1,721,107 research outputs found
DEVELOPMENT OF INNOVATIVE VIRUSES WITH ENHANCED IMMUNOSTIMULATORY ACTIVITIES AGAINST GLIOBLASTOMA
No full textGlioblastoma (GBM) is a deadly tumor of the central nervous system, with a median overall survival
of 15 to 16 months after tumor diagnosis. While standard treatments such as surgical resection,
radiotherapy, and chemotherapy can help manage symptoms and prolong survival, they are not
curative. Recent advances in immunotherapy have reignited interest in utilizing immunological
approaches to fight cancer. However, current immunotherapies failed in their journey from bench
to bedside for the treatment of GBM. The challenge of developing effective immune-based
approaches is compounded by the highly immunosuppressive GBM tumor microenvironment and
by the inadequacy of current preclinical models in fully recapitulating the complex biology of GBM
tumors. There is therefore the need to develop novel immunotherapeutic approaches to enhance
anti-GBM immunity and to establish innovative preclinical models to properly address immune-
mediated responses.
This PhD project aimed to enhance anti-tumor immunity via the delivery of the Class II Major
Histocompatibility Complex Transactivator (CIITA)-encoding gene (known as CIITA or AIR-1) to the
GBM tumor cells through a replication-deficient adenovirus (AdV). CIITA is the master regulator of
major histocompatability complex class II (MHC-II) molecules, expression of which is largely limited
to professional antigen presenting cells (APCs). Upon expression and translocation to the nucleus,
CIITA acts as a non-DNA binding transcriptional coactivator by interacting with the enhanceosome
complex. This complex consists of several constitutively-expressed DNA-bound factors
preassembled at MHC-II promoters. CIITA then nucleates various transcription factors and
chromatin modifiers necessary to activate the transcription of the human leukocyte antigen (HLA)-
DM, HLA-DO and invariant chain (Ii) molecules, which are involved in intracellular antigen
processing, as well as of the cell surface “classical” HLA-DR, HLA-DP and HLA-DQ glycoproteins,
which physically present antigens to CD4+ T helper cells. Based on this, we anticipated that AdV-
mediated delivery of CIITA would convert GBM cancer cells into APC-like cells capable of priming
and activating CD4+ Th cells, which is a necessary requirement for eliciting anti-tumor effector
immune responses.
The first chapter of the thesis results covers the development and characterization of an ex vivo
preclinical model consisting of patient-derived GBM organoids co-cultured with immune cells,
defined here as immunocompetent GBM organoids. This model served the purpose of functionally
evaluating immune-mediated responses against tumors. We observed that immunocompetent
GBM organoids allow to recapitulate tumor-immune cell crosstalk ex vivo and represent an
advanced model for functional ex vivo assays in a reproducible manner.
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In the second chapter of the thesis results, we achieved successful construction and production of
a CIITA-armed AdV (Ad-CIITA), utilizing a replication-defective Ad5 backbone. AdV controls included
a promoter-only vector (Ad-null), a CIITA transgene carrying a missense point mutation (Ad-CIITA
mutant), and a green fluorescent protein (GFP)-encoding transgene (Ad-GFP). We demonstrated a
successful induction of MHC-II expression at the cell membrane mediated through CIITA in infected
cell lines and primary GBM organoids. Infection with an AdV carrying a mutant form of CIITA
resulted in the cytoplasmic accumulation of CIITA without subsequent MHC-II expression.
In the third chapter of the thesis results, we tested the functionality of the CIITA-armed viruses to
initiate adaptive immune responses in immunocompetent GBM organoids. In our ex vivo model,
tumor organoids infected with Ad-CIITA underwent significant disruption and tumor cell death, an
effect that was exclusively observed in the presence of immune cells. Of note, Ad-CIITA mutant, but
not Ad-GFP and Ad-null, induced the same immune cell-mediated killing phenotype as Ad-CIITA.
These results indicate that the effect observed follows a CIITA-induced MHC-II-independent
mechanism, challenging the initial hypothesis of MHC-II-mediated antigen presentation as the
mechanism implicated in T cell-mediated killing. We further showed that cancer cell death required
direct contact between GBM and immune cells, though none of the canonical death pathways
seemed to be activated. In conclusion, our results suggest that the delivery of CIITA transgene via
AdV vectors could be an effective approach to enhance immune-mediated responses against GBM
Towards the application of alginate cell microencapsulation technologies to treat brain tumors
Full text linkEén van de grootste uitdagingen in de oncologie is het vinden van een succesvolle behandeling tegen hersentumoren. Ondanks geavanceerde behandelingsmogelijkheden, zoals tumormassa debulking door middel van bestraling en chemotherapie, is tumor recidief onvermijdelijk, met een overleving van minder dan 15 maanden. De aanwezigheid van de bloed-hersen barrière (BBB) bemoeilijkt behandeling. Dit proefschrift richt zich op de technologie van alginaat-gebaseerde cel inkapseling als een alternatieve behandelingsmethode voor hersentumoren. Deze technologie blijkt een effective behandeling tegen hersentumoren in preklinische modellen, maar mechanische stabiliteit van microcapsules, variatie tussen-laboratoria in coating en met name het uitsteken van cellen staan klinische toepassing in de weg. Deze cruciale problemen worden stap voor stap in dit proefschrift aangepakt, met als doel een nieuw inkapselingssysteem te ontwikkelen die klinische toepasbaar is
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Functionnal validation of a new therapeutic strategy preventing degeneration and associated cognitive impairments in murine models of Alzheimer’s Disease
No full textAucun traitement de la maladie d’Alzheimer (MA) n’existe, justifiant le développement de stratégies thérapeutiques. La toxicité des oligomères solubles du peptide amyloïde β (Aβ) est centrale dans les pertes synaptiques et cellulaires précoces dans la maladie. Dans le cadre de cette hypothèse, nous proposons qu’empêcher ces effets puisse prévenir le déclin cognitif dans la MA. Les facteurs neurotrophiques sont de bons candidats pour prévenir la mort cellulaire mais nécessitent une application ciblée et continue. Nous avons utilisé la technologie d’encapsulation cellulaire pour produire des bioréacteurs implantables contenant des cellules C2C12 sécrétant le facteur neurotrophique ciliaire (CNTF). Notre objectif était d’établir la preuve du concept que la production à long terme de CNTF in situ dans le cerveau puisse prévenir les déficits cognitifs liés à l’Aβ.Nos études prouvent que le CNTF produit par les bioréacteurs prévient la cytotoxicité et l’apoptose induites par le peptide Aβ in vitro. La neuroprotection dépend de l’activation de la PI3-Kinase et du facteur STAT3. In vivo, l’implantation des bioréacteurs dans le cerveau prévient les troubles cognitifs induits par l’injection icv d’Aβ ou retarde leur apparition chez la souris Tg2576. Dans nos deux modèles précliniques de la MA, la protection comportementale est associée au maintien des protéines synaptiques dans l’hippocampe. Aussi, la production in situ de CNTF est une approche thérapeutique préventive efficace contre la toxicité et les déficits cognitifs liés à l’Aβ. Ces résultats suggèrent également que l’implantation de cellules encapsulées est un bon procédé pour délivrer des molécules thérapeutiques au cerveauNo cure against Alzheimer’s Disease (AD) exists yet, justifying the development of therapeutic strategies. Toxicity of soluble amyloid β peptide is a key-player in early synaptic and cellular loss in AD. According to this hypothesis, we propose that preventing Aβ peptide effects could prevent cogninitive decline in AD. Neurotrophic factors are good candidates to prevent cell death but require a targeted and continuous delivery. We used the cell encapsulation technology to produce graftable bioreactors that contain C2C12 cells secreting the Ciliary Neurotrophic factor (CNTF). Our goal was to realize the proof-of-concept that CNTF long term in situ delivery could prevent Aβ-induced cognitive decline.Our studies prove that bioreactor-produced CNTF prevents Aβ-induced cytotoxicity and apoptosis in vitro. Neuroprotection relies on PI3K and STAT3 activation. In vivo, bioreactor implantation in brain prevents cognitive impairment induced by Aβ icv injection or delays their appearance in Tg2576 mice. In both of our preclinical model of AD, behavioral protection was associated with synapse maintenance in hippocampus.Therefore, in situ long term CNTF delivery is an efficient preventive therapeutic strategy against toxicity and Aβ-linked cognitive disturbances. These results also suggest that encapsulated cells graft is a good way to deliver therapeutic molecules to the brai
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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