Published on March 13, 2014
Proximal markers Good Biomarker Sciences www.gbsleiden.nl
Biomarker development laboratory. Haemostasis and inflammation models and biomarkers Immunogenicity / toxicity --- NEW: Disease markers Phase I-IIa unit Pharmacodynamic biomarkers Amyloid research
Our model • A research CRO guided by customer requests, and own idea’s new biomarkers models and platforms; be a partner in interpretation
ER ER ER UPR Inflammasome Cellular mechanisms
ER ER ER UPR Inflammasome high/low metabolic Lipid FFA Glucose virus PAMPS/DAMPSo.a. TLR4/LPS Specific triggers Homocysteine (B12) Alcohol Hypoxia Transfat Palmitate Uric acid Peroxynitrite glucosamine In the cell Mito Pro-apoptotic Anti-apoptotic Markers (CRP) Oxidation C/EBP-β (LPS, age) Cathepsin B/D Il-18 IL-1-beta Chaperone reduction NFkB early late Immunity pyroptosis Poluttants Asbestos Crystals amyloid
Not coping: Failure UPR • Debris in the cell – Cellular death • Activation inflammasome – Cellular death
After Hosoi, 2010 No balance anymore: debris
Final phase Inflammasome activation • Pyroptosis (inflammatory cell death) • Markers: Il-18, IL-1β (pain), Cathepsins • Auto-antibody increases
Aβequivalents(fg/mL) Evaluation of CSF Samples: EP-AD * * ** * * 2,000 ** p<0.001 1,500 1,000 500 0 Control MCI AD N = 6 2 N=50 N=79 Average signal 130.5 563.2 364.1 EP-AD detects aggregated Aβ in CSF of AD and MCI patients. All 3 groups are statistically significantly distinct. Overlap !
Late stage markers • Il-18, Il-1β, Cathepsins • Auto-antibody titers
Detection of auto-antibodies a) Many are present (low level) from birth on b) Disease specific patterns occur for multiple antigens per disease with an increase in titer and shift in type. c) Example HIV-infected people are “loaded” with auto-antibodies
Fattal. Immunol 130, 2010:337.
miRNA as disease markers
Signature of tissue state and disease
Exosomes and microparticles, HDL and carriers stabilise miRNA in biological fluids
Plasma contains MPs from different origin
Plasma contains MPs from different origin Tumor
New: MicroRNA-21 • Elevated in blood in cases with colorectal cancer • Established as diagnostic and prognostic biomarker Natl Cancer Inst 2013, 105:849-59. + Functionality • Inhibition improves sensitivity to chemotherapy.
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