

This paper presents the development and test of an Internet of Things (IoT) system for monitoring and control of electric vehicles. The IoT architecture, which was developed using the Firebase platform, allows the synchronization of the vehicles' data to the online server, as well as the access to the data outside of the vehicle, though the Internet. The smart charging system proposed in this paper allows the control of the electric vehicle's battery charging current in real time, based on the demand at the residence (home current), which is measured using a residential wireless sensor network (WSN). An Android mobile app was developed to access the vehicle's data. This app communicates with the wireless sensor nodes of an intra-vehicular wireless sensor network (IVWSN), which was developed using the Bluetooth Low Energy (RLE) protocol. A real time notification system was also implemented to alert users about certain events, such as low battery and full battery charge. The main features of the proposed IoT system are validated through experimental results.This work is supported by FCT with the reference project UID/EEA/04436/2013, COMPETE 2020 with the code POCI 01-0145-FEDER-006941

Georeferenced analysis of urban nightlife and noise based on mobile phone data

Urban environments are characterized by a complex soundscape that varies across different periods and geographical zones. This paper presents a novel approach for analyzing nocturnal urban noise patterns and identifying distinct zones using mobile phone data. Traditional noise-monitoring methods often require specialized equipment and are limited in scope. Our methodology involves gathering audio recordings from city sensors and localization data from mobile phones placed in urban areas over extended periods with a focus on nighttime, when noise profiles shift significantly. By leveraging machine learning techniques, the developed system processes the audio data to extract noise features indicative of different sound sources and intensities. These features are correlated with geographic location data to create comprehensive city noise maps during nighttime hours. Furthermore, this work employs clustering algorithms to identify distinct noise zones within the urban landscape, characterized by their unique noise signatures, reflecting the mix of anthropogenic and environmental noise sources. Our results demonstrate the effectiveness of using mobile phone data for nocturnal noise analysis and zone identification. The derived noise maps and zones identification provide insights into noise pollution patterns and offer valuable information for policymakers, urban planners, and public health officials to make informed decisions about noise mitigation efforts and urban development.This work was supported by the Fundação para a Ciência e Tecnologia under Grant [UIDB/00315/2020]; and by the project “BLOCKCHAIN.PT (RE-C05-i01.01—Agendas/Alianças Mobilizadoras para a Reindustrialização, Plano de Recuperação e Resiliência de Portugal” in its component 5—Capitalization and Business Innovation and with the Regulation of the Incentive System “Agendas for Business Innovation”, approved by Ordinance No. 43-A/2022 of 19 January 2022)

Development of a proposed single-phase series active power filter without external power sources

The quality of electric power is receiving more and more attention from part of consumers, Distribution System Operators (DSO), Transmission System Operators (TSO) and other competent entities related to the electrical power system. Once the electrical Power Quality (PQ) problems have direct implications for business productivity, causing high economic losses, it is mandatory to develop solutions that mitigate these problems. Active Power Filters (APFs) are power electronic equipment capable of compensating PQ problems that have the ability to dynamically adjust their modes of operation in response to changes in load or in the power system. Among these solutions, the Series Active Power Filter (SeAPF) is specially conceived to deal with problems related to the power system voltage amplitude and waveform. Despite the ability to compensate voltage sags, voltage swells, voltage harmonics, and voltage imbalances in three-phase systems, the SeAPF has not achieved much success neither has not been widely adopted. The lack of interest in this equipment can be largely justified by its high cost and also because of some limitations presented by the SeAPF conventional topology. In this paper is presented a novel topology, as well as the control algorithms of a single-phase SeAPF that is connected directly to the power grid without the use of coupling transformers and that does not require the use of external power sources. The topology and control algorithms of the SeAPF proposed in this paper were firstly evaluated by means of simulation results obtained with PSIM software and, once validated, a laboratory prototype was developed, being presented experimental results that support the correct operation of the proposed system.This work has been supported by FCT – Fundação para a Ciência e Tecnologia within the Project Scope: UID/CEC/00319/2019. This work is financed by the ERDF – COMPETE 2020 Programme, and by FCT within project SAICTPAC/0004/2015-POCI-01-0145-FEDER-016434 and by FCT within project PTDC/EEI-EEE/28813/2017. Mr. Luis A. M. Barros is supported by the doctoral scholarship PD/BD/143006/2018 granted by the Portuguese FCT agency

Interfacing power electronics systems for smart grids: innovative perspectives of unified systems and operation modes

The power distribution grid is centrally managed concerning the requirements of the end-users, however, with the appearance of smart grids, new technologies arc arising. Therefore, distributed energy resources, mainly, renewables, energy storage systems, electric mobility, and power quality are viewed as encouraging contributions for improving power management. In these circumstances, this paper presents a power electronics perspective for the power distribution grid, considering innovative features, and including a power quality perception. Throughout the paper are presented relevant concepts for a concrete realization of a smart grid, supported by the integration of power electronics devices as the interface of the mentioned technologies. Aiming to support the innovative power electronics systems for interfacing the mentioned technologies in smart grids, a set of developed power electronics equipment was developed and, along with the paper, are shown and described, supporting the most important contributions of this paper.This work has been supported by FCT -Fundação para a Ciencia e Tecnologia within the R&D Units Project Scope: UIDB/00319/2020. This work has been supported by the FCT Project newERA4GRIDs PTDC/EEI-EEE/30283/2017

Precipitation diurnal cycle assessment of satellite-based estimates over Brazil

The main objective of this study is to assess the ability of several high-resolution satellite-based precipitation estimates to represent the Precipitation Diurnal Cycle (PDC) over Brazil during the 2014–2018 period, after the launch of the Global Precipitation Measurement satellite (GPM). The selected algorithms are the Global Satellite Mapping of Precipitation (GSMaP), The Integrated Multi-satellitE Retrievals for GPM (IMERG) and Climate Prediction Center (CPC) MORPHing technique (CMORPH). Hourly rain gauge data from different national and regional networks were used as the reference dataset after going through rigid quality control tests. All datasets were interpolated to a common 0.1° × 0.1° grid every 3 h for comparison. After a hierarchical cluster analysis, seven regions with different PDC characteristics (amplitude and phase) were selected for this study. The main results of this research could be summarized as follow: (i) Those regions where thermal heating produce deep convective clouds, the PDC is better represented by all algorithms (in term of amplitude and phase) than those regions driven by shallow convection or low-level circulation; (ii) the GSMaP suite (GSMaP-Gauge (G) and GSMaP-Motion Vector Kalman (MVK)), in general terms, outperforms the rest of the algorithms with lower bias and less dispersion. In this case, the gauge-adjusted version improves the satellite-only retrievals of the same algorithm suggesting that daily gauge-analysis is useful to reduce the bias in a sub-daily scale; (iii) IMERG suite (IMERG-Late (L) and IMERG-Final (F)) overestimates rainfall for almost all times and all the regions, while the satellite-only version provide better results than the final version; (iv) CMORPH has the better performance for a transitional regime between a coastal land-sea breeze and a continental amazonian regime. Further research should be performed to understand how shallow clouds processes and convective/stratiform classification is performed in each algorithm to improve the representativity of diurnal cycle

Swarm-based Descriptor Combination and its Application for Image Classification

In this paper, we deal with the descriptor combination problem in image classification tasks. This problem refers to the definition of an appropriate combination of image content descriptors that characterize different visual properties, such as color, shape and texture. In this paper, we propose to model the descriptor combination as a swarm-based optimization problem, which finds out the set of parameters that maximizes the classification accuracy of the Optimum-Path Forest (OPF) classifier. In our model,  a descriptor is seen as a pair composed of a feature extraction algorithm and a suitable distance function. Our strategy here is to combine distance scores defined by different descriptors, as well as to employ them to weight OPF edges, which connect samples in the feature space. An extensive evaluation of several swarm-based optimization techniques was performed. Experimental results have demonstrated the robustness of the proposed combination approach