Brain is one of the safe sanctuaries for HIV and, in turn, continuously supplies active viruses to the periphery. Additionally, HIV infection in brain results in several mild-to-severe neuro-immunological complications termed neuroAIDS. One-tenth of HIV-infected population is addicted to recreational drugs such as opiates, alcohol, nicotine, marijuana, etc. which share common target-areas in the brain with HIV. Interestingly, intensity of neuropathogenesis is remarkably enhanced due to exposure of recreational drugs during HIV infection. Current treatments to alleviate either the individual or synergistic effects of abusive drugs and HIV on neuronal modulations are less effective at CNS level, basically due to impermeability of therapeutic molecules across blood-brain barrier (BBB). Despite exciting advancement of nanotechnology in drug delivery, existing nanovehicles such as dendrimers, polymers, micelles, etc. suffer from the lack of adequate BBB penetrability before the drugs are engulfed by the reticuloendothelial system cells as well as the uncertainty that if and when the nanocarrier reaches the brain. Therefore, in order to develop a fast, target-specific, safe, and effective approach for brain delivery of anti-addiction, anti-viral and neuroprotective drugs, we exploited the potential of magnetic nanoparticles (MNPs) which, in recent years, has attracted significant importance in biomedical applications. We hypothesize that under the influence of external (non-invasive) magnetic force, MNPs can deliver these drugs across BBB in most effective manner. Accordingly, in this dissertation, I delineated the pharmacokinetics and dynamics of MNPs bound anti-opioid, anti-HIV and neuroprotective drugs for delivery in brain. I have developed a liposome-based novel magnetized nanovehicle which, under the influence of external magnetic forces, can transmigrate and effectively deliver drugs across BBB without compromising its integrity. It is expected that the developed nanoformulations may be of high therapeutic significance for neuroAIDS and for drug addiction as well.

Tato disertační práce se zabývá metodami modelování elektronického zařízení letadel. První část je stručným přehledem klasických metod modelování systémů a adaptivních, fuzzy a hybridních metod používaných převážně k black-box modelování. Cílem práce je vytvořit algoritmus pro identifikaci a modelování obecného systému, který může být nelineární, dynamický a velmi složitý, například co do množství rozměrů. Předpokládá se, že model má několik vstupů a výstupů. V hlavní části práce je rozebrána metoda, která patří mezi hybridní systémy, protože kombinuje fuzzy systém s parametricky definovanými pravidly a regresní neuronovou síť. Nejprve je zmíněn základní princip regresní sítě a způsob určení jejího parametru strmosti, dále se kapitola zabývá zavedením fuzzy pravidel do této sítě. Třetí část se zabývá jedním z hlavních bodů práce, paralelními výpočty. Výsledný algoritmus je navržen pro paralelní zpracování, protože výpočetní čas může být v případě složitějších modelů příliš vysoký, případně nelze výsledky získané ze sítě vyhodnotit pomocí výpočtu v jednom vlákně. V závěru práce je metoda ověřena na datech získaných z měření zmenšeného modelu letadla. Ověření je provedeno pomocí střední kvadratické odchylky a srovnáním s odpovídajícím modelem vytvořeným pomocí vícevrstvé neuronové sítě trénované zpětným šířením chyby s algoritmem Levenberg-Marquardt.

Alors que le rôle dans la protection contre des pathogènes par le système immunitaire est bien compris, son rôle dans la progression tumoral est bien plus complexe avec certains mécanismes protecteurs tandis que d’autres sont néfastes. Le principal rôle physiologique du cerveau est lui de percevoir et intégrer les stimuli physiques et sociaux, d’intégrer ces signaux et de moduler l’activité des processus physiologiques de l’organisme pour s’adapter à ces conditions. Bien que les systèmes nerveux et immunitaires aient longtemps été considérés comme fonctionnant indépendamment, de multiples études cliniques et précliniques ont formellement démontré que ces deux systèmes pouvaient se réguler réciproquement. Bien que de nombreuses études visent à mieux comprendre les interactions entre les systèmes nerveux et immunitaire, de nombreuses questions restent sans réponses. Alors que les études cliniques ont prouvé un rôle positif dans la progression tumorale du bien-être, les mécanismes moléculaires ne sont pas encore compris. De plus, de nombreuses études ont essayé de trouver si les cytokines pouvaient être utilisées comme biomarqueurs diagnostic ou prédictif de la réponse au traitement dans les maladies psychiatriques, aucune cytokine étudiée à cette date n’a été démontrée comme suffisamment sensible ou spécifique pour être utilisée comme test diagnostique. Au cours de mes travaux de thèses, j’ai travaillé sur deux projets distincts étudiant les relations entre systèmes nerveux et immunitaires. Le but de mon premier projet a été d’identifier des mécanismes par lesquels un environnement enrichi (EE) associé à une meilleure activité sensorielle, cognitive et motrice pouvait impacter la progression métastatique chez la souris. Nous avons découvert que l’EE avait un effet protecteur dans la prise métastatique pulmonaire. Cette protection est associée à une diminution du niveau de corticostérone sérique, une augmentation de l’inflammation pulmonaire après extravasation de cellules tumorales circulantes. Cette protection est abolie en absence de signalisation sur récepteur aux glucocorticoïdes dans les monocytes inflammatoires. Alors que les monocytes inflammatoires sont généralement décrits comme favorisant la progression tumorale, ils peuvent aussi avoir une action antitumorale, suggérant que leur rôle est bien plus complexe qu’actuellement décrit. Nos résultats ont mis en avant un mécanisme antitumoral de reprogrammation dépendant des glucocorticoïdes des monocytes inflammatoires inhibant la progression métastatique. Mon second projet avait pour but d’identifier des biomarqueurs de la réponse aux traitements de patients ayant un premier épisode psychotique (FEP). Nous avons eu la possibilité d’accéder une cohorte de sérums et données cliniques de 325 patients FEP, tous les patients ont été traités avec le même antipsychotique. Nous avons d’abord utilisé une approche de clustering hiérarchique non supervisé pour stratifier les 325 patients dans 4 sous-groupes en utilisant uniquement leur symptomatologie. Un sous-groupe (C1A) après comparaison avec le reste de la cohorte, montre une symptomatologie plus sévère ainsi qu’un taux de réponse le plus faible après 4 semaines de traitement. Le groupe C1A montre aussi une augmentation du niveau de plusieurs biomarqueurs sériques pro-inflammatoire permettant une validation externe de cette stratification. L’utilisation de 6 variables biologiques (IL-15, protéine c-réactive, CXCL-12, niveaux d’IgG anti CMV et anti Toxoplasma gondii) et de 2 variables cliniques (Âge et utilisation de drogues récréationnelle) a permis de prédire la réponse après traitement. La précision de prédiction après validation croisée est très bonne avec une aire sous courbe moyenne de 81.0% (± 0.05). Une confirmation de ces résultats dans d’autres essais cliniques pourrait amener le développement d’une nouvelle approche basée sur le dosage de biomarqueurs sériques dans le choix du traitement chez les patients psychotiques. / While the immune system is well known for its protective role against infectious pathogens, its role in cancer progression is more complex with some immune mechanisms being protective while others are detrimental. The primary physiological role of the brain is to perceive external physical and social conditions, assess their implications for organismal well-being and modulate the activity of internal physiological processes to optimally adapt to those external conditions. Immune and the nervous systems have long been considered to operate independently from each other, many preclinical and clinical studies have clearly demonstrated that these two systems interact and regulate each other. Despite more and more studies aim at investigating the interactions between the nervous and the immune systems, important issues remain to be elucidated. For example, while human studies have demonstrated a positive impact of well-being on cancer progression, the underlying molecular mechanisms have not been elucidated. On another topic, and while many investigators have investigated whether cytokines could be used as diagnosis or prognosis biomarkers is psychiatric diseases, none of the cytokine studied to date have proven to possess the sensitivity and specificity expected for an accepted diagnostic test value. During my PhD, I have worked on two different projects both related to the interactions between the nervous and the immune system. The goal of my first project was to elucidate the mechanisms by which enriched environment conductive to enhanced sensory, cognitive and motor stimulation impact metastatic progression in mice. We have found that mice housed in enriched environment were protected from lung metastasis. Protection was associated with lower serum corticosterone levels, increased lung inflammation following extravasation of circulating tumour cells, and rapid killing of early infiltrating tumour cells. Protection was abolished when inflammatory monocytes were deficient in glucocorticoid receptor signalling. Thus, while inflammatory monocytes have been shown to promote cancer progression, our results disclosed a novel anti-tumour mechanism whereby glucocorticoid receptor-dependent reprogramming of inflammatory monocytes can inhibit cancer metastasis. The goal of my second project was to identify immune-related biomarkers of remission in first-episode psychotic (FEP) patients. To this aim, we have taken advantage of our privileged access to clinical data and serum samples from 325 FEP patients who have all been treated with an atypical antipsychotic. We have first used a hierarchical unsupervised clustering approach to stratify 325 FEP patients into four subtypes based on their clinical symptoms. Compared to the rest of the cohort, one subtype (C1A) exhibited more severe positive and negative symptoms and were the most at risk of being non-remitters following treatment for 4 weeks. C1A patients also exhibited higher levels of several pro-inflammatory biomarkers therefore providing an external validation to our clustering approach. Most importantly, six biological variables (serum levels of IL-15, C reactive protein, CXCL-12, anti- cytomegalovirus and anti-Toxoplasma immunoglobulins) and two clinical variables (age, recreational drug use), predicted early remission following treatment with Amisulpride in C1A patients. Prediction accuracy assessed by cross-validation calculated by 10,000 iterations of 4-fold cross-validation was very good with a mean area under the curve (AUC) of 81.0% ± 0.05. Further validation of our results in future clinical trials would pave the way for the development of a blood-based assisted clinical decision support system for the choice of treatment in psychotic patients.

In dieser Arbeit soll auf das gesellschaftliche Problem der Altersgebrechlichkeit (Frailty) aufmerksam gemacht werden. Die Bedeutung für jedes Individuum, gebrechlich, frail zu altern und damit den Verlust an Lebensqualität und eine vorzeitige Mortalität zu riskieren wird deutlich gemacht. Das Alterssyndrom wäre einfach zu diagnostizieren, fällt aber dennoch zurzeit durch ein Raster. Deshalb wird ein Kodierungsvorschlag für Frailty entworfen, aus dem sich gezielte individuelle Therapie- und Rehabilitationsmaßnahmen ableiten lassen. Der Zusammenhang von altersphysiologischen immuno-neuro-endokrinen Veränderungen und der Frailty bilden die Grundlage für eine Präventionskaskade: F1, F2; F3 in Anlehnung der „U“-Untersuchungen für Kinder.

No description available.

Pediatric medulloblastoma (MB) is a cerebellar brain tumor namely characterized by its origination in early development, as early as embryogenesis. MB is thought to originate from the highly heterogeneous granular neuron precursor (GNP) cell population that resides within the rhombic lip of the dorsal hindbrain region, and is particularly susceptible to the effects of the oncogenic Sonic Hedgehog (SHH) signaling pathway. Patched 1 (Ptch1), typically a transmembrane SHH pathway tumor suppressor gene, is mutated in 20% of MB cases, otherwise known as SHH-group MBs. This mutation in MB presents as a loss of heterozygosity (LOH), where the wild type allele of Ptch 1 is deleted. Ptch 1 receptor silencing activates downstream target genes such as proto-oncogene Smoothened (Smo) and allows for the initiation of tumorigenesis. However, the molecular basis for Ptch1 LOH in MB remains elusive. We have discovered a cancer-testis antigen, Protamine 1 (Prm 1), that is present in the Ptch 1 locus in SHH-group MB tumors. By utilization of the RNAscope technique, we confirm mRNA expression of Prm 1 in cerebellar tumor tissue, predominantly from tumor cells, but not in stromal cells. These studies reveal that tumor cells highjack the promoter of Ptch 1 to express Prm 1, promoting tumor progression. These findings establish the mechanism for Ptch 1 LOH in SHH-group MB, and provide the rationale to define the cell of origin for SHH group MB based on Prm 1 expression. / Biomedical Sciences

Background: IDH-wild-type glioblastoma (GBM) is the most frequent brain-derived malignancy. Despite intense research efforts, it is still associated with a very poor prognosis. Several parameters were identified as prognostic, including general physical performance. In neuro-oncology (NO), special emphasis is put on focal deficits and cognitive (dys-)function. The Neurologic Assessment in Neuro-Oncology (NANO) scale was proposed in order to standardize the assessment of neurological performance in NO. This study evaluated whether NANO scale assessment provides prognostic information in a standardized collective of GBM patients. Methods: The records of all GBM patients treated between 2014 and 2019 at our facility were retrospectively screened. Inclusion criteria were age over 18 years, at least 3 months postoperative follow-up, and preoperative and postoperative cranial magnetic resonance imaging. The NANO scale was assessed pre- and postoperatively as well as at 3 months follow-up. Univariate and multivariate survival analyses were carried to investigate the prognostic value. Results: One hundred and thirty-one patients were included. In univariate analysis, poor postoperative neurological performance (HR 1.13, p = 0.004), poor neurological performance at 3 months postsurgery (HR 1.37, p < 0.001), and neurological deterioration during follow-up (HR 1.38, p < 0.001), all assessed via the NANO scale, were associated with shorter survival. In multivariate analysis including other prognostic factors such as the extent of resection, adjuvant treatment regimen, or age, NANO scale assessment at 3 months postoperative follow-up was independently associated with survival prediction (HR 1.36, p < 0.001). The optimal NANO scale cutoff for patient stratification was 3.5 points. Conclusion: Neurological performance assessment employing the NANO scale might provide prognostic information in patients suffering from GBM.

No description available.

No description available.

No description available.