Degradation of HIF-1alpha under Hypoxia Combined with Induction of Hsp90 Polyubiquitination in Cancer Cells by Hypericin: a Unique Cancer Therapy

The perihydroxylated perylene quinone hypericin has been reported to possess potent anti-metastatic and antiangiogenic activities, generated by targeting diverse crossroads of cancer-promoting processes via unique mechanisms. Hypericin is the only known exogenous reagent that can induce forced poly-ubiquitination and accelerated degradation of heat shock protein 90 (Hsp90) in cancer cells. Hsp90 client proteins are thereby destabilized and rapidly degraded. Hsp70 client proteins may potentially be also affected via preventing formation of hsp90-hsp70 intermediate complexes. We show here that hypericin also induces enhanced degradation of hypoxia-inducible factor 1α (HIF-1α) in two human tumor cell lines, U87-MG glioblastoma and RCC-C2VHL−/− renal cell carcinoma and in the non-malignant ARPE19 retinal pigment epithelial cell line. The hypericin-accelerated turnover of HIF-1α, the regulatory precursor of the HIF-1 transcription factor which promotes hypoxic stress and angiogenic responses, overcomes the physiologic HIF-1α protein stabilization which occurs in hypoxic cells. The hypericin effect also eliminates the high HIF-1α levels expressed constitutively in the von-Hippel Lindau protein (pVHL)-deficient RCC-C2VHL−/− renal cell carcinoma cell line. Unlike the normal ubiquitin-proteasome pathway-dependent turnover of HIF-α proteins which occurs in normoxia, the hypericin-induced HIF-1α catabolism can occur independently of cellular oxygen levels or pVHL-promoted ubiquitin ligation of HIF-1α. It is mediated by lysosomal cathepsin-B enzymes with cathepsin-B activity being optimized in the cells through hypericin-mediated reduction in intracellular pH. Our findings suggest that hypericin may potentially be useful in preventing growth of tumors in which HIF-1α plays pivotal roles, and in pVHL ablated tumor cells such as renal cell carcinoma through elimination of elevated HIF-1α contents in these cells, scaling down the excessive angiogenesis which characterizes these tumors

An iconic language for the graphical representation of medical concepts

<p>Abstract</p> <p>Background</p> <p>Many medication errors are encountered in drug prescriptions, which would not occur if practitioners could remember the drug properties. They can refer to drug monographs to find these properties, however drug monographs are long and tedious to read during consultation. We propose a two-step approach for facilitating access to drug monographs. The first step, presented here, is the design of a graphical language, called VCM.</p> <p>Methods</p> <p>The VCM graphical language was designed using a small number of graphical primitives and combinatory rules. VCM was evaluated over 11 volunteer general practitioners to assess if the language is easy to learn, to understand and to use. Evaluators were asked to register their VCM training time, to indicate the meaning of VCM icons and sentences, and to answer clinical questions related to randomly generated drug monograph-like documents, supplied in text or VCM format.</p> <p>Results</p> <p>VCM can represent the various signs, diseases, physiological states, life habits, drugs and tests described in drug monographs. Grammatical rules make it possible to generate many icons by combining a small number of primitives and reusing simple icons to build more complex ones. Icons can be organized into simple sentences to express drug recommendations. Evaluation showed that VCM was learnt in 2 to 7 hours, that physicians understood 89% of the tested VCM icons, and that they answered correctly to 94% of questions using VCM (versus 88% using text, <it>p </it>= 0.003) and 1.8 times faster (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>VCM can be learnt in a few hours and appears to be easy to read. It can now be used in a second step: the design of graphical interfaces facilitating access to drug monographs. It could also be used for broader applications, including the design of interfaces for consulting other types of medical document or medical data, or, very simply, to enrich medical texts.</p

Cognitive Ability Evaluation using Virtual Reality and Eye Tracking

This work aims to create a virtual reality (VR) representation of Ravens progressive matrices (RPM) and apply available eye tracking (ET) technology to determine where the test person\u27s eye gaze is located during the test. RPM are developed to evaluate abstract reasoning and there is a possibility to further understand the mental processes of the test person by adding ET. The result of this project is a test scenario where the user completes ten tasks from RPM in a VR environment. Reports containing heat maps and trajectories describing the eye gaze together with times and results of the tasks are automatically generated after the test has been completed. This extended information which is automatically gathered is meant to further expand the toolbox that psychologists use when performing psychological testing and might aid them in improving the accuracy of the results obtained from these tests

Generation of STEP AP214 models from discrete event systems for process planning and control

The aim of this paper is to show how the international standard STEP-AP214 can be used for communication and storing of process specifications. Even though there are several software tools available for the generation of both product and resource information systems, there is still a lack of tools related to the STEP standard for producing process information, e.g., sequence of operations and system capabilities for resource allocation. Therefore, such a tool is suggested, which makes use of a high-level language for discrete-event systems based on process algebra and Petri nets. This language, called process algebra Petri net), has been developed in accordance with the process relations defined in STEP-AP214. More specifically, it is shown how process specifications created with the PPN tool can be mapped to the STEP AP-214 format. Note to Practioners-Rapidly changing market needs is making demands on flexibility and ability to shorten lead times. Standards for exchanging information, as well as formal methods for automatic development of programmable controller code have been important research topics for many years. There are a lot of software tools available for the generation of both product- and resource information, but there is still a lack of tools for producing process information. Moreover, the connection between information exchange standards and such tools is absent, which makes the development of programmable controller code an isolated activity. This activity is often time consuming and performed in an ad hoc manner resulting in unnecessary production delay. The aim of this paper is to show how the international standard STEP-AP214 (a standard for exchange of product-, process-, and resource related information) can be used for communicating and storing process specifications. In order to achieve this, a tool which makes use of a formal high-level language is suggested. This tool can be used for automatic control generation and has been developed in accordance with the process relations defined in STEP-AP214. A further aim is to shown how the mentioned tool can be used to specify complex systems in a compact, yet highly readable manner, which is a crucial incentive for industry to use formal methods. The presented method will guarantee-that expected information is delivered quickly and without errors caused by the human factor, something that is very important in our ambition to achieve shortened lead times. The quick information exchange also makes it possible to perform simulation, supervisor synthesis, and verification early in the development phase. This is a first attempt at using a formal language for creating a tool that can automatically generate specifications in accordance with the international STEP-standard

Knowledge Acquisition and Modeling in Clinical Information Systems: A Case Study

The goal of the MedView project is to develop models, methods, and tools to support clinicians in their daily work and research. MedView is based on a formal declarative model, which constitutes the main governing principle in MedView, not only in the formalization of knowledge, but in visualization models and in the design and implementation of individual tools and the system as a whole as well. Tools are provided for modeling, acquiring, and sharing knowledge, and for visualization and analysis of data

SOMWeb: A Semantic Web-Based System for Supporting Collaboration of Distributed Medical Communities of Practice

Background: Information technology (IT) support for remote collaboration of geographically distributed communities of practice (CoP) in health care must deal with a number of sociotechnical aspects of communication within the community. In the mid-1990s, participants of the Swedish Oral Medicine Network (SOMNet) began discussing patient cases in telephone conferences. The cases were distributed prior to the conferences using PowerPoint and email. For the technical support of online CoP, Semantic Web technologies can potentially fulfill needs of knowledge reuse, data exchange, and reasoning based on ontologies. However, more research is needed on the use of Semantic Web technologies in practice. Objectives: The objectives of this research were to (1) study the communication of distributed health care professionals in oral medicine; (2) apply Semantic Web technologies to describe community data and oral medicine knowledge; (3) develop an online CoP, Swedish Oral Medicine Web (SOMWeb), centered on user-contributed case descriptions and meetings; and (4) evaluate SOMWeb and study how work practices change with IT support. Methods: Based on Java, and using the Web Ontology Language and Resource Description Framework for handling community data and oral medicine knowledge, SOMWeb was developed using a user-centered and iterative approach. For studying the work practices and evaluating the system, a mixed-method approach of interviews, observations, and a questionnaire was used. Results: By May 2008, there were 90 registered users of SOMWeb, 93 cases had been added, and 18 meetings had utilized the system. The introduction of SOMWeb has improved the structure of meetings and their discussions, and a tenfold increase in the number of participants has been observed. Users submit cases to seek advice on diagnosis or treatment, to show an unusual case, or to create discussion. Identified barriers to submitting cases are lack of time, concern about whether the case is interesting enough, and showing gaps in one’s own knowledge. Three levels of member participation are discernable: a core group that contributes most cases and most meeting feedback; an active group that participates often but only sometimes contribute cases and feedback; and a large peripheral group that seldom or never contribute cases or feedback. Conclusions: SOMWeb is beneficial for individual clinicians as well as for the SOMNet community. The system provides an opportunity for its members to share both high quality clinical practice knowledge and external evidence related to complex oral medicine cases. The foundation in Semantic Web technologies enables formalization and structuring of case data that can be used for further reasoning and research. Main success factors are the long history of collaboration between different disciplines, the user-centered development approach, the existence of a “champion” within the field, and nontechnical community aspects already being in place