| 1. |
- Apweiler, Rolf, et al.
(author)
-
Approaching clinical proteomics : current state and future fields of application in cellular proteomics
- 2009
-
In: Cytometry. Part A : the journal of the International Society for Analytical Cytology. - : Wiley. - 1552-4922. ; 75A:10, s. 816-832
-
Research review (peer-reviewed)abstract
- Recent developments in proteomics technology offer new opportunities for clinical applications in hospital or specialized laboratories including the identification of novel biomarkers, monitoring of disease, detecting adverse effects of drugs, and environmental hazards. Advanced spectrometry technologies and the development of new protein array formats have brought these analyses to a standard, which now has the potential to be used in clinical diagnostics. Besides standardization of methodologies and distribution of proteomic data into public databases, the nature of the human body fluid proteome with its high dynamic range in protein concentrations, its quantitation problems, and its extreme complexity present enormous challenges. Molecular cell biology (cytomics) with its link to proteomics is a new fast moving scientific field, which addresses functional cell analysis and bioinformatic approaches to search for novel cellular proteomic biomarkers or their release products into body fluids that provide better insight into the enormous biocomplexity of disease processes and are suitable for patient stratification, therapeutic monitoring, and prediction of prognosis. Experience from studies of in vitro diagnostics and especially in clinical chemistry showed that the majority of errors occurs in the preanalytical phase and the setup of the diagnostic strategy. This is also true for clinical proteomics where similar preanalytical variables such as inter- and intra-assay variability due to biological variations or proteolytical activities in the sample will most likely also influence the results of proteomics studies. However, before complex proteomic analysis can be introduced at a broader level into the clinic, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement, and data analysis is another issue which has to be improved. In this report, we discuss the recent advances and applications that fulfill the criteria for clinical proteomics with the focus on cellular proteomics (cytoproteomics) as related to preanalytical and analytical standardization and to quality control measures required for effective implementation of these technologies and analytes into routine laboratory testing to generate novel actionable health information. It will then be crucial to design and carry out clinical studies that can eventually identify novel clinical diagnostic strategies based on these techniques and validate their impact on clinical decision making.
|
|
| 2. |
- Apweiler, Rolf, et al.
(author)
-
Approaching clinical proteomics : current state and future fields of application in fluid proteomics
- 2009
-
In: Clinical Chemistry and Laboratory Medicine. - 1434-6621 .- 1437-4331. ; 47:6, s. 724-744
-
Research review (peer-reviewed)abstract
- The field of clinical proteomics offers opportunities to identify new disease biomarkers in body fluids, cells and tissues. These biomarkers can be used in clinical applications for diagnosis, stratification of patients for specific treatment, or therapy monitoring. New protein array formats and improved spectrometry technologies have brought these analyses to a level with potential for use in clinical diagnostics. The nature of the human body fluid proteome with its large dynamic range of protein concentrations presents problems with quantitation. The extreme complexity of the proteome in body fluids presents enormous challenges and requires the establishment of standard operating procedures for handling of specimens, increasing sensitivity for detection and bioinformatical tools for distribution of proteomic data into the public domain. From studies of in vitro diagnostics, especially in clinical chemistry, it is evident that most errors occur in the preanalytical phase and during implementation of the diagnostic strategy. This is also true for clinical proteomics, and especially for fluid proteomics because of the multiple pretreatment processes. These processes include depletion of high-abundance proteins from plasma or enrichment processes for urine where biological variation or differences in proteolytic activities in the sample along with preanalytical variables such as inter- and intra-assay variability will likely influence the results of proteomics studies. However, before proteomic analysis can be introduced at a broader level into the clinical setting, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement and data analysis needs to be improved. In this review, we discuss the recent technological advances and applications that fulfil the criteria for clinical proteomics, with the focus on fluid proteomics. These advances relate to preanalytical factors, analytical standardization and quality-control measures required for effective implementation into routine laboratory testing in order to generate clinically useful information. With new disease biomarker candidates, it will be crucial to design and perform clinical studies that can identify novel diagnostic strategies based on these techniques, and to validate their impact on clinical decision-making.
|
|
| 3. |
- Dyrskjot, Lars, et al.
(author)
-
Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer : A Prospective Multicentre Validation Study
- 2017
-
In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:3, s. 461-469
-
Journal article (peer-reviewed)abstract
- Background: Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) is life-threatening and cannot be accurately predicted using clinical and pathological risk factors. Biomarkers for stratifying patients to treatment and surveillance are greatly needed. Objective: To validate a previously developed 12-gene progression score to predict progression to MIBC in a large, multicentre, prospective study. Design, setting, and participants: We enrolled 1224 patients in ten European centres between 2008 and 2012. A total of 750 patients (851 tumours) fulfilled the inclusion and sample quality criteria for testing. Patients were followed for an average of 28 mo (range 0-76). A 12-gene real-time qualitative polymerase chain reaction assay was performed for all tumours and progression scores were calculated using a predefined formula and cut-off values. Outcome measurements and statistical analysis: We measured progression to MIBC using Cox regression analysis and log-rank tests for comparing survival distributions. Results and limitations: The progression score was significantly (p < 0.001) associated with age, stage, grade, carcinoma in situ, bacillus Calmette-Guerin treatment, European Organisation for Research and Treatment of Cancer risk score, and disease progression. Univariate Cox regression analysis showed that patients molecularly classified as high risk experienced more frequent disease progression (hazard ratio 5.08, 95% confidence interval 2.2-11.6; p < 0.001). Multivariable Cox regression models showed that the progression score added independent prognostic information beyond clinical and histopathological risk factors (p < 0.001), with an increase in concordance statistic from 0.82 to 0.86. The progression score showed high correlation (R-2 = 0.85) between paired fresh-frozen and formalin-fixed paraffin-embedded tumour specimens, supporting translation potential in the standard clinical setting. A limitation was the relatively low progression rate (5%, 37/ 750 patients). Conclusions: The 12-gene progression score had independent prognostic power beyond clinical and histopathological risk factors, and may help in stratifying NMIBC patients to optimise treatment and follow-up regimens. Patient summary: Clinical use of a 12-gene molecular test for disease aggressiveness may help in stratifying patients with non-muscle-invasive bladder cancer to optimal treatment regimens.
|
|
| 4. |
- Fristrup, Niels, et al.
(author)
-
Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle Invasive Bladder Cancer
- 2013
-
In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:2, s. 339-349
-
Journal article (peer-reviewed)abstract
- Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.
|
|
| 5. |
- Hedegaard, Jakob, et al.
(author)
-
Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
- 2016
-
In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 30:1, s. 27-42
-
Journal article (peer-reviewed)abstract
- Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
|
|
| 6. |
- Karlsen, Reinert Huseby, et al.
(author)
-
Landscape controls on spatiotemporal discharge variability in a boreal catchment
- 2016
-
In: Water resources research. - 0043-1397 .- 1944-7973. ; 52:8, s. 6541-6556
-
Journal article (peer-reviewed)abstract
- Improving the understanding of how stream flow dynamics are influenced by landscape characteristics, such as soils, vegetation and terrain, is a central endeavor of catchment hydrology. Here we investigate how spatial variability in stream flow is related to landscape characteristics using specific discharge time series from 14 partly nested subcatchments in the Krycklan basin (0.12 - 68 km(2)). Multivariate principal component analyses combined with univariate analyses showed that while variability in landscape characteristics and specific discharge were strongly related, the spatial patterns varied with season and wetness conditions. During spring snowmelt and at the annual scale, specific discharge was positively related to the sum of wetland and lake area. During summer, when flows are lowest, specific discharge was negatively related to catchment tree volume, but positively related to deeper sediment deposits and catchment area. The results indicate how more densely forested areas on till soils become relatively drier during summer months, while wet areas and deeper sediment soils maintain a higher summer base flow. Annual and seasonal differences in specific discharge can therefore be explained to a large extent by expected variability in evapotranspiration fluxes and snow accumulation. These analyses provide an organizing principle for how specific discharge varies spatially across the boreal landscape, and how this variation is manifested for different wetness conditions, seasons and time scales.
|
|
| 7. |
- Karlsen, Reinert Huseby, 1983-
(author)
-
Spatiotemporal streamflow variability in a boreal landscape : Importance of landscape composition for catchment hydrological functioning
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- The understanding of how different parts of a landscape contribute to streamflow by storing and releasing water has long been a central issue in hydrology. Knowledge about what controls streamflow dynamics across landscapes can further our understanding of how catchments store and release water, facilitate predictions for ungauged catchments, and improve the management of water quality and resources. This thesis makes use of data from the Krycklan catchment in northern Sweden. Streamflow data from 14 catchments (0.12 - 68 km2) with variable landscape characteristics such as topography, vegetation, wetland cover, glacial till soils and deeper sediment soils were used to investigate spatial patterns and controls on runoff.The differences in specific discharge (discharge per unit catchment area) between nearby catchments were large at the annual scale, and have the same magnitude as predicted effects of a century of climate change or the observed effects of major forestry operations. This variability is important to consider when studying the effects of climate change and land use changes on streamflow, as well as for our understanding of geochemical mass balances. Streamflow from different catchments was strongly related to landscape characteristics. The distribution of wetland areas had a particularly strong influence, with an annual specific discharge 40-80% higher than catchments with high tree volume on till soils. During drier periods, catchments with deeper sediment soils at the lower elevations of Krycklan had a higher base flow compared to both forested till and wetland catchments. This pattern was reversed at high flows. The storages releasing water to streams in downstream sediment areas were able to maintain base flow for longer periods and were less influenced by evapotranspiration compared to the more superficial till and wetland systems.The results of this thesis have led to a better understanding of the landscape wide patterns of streamflow during different seasons and time scales. The strong associations to landscape characteristics and variable spatial patterns with season and antecedent conditions form the basis for a conceptual understanding of the processes and spatial patterns that shape the heterogeneity of streamflow responses in boreal catchments.
|
|
| 8. |
|
|
| 9. |
- Karlsen, Reinert, et al.
(author)
-
The assumption of uniform specific discharge : unsafe at Any time?
- 2016
-
In: Hydrological Processes. - : Wiley. - 0885-6087 .- 1099-1085. ; 0:21, s. 3978-3988
-
Journal article (peer-reviewed)abstract
- Nearby catchments in the same landscape are often assumed to have similar specific discharge (runoff per unit catchment area). Five years of streamflow from 14 nested catchments in a 68km(2) landscape was used to test this assumption, with the hypothesis that the spatial variability in specific discharge is smaller than the uncertainties in the measurement. The median spatial variability of specific discharge, defined as subcatchment deviation from the catchment outlet, was 33% at the daily scale. This declined to 24% at a monthly scale and 19% at an annual scale. These specific discharge differences are on the same order of magnitude as predicted for major land-use conversions or a century of climate change. Spatial variability remained when considering uncertainties in specific discharge, and systematic seasonal patterns in specific discharge variation further provide confidence that these differences are more than just errors in the analysis of catchment area, rainfall variability or gauging. Assuming similar specific discharge in nearby catchments can thus lead to spurious conclusions about the effects of disturbance on hydrological and biogeochemical processes.
|
|
| 10. |
- Marschall, Tobias, et al.
(author)
-
Computational pan-genomics : status, promises and challenges
- 2018
-
In: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1467-5463 .- 1477-4054. ; 19:1, s. 118-135
-
Journal article (peer-reviewed)abstract
- Many disciplines, from human genetics and oncology to plant breeding, microbiology and virology, commonly face the challenge of analyzing rapidly increasing numbers of genomes. In case of Homo sapiens, the number of sequenced genomes will approach hundreds of thousands in the next few years. Simply scaling up established bioinformatics pipelines will not be sufficient for leveraging the full potential of such rich genomic data sets. Instead, novel, qualitatively different computational methods and paradigms are needed. We will witness the rapid extension of computational pan-genomics, a new sub-area of research in computational biology. In this article, we generalize existing definitions and understand a pan-genome as any collection of genomic sequences to be analyzed jointly or to be used as a reference. We examine already available approaches to construct and use pan-genomes, discuss the potential benefits of future technologies and methodologies and review open challenges from the vantage point of the above-mentioned biological disciplines. As a prominent example for a computational paradigm shift, we particularly highlight the transition from the representation of reference genomes as strings to representations as graphs. We outline how this and other challenges from different application domains translate into common computational problems, point out relevant bioinformatics techniques and identify open problems in computer science. With this review, we aim to increase awareness that a joint approach to computational pan-genomics can help address many of the problems currently faced in various domains.
|
|
