Quantitative analysis of airway abnormalities in CT

A coupled surface graph cut algorithm for airway wall segmentation from Computed Tomography (CT) images is presented. Using cost functions that highlight both inner and outer wall borders, the method combines the search for both borders into one graph cut. The proposed method is evaluated on 173 manually segmented images extracted from 15 different subjects and shown to give accurate results, with 37% less errors than the Full Width at Half Maximum (FWHM) algorithm and 62% less than a similar graph cut method without coupled surfaces. Common measures of airway wall thickness such as the Interior Area (IA) and Wall Area percentage (WA%) was measured by the proposed method on a total of 723 CT scans from a lung cancer screening study. These measures were significantly different for participants with Chronic Obstructive Pulmonary Disease (COPD) compared to asymptomatic participants. Furthermore, reproducibility was good as confirmed by repeat scans and the measures correlated well with the outcomes of pulmonary function tests, demonstrating the use of the algorithm as a COPD diagnostic tool. Additionally, a new measure of airway wall thickness is proposed, Normalized Wall Intensity Sum (NWIS). NWIS is shown to correlate better with lung function test values and to be more reproducible than previous measures IA, WA% and airway wall thickness at a lumen perimeter of 10 mm (PI10)

HEPATITIS B DATABASE

Master'sMASTER OF SCIENC

Understanding Drug Uptake and Binding within Targeted Disease Micro-Environments in Patients: A New Tool for Translational Medicine

For many common global diseases, such as cancer, diabetes, neurodegenerative and cardiovascular diseases there is an unmet need for diagnosing early indications of disease that could enable medical intervention and early treatment. For example, cigarette smoking causes a variety of deadly diseases including lung cancer, hypertension, chronic obstructive pulmonary disease (COPD) and cardiovascular diseases. The treatment of these diseases will require detailed knowledge of targeted pathways involved in disease pathogenesis but also the mode of drug actions at the biological location on these targets. New methods, such as matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) are ready to provide insights into the fate (destinations and distributions) of administered drugs. Translational medicine is a new area of research where expert from different disciplines involved in basic science and clinical disciplines meet and join forces. The ultimate goal is to identify bridging comprehension that forms a knowledge base that can be used by society to develop a better treatment and medicine for patients

Direct demonstration of tissue uptake of an inhaled drug: proof-of-principle study using matrix assisted laser desorption ionization mass spectrometry imaging

Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound effects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying MALDI mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster size. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in 4/5 subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3-80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in man applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings

Standardization and Utilization of Biobank Resources in Clinical Protein Sciene with Examples of Emerging Applications

Biobanks are a major resource to access and measure biological constituents that can be used to monitor the status of health and disease, both in unique individual samples and within populations. Most “omic” activities rely on access to these collections of stored samples to provide the basis for establishing the ranges and frequencies of expression. Furthermore, information about the relative abundance and form of protein constituents found in stored samples provides an important historical index for comparative studies of inherited, epidemic, and developing disease. Standardizations of sample quality, form, and analysis are an important unmet need and requirement for gaining full benefit from collected samples. Coupled to this standard is the provision of annotation describing clinical status and metadata of measurements of clinical phenotype that characterizes the sample. Today we have not yet achieved consensus on how to collect, manage, and build biobank archives in order to reach goals where these efforts are translated into value for the patient. Several initiatives (OBBR, ISBER, BBMRI) that disseminate best practice examples for biobanking are expected to play an important role in ensuring the need to preserve the sample integrity of biosamples stored for periods that reach one or several decades. These developments will be of great value and importance to programs such as the Chromosome Human Protein Project (C-HPP) that will associate protein expression in healthy and disease states with genetic foci along of each of the human chromosomes

Direct Demonstration of Tissue Uptake of an Inhaled Drug: Proof-of-Principle Study Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging

Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster sizes. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings

Twins studies as a model for studies on the interaction between smoking and genetic factors in the development of chronic bronchitis

Smoking is the main risk factor for COPD (chronic obstructive pulmonary disease) but genetic factors are of importance, since only a subset of smokers develops the disease. Sex differences have been suggested both in disease prevalence and response to environmental exposures. Furthermore, it has been shown that acquisition of 'addiction' to smoking is partly genetically mediated. Disease cases and smoking habits were identified in 44919 twins aged > 40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. The results showed that chronic bronchitis seems to be more prevalent among females, and that the heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared by smoking. In addition, 392 twins have been invited to a clinical investigation to evaluate: (i) to what extent genetic factors contribute to individual differences (variation) in FEV1 (forced expiratory volume in 1 s), vital capacity and l (diffusion capacity), taking sex into consideration, and (ii) whether smoking behaviour and respiratory symptoms influence these estimates

Erratum to: Association of chromosome 19 to lung cancer genotypes and phenotypes

The Chromosome 19 Consortium, a part of the Chromosome-Centric Human Proteome Project (C-HPP, http://www.C-HPP.org ), is tasked with the understanding chromosome 19 functions at the gene and protein levels, as well as their roles in lung oncogenesis. Comparative genomic hybridization (CGH) studies revealed chromosome aberration in lung cancer subtypes, including ADC, SCC, LCC, and SCLC. The most common abnormality is 19p loss and 19q gain. Sixty-four aberrant genes identified in previous genomic studies and their encoded protein functions were further validated in the neXtProt database ( http://www.nextprot.org/ ). Among those, the loss of tumor suppressor genes STK11, MUM1, KISS1R (19p13.3), and BRG1 (19p13.13) is associated with lung oncogenesis or remote metastasis. Gene aberrations include translocation t(15, 19) (q13, p13.1) fusion oncogene BRD4-NUT, DNA repair genes (ERCC1, ERCC2, XRCC1), TGFβ1 pathway activation genes (TGFB1, LTBP4), Dyrk1B, and potential oncogenesis protector genes such as NFkB pathway inhibition genes (NFKBIB, PPP1R13L) and EGLN2. In conclusion, neXtProt is an effective resource for the validation of gene aberrations identified in genomic studies. It promises to enhance our understanding of lung cancer oncogenesis

Developments for a growing Japanese patient population: Facilitating new technologies for future health care

Lung cancer, COPD and cardiovascular diseases are highlighted as some of the most common disease that cause mortality, and for that reason are the most active areas for drug development. This perspective paper overviews the urgent need to develop a health care system for a rapidly growing patient population in Japan, including forthcoming demands on clinical care, expecting outcomes, and economics. There is an increasing requirement to build on the strengths of the current health care system, thereby delivering urgent solutions for the future. There is also a declaration from the Ministry of Health, Labour and Welfare (MHLW), to develop new biomarker diagnostics, which is intended for patient stratification, aiding in diagnostic phenotype selection for responders to drug treatment of Japanese patients. This perspective was written by the panel in order to introduce novel technologies and diagnostic capabilities with successful implementation. The next generation of personalized drugs for targeted and stratified patient treatment will soon be available in major disease areas such as, lifestyle-related cancers, especially lung cancers with the highest mortality including a predisposing disorder chronic obstructive pulmonary disease, cardiovascular disease, and other diseases. Mass spectrometric technologies can provide the "phenotypic fingerprint" required for the concept of Personalized Medicine. Mass spectrometry-driven target biomarker diagnoses in combination with high resolution computed tomography can provide a critical pathway initiative facilitated by a fully integrated e-Health infrastructure system. We strongly recommend integrating validated biomarkers based on clinical proteomics, medical imaging with clinical care supported by e-Health model to support personalized treatment paradigms to reduce mortality and healthcare costs of chronic and co-morbid diseases in the elderly population of Japan. (C) 2011 Published by Elsevier B.V