Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC50). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations

Interstitial fluid: the overlooked component of the tumor microenvironment?

Background: The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase, together constituting the tissue microenvironment. Here we focus on the interstitial fluid phase of tumors, i.e., the fluid bathing the tumor and stromal cells. Novel knowledge on this compartment may provide important insight into how tumors develop and how they respond to therapy. Results: We discuss available techniques for interstitial fluid isolation and implications of recent findings with respect to transcapillary fluid balance and uptake of macromolecular therapeutic agents. By the development of new methods it is emerging that local gradients exist in signaling substances from neoplastic tissue to plasma. Such gradients may provide new insight into the biology of tumors and mechanistic aspects linked to therapy. The emergence of sensitive proteomic technologies has made the interstitial fluid compartment in general and that of tumors in particular a highly valuable source for tissue-specific proteins that may serve as biomarker candidates. Potential biomarkers will appear locally at high concentrations in the tissue of interest and will eventually appear in the plasma, where they are diluted. Conclusions: Access to fluid that reliably reflects the local microenvironment enables us to identify substances that can be used in early detection and monitoring of disease

Biomedical informatics and translational medicine

Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics (e.g., bioinformatics, imaging informatics, clinical informatics, and public health informatics) may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics (Decision Support, Natural Language Processing, Standards, Information Retrieval, and Electronic Health Records) and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners ("biomedical informaticians") can be essential members of translational medicine teams

Solid targetry at the TESLA Accelerator Installation

According to the concept of the TESLA Accelerator Installation, the channel for production of radioisotopes has to routinely produce Tl-201, In-111, Ga-67, I-123 and F-18, and a number of other radionuclides for experimental purposes. The production of I-123 and F-18 will be performed in dedicated, commercial target stations, while a versatile solid target irradiation system is designed for the routine and experimental production of all other radioisotopes. The solid target station is designed to accept targets for both the 7degrees and 90degrees irradiation geometry. The targets used for the routine production will be prepared by electroplating on a silver substrate. They can be irradiated with a 1.5 kW beam using the 7degrees geometry. The cooling of these targets is enhanced by fins on the back of the silver substrate designed so that the highest temperature on the surface of the target does not exceed 110degreesC. The irradiation procedures will conform to the GMP requirements for the production of radio pharmaceuticals. The irradiated targets will be transported directly into the appropriate hot cell for radiochemical processing, All cells will be equipped with a target dissolution unit for etching the irradiated, electroplated film. After decontamination and sufficient cooling down, these targets will be reused several times. (C) 2001 Elsevier Science B.V. All rights reserved.20th World Conferenceof the International-Nuclear-Target-Development-Society (INTDS), Oct 02-06, 2000, Antwerp, Belgiu

WHO/ILO work-related burden of disease and injury: Protocol for systematic reviews of occupational exposure to dusts and/or fibres and of the effect of occupational exposure to dusts and/or fibres on pneumoconiosis

BACKGROUND: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing a joint methodology for estimating the national and global work-related burden of disease and injury (WHO/ILO joint methodology), with contributions from a large network of experts. In this paper, we present the protocol for two systematic reviews of parameters for estimating the number of deaths and disability-adjusted life years attributable to pneumoconiosis from occupational exposure to dusts and/or fibres, to inform the development of the WHO/ILO joint methodology. OBJECTIVES: We aim to systematically review studies on occupational exposure to dusts and/or fibres (Systematic Review 1) and systematically review and meta-analyse estimates of the effect of occupational exposure to dusts and/or fibres on pneumoconiosis (Systematic Review 2), applying the Navigation Guide systematic review methodology as an organizing framework. DATA SOURCES: Separately for Systematic Reviews 1 and 2, we will search electronic academic databases for potentially relevant records from published and unpublished studies, including Medline, EMBASE, Web of Science and CISDOC. We will also search electronic grey literature databases, Internet search engines and organizational websites; hand-search reference list of previous systematic reviews and included study records; and consult additional experts. STUDY ELIGIBILITY AND CRITERIA: We will include working-age (>/=15years) study participants in the formal and informal economy in any WHO and/or ILO Member State but exclude children (<15years) and unpaid domestic workers. Eligible risk factors will be dusts and/or fibres from: (i) asbestos; (ii) silica; and/or (iii) coal (defined as pure coal dust and/or dust from coal mining). Included outcomes will be (i) asbestosis; (ii) silicosis; (iii) coal worker pneumoconiosis; and (iv) unspecified pneumoconiosis. For Systematic Review 1, we will include quantitative prevalence studies of occupational exposure to dusts and/or fibres (i.e. no versus any exposure) stratified by country, sex, age and industrial sector or occupation. For Systematic Review 2, we will include randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of any occupational exposure to dusts and/or fibres on the prevalence of, incidence of or mortality due to pneumoconiosis, compared with the theoretical minimum risk exposure level of no exposure. STUDY APPRAISAL AND SYNTHESIS METHODS: At least two review authors will independently screen titles and abstracts against the eligibility criteria at a first stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. At least two review authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. For Systematic Review 2, if feasible, we will combine relative risks using meta-analysis. We will report results using the guidelines for accurate and transparent health estimates reporting (GATHER) for Systematic Review 1 and the preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) for Systematic Review 2. PROSPERO REGISTRATION NUMBER: CRD42018084131