IL-6, a central acute-phase mediator, as an early biomarker for exposure to zinc-based metal fumes.

AIMS: Systemic C-reactive protein (CRP) increases 1day after short-term inhalation of welding fumes containing zinc and/or copper. The aim of the current study was to find further, possibly earlier systemic biomarkers after inhalation of different welding fumes containing zinc and traces of aluminum, with or without copper, as these metal combinations become more common in modern joining technology. METHODS: The study group consisted of 15 non-smoking male volunteers with healthy lung function data and without any occupational metal fume exposure. On 4 different exposure days, the members of the study group were exposed under controlled conditions to ambient air or 3 different welding fumes for 6h. Spirometric and impulse oscillometric measurements and differential blood counts were performed and serum samples were collected before exposure and 6, 10 and 29h after start of exposure. The biomarker concentrations in serum were measured by electrochemiluminescent assays. RESULTS: Systemic increases of IL-6 peaked significantly at 10h compared to baseline ("ZincZinc": P=0.0005 (median increase (m. incr.)=1.36pg/mL); "ZincAlu": P=0.0012 (m. incr.=1.48pg/mL); "AluBronze": P=0.0005 (m. incr.=2.66pg/mL)). At 29h, CRP and serum amyloid A (SAA) increased distinctively ("ZincZinc": P=0.032 (m. incr.=0.65µg/mL) [CRP], 0.077 (m. incr.=0.61µg/mL) [SAA]; "ZincAlu": P=0.001 (m. incr.=1.15µg/mL) [CRP], 0.0024 (m. incr.=0.94µg/mL) [SAA]; "AluBronze": P=0.002 (m. incr.=2.5µg/mL) [CRP], 0.002 (m. incr.=0.97µg/mL) [SAA]). The median increases of CRP and IL-6 were most pronounced for the welding fume which contained besides zinc also copper (AluBronze). For differentiating AluBronze from control exposure, receiver operating characteristic (ROC) curve analysis was performed and the area under the ROC curve (AUC) for the IL-6 increases (10h versus 0h) was 0.931. The additional inflammatory mediators [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interferon-γ (IFN-γ), cell counts] and the lung function parameters did not show any significant changes after exposure. CONCLUSIONS: Consistent with its role of the mediation of the acute-phase response, systemic increases of IL-6 after welding fume exposure peak at 10h before the increases of the acute-phase reactants CRP and SAA at 29h. IL-6 may represent a highly sensitive and early biomarker for the exposure to metal fumes containing zinc and copper. As IL-6, CRP and SAA are independent, strong risk markers for future cardiovascular diseases, these data may particularly be important for long-term welders with respect to their cardiovascular health.

Molecular imaging of tumor metabolism and apoptosis.

Increased metabolism in a number of cellular pathways is a common feature of malignant tumors. This metabolic hallmark of neoplastic tissue led to the development of radiopharmaceuticals for the assessment of transport and enzymatic activity for tumor diagnosis and staging. The malignant transformation causes the activation of oncogenic proteins and signaling pathways that stimulate glycolysis. The resulting high-glucose metabolism of cancer cells allows PET imaging using FDG. Other molecules frequently applied in preclinical and clinical studies are ¹¹C-methionine, tyrosine analogs and choline-based tracers. Using quantitative procedures they enable therapy monitoring by assessment of changes in transport and metabolization. As apoptosis is an important mechanism of cell death in tumors responding to treatment, non-invasive assessment of apoptosis using tracers for detection of phosphatidyl-serine presentation and/or caspase activation could be used as a surrogate marker for therapeutic efficacy.

Development of molecular techniques for imaging and treatment of tumors.

With the advances in molecular biology and biochemistry new imaging and treatment modalities based on the biological properties of tissues have been developed. In oncology, the major progress has been achieved using peptide and antibody targeting vectors. Besides the identification of new target structures, progress in molecular biology also made new techniques for the development of new biomolecules. This relies on the identification of lead compounds and on the screening of various derivatives of these compounds one at a time. The principle of high-troughput methods for the identification of novel high affinity binders is to generate a vast library of possible variants of the molecule of interest and screen the population for the few variants that show the property of interest. The attracting feature of the concept arises from the huge number of candidate molecules that can be used for further evaluation. After the characterization of the structure-function relationships for the lead compounds found in this process further improvement by rational design of analogs can be performed.

[Iodide enrichment in malignant tumours after gene transfer]. / Gentechnisch modulierte Iodidanreicherung in malignen Tumoren.

After the cloning of the gene encoding the sodium-iodide symporter several trials were made to develop a radioiodine treatment for multiple tumour entities based on NIS gene transfer. These studies revealed in vitro as well as in vivo a tremendous enhancement of iodide accumulation, which was followed by a rapid efflux. Therapy effects were observed in vitro by clonogenic assays and in vivo by growth inhibition of the treated tumours. However, the interpretation of these results were largely different. Problems of radioiodine therapy after NIS transfer are low efficiency of gene transfer and the short exposure time for the tumours caused by the rapid efflux. Trials to enhance therapeutic efficiency by co-transfer of the gene encoding thyroperoxidase failed due to the low enzyme activity.