Background: Lung cancer is the leading cause of cancer mortality worldwide. Tobacco smoking is its primary cause, and yet the precise molecular alterations induced by smoking in lung tissue that lead to lung cancer and impact survival have remained obscure. A new framework of research is needed to address the challenges offered by this complex disease.

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance.

The employment of the sensitive comet assay, which is able to detect early the effects of a recent exposure to genotoxic substances, allowed us to find a slight DNA damage, only on exfoliated buccal cells of day hospital nurses, the group handling the highest amount of drugs during the administration process. This finding suggests that comet assay on exfoliated buccal cells could represent a useful tool to evaluate early and still repairable genotoxic effects of exposure to antineoplastic drug mixtures and then contribute to the improvement of the hospital safety practices.

word count: 250 Text word count: 2894 2 ABSTRACT Purpose: The disease course of multiple sclerosis (MS) is unpredictable and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloidtracers is a promising tool to evaluate white matter (WM) damage and repair. Our aims were to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-Amyloid1-42 (Aβ) levels, amyloid tracer uptake and brain volumes.Methods: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18 F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation with statistical parametric mapping software was performed. Non-parametric statistical analyses for between-group comparisons and regression analyses were conducted. Results:We found a lower SUV in DWM compared to NAWM (p<0.001) in all patients.A decreased NAWM-SUV in active compared to non-active group was observed (p<0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p=0.01). Interestingly, CSF Aβ concentration was a predictor of both NAWM-SUV (r=0.79; p=0.01) and NAWM volume (r=0.81, p=0.01). Conclusions:The correlation between CSF Aβ levels and NAWM-SUV suggests that the predictive role of β-amyloid may be linked to myelin early damage and may reflect the disease activity and the clinical progression.

Background and ObjectivesRecent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset.MethodsThis study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO)18F-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP18F-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had18F-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of18F-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression.ResultsCompared with HCs, patients with presymptomatic MS had 32% larger CPs (β = 0.38,p= 0.001), which were not dissimilar to MS CPs (p= 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p= 0.04), although no differences in18F-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163+mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased18F-DPA-714 uptake.DiscussionWe identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development.Trial Registration InformationAPHP-20210727144630, EudraCT-Number: 2008-004174-40; ClinicalTrials.gov:NCT02305264,NCT01651520, andNCT02319382.

No abstract

Background According to the 2018 NIA-AA research framework, Alzheimer’s disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition—assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis—is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers. Methods We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated. Results Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers’ profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%. Conclusions The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.