| 1. |
- Anande, Govardhan, et al.
(författare)
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RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia
- 2020
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 26:14, s. 3597-3607
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.
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| 2. |
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| 3. |
- Delaby, Constance, et al.
(författare)
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Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.
- 2022
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:10, s. 1868-1879
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Tidskriftsartikel (refereegranskat)abstract
- The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests.We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients.The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis.This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.
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| 4. |
- Hornung, R, et al.
(författare)
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Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 11293-
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Tidskriftsartikel (refereegranskat)abstract
- Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.
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| 5. |
- Khalil, Michael, et al.
(författare)
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Neurofilaments as biomarkers in neurological disorders - towards clinical application.
- 2024
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Ingår i: Nature Reviews Neurology. - 1759-4758 .- 1759-4766. ; 20:5, s. 269-287
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament proteins have been validated as specific body fluid biomarkers of neuro-axonal injury. The advent of highly sensitive analytical platforms that enable reliable quantification of neurofilaments in blood samples and simplify longitudinal follow-up has paved the way for the development of neurofilaments as a biomarker in clinical practice. Potential applications include assessment of disease activity, monitoring of treatment responses, and determining prognosis in many acute and chronic neurological disorders as well as their use as an outcome measure in trials of novel therapies. Progress has now moved the measurement of neurofilaments to the doorstep of routine clinical practice for the evaluation of individuals. In this Review, we first outline current knowledge on the structure and function of neurofilaments. We then discuss analytical and statistical approaches and challenges in determining neurofilament levels in different clinical contexts and assess the implications of neurofilament light chain (NfL) levels in normal ageing and the confounding factors that need to be considered when interpreting NfL measures. In addition, we summarize the current value and potential clinical applications of neurofilaments as a biomarker of neuro-axonal damage in a range of neurological disorders, including multiple sclerosis, Alzheimer disease, frontotemporal dementia, amyotrophic lateral sclerosis, stroke and cerebrovascular disease, traumatic brain injury, and Parkinson disease. We also consider the steps needed to complete the translation of neurofilaments from the laboratory to the management of neurological diseases in clinical practice.
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| 6. |
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| 7. |
- Lleó, Alberto, et al.
(författare)
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Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study
- 2019
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 742-753
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.METHODS: We included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.RESULTS: CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.DISCUSSION: All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.
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| 8. |
- Mareschal, Sylvain, et al.
(författare)
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Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:4, s. 1003-1016
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Tidskriftsartikel (refereegranskat)abstract
- Although copy number alterations (CNAs) and translocations constitute the backbone of the diagnosis and prognostication of acute myeloid leukemia (AML), techniques used for their assessment in routine diagnostics have not been reconsidered for decades. We used a combination of 2 next-generation sequencing-based techniques to challenge the currently recommended conventional cytogenetic analysis (CCA), comparing the approaches in a series of 281 intensively treated patients with AML. Shallow whole-genome sequencing (sWGS) outperformed CCA in detecting European Leukemia Net (ELN)-defining CNAs and showed that CCA overestimated monosomies and suboptimally reported karyotype complexity. Still, the concordance between CCA and sWGS for all ELN CNA-related criteria was 94%. Moreover, using in silico dilution, we showed that 1 million reads per patient would be enough to accurately assess ELN-defining CNAs. Total genomic loss, defined as a total loss 200 Mb by sWGS, was found to be a better marker for genetic complexity and poor prognosis compared with the CCA-based definition of complex karyotype. For fusion detection, the concordance between CCA and whole-transcriptome sequencing (WTS) was 99%. WTS had better sensitivity in identifying inv(16) and KMT2A rearrangements while showing limitations in detecting lowly expressed PML-RARA fusions. Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.
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| 9. |
- Neddermeyer, Anne, et al.
(författare)
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A new mutant NPM1/IDH2R140- and PML-RARA-associated lncRNA MALNC plays a role in AML biology, prognosis and drug response
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by poor prognosis that requires better understanding of its disease biology and new tools for suitable risk stratification and effective treatments. Long non-coding RNAs (lncRNAs) are involved in numerous molecular mechanisms, are implicated in tumor biology and can serve as clinical biomarkers, yet their role remains mostly unclear in AML. In this study, the aim was to discover and characterize lncRNAs implicated in AML and to describe their role in AML biology. Further aims were to explore their use as prognostic or predictive biomarkers. Using whole-transcriptome analysis, a novel lncRNA, here named MALNC, was identified. MALNC had elevated expression in two large AML cohorts compared to normal CD34+ cells. Clinical correlation analyses indicated that MALNC was almost uniquely expressed in patients with PML-RARA fusion gene and with co-mutated isocitrate dehydrogenase-2 R140 and nucleophosmin-1 (IDH2R140/NPM1). MALNC expression was specifically high at the promyelocytic stage and decreased with maturation in leukemic and normal cells. High MALNC expression associated independently with better overall survival. CRISPR-Cas9-knockout in promyelocytic cell lines impaired proliferation, colony formation and all-trans retinoic acid (ATRA)-induced differentiation. Also, MALNC-knockout dramatically sensitized cells to arsenic trioxide (ATO), ATO-ATRA combinatorial and Bcl-2-inhibitor venetoclax treatment as well as associated with cyclin-dependent kinase (Cdk)-inhibitor resistance. In conclusion, MALNC is overexpressed in certain subgroups of AML and could play a role during normal and leukemic hematopoietic maturation. Furthermore, it correlates with response to anti-leukemic drugs, which suggests a role as a predictive marker to drug response and survival in AML.
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| 10. |
- Quaglia, Milena, et al.
(författare)
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Better Measurement for Improved Diagnosis and Management of Alzheimer's Disease : Update on the Empir Neuromet Project
- 2018
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14, s. P759-P760
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The development of novel therapies for Alzheimer’s Disease (AD) is constrained by the lack of available methods for preclinical diagnosis, despite extensive research on biomarker identification. Here, we present an update of progress from EMPIR NeuroMET, a project combining diverse expertise from five National Measurement Institutes (NMIs), with clinicians and academics, to overcome limitations in measurement methods in neurodegenerative disease diagnosis and treatment.
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| 11. |
- Reijs, Babette L R, et al.
(författare)
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The Central Biobank and Virtual Biobank of BIOMARKAPD: A Resource for Studies on Neurodegenerative Diseases.
- 2015
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Biobanks are important resources for biomarker discovery and assay development. Biomarkers for Alzheimer's and Parkinson's disease (BIOMARKAPD) is a European multicenter study, funded by the EU Joint Programme-Neurodegenerative Disease Research, which aims to improve the clinical use of body fluid markers for the diagnosis and prognosis of Alzheimer's disease (AD) and Parkinson's disease (PD). The objective was to standardize the assessment of existing assays and to validate novel fluid biomarkers for AD and PD. To support the validation of novel biomarkers and assays, a central and a virtual biobank for body fluids and associated data from subjects with neurodegenerative diseases have been established. In the central biobank, cerebrospinal fluid (CSF) and blood samples were collected according to the BIOMARKAPD standardized pre-analytical procedures and stored at Integrated BioBank of Luxembourg. The virtual biobank provides an overview of available CSF, plasma, serum, and DNA samples at each site. Currently, at the central biobank of BIOMARKAPD samples are available from over 400 subjects with normal cognition, mild cognitive impairment (MCI), AD, frontotemporal dementia (FTD), vascular dementia, multiple system atrophy, progressive supranuclear palsy, PD, PD with dementia, and dementia with Lewy bodies. The virtual biobank contains information on over 8,600 subjects with varying diagnoses from 21 local biobanks. A website has been launched to enable sample requests from the central biobank and virtual biobank.
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| 12. |
- Teunissen, Charlotte E, et al.
(författare)
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Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative Dementias.
- 2023
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Ingår i: Molecular & cellular proteomics : MCP. - : Elsevier BV. - 1535-9484 .- 1535-9476. ; 22:10
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative dementias are progressive diseases that cause neuronal network breakdown in different brain regions often because of accumulation of misfolded proteins in the brain extracellular matrix, such as amyloids or inside neurons or other cell types of the brain. Several diagnostic protein biomarkers in body fluids are being used and implemented, such as for Alzheimer's disease. However, there is still a lack of biomarkers for co-pathologies and other causes of dementia. Such biofluid-based biomarkers enable precision medicine approaches for diagnosis and treatment, allow to learn more about underlying disease processes, and facilitate the development of patient inclusion and evaluation tools in clinical trials. When designing studies to discover novel biofluid-based biomarkers, choice of technology is an important starting point. But there are so many technologies to choose among. To address this, we here review the technologies that are currently available in research settings and, in some cases, in clinical laboratory practice. This presents a form of lexicon on each technology addressing its use in research and clinics, its strengths and limitations, and a future perspective.
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| 13. |
- Teunissen, Charlotte E, et al.
(författare)
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White paper by the Society for CSF Analysis and Clinical Neurochemistry: Overcoming barriers in biomarker development and clinical translation
- 2018
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Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10, s. 2-8
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Tidskriftsartikel (refereegranskat)abstract
- Body fluid biomarkers have great potential for different clinical purposes, including diagnosis, prognosis, patient stratification and treatment effect monitoring. This is exemplified by current use of several excellent biomarkers, such as the Alzheimer's disease cerebrospinal fluid (CSF) biomarkers, anti-neuromyelitis optica antibodies and blood neurofilament light. We still, however, have a strong need for additional biomarkers and several gaps in their development and implementation should be filled. Examples of such gaps are i) limited knowledge of the causes of neurological diseases, and thus hypotheses about the best biomarkers to detect subclinical stages of these diseases; ii) the limited success translating discoveries obtained by e.g. initial mass spectrometry proteomic low-throughput studies into immunoassays for widespread clinical implementation; iii) lack of interaction among all stakeholders to optimise and adapt study designs throughout the biomarker development process to medical needs, which may change during the long period needed for biomarker development.The Society for CSF Analysis and Clinical Neurochemistry (established in 2015) has been founded as a concerted follow-up of large standardisation projects, including BIOMARKAPD and SOPHIA, and the BioMS-consortium.The main aims of the CSF society are to exchange high level international scientific experience, to facilitate the incorporation of CSF diagnostics into clinical practice and to give advice on inclusion of CSF analysis into clinical guidelines. The society has a broad scope, as its vision is that the gaps in development and implementation of biomarkers are shared among almost all neurological diseases and thus they can benefit from the activities of the society.
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| 14. |
- Uhlig, Martin, et al.
(författare)
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Two-Dimensional Aggregation and Semidilute Ordering in Cellulose Nanocrystals
- 2016
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Ingår i: Langmuir. - : American Chemical Society. - 0743-7463 .- 1520-5827. ; 32:2, s. 442-450
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Tidskriftsartikel (refereegranskat)abstract
- The structural properties and aggregation behavior of carboxymethylated cellulose nanocrystals (CNC-COOH) were analyzed with small angle neutron scattering (SANS), transmission electron microscopy (TEM), atomic force microscopy (AFM), and dynamic light scattering (DLS) and compared to sulfuric acid hydrolyzed cellulose nanocrystals (CNC-SO3H). The CNC-COOH system, prepared from single carboxymethylated cellulose nanofibrils, was shown to laterally aggregate into 2D-stacks that were stable both in bulk solution and when adsorbed to surfaces. CNC-SO3H also showed a 2D aggregate structure with similar cross sectional dimensions (a width to height ratio of 8) as CNC-COOH, but a factor of 2 shorter length. SANS and DLS revealed a reversible ordering of the 2D aggregates under semidilute conditions, and a structure peak was observed for both systems. This indicates an early stage of liquid crystalline arrangement of the crystal aggregates, at concentrations below those assessed using birefringence or polarized optical microscopy.
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| 15. |
- Österroos, Albin, et al.
(författare)
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Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia
- 2020
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Ingår i: Blood Cancer Journal. - : NATURE PUBLISHING GROUP. - 2044-5385. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Relevant molecular tools for treatment stratification of patients >= 65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients >= 65 years. Intensively treated patients withNPM1andIDH2(R172)mutations had longer overall survival (OS), whereas mutatedTP53conferred lower CR rates and shorter OS.FLT3-ITDandTP53mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutatedTP53, compared to 97% CR in low-risk patients defined by high expression ofZBTB7AandEEPD1withoutTP53mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
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