| 1. |
- Mason, James E., et al.
(författare)
-
A cross-sectional and longitudinal analysis of pre-diagnostic blood plasma biomarkers for early detection of pancreatic cancer
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:21
-
Tidskriftsartikel (refereegranskat)abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death that typically presents at an advanced stage. No reliable markers for early detection presently exist. The prominent tumor stroma represents a source of circulating biomarkers for use together with cancer cell-derived biomarkers for earlier PDAC diagnosis. CA19-9 and CEA (cancer cell-derived biomarkers), together with endostatin and collagen IV (stroma-derived) were examined alone, or together, by multivariable modelling, using pre-diagnostic plasma samples (n = 259 samples) from the Northern Sweden Health and Disease Study biobank. Serial samples were available for a subgroup of future patients. Marker efficacy for future PDAC case prediction (n = 154 future cases) was examined by both cross-sectional (ROC analysis) and longitudinal analyses. CA19-9 performed well at, and within, six months to diagnosis and multivariable modelling was not superior to CA19-9 alone in cross-sectional analysis. Within six months to diagnosis, CA19-9 (AUC = 0.92) outperformed the multivariable model (AUC = 0.81) at a cross-sectional level. At diagnosis, CA19-9 (AUC = 0.995) and the model (AUC = 0.977) performed similarly. Longitudinal analysis revealed increases in CA19-9 up to two years to diagnosis which indicates a window of opportunity for early detection of PDAC.
|
|
| 2. |
- Björkblom, Benny, et al.
(författare)
-
Distinct metabolic hallmarks of WHO classified adult glioma subtypes
- 2022
-
Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 24:9, s. 1454-1468
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gliomas are complex tumors with several genetic aberrations and diverse metabolic programs contributing to their aggressive phenotypes and poor prognoses. This study defines key metabolic features that can be used to differentiate between glioma subtypes, with potential for improved diagnostics and subtype targeted therapy.METHODS: Cross-platform global metabolomic profiling coupled with clinical, genetic, and pathological analysis of glioma tissue from 224 tumors - oligodendroglioma (n=31), astrocytoma (n=31) and glioblastoma (n=162) - were performed. Identified metabolic phenotypes were evaluated in accordance with the WHO classification, IDH-mutation, 1p/19q-codeletion, WHO-grading 2-4, and MGMT promoter methylation.RESULTS: Distinct metabolic phenotypes separate all six analyzed glioma subtypes. IDH-mutated subtypes, expressing 2-hydroxyglutaric acid, were clearly distinguished from IDH-wildtype subtypes. Considerable metabolic heterogeneity outside of the mutated IDH pathway were also evident, with key metabolites being high expression of glycerophosphates, inositols, monosaccharides and sugar alcohols and low levels of sphingosine and lysoglycerophospholipids in IDH-mutants. Among the IDH-mutated subtypes, we observed high levels of amino acids, especially glycine and 2-aminoadipic acid, in grade 4 glioma, and N-acetyl aspartic acid in low-grade astrocytoma and oligodendroglioma. Both IDH-wildtype and mutated oligodendroglioma and glioblastoma were characterized by high levels of acylcarnitines, likely driven by rapid cell growth and hypoxic features. We found elevated levels of 5-HIAA in gliosarcoma and a subtype of oligodendroglioma not yet defined as a specific entity, indicating a previously not described role for the serotonin pathway linked to glioma with bimorphic tissue.CONCLUSION: Key metabolic differences exist across adult glioma subtypes.
|
|
| 3. |
- Björkblom, Benny, et al.
(författare)
-
Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma
- 2020
-
Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 122:2, s. 221-232
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.
|
|
| 4. |
- Dudka, Ilona, et al.
(författare)
-
Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status
- 2020
-
Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses.Methods: Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (H-1 HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by H-1/P-31 NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort.Results: The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and alpha-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in beta-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress.Conclusions: Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients.
|
|
| 5. |
- Jonsson, Pär, et al.
(författare)
-
Identification of Pre-Diagnostic Metabolic Patterns for Glioma Using Subset Analysis of Matched Repeated Time Points
- 2020
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary: Reprogramming of cellular metabolism is a major hallmark of cancer cells, and play an important role in tumor initiation and progression. The aim of our study is to discover circulating early metabolic markers of brain tumors, as discovery and development of reliable predictive molecular markers are needed for precision oncology applications. We use a study design tailored to minimize confounding factors and a novel machine learning and visualization approach (SMART) to identify a panel of 15 interlinked metabolites related to glioma development. The presented SMART strategy facilitates early molecular marker discovery and can be used for many types of molecular data.Abstract: Here, we present a strategy for early molecular marker pattern detection-Subset analysis of Matched Repeated Time points (SMART)-used in a mass-spectrometry-based metabolomics study of repeated blood samples from future glioma patients and their matched controls. The outcome from SMART is a predictive time span when disease-related changes are detectable, defined by time to diagnosis and time between longitudinal sampling, and visualization of molecular marker patterns related to future disease. For glioma, we detect significant changes in metabolite levels as early as eight years before diagnosis, with longitudinal follow up within seven years. Elevated blood plasma levels of myo-inositol, cysteine, N-acetylglucosamine, creatinine, glycine, proline, erythronic-, 4-hydroxyphenylacetic-, uric-, and aceturic acid were particularly evident in glioma cases. We use data simulation to ensure non-random events and a separate data set for biomarker validation. The latent biomarker, consisting of 15 interlinked and significantly altered metabolites, shows a strong correlation to oxidative metabolism, glutathione biosynthesis and monosaccharide metabolism, linked to known early events in tumor development. This study highlights the benefits of progression pattern analysis and provide a tool for the discovery of early markers of disease.
|
|
| 6. |
- Loo, Ruey Leng, et al.
(författare)
-
Strategy for improved characterization of human metabolic phenotypes using a COmbined Multi-block Principal components Analysis with Statistical Spectroscopy (COMPASS)
- 2020
-
Ingår i: Bioinformatics. - : Oxford University Press. - 1367-4803 .- 1367-4811 .- 1460-2059. ; 36:21, s. 5229-5236
-
Tidskriftsartikel (refereegranskat)abstract
- Motivation: Large-scale population omics data can provide insight into associations between gene-environment interactions and disease. However, existing dimension reduction modelling techniques are often inefficient for extracting detailed information from these complex datasets.Results: Here, we present an interactive software pipeline for exploratory analyses of population-based nuclear magnetic resonance spectral data using a COmbined Multi-block Principal components Analysis with Statistical Spectroscopy (COMPASS) within the R-library hastaLaVista framework. Principal component analysis models are generated for a sequential series of spectral regions (blocks) to provide more granular detail defining sub-populations within the dataset. Molecular identification of key differentiating signals is subsequently achieved by implementing Statistical TOtal Correlation SpectroscopY on the full spectral data to define feature patterns. Finally, the distributions of cross-correlation of the reference patterns across the spectral dataset are used to provide population statistics for identifying underlying features arising from drug intake, latent diseases and diet. The COMPASS method thus provides an efficient semi-automated approach for screening population datasets.
|
|
| 7. |
- Uusi-Tarkka, Eija-Katriina, et al.
(författare)
-
Mechanical and Thermal Properties of Wood-Fiber-Based All-Cellulose Composites and Cellulose-Polypropylene Biocomposites
- 2023
-
Ingår i: Polymers. - : MDPI AG. - 2073-4360. ; 15:3
-
Tidskriftsartikel (refereegranskat)abstract
- This article explores wood-fiber-based fabrics containing Lyocell yarn in the warp and Spinnova–Lyocell (60%/40%) yarn in the weft, which are used to form unidirectional all-cellulose composites (ACC) through partial dilution in a NaOH–urea solution. The aim is to investigate the role of the yarn orientation in composites, which was conducted by measuring the tensile properties in both the 0° and 90° directions. As a reference, thermoplastic biocomposites were prepared from the same fabrics, with biobased polypropylene (PP) as the matrix. We also compared the mechanical and thermal properties of the ACC and PP biocomposites. The following experiments were carried out: tensile test, TGA, DSC, DMA, water absorption test and SEM. The study found no significant difference in tensile strength regarding the Spinnova–Lyocell orientation between ACC and PP biocomposites, while the composite tensile strength was clearly higher in the warp (Lyocell) direction for both composite variants. Elongation at break doubled in ACC in the Lyocell direction compared with the other samples. Thermal analysis showed that mass reduction started at a lower temperature for ACC, but the thermal stability was higher compared with the PP biocomposites. Maximum thermal degradation temperature was measured as being 352 °C for ACC and 466 °C for neat PP, and the PP biocomposites had two peaks in the same temperature range (340–474 °C) as ACC and neat PP combined. ACCs absorbed 93% of their own dry weight in water in just one hour, whereas the PP biocomposites BC2 and BC4 absorbed only 10% and 6%, respectively. The study highlights the different properties of ACC and PP reference biocomposites that could lead to further development and research of commercial applications for ACC.
|
|
