Combination therapies in a patient-derived glioblastoma model

__Abstract__ Glioblastoma is the most malignant primary brain tumor. Glioblastoma is originating from the supportive tissue of the brain, the glial cells. Despite increased research, mortality rates have not decreased significantly. Standard therapy consists of surgical resection, temozolomide and radiation therapy. The survival rate is despite maximum treatment 14.6 months. We are currently learning more about markers that correlate to response to treatment, the most important being the MGMT promoter methylation status. One of the issues that prevents treatments from being effective is the multiple escape routes glioblastoma has, to circumvent cell death. We aim to tackle this issue using combination therapies in a representative model, namely the patient-derived glioblastoma stem-like cell (GSC) model. This model reflects the molecular characteristics of the original tumor. This model allows studying novel treatment strategies in the context of heterogeneity in response to therapy, and in the context of analyzing molecular differences underlying response. In this thesis, we apply these concepts in a broad range of treatment modalities including combination therapeutics. We aim at optimizing the treatment with enhancers of radiation and of experimental oncolytic virotherapy. We have also used the approach of clinical drug screening in order to repurpose clinical drugs. We aimed at finding clinically applied drugs that may be candidates for glioblastoma treatment. Part I of this manuscript describes studies on new therapeutic regimens using HDACi in combination with radiation, and using a large clinical drug screen. In Chapter 3 we show that the histone deacetylase inhibitors (HDACi) SAHA, VPA, MS275, LBH589 and Scriptaid, are radiosensitizers in a significant proportion of GSCs. The observed variations in sensitivity show a relationship with molecular characteristics of the specific cultures. Regarding the clinically most relevant HDACi (SAHA and LBH589), differences in the DNA damage and apoptotic response were found between responsive and resistant cultures. Various identified associated molecules that warrant further exploration as candidate response markers are pChek2 for both SAHA/radiation (RTx) and LBH589/RTx, and in addition Bcl-XL for LBH589/RTx with positive predictive values of 90% and 100%. In Chapter 4 we emphasize the efficacy of the Bcl-2 family pathway inhibition by Obatoclax to reach sensitization of GSCs to HDACi and HDACi/RTx, circumventing a tumor-related resistance mechanism to treatment. The Bcl-2 family proteins are heterogeneously expressed in glioblastoma and 30% to 60% of tumors shows overexpression. We demonstrate that Obatoclax synergized with HDACi and showed efficacy in a large set of GSCs. This pathway is an adequate target to inhibit, in order to achieve better therapeutic efficacy, also in HDACi/RTx therapy. We identified predictive gene expression profiles for the combination treatments with Obatoclax that are associated with cellular regulatory functions. In Chapter 5 we screened a large drug collection in order to repurpose clinical drugs for the treatment of glioblastoma. This has led to the identification of three clinical compounds that have potential for treating glioblastoma: amiodarone, clofazimine and triptolide. The drugs were selected based on efficacy in GSCs and lack of toxicity in normal human astrocytes. Twenty GSCs were tested for this purpose. Clofazimine and triptolide have previously been identified as potent inhibitors of immortalized glioma cell lines. Amiodarone is a novel candidate for glioblastoma treatment as a single agent. Part II of this manuscript describes studies on combination therapeutics for oncolytic virus therapy with Delta24-RGD. Delta24-RGD is a conditionally replicating oncolytic virus that has ended phase I/II testing in patients with glioblastoma. To enhance efficacy of oncolytic virus therapy, combination therapies are needed. First of all we tested whether anti-epileptic drugs interacted with Delta24-RGD efficacy. The three agents valproic acid (a weak HDACi), phenytoin and levetiracetam were studied. HDACi have been reported to alter oncolytic viral activity. In Chapter 6 we illustrate that therapeutic levels of the most frequently prescribed anticonvulsants valproic acid, phenytoin and levetiracetam do not negatively influence the oncolytic activity of Delta24-RGD. In some cells, additive effects between drugs and the virus were observed. In Chapter 7 we show that the novel pan-HDACi Scriptaid and LBH589, which have stronger HDACi activity than valproic acid, exert enhanced anti-tumor activity in combination with Delta24-RGD in GSCs. These HDACi induced slight up-regulation of cell surface integrins, facilitating adenoviral entry and leading to increased levels of viral gene expression. The HDACi induced cell death pathways in the GSCs, thereby accelerating the virus-induced killing of the infected cells but slightly hampering the viral progeny production. The concerted action of these two treatment modalities leads to improved anti-tumor efficacy and shows limited toxicity in normal human astrocytes. Taken together, Scriptaid and LBH589 offer opportunities as potential candidates for future Delta24-RGD combination studies. Triggered by the long duration of the process of implementation of novel drugs in clinical practice, we aimed at finding effective viral sensitizers by performing a clinical drug screen. Chapter 8 describes the identification of four effective viral sensitizers for oncolytic virotherapy, including fluphenazine, indirubin, lofepramine and ranolazine. We reveal interaction of the drugs with important viral oncolytic cell death mechanism as shown in silico and in vitro. These drugs, that are known to pass the blood brain barrier, are not only applicable in glioblastoma but show synergy with Delta24-RGD in multiple cancer types. Moreover, all drugs showed synergistic activity with other oncolytic viruses as well

Gestão Centrada No Ser Humano: O Caso de dois Coordenadores de Cursos de IES de Foz do Iguaçu

No artigo analisa-se a mudança de paradigma que ocorreu no gerenciamento a partir do desenvolvimento da teoria dos sistemas abertos. Caracteriza-se e analisa-se, também, de maneira comparativa o estilo tradicional de gerenciamento baseado no modelo Estratégia- Estrutura-Sistemas, orientado para tarefas com o estilo gerencial baseado no modelo Objetivos-Processos-Pessoas, orientado para pessoas. Descreve-se e analisa-se a evolução do conceito de organização na era industrial. Enfatiza-se a importância da compreensão de que se vive numa sociedade de organizações. Descreve-se a importância das organizações como mecanismo de crescimento econômico e de controle social. Finaliza-se o texto enfatizando a importância do ser humano para se atingir resultados organizacionais na chamada sociedade do conhecimento

Aprendizagem Gerencial Construtivista: O Caso de Supervisão em Estágios Acadêmicos

Neste texto, procura-se especular teoricamente a possibilidade de criação de uma pedagogia gerencial ancorada nos fundamentos da pedagogia freireana. O norteamento do texto se dá no pressuposto de que a aprendizagem gerencial deve levar em conta toda a multidimensionalidade do ser humano. O gerente humanista deve ser capaz de complementar a sua aprendizagem formal no seu ambiente de prática por meio da ação e da reflexão. Acredita-se que a aprendizagem é um processo inacabado e infinito. Finaliza-se o ensaio com a convicção de que aprender é o ponto de partida e o ponto de chegada no processo de tornarse um ser humano mais humano e mais flexível

Currarino's triad diagnosed in an adult woman.

_Purpose_ To report on a female patient diagnosed with Currarino's triad in adulthood. _Case report_ This case presents an adult patient with a medical history of a congenital anal atresia, a partial sacral agenesis, and a surgically treated ectopic anus. After a coincidentally observed presacral mass by MRI, due to unexplained constipation later in adulthood, Currarino's triad was suspected in this patient. This triad consists of anorectal malformation(s), sacrococcygeal defects and a presacral mass of various origin. Further investigation confirmed the mass to be a meningocele, and showed a tethered cord and a syrinx. _Conclusions_ In (young) patients with anorectal malformations, although having no other symptoms, further examination might be required to exclude Currarino's triad. Importance of early diagnosis and multidisciplinary assessment is recommended to establish adequate treatment if needed

ABT-888 enhances cytotoxic effects of temozolomide independent of MGMT status in serum free cultured glioma cells

Background: The current standard of care for Glioblastoma Multiforme (GBM) consists of fractionated focal irradiation with concomitant temozolomide (TMZ) chemotherapy. A promising strategy to increase the efficacy of TMZ is through interference with the DNA damage repair machinery, by poly(ADP-ribose) polymerase protein inhibition(PARPi). The o

Book Notes

Dense and green building typologies. Research, policy and practice perspectives by Thomas Schr\uf6pfer and Sacha Menz, Springer, Briefs in Architectural Design and Technology, Singapore, 2019, 119 pp. ISBN 978-981-13-0712-6.Gridded worlds. An urban anthology edited by Reuben Rose-Redwood and Liora Bigon, Springer, Cham, Switzerland, 2018, 293 pp. ISBN 978-3-319-76489-4. The Venice variations. Tracing the architectural imagination by Sophia Psarra, UCL Press, London, UK, 2018, 306 pp. ISBN 978-1-78735-241-4. Landscape as forma mentis. Interpreting the integral dimension of the anthropic space. Magnolia by Nicola Scardigno, FrancoAngeli, Milano, Italy, 2018, 207 pp. ISBN 978-88-917-6880-3.The poverty of territorialism. A Neo-Medieval view of Europe and European planning by Andreas Falludi, Edward Elgar Publishing, Elgar studies in planning theory, policy and practice Cheltenham, UK and Northampton, USA, 2018, 179 pp. ISBN 978-1-78897-360-1. Housing Estates in Europe. Poverty, Ethnic Segregation and Policy Challenges edited by Daniel Baldwin Hess, Tiit Tammaru and Maarten van Ham, The Urban Book Series, Springer Nature Switzerland, 2018, 424 pp ISBN 978-3-319-92812-8. The everyday experiences of reconstruction and regeneration: from vision to reality in Birmingham and Coventry byDavid Adams and Peter Larkham, Routledge, Abingdon, UK, 2019, 196 pp. ISBN 978–1–4724–7117–8.Towers for the welfare state: an architectural history of British multi-storey housing 1945–1970 by Stefan Muthesiusand Miles Glendinning, Scottish Centre for Conservation Studies, Edinburgh, UK, 2017, 266 pp. ISBN 978–1–9999205–2–4

Book review "The mathematics of urban morphology"

Book reviewThe mathematics of urban morphology, edited by Luca D’Acci, Birkh\ue4user, Springer Nature Switzerland, Cham, Switzerland, 2019, 564 pp. ISBN 978–3–030–12380–2

Typology based on three density variables central to Spacematrix using cluster analysis

[EN] Since the publication of the book ‘Spacematrix. Space, density and urban form’ (Berghauser Pont and Haupt, 2010), the Spacematrix method has been linked back to its theoretical foundations by Steadman (2013), is further developed using the measure of accessible density to arrive at a density measure that more closely relates to the environment as experienced by people moving through the city (Berghauser Pont and Marcus, 2014) which then is used to arrive at a multi-scalar density typology (Berghauser Pont et al. 2017). This paper will take yet another step in the development of the Spacematrix method by including the measure of network density in the classification which until now was not used to its full potential. Important for successful classification is the ability to ascertain the fundamental characteristics on which the classification is to be based where the work of Berghauser Pont and Haupt (2010) will be followed addressing three key variables: Floor Space Index (FSI), Ground Space Index (GSI) and Network density (N) where especially the last was not fully included in the earlier work. Besides a typology based on these three variables, this paper will also result in a robust statistical method that can later be used on larger samples for city-scale comparisons. Two statistical methods are tested: hierarchical clustering and centroid-based clustering and besides a general discussion about their strong and weak points, the paper shows that the hierarchical method is more convincing in distinguishing differences in both building type and street pattern that is especially captured with Network density (N). As this method is not useful for large datasets we propose a combination of the two clustering methods as the way forward.Berghauser Pont, M.; Olsson, J. (2018). Typology based on three density variables central to Spacematrix using cluster analysis. En 24th ISUF International Conference. Book of Papers. Editorial Universitat Politècnica de València. 1337-1348. https://doi.org/10.4995/ISUF2017.2017.5319OCS1337134

The Spacemate - Density and the Typomorphology of the Urban Fabric

This article deals with current changes in the urbanplanning and design practice, and presents a toolbased on the knowledge of the relationbetween physical density and urban form:The Spacemate

A SYSTEMATIC REVIEW OF MULTIFUNCTIONAL STREETS_Final research report

A state-of-the-art, quantitative systematic review of scientific literature on the theme of multifunctional streets was conducted, including scientific papers of the last 10 years, filtered from Web of Science and Scopus. The review is part of a 3-year research project (2019-2021) named: “Smart streets” (Smarta gator) led by Alexander St\ue5hle (KTH Royal Institute of Technology) and financed by Vinnova (Swedish governmental agency for Innovation systems). The research project aims to develop a Street Multifunctionality Index (Gatufunktionsindex) to assess how existing and designed streets combine five different street functions - Social, Ecologic, Economic, Technical and Traffic - and also produce design guidelines for the design and planning of future multifunctional streets, either in new infrastructure or via retrofits. Within this project, the aim of the systematic review is twofold: first, to assess the degree in which the multifunctionality of streets is addressed in recent literature and provide an overview of the field by identifying where the general literature on the subject is trending, which are the recurrent issues studied, what themes are missing or being understudied; second, since an end product of the research project is to provide guidelines for urban design and planning practice, the review aims to identify the physical factors which have been empirically proven to support the different street functions, and especially those which support multiple functions. The second aim is pursued through focused thematic reviews, which complement the general overview of the field