<p dir="ltr">Human brain tumors present significant challenges due to their heterogeneous nature, known as intra-tumoral heterogeneity (ITH), which evolves over space and time, leading to treatment resistance and poor patient outcomes. Current diagnostic methods rely on pre-surgical imaging and single biopsy samples, providing only a partial understanding of the tumor microenvironment (TME) and often resulting in incomplete targeting of tumor mutations, leaving residual disease vulnerable to recurrence. Our hypothesis proposes a novel approach: utilizing multimodal and multiparametric <i>in vivo</i> imaging to map the cellular and molecular characteristics of the TME. By correlating imaging signatures with underlying somatic and genomic aberrations, we aim to develop a predictive model guiding personalized targeted therapies to effectively address the heterogeneity of brain tumors.</p><p dir="ltr">To achieve this goal, we designed, tested, and validated a predictive model through a pilot study using clinical MRI scans and one stereotactic biopsy sample. Subsequently, we optimized a multimodal and multiparametric imaging protocol including MRI and PET scans, to acquire comprehensive morphological, functional, and molecular data from the TME. Additionally, we established a detailed pipeline for subject recruitment, data collection, and post-processing to ensure the robustness and reliability of our model.</p><p dir="ltr">This innovative approach has the potential to overcome the limitations of current diagnostic methods by providing a comprehensive understanding of the TME using minimally-invasive imaging techniques. By correlating imaging data with ground truth pathology and genomics, this model will enhance brain tumor diagnosis and facilitate the implementation of targeted therapies, ultimately improving treatment response and patient outcomes.</p>

OBJETIVO: Avaliar a relação entre mensurações de gordura (subcutânea e periprostática) realizadas em ressonância magnética, com o prognóstico do paciente portador de câncer de próstata. MATERIAIS E MÉTODOS: A mensuração da gordura periprostática e subcutânea com exame de ressonância magnética com ênfase na próstata foram realizadas em 58 pacientes com o diagnóstico histopatológico de câncer de próstata. Dados demográficos, clínicos e patológicos dos pacientes foram coletados e a correlação com o prognóstico, realizada. RESULTADOS: Na análise univariada, as gorduras periprostática e a subcutânea indicaram serem preditores de evolução desfavorável com significância estatística para o observador 1, no caso da gordura periprostática e para o observador 2 no caso da gordura subcutânea. Na análise multivariada, não houve associação com significância estatística. CONCLUSÃO: A associação entre obesidade e o câncer de próstata é complexa. Os dados obtidos neste estudo indicam que a medida da gordura periprostática, pelas imagens em T2, na RM, podem ser um preditor independente, da evolução desfavorável de pacientes com neoplasia de próstata / PURPOSE: Evaluate the relationship between fat measurements (subcutaneous and periprostatic) performed on MRI, with the prognosis of the patient with prostate cancer. MATERIALS AND METHODS: Measurements of periprostatic and subcutaneous fat with magnetic resonance imaging with emphasis on the prostate were performed in 58 patients with the histopathological diagnosis of prostate cancer. Demographic, clinical and pathological data of the patients were collected and the correlation with the prognosis was performed. RESULTS: In the univariate analysis, the periprostatic and subcutaneous fat were predictors of unfavorable evolution with statistical significance for the observer 1, in the case of the periprostatic fat and for the observer 2 in the case of the subcutaneous fat. In the multivariate analysis, there was no association with statistical significance. CONCLUSION: The association between obesity and prostate cancer is complex. The data obtained in this study indicate that the measurement of periprostatic fat by T2-weighted images in MRI may be an independent predictor of the unfavorable evolution of patients with prostate neoplasia

A better understanding of tumour heterogeneity is central for accurate diagnosis, targeted therapy and personalised treatment of glioblastoma patients. This thesis aims to investigate whether pre-operative multi-parametric magnetic resonance imaging (MRI) can provide a useful tool for evaluating inter-tumoural and intra-tumoural heterogeneity of glioblastoma. For this purpose, we explored: 1) the utilities of habitat imaging in combining multi-parametric MRI for identifying invasive sub-regions (I & II); 2) the significance of integrating multi-parametric MRI, and extracting modality inter-dependence for patient stratification (III & IV); 3) the value of advanced physiological MRI and radiomics approach in predicting epigenetic phenotypes (V). The following observations were made: I. Using a joint histogram analysis method, habitats with different diffusivity patterns were identified. A non-enhancing sub-region with decreased isotropic diffusion and increased anisotropic diffusion was associated with progression-free survival (PFS, hazard ratio [HR] = 1.08, P < 0.001) and overall survival (OS, HR = 1.36, P < 0.001) in multivariate models. II. Using a thresholding method, two low perfusion compartments were identified, which displayed hypoxic and pro-inflammatory microenvironment. Higher lactate in the low perfusion compartment with restricted diffusion was associated with a worse survival (PFS: HR = 2.995, P = 0.047; OS: HR = 4.974, P = 0.005). III. Using an unsupervised multi-view feature selection and late integration method, two patient subgroups were identified, which demonstrated distinct OS (P = 0.007) and PFS (P < 0.001). Features selected by this approach showed significantly incremental prognostic value for 12-month OS (P = 0.049) and PFS (P = 0.022) than clinical factors. IV. Using a method of unsupervised clustering via copula transform and discrete feature extraction, three patient subgroups were identified. The subtype demonstrating high inter-dependency of diffusion and perfusion displayed higher lactate than the other two subtypes (P = 0.016 and P = 0.044, respectively). Both subtypes of low and high inter-dependency showed worse PFS compared to the intermediate subtype (P = 0.046 and P = 0.009, respectively). V. Using a radiomics approach, advanced physiological images showed better performance than structural images for predicting O6-methylguanine-DNA methyltransferase (MGMT) methylation status. For predicting 12-month PFS, the model of radiomic features and clinical factors outperformed the model of MGMT methylation and clinical factors (P = 0.010). In summary, pre-operative multi-parametric MRI shows potential for the non-invasive evaluation of glioblastoma heterogeneity, which could provide crucial information for patient care.

Darbo tikslas – sukurti bendrą prieigos tinklo modeliavimo metodiką bei jos programinę realizaciją, atitinkančią šiuos reikalavimus: • n užduotų prieigos tinklo parametrų reikšmių optimalus nustatymas pagal m užduotų prieigos tinklo kokybės apribojimų, kai n ≥ 1, o m ≥ 0; • optimalus stočių koordinačių nustatymas mobiliojo telefono ryšio tinklui; • optimalus stočių koordinačių nustatymas laidinio telefono ryšio tinklui; Darbo pradžioje apžvelgiamos telekomunikacijų sektoriaus užduotys, kurios gali būti sprendžiamos kombinatorinio optimizavimo metodais. Taipogi pristatomi ir suklasifikuojami galimi šių užduočių sprendimo metodai. Tiriamojoje darbo dalyje pristatomas daugiaparametrinis prieigos tinklo optimizavimo algoritmas integruotas su stočių išdėstymo algoritmais. Stočių išdėstymui pateikiami du meta-euristiniai algoritmai: • Skruzdžių kolonijos algoritmas, papildytas lokalios paieškos procedūra; • Genetinis algoritmas, papildytas lokalios paieškos procedūra. Minėtų algoritmų realizacijos skirstomos pagal šias prieigos tinklo ryšio topologijas: • Mobiliojo telefono ryšio tinklui; • Fiksuoto telefono ryšio tinklui. Esminiai darbe pasiekti rezultatai: • Sukurta universali metodika, leidžianti kurti realius prieigos tinklo modelius; • Sukurta šios metodikos programinė realizacija. Darbe nagrinėjamų uždavinių ir algoritmų pagrindu buvo paskelbti ir pristatyti šie straipsniai: • „Prieigos tinklo parametrų optimalaus... [toliau žr. visą tekstą] / The objective of this work is creation of telecommunication network approach algorithm and its realization. The created algorithm must fulfill following requirements: • optimal values evaluation of n given network approach parameters with m given network approach quality constrains, where n ≥ 1, o m ≥ 0; • optimal solution for transmitters placement problem in mobile phone network; • optimal solution for transmitters placement problem in fixed phone network; In the beginning of this paper we present a set of telecommunication segment problems which can be solved using combinatorial optimization methods. Also we present a set of combinatorial optimization methods which can be used for solving these problems. Finally we present a graphical classification of analyzed problems and connect it with algorithms which are capable for solving it. In the research part of this paper we present a multi parametric network approach optimization algorithm united with algorithms for placing transmitters. Next we present two Meta heuristics based optimization algorithms: • Ant Colony Optimization algorithm with local search procedure; • Genetic algorithm with local search procedure. The realization of these two algorithms depends on the topology of the network approach being analyzed. In this paper we analyze two most common types of network approaches: • Mobile phone network approach; • Fixed phone network approach. The two main achievements of... [to full text]

Une mutation du gène SYN1 a récemment été découverte chez plusieurs membres d'une grande famille canadienne-française ségréguant troubles du langage, épilepsie focale, et troubles du spectre autistique (TSA). Bien qu'aucune anomalie macroscopique apparente n'ait pu être identifiée dans les données d’imagerie par résonance magnétique (IRM) cérébrales, nous avons émis l'hypothèse que des modalités d'IRM quantitatives sensibles à la microstructure et à la composition des tissus permettraient l’identification d’anomalies subtiles. Nous avons fait l’acquisition de données IRM multimodale chez 13 sujets porteurs de la mutation SYN1_Q555x et 13 sujets contrôles appareillés pour l’âge et le sexe. Une analyse statistique de groupe a été effectuée sur les cartes paramétriques corticales surfaciques afin de caractériser l’effet de la mutation sur plusieurs paramètres physiques quantitatifs. En résumé, des altérations ont été observées dans le réseau langagier, de même qu’une latéralisation anormale de celui-ci sur l’hémisphère droit. Les changements les plus significatifs dans ces régions sont une diminution de la diffusivité moyenne et une augmentation de l’anisotropie fractionnelle. Un modèle biophysique est proposé pour expliquer ces résultats, qui suggèrent une augmentation de la densité ou de la fraction volumique du neuropile. Cette étude est, à notre connaissance, la première à utiliser avec succès l'imagerie de diffusion et multiparamétrique conjointement à une méthodologie de cartographie surfacique pour détecter des anomalies corticales chez un groupe de sujets avec un génotype bien défini lié aux troubles du langage, à l'épilepsie et aux TSA. Cette étude démontre également que l'IRM de diffusion, bien que traditionnellement considérée comme une modalité spécifique à la matière blanche, peut effectivement être utilisée conjointement à une cartographie de surface pour caractériser une pathologie corticale subtile non détectable autrement, même si seul un groupe relativement restreint de sujets est disponible. / A mutation of the SYN1 gene has recently been discovered in several members of a large French-Canadian family segregating language disorders, focal epilepsy, and autism spectrum disorders (ASD). Although no apparent macroscopic abnormality could be identified in brain magnetic resonance imaging (MRI) data, we hypothesized that quantitative MRI modalities sensitive to tissue microstructure and composition could allow the identification of subtle anomalies. We acquired multimodal MRI data from 13 SYN1_Q555x mutation carriers and 13 healthy controls matched for age and sex. A surface-based group statistical analysis was performed on the cortical parametric maps to characterize the effect of the mutation on several quantitative physical parameters. In summary, alterations were found in the language network, as well as abnormal lateralization of the latter over the right hemisphere. The most significant changes in these regions are a decrease in mean diffusivity and an increase in fractional anisotropy. A biophysical model is proposed to explain these results, which suggest an increase in neuropil density or volume fraction. This study is, to our knowledge, the first to successfully use diffusion imaging and multiparametric mapping in a surface-based approach to detect cortical anomalies in a group of subjects with a well-defined genotype linked to language impairments, epilepsy and ASD. Importantly, this study also shows that diffusion MRI, although traditionally seen as a white matter modality, can effectively be used in a surface-based approach to characterize subtle cortical pathology not detectable otherwise, even when only a relatively small group of subjects is available.

La cytométrie de masse CMM) a révolutionné l'étude de la diversité cellulaire et phénotypique, en augmentant de manière significative le nombre de marqueurs pouvant être analysés simultanément (41 à ce jour). En permettant de définir précisément l'état des populations de lymphocytes, notamment en ce qui concerne leur différenciation, activation et leur entrée dans le cycle cellulaire, la CMM a mis au jour de petits sous-ensembles jusqu'ici inconnus. Dans cette étude, la CMM a été utilisée pour tenter de mieux caractériser les réservoirs du VIH. Avec l'introduction de la thérapie antirétrovirale combinée (ART) en 1996, l'infection par le VIH est passée d'un destin fatal à une maladie chronique gérable avec une durée de vie normale grâce à une réduction de la réplication virale active (la quantité de virus est en deçà des limites de détection optimales). Cependant, si le traitement est interrompu, la charge virale chez le patient augmente à nouveau du fait des réservoirs de provirus viables localisés dans des populations de cellules à longue durée de vie et qui ne peuvent pas être éliminées par les traitements actuels. Ces cellules infectées réservoirs constituent un obstacle majeur à l'éradication du VIH. Le réservoir le mieux caractérisé est celui des lymphocytes T CD4+ et est principalement hébergé dans les TCM, les TTM, les TSCM et les Tfh. Une première étude nous a permis d’évaluer les stades du cycle cellulaire en association à des marqueurs de différenciation, d'activation et d'épuisement, pour aboutir à une évaluation poussée de l'état de quiescence des lymphocytes T CD4 susceptibles d’abriter les réservoirs latents de VIH. Cette large analyse multiplexe démontre que certains sous-ensembles des LTCD4+CD25-HLA-DR- classiquement considérés "au repos"- contiennent en fait des quantités notables de cellules en cycle ou exprimant des récepteurs inhibiteurs, ouvrant de nouvelles voies pour une redéfinition des cellules T CD4 quiescentes du sang périphérique. Une deuxième étude avait pour but de définir les populations de LT CD4 produisant du VIH in vivo. Nous avons développé une analyse multiparamétrique sur des cellules de patients VIH+ sous ART et en phase d’interruption thérapeutique (ATI). Cette étude met en évidence que les cellules CD3+CD4+CD32high expriment un fort taux de marqueurs d’activation et reçoivent d’importants signaux d’activation via des cytokines, à l'inverse des cellules CD32a-. D'autre part, l'analyse des LTCD4+ producteurs de VIH (exprimant la protéine de capside p24), nous a permis de détecter un très faible nombre de cellules positives p24+ (inférieur à 0,004% en phase d’ATI mais aucun avant). Le phénotype des cellules productrices a ensuite été mis en évidence. Il s’agit de lymphocytes T n’exprimant pas de CD8, enrichis d’un facteur 4 en cellules TSCM, et d'un facteur 2 en TFH. Ces populations sont très enrichies en cellules activées co-exprimant 3 marqueurs d’activation (augmentés d’un facteur 20) et sont en cycle (Ki67+) et/ou sur-expriment des molécules de contrôle immunitaire (ICP) avec un enrichissement d’un facteur 500. Ceci nous permet de détecter des cellules productrices avec des fréquences beaucoup plus élevées dans ces populations TCD3+CD8- en cycle à hauteur de 0,08%, et en phase G2 (2,46%), mais également dans les cellules présentant une poly-expression des 4 immune-checkpoints (2,27%). L’avènement de la cytométrie de masse a augmenté de façon exponentielle les informations que nous pouvions obtenir sur une cellule. Grâce à cet outil, l’identification du cycle cellulaire, en corrélation avec différents marqueurs phénotypiques, permet d’explorer des informations jusque-là inaccessibles, entre autre l’analyse des réservoirs latents et productif du VIH. Ce travail permet ainsi de caractériser le plus précisément possible ces cellules productrices de VIH, mais aussi les cellules latentes, et potentiellement réservoirs du virus. / Mass cytometry (CMM) has revolutionized the study of cell and phenotypic diversity, significantly increasing the number of markers that can be analyzed simultaneously (41 to date). By making it possible to precisely define the state of the lymphocyte populations, particularly regarding their differentiation, activation and entry into the cell cycle, the CMM has revealed small subsets so far unknown. In this study, the CMM was used to try to better characterize the HIV’s reservoirs. With the introduction in 1996 of Combined Antiretroviral Therapy (ART), HIV infection has shifted from a fatal destiny to a manageable chronic disease with a normal life span through a reduction in active viral replication (the amount of virus is below optimal detection limits). However, if treatment is interrupted, the viral load increases again in the patient due to viable provirus reservoirs located in long-lived cell populations that cannot be eliminated by current treatments. These reservoirs constitute a major obstacle to the eradication of HIV. The best characterized reservoir is that of CD4+ T cells and is mainly hosted in TCM, TTM, TSCM and Tfh. A first study allowed us to evaluate the stages of the cell cycle in association with markers of differentiation, activation and exhaustion, leading to a thorough assessment of the quiescent state of CD4 T cells likely to harbour latent reservoirs of HIV. This broad multiplex analysis demonstrates that some subsets of LTCD4+CD25-HLA-DR- classically considered "at rest" – do actually contain significant amounts of cells in cycling or expressing inhibitory receptors, opening new pathways for redefining CD4 T quiescent cells from peripheral blood. A second study aimed to define CD4+ T Cells populations producing HIV in vivo. We have developed a multiparametric analysis on cells of HIV+ patients under ART and in therapeutic interruption phase (ATI). This study shows that CD3+CD4+CD32high cells express a high level of activation markers and receive important activation signals via cytokines, unlike CD32a- cells. On the other hand, the analysis of HIV-producing LTCD4+ (expressing the p24 capsid protein), allowed us to detect a very small number of p24+ positive cells (less than 0.004% in ATI phase but none before). The phenotype of the producing cells was then highlighted. These are T lymphocytes that do not express CD8, enriched with a factor 4 in TSCM cells, and a factor 2 in TFH. These populations are highly enriched in activated cells co-expressing 3 activation markers (increased by a factor of 20) and are in cycle (Ki67+) and/or over-express immune control molecules (ICPs) with an enrichment of a factor of 500. This allows us to detect producing cells with much higher frequencies in these TCD3+CD8- populations in cycles up to 0.08%, and in G2 phase (2.46%), but also in cells with poly-expression of 4 immune-checkpoints (2.27%). The advent of mass cytometry has exponentially increased the information we could get on a cell. Thanks to this tool, cell cycle identification, in correlation with different phenotypic markers, makes possible the exploration of previously inaccessible information, including the analysis of latent and productive reservoirs of HIV. This work enables us to characterize as precisely as possible these HIV-producing cells, but also the latent cells, and potentially reservoirs of the virus.

[pt] O tema qualidade do ar em ambientes internos é de suma importância para a sociedade devido ao seu impacto na saúde humana, e pela maior permanência de indivíduos em ambientes sem circulação de ar natural. Este trabalho descreve o desenvolvimento de um sistema portátil e de baixo custo para monitoramento de grandezas atmosféricas ligadas à qualidade do ar em ambientes internos, composto por sensores integrados a unidades locais, incluindo um sistema remoto hospedado na nuvem para armazenar os resultados das medições desses sensores. Apresentam-se as diretrizes e documentos normativos e regulatórios relacionados ao tema, além das tecnologias para sensoriamento utilizadas. Após o desenvolvimento e caracterização dos sensores, as unidades foram distribuídas em ambientes universitários com distintas dinâmicas de uso, onde o gradiente espacial das grandezas atmosféricas foi avaliado e analisado segundo os requisitos para qualidade do ar publicados na regulamentação vigente. Com o monitoramento multiparamétrico identificou-se a heterogeneidade da distribuição dos valores das grandezas, dependente da dinâmica de ocupação e das condições de ventilação, especialmente para as concentrações de CO2. Este parâmetro superou os valores recomendados pela agência reguladora em todos os ensaios realizados em sala de aula, e maiores valores mostraram-se fortemente associados à região do espaço mais próxima das vias aéreas superiores dos ocupantes. Os resultados apontam para a importância de monitoramento contínuo e em vários pontos de um plano posicionado a uma distância estratégica do piso, conforme a dinâmica de ocupação e posição média da emissão de gases pelo processo respiratório. / [en] The topic of indoor air quality is of paramount importance to society due to its impact on human health and the increasing number of individuals staying in environments with no natural air circulation. This work describes the development of the system, low-cost and portable, for monitoring atmospheric quantities linked to indoor air quality, composed of sensors integrated into local units, including a remote system hosted in the cloud to store the results of measurements of these sensors. The normative and regulatory guidelines and documents related to the theme are presented, in addition to the sensing technologies used. After the development and characterization of the sensors, the units were distributed in university environments with different dynamics of use, where the spatial gradient of the atmospheric quantities was evaluated and analyzed according to the requirements for air quality published in the current regulation. With multiparametric monitoring, the heterogeneity of the distribution of the values of the quantities was identified, depending on the dynamics of occupation and ventilation conditions, especially for CO2 concentrations. This parameter exceeded the values recommended by the regulatory agency in all tests performed in the classroom, and higher values were shown to be strongly associated with the region of space closest to the occupants upper airways. The results point to the importance of continuous monitoring and at various points in a plane positioned at a strategic distance from the floor, according to the dynamics of occupation and the average position of the emission of gases by the respiratory process.

Background Previous research has emphasized the importance of objectivity in voice quality evaluation. Acoustic voice quality index (AVQI) is a multiparametric objective index, that quantifies overall voice quality. Over the past decade, international studies have demonstrated strong diagnostic accuracy and sensitivity of AVQI to voice disorders. Ithas yet been inconclusive whether AVQI is independent of factors such as age and gender or if AVQI is affected by different types of continuous speech segments.  Aim  The aim of this study is to gather descriptive data regarding AVQI’s performance in a healthy Swedish-speaking population. Another objective is to investigate the potential impact of varying characteristics, such as age and gender, and type of continuous speech samples on the AVQI values.  Method  The present study gathered speech samples from 137 participants aged 20 to 90 years with a balanced gender distribution. These samples contained two different types of continuous speech, from which separate AVQI valuesin the acoustic analysis were computed. An analysis of covariance (ANCOVA) was then used to study the effects of age, gender, and type of continuous speech used on the resulting AVQI values.  Results  Descriptive normative data was gathered for the overall voice quality of the age groups included in this study. A statistically significant main effect of age on the AVQI values was observed. Statistical analysis revealed no significant effect of speech type, speaker gender or the interaction of age and gender on the AVQI values.   Conclusions  In conclusion, the present study offered data for AVQI values in the Swedish-speaking population. AVQI scores were higher in older participants compared to the younger participants. No other significant effects were found in this study. AVQI values obtained in this study and comparisons carried out with international AVQI values indicatepotentially successful use of the acoustic voice quality index in the Swedish-speaking population with some precautions.

Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRDpos patients (HR 3.8, p = 0.006). Overall survival of MRDneg non-responders was comparable to MRDneg responders. The inter-rater-reliability for MRD detection was high with a Krippendorffs α of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31 minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.

[pt] Esta tese investiga e desenvolve algoritmos baseados em relaxação Lagrangiana e técnica de desagregação multiparamétrica normalizada para resolver problemas não convexos de programação inteira-mista quadrática com restrições quadráticas. Primeiro, é realizada uma revisão de técnias de relaxação para este tipo de problema e subclasses do mesmo. Num segundo momento, a técnica de desagregação multiparamétrica normalizada é aprimorada para sua versão reformulada onde o tamanho dos subproblemas a serem resolvidos tem seu tamanho reduzido, em particular no número de variáveis binárias geradas. Ademais, dificuldas em aplicar a relaxação Lagrangiana a problemas não convexos são discutidos e como podem ser solucionados caso o subproblema dual seja substituído por uma relaxação não convexa do mesmo. Este método Lagrangiano modificado é comparado com resolvedores globais comerciais e resolvedores de código livre. O método proposto convergiu em 35 das 36 instâncias testadas, enquanto o Baron, um dos resolvedores que obteve os melhores resultados, conseguiu convergir apenas para 4 das 36 instâncias. Adicionalmente, mesmo para a única instância que nosso método não conseguiu resolver, ele obteve um gap relativo de menos de 1 por cento, enquanto o Baron atingiu um gap entre 10 por cento e 30 por cento para a maioria das instâncias que o mesmo não convergiu. / [en] This thesis investigates and develops algorithms based on Lagrangian relaxation and normalized multiparametric disaggregation technique to solve nonconvex mixed-integer quadratically constrained quadratic programming. First, relaxations for quadratic programming and related problem classes are reviewed. Then, the normalized multiparametric disaggregation technique is improved to a reformulated version, in which the size of the generated subproblems are reduced in the number of binary variables. Furthermore, issues related to the use of the Lagrangian relaxation to solve nonconvex problems are addressed by replacing the dual subproblems with convex relaxations. This method is compared to commercial and open source off-the-shelf global solvers using randomly generated instances. The proposed method converged in 35 of 36 instances, while Baron, the benchmark solver that obtained the best results only converged in 4 of 36. Additionally, even for the one instance the methods did not converge, it achieved relative gaps below 1 percent in all instances, while Baron achieved relative gaps between 10 percent and 30 percent in most of them.