Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy

Conceptual Design Tool for Structural Layout Optimization in the Early Design Phase

This thesis develops a conceptual design tool capable of generating optimized structural layout suggestions for building design in the early design phase. The structural layout of a building is the arrangement and design of the load-bearing elements that support the weight of the building and resist external forces. The structural layout in this project solely consists of prefabricated reinforced (RC) elements. The use of prefabricated RC elements is embedded in the Danish construction industry and will likely remain so in the foreseeable future. Therefore, there is great potential for more effective use of concrete in terms of sustainability and decreasing cost. The proposed design tool can help fulfill this potential. Action Research (AR) is used to create the conceptual framework of the design tool. The AR analysis consists of semi-structured interviews and a co-creation workshop where architects, engineers, and contractors contribute to the development of the design tool to ensure that the final tool conforms to real-world practice. The final design tool is based on this framework and developed using four core principles: optimization, interactivity, dissemination, and automation. A novel parametric modeling method is developed in the design tool called Adjacent Polygon (APoly) representation. The APoly method creates a dynamic parametric representation of a given building plan to generate diverse yet feasible structural layout suggestions. The evaluation modules of different structural typologies are constructed using surrogate models in the form of Neural Networks. The surrogate models are combined in a hierarchical structure to create an algorithm capable of predicting the optimized geometry and corresponding cost for a structural element based on the external conditions inputted into the algorithm. The entire network of prediction models is then combined with a meta-heuristic optimization algorithm in the form of a Genetic Algorithm (GA) to create a surrogate-assisted optimization framework. A repair algorithm is incorporated into the GA to increase the number of valid solutions generated during each optimization iteration to decrease the convergence time. The performance and reliability of the design tool are validated through two groups of local and global case studies. The first group consists of parameter sensitivity studies on the local approximation modules for each structural typology. The second group of validation studies examines the design tool’s effectiveness across relevant building plans and scenarios. The corresponding results demonstrate that the tool can effectively adapt to these different settings and produce optimized structural layout suggestions. It is also demonstrated that the design tool can conduct multi-objective optimization and produce a front of Pareto optimal solutions

Kraftoverføringens kulturminner

Dette er den tredje av NVEs fire temaplaner om vassdrags- og energisektorens kulturminner. Denne gangen handler det om historien til en av de viktigste bærebjelkene i vårt moderne velferdssamfunn: overføringssystemet som er en sentral del av elektrisitetsforsyningen, de forbindelsene som bringer strømmen fra kraftstasjonene til forbrukern

Kortlægning af forskningslitteratur om effekter af måder at udøve offentlig ledelse på: Empirisk evidens i en dansk kontekst

Denne litteraturkortlægning er en af tre separate ’Litteraturkortlægninger af ledelsesforskning og forskning i lederuddannelser’, som Dansk Center for Forskningsanalyse ved Aarhus Universitet udfører for Styrelsen for Forskning og Uddannelse. De tre kortlægninger omhandler eksisterende litteratur indenfor effekt og effektmåling af offentlige lederuddannelser, effekter af måder at udøve offentlig ledelse på og effekter af didaktiske virkemidler og rammer for udvikling og efteruddannelse af offentlig ledere.&nbsp

Multi-Modality Therapeutics with Potent Anti-Tumor Effects: Photochemical Internalization Enhances Delivery of the Fusion Toxin scFvMEL/rGel

BACKGROUND: There is a need for drug delivery systems (DDS) that can enhance cytosolic delivery of anti-cancer drugs trapped in the endo-lysosomal compartments. Exposure of cells to specific photosensitizers followed by light exposure (photochemical internalization, PCI) results in transfer of agents from the endocytic compartment into the cytosol. METHODOLOGY AND PRINCIPAL FINDINGS: The recombinant single-chain fusion construct scFvMEL/rGel is composed of an antibody targeting the progenitor marker HMW-MAA/NG2/MGP/gp240 and the highly effective toxin gelonin (rGel). Here we demonstrate enhanced tumor cell selectivity, cytosolic delivery and anti-tumor activity by applying PCI of scFvMEL/rGel. PCI performed by light activation of cells co-incubated with scFvMEL/rGel and the endo-lysosomal targeting photosensitizers AlPcS(2a) or TPPS(2a) resulted in enhanced cytotoxic effects against antigen-positive cell lines, while no differences in cytotoxicity between the scFvMEL/rGel and rGel were observed in antigen-negative cells. Mice bearing well-developed melanoma (A-375) xenografts (50-100 mm(3)) were treated with PCI of scFvMEL/rGel. By 30 days after injection, approximately 100% of mice in the control groups had tumors>800 mm(3). In contrast, by day 40, 50% of mice in the PCI of scFvMEL/rGel combination group had tumors<800 mm(3) with no increase in tumor size up to 110 days. PCI of scFvMEL/rGel resulted in a synergistic effect (p<0.05) and complete regression (CR) in 33% of tumor-bearing mice (n = 12). CONCLUSIONS/SIGNIFICANCE: This is a unique demonstration that a non-invasive multi-modality approach combining a recombinant, targeted therapeutic such as scFvMEL/rGel and PCI act in concert to provide potent in vivo efficacy without sacrificing selectivity or enhancing toxicity. The present DDS warrants further evaluation of its clinical potential

Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy

Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface

Role of ER Stress Response in Photodynamic Therapy: ROS Generated in Different Subcellular Compartments Trigger Diverse Cell Death Pathways

We have analyzed the molecular mechanisms of photoinduced cell death using porphyrins with similar structure differing only in the position of the ethylene glycol (EG) chain on the phenyl ring. Meta- and para-positioned EG chains targeted porphyrins to different subcellular compartments. After photoactivation, both types of derivatives induced death of tumor cells via reactive oxygen species (ROS). Para derivatives pTPP(EG)4 and pTPPF(EG)4 primarily accumulated in lysosomes activated the p38 MAP kinase cascade, which in turn induced the mitochondrial apoptotic pathway. In contrast, meta porphyrin derivative mTPP(EG)4 localized in the endoplasmic reticulum (ER) induced dramatic changes in Ca2+ homeostasis manifested by Ca2+ rise in the cytoplasm, activation of calpains and stress caspase-12 or caspase-4. ER stress developed into unfolded protein response. Immediately after irradiation the PERK pathway was activated through phosphorylation of PERK, eIF2α and induction of transcription factors ATF4 and CHOP, which regulate stress response genes. PERK knockdown and PERK deficiency protected cells against mTPP(EG)4-mediated apoptosis, confirming the causative role of the PERK pathway