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Background: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined.
Methods: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNγ) enzyme linked immunospot assay (ELISPOT).
Results: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients.
Conclusions: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.
Trial registration: NCT01598129. Registered 19/04/2012
Um zukünftig den städtischen Verkehr – vor allem in Städten und Regionen mit Bevölkerungszuwächsen – ökologisch nachhaltiger abzuwickeln und gleichzeitig die Stadt als attraktiven Wohnort zu gestalten, wird aktuell in Forschung und Praxis eine Vielzahl unterschiedlicher Konzepte diskutiert und erprobt. Eine mögliche stadtplanerische Maßnahme in diesem Kontext ist die Entwicklung autofreier oder autoreduzierter Stadtquartiere. Im Rahmen bisheriger wissenschaftlicher Untersuchungen sind die Voraussetzungen für die Umsetzung solcher Konzepte meist eher unzureichend dokumentiert und analysiert worden. In dieser Forschungsarbeit wurde deshalb untersucht, welche Relevanz verschiedene stadt- und projektbezogene Rahmenbedingungen und Einflussfaktoren bei der Entwicklung autofreier bzw. autoreduzierter Stadtquartiere besitzen.
Wenngleich bei der Realisierung autofreier oder autoreduzierter Projekte zahlreiche Faktoren wirksam sind, können als Ergebnis der Untersuchung vor allem zwei Aspekte als entscheidend für eine erfolgreiche Umsetzung solcher Projekte betrachtet werden. Dies ist zunächst eine ausreichende Unterstützung der Projekte durch die städtische Politik und Verwaltung. Als zweiter wesentlicher Einflussfaktor kann eine Förderung autofreier und autoreduzierter Projekte durch private Initiativen und Vereine gelten.
Trotz einer fast 30-jährigen Forschungs- und Umsetzungshistorie stellen Projekte zum Aufbau integrierter Datenhaushalte (Data Warehouses) für Unternehmen immer noch eine große Herausforderung dar. Gerade in Data Warehouse-Projekten bei Finanzdienstleistern führt eine hohe semantische Komplexität häufig zu Projektverzögerungen oder zum Scheitern der Vorhaben. Dies zeigt die Arbeit anhand von explorativen Fallstudien auf und fragt nach den Gründen für diesen typischen Verlauf. Eine mögliche Ursache liegt in einer unzureichenden Kommunikation zwischen den Projektbeteiligten, was zu Missverständnissen in der Konzeption und somit zu Fehlimplementierungen führt, die – gerade wenn sie spät erkannt werden – deutliche Verzögerungen und Budgetüberschreitungen zur Folge haben. Ausgehend von diesen beobachteten Praxisproblemen sucht die vorliegende Arbeit auf der Grundlage des Design-Science-Research nach Lösungsansätzen: unter Übertragung der Erkenntnisse der Kommunikationstheorie wurden drei Artefakte entwickelt, sukzessive verbessert und validiert. Die Paper zeigen auf, dass sich durch den Einsatz formalisierter Templates, eines verbesserten Vorgehensmodells in Verbindung mit einem korrespondieren Softwaretool das Kommunikationsverhalten in den Projekten verbessern lässt und somit eine höhere Projekt-Performance erreicht wird. Hierzu wurden insgesamt sechs Projekte zum Aufbau von Data Warehouses im Finanzdienstleistungsumfeld in Fallstudien analysiert und zudem Experten-Interviews mit den Projektbeteiligten durchgeführt, die im Ergebnis die positive Wirkung der Artefakte unterstützen.
Basierend auf den Daten der Erhebung „Gesundheit in Deutschland Aktuell“ von 2010 (GEDA2010)vom Robert Koch-Institut wird in dieser Dissertation der Frage nachgegangen, wie sich
Arbeitsbedingungen auf die Gesundheit und das Gesundheitsverhalten auswirken und eine systematische Analyse für Deutschland durchgeführt. Dabei werden sowohl Aspekte der Geschlechterforschung als auch der Erforschung sozialer Ungleichheiten mitbetrachtet. Die Ergebnisse liefern unteranderem Hinweise darauf, dass Gesundheitsverhalten als Coping-Strategie in stressreichen Arbeitssituationen, die beispielsweise durch Leistungsdruck oder Schichtarbeit gekennzeichnet sind, genutzt wird.
SAFE Newsletter : 2016, Q2
(2016)
Random ordinary differential equations (RODEs) are ordinary differential equations (ODEs) which have a stochastic process in their vector field functions. RODEs have been used in a wide range of applications such as biology, medicine, population dynamics and engineering and play an important role in the theory of random dynamical systems, however, they have been long overshadowed by stochastic differential equations.
Typically, the driving stochastic process has at most Hoelder continuous sample paths and the resulting vector field is, thus, at most Hoelder continuous in time, no matter how smooth the vector function is in its original variables, so the sample paths of the solution are certainly continuously differentiable, but their derivatives are at most Hoelder continuous in time. Consequently, although the classical numerical schemes for ODEs can be applied pathwise to RODEs, they do not achieve their traditional orders.
Recently, Gruene and Kloeden derived the explicit averaged Euler scheme by taking the average of the noise within the vector field. In addition, new forms of higher order Taylor-like schemes for RODEs are derived systematically by Jentzen and Kloeden.
However, it is still important to build higher order numerical schemes and computationally less expensive schemes as well as numerically stable schemes and this is the motivation of this thesis. The schemes by Gruene and Kloeden and Jentzen and Kloeden are very general, so RODEs with special structure, i.e., RODEs with Ito noise and RODEs with affine structure, are focused and numerical schemes which exploit these special structures are investigated.
The developed numerical schemes are applied to several mathematical models in biology and medicine. In order to see the performance of the numerical schemes, trajectories of solutions are illustrated. In addition, the error vs. step sizes as well as the computational costs are compared among newly developed schemes and the schemes in literature.
The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by β-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2–4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted.
Dang Hyang Astapaka and his cultural geography in spreading Vajrayana Buddhism in medieval Bali
(2016)
The sway of Hinduism and Buddhism in Indonesia archipelago had imprinted deep cultural heritages in various modes. The role of holy persons and kings were obvious in the spread of these religious and philosophical traditions. Dang Hyang Asatapaka, a Buddhist priest from East Java had travelled to Bali in spreading Vajrayana sect of Mahayana Buddhist in 1430. He came to Bali as the ruler of Bali invited him to officiate Homa Yajna together with his uncle Dang Hyang Nirartha, who had stayed earlier in Bali. Impressed with deep knowledge and spiritual acumen of him, the ruler Waturenggong King appointed him as a purohito (palace priest), whose jobs were to give spiritual consultation and political advisor in ruling the country. During his life times in Bali, he travelled from one place to another spreading Vajrayana sect of Buddhism. Lastly he settled in Budakeling village in East Bali where he built gerya (house) and temples for worship and meditation. From here he, his descents, and followers spread the Vajrayana to all over Bali and Lombok. He left us with Vajrayana sect of Buddhism, which was assimilated with Saivism. Dang Hyang Astapaka and his uncle Dang Hyang Nirartha were the advocators of Saiva-Buddha cult in Bali backed up by the rulers.
Understanding the shift from micro to macro-prudential thinking: a discursive network analysis
(2016)
While some economists argued for macro-prudential regulation pre-crisis, the macro-prudential approach and its emphasis on endogenously created systemic risk have only gained prominence post-crisis. Employing discourse and network analysis on samples of the most cited scholarly works on banking regulation as well as on systemic risk (60 sources each) from 1985 to 2014, we analyze the shift from micro to macro-prudential thinking in the shift to the post crisis period. Our analysis demonstrates that the predominance of formalism, particularly, partial equilibrium analysis along with the exclusion of historical and practitioners’ styles of reasoning from banking regulatory studies impeded economists from engaging seriously with the endogenous sources of systemic risk prior to the crisis. Post-crisis, these topics became important in this discourse, but the epistemological failures of banking regulatory studies pre-crisis were not sufficiently recognized. Recent attempts to conceptualize and price systemic risk as a negative externality point to the persistence of formalism and equilibrium thinking, with its attending dangers of incremental innovation due to epistemological barriers constrains theoretical progress, by excluding observed phenomena, which cannot yet be accommodated in mathematical models.