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RISKMAN RA2: Life-time prediction bu micro & nanosensors and diagnostic tools
Draft version of an IP -or NoE proposal (6th FP) submitted under thematic area 3
(Nanotechnology and Nanosciences, knowledge-based multifunctional materials, new
production processes and devices)
Reduction of hospital mortality by micro/nanotechnology-based diagnostic tools
Acronym: Nano-ROM
Nosocomial (= hospital-acquired) infections and cancer are primarily responsible for the
continuously increasing incidence of mortality in hospitals. In counteracting this
development, early preventive diagnosis is critical. Here, new rapid , nano- and microbased
diagnostic systems show great potential The major objective of the project is to develop
improved strategies for diagnosis, prognosis, more effective and personalised therapy for
combating nosocomial infections and cancer. The proposed multidisciplinary and
nanotechnology-assisted approach is aiming to reduce mortality rates in hospitals by
translating research results into applications which enable early diagnosis, reliable prognosis,
medical condition- and patient-tailored therapies and are implementable in the daily clinical
practise. One task of the project is the establishment of novel assays for fast and reliable
diagnosis of nosocomial infections (in particular sepsis) including antibiotic resistance testing
and expert system-based decision support systems (DSS). The second task is the development
of new diagnostic markers for high incidence cancers (lung, breast, colon, prostate etc.) and
tumour cells circulating in the blood (minimal residual disease) which allow on one hand
early diagnosis and on second hand differentiation of clinically and histologically uniform
tumors into (so far undistinguishable) cancer subclasses enabling more differentiated
prognoses and new patient-tailored, therapeutic strategies.
Aim:
The aim of the proposed multidisciplinary consortium is to generate new
micro/nanotechnology-based diagnostic, prognostic and therapeutic strategies to reduce the
incidence of mortality in hospitals. The project will focus on the development of novel and
fast diagnostic tests for nosocomial infections (in particular sepsis) and molecular markers for
diagnosis and more differentiated prognosis of high incidence cancers (lung, breast, colon,
prostate etc.) including surveillance of metastasis (minimal residual disease).
Rationale:
Recent studies have elucidated a significant and not longer ignorable increase in hospital
mortality. The leading causes for death beside coronary heart diseases are cancer and hospitalacquired (nosocomial) infections.
Cancer
About 53 million people die from cancer every year. In the developed world cancer accounts
for 21% of all deaths. Lung cancer is the commonest cause of cancer death in the western
world, followed by breast, colorectal and prostate cancer. Unfortunately cancer incidence and
mortality are continuously growing. Therefore actions for combating cancer based on early
detection of both primary tumours and metastasising tumour cells become a big issue.
Whereas cancer detected at an early stage in most cases is curable, tumour metastasis as such
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is the main cause of lethality in cancer patients. Cellular metastasis is based on detachment of
cells from the primary tumour, invasiveness through surrounding tissues and blood vessels
and active migration towards the tissue where secondary tumours develop. Therefore,
researchers are intensively working on diagnostic strategies which allow the detection of
circulating tumour cells in the blood (minimal residual disease, MRD) before a secondary
tumour can develop. Similar to an early detection of the primary tumour, the identification of
circulating tumour cells would significantly increase cancer survival rates due to the
possibility of case-specific and early therapeutic intervention.
Hospital-acquired (nosocomial) infections
Nosocomial (= hospital-acquired) infections typically affect patients who are immunocompromised because of age, underlying diseases, or medical or surgical treatments.
Nosocomial infections result in substantial morbidity, prolonged hospital stay, increases in
direct patient care costs and last but not least mortality. Although our understanding of the
epidemiology of nosocomial infections has increased dramatically over the last two decades,
the incidence of nosocomial infections continues to affect about 5% of hospitalised patients.
Sepsis
Sepsis can be defined as the body’s response to an infection. An infection is caused by
microorganisms (usually bacteria) invading the body, and can be limited to a particular body
region (e.g., a tooth abscess) or can be widespread in the bloodstream (often called
"septicemia" or "blood poisoning").
Sepsis is the leading cause of death in noncoronary intensive care unit (ICU) patients and the
11th leading cause of death overall in the US (Centers for Disease Control and prevention
CDC, National Vital Statistics Report, 2000). Despite enormous investment in intensive care,
sepsis has been associated with mortality rates ranging from 28% to 50%. It is estimated that
more than 700.000 individuals develop severe sepsis (sepsis associated with acute organ
dysfunction, hypoperfusion or shock) in the US each year, with similar estimates for Europe.
Extrapolated to a global population, this represents several million cases of severe sepsis
annually worldwide and 1400 people dying from sepsis every day worldwide.
The CDC recently published a report showing that U.S. sepsis cases had increased by more
than 300 percent in the past 25 years. The healthcare cost of the condition amounts to more
than $17 billion in the United States and more than $7 billion in Europe. In the next decade a
further striking increase in sepsis incidence is expected.
Advances in medical technologies and procedures may contribute to the rise in cases of
sepsis. Among these are increasingly aggressive cancer therapies and the increasing use of
invasive devices and procedures for a variety of medical conditions. Overall, improvements in
the survival rates of patients predisposed to sepsis, such as the elderly, premature neonates,
and patients with comorbid conditions will also contribute to the increased incidence of this
disease. Also, the widespread use of broad-spectrum antibiotics has increased the rates of both
antibiotic resistance and nosocomial infections, which will have a direct impact on the
incidence of sepsis (Opal and Cohen, 1999).
General Approach and Methods:
Cancer
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One part of the proposed project is aimed at uncovering mechanisms underlying cancer and
metastasis by using micro/nanotechnology-related tools such as DNA microarrays,
highthroughput proteomic devices, tissue arrays as well as microfluidics-, biosensor-based or
single molecule- techniques to identify „biomarkers“ which can be used for an improved,
more differentiated cancer diagnosis/prognosis and therapy thus reducing mortality.
Prerequisite for the identification of reliable cancer –and metastasis biomarker are large
tumour collectives, extensive studies on tumour gene and protein expression, on tumourspecific changes in gene copy numbers (matrix-CGH) and finally the identification of key
molecules from the huge data sets generated by applying state-of-the-art bioinformatic
tools/expertise. The proposed multidisciplinary consortium possesses the necessary knowhow and background to succeed due to its expertise in the fields of clinical oncology,
genomics, proteomics, bioinformatics and bionanotechnology.
The ultimate goal of the cancer part of the project is to develop rather simple (suitable for
clinical practise) and sensitive diagnostic strategies based on the biomarkers identified. These
can include medium-density oligonucleotide microarrays including marker genes (flat arrays,
lab-on-the-chip systems), new, strongly predicative/prognostic antibodies for immune
histochemistry and single molecule detection-based assays for minimal residual disease
diagnosis.
Sepsis
The other part of the project will focus on developing fast and reliable diagnostic tools for
sepsis causing microbes and their respective antibiotic resistances using DNA microarrays
and microfluidics (lab-on-the-chip) techniques. In addition, obtained results will be completed
by decision support software solutions based on expert systems. These are databases including
up-to-date knowledge of pathogens and their incidence in sepsis paired with probabilities for
those pathogens to develop specific mechanisms of antibiotic resistance.
A second focus of investigation will be uncovering host-pathogen interaction in sepsis using a
functional genomics approach on human and microbial whole genome microarrays. These
studies, requiring a lot of bioinformatics work, will eventually lead to new therapeutic
strategies in sepsis.
Potential participants
Organisation
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Role/Expertise of participant
ARC Seibersdorf research GmbHDevelopment of diagnostic DNA
(Seibersdorf, Austria)
microarrays:
Sepsis-specific pathogen
identification- and antibiotic
resistance chip plus DSS
Cancer diagnostic chips (incl.
minimal resisual disease)
Institute of Pathology (Graz,
Collection of tumor specimens
Austria) Coordinator of the
(lung,breast,prostate + colon)
Austrian initiative
cDNA microarrays, tissue arrays,
Chief Scientist
Dr. Christa Nöhammer
Prof. Kurt Zatloukal
Prof. Gerald Höfler
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„Establishment of
a national tumor-bank“
MorphoSys AG
(Martinsried, Germany)
Clinical Division of
Oncology, Dept. of Medicine
I, University Hospital
(Vienna, Austria)
University of Innsbruck
(Innsbruck, Austria)
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Cancer Reasearch UK
(London, United Kingdom)
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Institut Curie
(Paris, France)
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matrix-CGH, immunhistology
Prof. Helmut Popper
With its unique HuCAL® techno- Dr. Thomas von Rüden
logy (the Human Combinatorial
Antibody Library), MorphoSys is
developing the next generation of
therapeutic antibodies which can be
used not only for research and
diagnostics but also to treat disease
Clinical and experimental oncology Prof. Dr. Christoph Zielinski
Prostate center (dedicated to
prevention, treatment and research)
Large collection of serum,
peripheral blood cells and tumor
specimens (DNA Microarrays)
Group has collected 1800 frozen
breast carcinomas (up to 16 years
follow up), 1000 paired breast
tumor and blood samples; further
large collection of prostate samples
The institute has a large frozen
tumour bank and could be involved
in microarray expression analysis
after laser dissection, CGH arrays
and splice variant arrays.
Microarray Lab, human I.M.A.G.E.
clone collection
Dr. Helmut Klocker
Prof. Joyce Taylor-Papdimitriou
Dr. Ros Eeles
Dr. Henri Magdelenat
Functional Genome Analysis
Dr. Joerg Hoheisel
Deutsches
Krebsforschungszentrum
(Heidelberg, Germany)
9 Department Functional
I.M.A.G.E. clone collection, PCR Dr. Wilhelm Ansorge
Genomics Technology,
amplification, sequence verification,
EMBL (Heidelberg, Germany) production of 30K human cDNA
microarrays
10 Spanish National Cancer
Expression arrays have been
Dr. Javier Benitez
Centre (CNIO)
developed, CGH arrays and a high
(Madrid, Spain)
throughput system for SNP analysis
are currently under development.
11 University of Goteborg
This group has recently been
Prof. Gunnar Hansson
+ newly established SME
equipped with state-of-the-art
(Goteborg, Sweden)
highthroughput proteomic facilities
in close contact with an existing
Mass spectroscopy facility.
Proteomic comparison of tumour
samples.
12 Working group “ Molecular
Development/validation of
Prof. Heisig (= head of working
methods for determination of methods for isolation of targetgroup)
antibiotic resistance”
DNA, primer design, target
(Institute of pharmaceutical
(Institute of pharmaceutical
amplification
biology and microbiology,
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biology and microbiology,
University of Bonn, Germany)
13 Giessen Research Center in
Infectious Diseases
(Giessen, Germany)
14 International Sepsis Forum
Conception of an antibiotic
University of Bonn)
resistance chip
Functional genomics of hostProf. Dr.Trinad Chakraborty
pathogen interaction in sepsis and
septic multiorgan failure
The International Sepsis Forum
Dr. Jean Carlet (Paris, France)
(ISF) is a unique collaborative
Dr. Jean-Louis Vincent
effort between industry and
(Brussels, Belgium)
academia. It focuses on management Dr. Charles L.Sprung
of patients with severe sepsis.
(Jerusalem, Israel)
15 European Bioinformatics
The EBI focuses on building,
Dr. Alvis Brazma
Institute (EBI)
maintaining and providing
(Cambridge, United Kingdom) Biological databases and services
For data deposition/exploition.
Data warehouse, data analysis and
Modelling
16 iSenseIT
Oligonucleotide probe design,
Dr. Thomas Waschulzik
(Bremen, Germany)
design of multiplex PCR primers in
connection with microarray probe
design
17 Metrigenix
MetriGenix is a spin-off of Gene
Dr. Adam B. Steel
(Gaithersburg, MD, USA)
Logic, Inc. MetriGenix will use
its patented Flow-Thru Chip
(FTC) technology to provide
enhanced microarray-based assays
for medical diagnosis.
18 Cantion
Cantion designs, develops and
Dr. Carsten Faltum (CEO)
(Lyngby, Denmark)
manufactures advanced biochips
for label free detection of
molecules (cantilever technology)
19 Departments of Electronics and Research has focussed on the
Prof. Jon Cooper
Electrical Engineering,
development of microsystems for
Bioelectronics Research Centre biomedical research and on the
(University of Glasgow,
analysis of bioelectronic interfaces
United Kingdom)
(cooperations with Unilever,UK
and Gene Logic USA)
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Single molecule detection
Dr. Jerker Wildengren
(Stockholm, Sweden)
techniques (e.g. Fluorescence
correlation spectroscopy FCS),
characterisation of dynamic cell
structures, tools for single
molecule analysis in tissue and
body fluids
21 Institute for Biophysics,
Ultra-Sensitive High- Throughput Dr. Gerhard Schütz
University of Linz
Live-Cell Screening (for minimal
(Linz, Austria)
residual disease)
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