Multiple myeloma (MM) is a plasma cell cancer with poor survival, characterized by the expansion of multiple myeloma cells (MMCs) in the bone marrow. Using a microarray-based genome-wide screen for ...genes responding to DNA methyltransferases (DNMT) inhibition in MM cells, we identified RECQ1 among the most downregulated genes. RecQ helicases are DNA unwinding enzymes involved in the maintenance of chromosome stability. Here we show that RECQ1 is significantly overexpressed in MMCs compared to normal plasma cells and that increased RECQ1 expression is associated with poor prognosis in three independent cohorts of patients. Interestingly, RECQ1 knockdown inhibits cells growth and induces apoptosis in MMCs. Moreover, RECQ1 depletion promotes the development of DNA double-strand breaks, as evidenced by the formation of 53BP1 foci and the phosphorylation of ataxia-telangiectasia mutated (ATM) and histone variant H2A.X (H2AX). In contrast, RECQ1 overexpression protects MMCs from melphalan and bortezomib cytotoxicity. RECQ1 interacts with PARP1 in MMCs exposed to treatment and RECQ1 depletion sensitizes MMCs to poly(ADP-ribose) polymerase (PARP) inhibitor. DNMT inhibitor treatment results in RECQ1 downregulation through miR-203 deregulation in MMC. Altogether, these data suggest that association of DNA damaging agents and/or PARP inhibitors with DNMT inhibitors may represent a therapeutic approach in patients with high RECQ1 expression associated with a poor prognosis.
Background and purpose
The prognostic value of serum neurofilament light chain (sNfL), a biomarker of neurodegeneration, compared to other prognostic factors of amyotrophic lateral sclerosis (ALS) at ...the time of diagnosis, remains unclear.
Methods
Sera from ALS patients were prospectively collected at the first diagnostic visit in our centre. sNfL levels were determined by single molecule array in 207 ALS patients and in 21 healthy controls. The prognostic value of sNfL was compared with that of other known clinical prognostic factors using a Cox regression model and multivariate analysis.
Results
Serum neurofilament light chain levels were higher in ALS patients than in controls (P < 0.0001). Seven parameters were predictive of death in ALS: older age, bulbar onset, higher ALS Functional Rating Scale revised (ALSFRS‐R) score, greater weight loss, lower maximal inspiratory pressure, forced vital capacity and higher sNfL levels. A Cox regression model showed that sNfL (P < 0.0001), weight loss (P = 0.040) and site at onset (P = 0.048) were independent predictive factors of death. In a sub‐cohort restricted to 139 patients with complete spirometry data, sNfL level (P < 0.005) and forced vital capacity (P = 0.022) were independent factors predictive of death. In a subgroup of 142 patients in whom ALSFRS‐R score was available at several time points, sNfL levels positively correlated with ALSFRS‐R rate of decline (r = 0.571, P < 10−12).
Conclusions
Higher sNfL concentration is a strong and independent prognostic factor of death in ALS as early as the time of diagnosis.
The increasing number of people with advanced Alzheimer's disease (AD) represents a significant psychological and financial cost to the world population. Accurate detection of the earliest phase of ...preclinical AD is of major importance for the success of preventive and therapeutic strategies (Cullen et al., 2021). Advances in analytical techniques have been essential for the development of sensitive, specific and reliable diagnostic tests for AD biomarkers in biological fluids (cerebrospinal fluid and blood). Blood biomarkers hold promising potential for early and minimally invasive detection of AD, but also for differential diagnosis of dementia and for monitoring the course of the disease. The aim of this review is to provide an overview of current blood biomarkers of AD, from tau proteins and amyloid peptides to biomarkers of neuronal degeneration and inflammation, reactive and metabolic factors. We thus discuss the informative value of currently candidate blood biomarkers and their potential to be integrated into clinical practice for the management of AD in the near future.
•Five B. cinerea laccases were identified in sweet white wines.•A LC–MS/MRM method targeting laccase-2-BcLCC2 and laccase-3-BcLCC7 was developed.•Laccase-2-BcLCC2 and laccase-3-BcLCC7 were in higher ...amount in botrytized wines.
Botrytized sweet wines are made with berries infected by the fungus Botrytis cinerea. The aim of this study was to identify biomarkers of B. cinerea infection in sweet wines with a focus on laccases which are exocellular oxidase enzymes produced by this fungus during fruit contamination. Total proteins from six commercial sweet wines, including three naturally botrytized wines and three non-botrytized wines were analysed by LC-QTOF-MS. Five laccases, namely laccase-1-BcLCC1, laccase-2-BcLCC2, laccase-3-BcLCC7, laccase-8-BcLCC8 and laccase-12-BcLCC12, were identified in both types of wine. Then, a targeted proteomic approach by LC-MRM was used to semi-quantify laccase-2-BcLCC2 and laccase-3-BcLCC7, in the six samples. LC-MRM targeted analysis of the two enzymes allowed the discrimination of botrytized versus non-botrytized sweet white wines.
One of the main challenges in cancer management relates to the discovery of reliable biomarkers, which could guide decision-making and predict treatment outcome. In particular, the rise and ...democratization of high-throughput molecular profiling technologies bolstered the discovery of “biomarker signatures” that could maximize the prediction performance. Such an approach was largely employed from diverse OMICs data (i.e., genomics, transcriptomics, proteomics, metabolomics) but not from epitranscriptomics, which encompasses more than 100 biochemical modifications driving the post-transcriptional fate of RNA: stability, splicing, storage, and translation. We and others have studied chemical marks in isolation and associated them with cancer evolution, adaptation, as well as the response to conventional therapy. In this study, we have designed a unique pipeline combining multiplex analysis of the epitranscriptomic landscape by high-performance liquid chromatography coupled to tandem mass spectrometry with statistical multivariate analysis and machine learning approaches in order to identify biomarker signatures that could guide precision medicine and improve disease diagnosis. We applied this approach to analyze a cohort of adult diffuse glioma patients and demonstrate the existence of an “epitranscriptomics-based signature” that permits glioma grades to be discriminated and predicted with unmet accuracy. This study demonstrates that epitranscriptomics (co)evolves along cancer progression and opens new prospects in the field of omics molecular profiling and personalized medicine.
Background and Aims
Laccase enzymes produced by Botrytis cinerea are involved in the oxidation of phenolic substances during the development of grey mould, which causes significant economic losses. ...The aim of this work was to study the structural and activity characteristics of the laccase enzymes secreted by three B. cinerea strains that are involved in the development of grey mould.
Methods and Results
Laccase enzymes obtained from three B. cinerea strains one reference strain (B05.10) and two strains obtained from two French vineyards (VA612 and RM344) were characterised. Analysis by LC‐QTOF‐MS revealed that the three strains contained a mixture of Laccase‐2‐BcLCC2 and Laccase‐3‐BcLCC7. The structural characteristics of the laccases from the three strains, such as molecular weight and glycosylation degree, were identical. Nevertheless, their catalytic activities were significantly different.
Conclusions
Differences in catalytic activities could be due either to possible differences in the relative amount of Laccase‐2‐BcLCC2 and Laccase‐3‐BcLCC7 produced by each strain or to differences in the glycosidic fraction of the enzymes.
Significance of the Study
The severity of the infection caused by B. cinerea may be not only related to the infection level but also to the strain involved.
This study focused on the search for new biomarkers based on liquid chromatography-multiple reaction monitoring (LC-MRM) proteomics profiling of whole saliva from patients with periodontitis compared ...to healthy subjects. The LC-MRM profiling approach is a new and innovative method that has already been validated for the absolute and multiplexed quantification of biomarkers in several diseases. The dataset for this study was produced using LC-MRM to monitor protein levels in a multiplex assay, it provides clinical information on salivary biomarkers of periodontitis. The data presented here is an extension of our recently published research article (Mertens et al., 2017) 1.
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According to the state of mitochondrial respiration, the respiratory chain generates superoxide anions converted into hydrogen peroxide. Two uncoupling proteins (UCP) able to modulate the coupling ...between the respiratory chain and ATP synthesis are now identified and could be involved in mitochondrial H2O2 generation. UCP1 is specific to brown adipose tissue (BAT) whereas UCP2 is expressed in numerous tissues, particularly in monocytes/macrophages. Preincubation of BAT mitochondrial fractions with GDP, an inhibitor of UCP1, induced a rise in mitochondrial membrane potential (assessed by rhodamine 123 uptake) and H2O2 production. An uncoupling agent reversed this effect. Liver mitochondria exhibited a similar phenotype. GDP was also able to raise membrane potential and H2O2 production of the mitochondria from nonparenchymal cells expressing UCP2, but was completely ineffective on mitochondria from hepatocytes deprived of UCP2. The GDP effect was also observed with mitochondrial fractions of the spleen or thymus, which highly expressed UCP2. Altogether, these results strongly suggest that UCP2 is sensitive to GDP and that the UCPs, particularly UCP2, are able to modulate H2O2 mitochondrial generation. This supports a role for UCP2 in cellular (patho‐) physiological processes involving free radicals generated by mitochondria, such as oxidative damage, inflammation, or apoptosis.—Nègre‐Salvayre, A., Hirtz, C., Carrera, G., Cazenave, R., Troly, M., Salvayre, R., Pénicaud, L., Casteilla, L. A role for uncoupling protein‐2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 11, 809–815 (1997)
To ensure reliable diagnosis and treatment consistently throughout healthcare, metrological quality assurance is essential. There are, however, many observations in the social sciences and ...healthcare, such as the memory tests studied here, which have been ‘claimed’ to be measurements but in fact have not been fully metrologically legitimated. We have already argued in favour of extending traditional metrological underlying principles to cover social measurements, including the development of construct specification equations (CSE) considered as ‘recipes for certified reference materials (CRM)’ for traceability, analogous to CRMs in metrology in chemistry. Although the CSE approach has to date been used mostly to explain and validate test item attributes, this paper turns to focus on causal explanations of person characteristics. We describe methods and preliminary results developed in the European EMPIR NeuroMET projects, which may be used for providing quality assured measurement of disease progression and treatment benefits for patients with neurodegenerative conditions.
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