Improved NGS-based detection of microsatellite instability using tumor-only data.

Microsatellite instability (MSI) is a molecular signature of mismatch repair deficiency (dMMR), a predictive marker of immune checkpoint inhibitor therapy response. Despite its recognized pan-cancer value, most methods only support detection of this signature in colorectal cancer. In addition to the tissue-specific differences that impact the sensitivity of MSI detection in other tissues, the performance of most methods is also affected by patient ethnicity, tumor content, and other sample-specific properties. These limitations are particularly important when only tumor samples are available and restrict the performance and adoption of MSI testing. Here we introduce MSIdetect, a novel solution for NGS-based MSI detection. MSIdetect models the impact of indel burden and tumor content on read coverage at a set of homopolymer regions that we found are minimally impacted by sample-specific factors. We validated MSIdetect in 139 Formalin-Fixed Paraffin-Embedded (FFPE) clinical samples from colorectal and endometrial cancer as well as other more challenging tumor types, such as glioma or sebaceous adenoma or carcinoma. Based on analysis of these samples, MSIdetect displays 100% specificity and 96.3% sensitivity. Limit of detection analysis supports that MSIdetect is sensitive even in samples with relatively low tumor content and limited microsatellite instability. Finally, the results obtained using MSIdetect in tumor-only data correlate well (R=0.988) with what is obtained using tumor-normal matched pairs, demonstrating that the solution addresses the challenges posed by MSI detection from tumor-only data. The accuracy of MSI detection by MSIdetect in different cancer types coupled with the flexibility afforded by NGS-based testing will support the adoption of MSI testing in the clinical setting and increase the number of patients identified that are likely to benefit from immune checkpoint inhibitor therapy.

Social and physical neighbourhood characteristics and loneliness among older adults: results from the MINDMAP project.

BACKGROUND: Loneliness is associated with several adverse mental and physical health outcomes in older adults. Previous studies have shown that a variety of individual-level and perceived area-level characteristics are associated with loneliness. This study examined the associations of objectively measured social and physical neighbourhood characteristics with loneliness. METHODS: We used cross-sectional data from 1959 older adults (63-98 years) who participated in the Longitudinal Ageing Study Amsterdam (LASA; wave 2011/12) and the Health and Living Conditions of the Population of Eindhoven and Surroundings study (GLOBE; wave 2014) in the Netherlands. Study-specific loneliness scores were harmonised across both cohort studies and divided into tertiles denoting low, medium and high levels of loneliness. Objectively measured neighbourhood characteristics, including area-level percentages of low educated residents, social security beneficiaries and unoccupied dwellings, average income, crime levels and land use mix, were linked to individual-level data. Multinomial logistic regression analyses were conducted to examine the associations of interest. RESULTS: There was no statistical evidence for an association of the included neighbourhood characteristics with loneliness. Although not statistically significant, the observed associations suggested that participants living in neighbourhoods with more heterogeneous land use mix were less likely to have a medium and high level of loneliness than those living in more homogeneous neighbourhoods in terms of land use mix (ORmedium=0.54, 95% CI=0.18-1.67; ORhigh=0.67, 95% CI=0.21-2.11). CONCLUSION: The results indicate that the included objectively measured social and physical neighbourhood characteristics are not associated with loneliness in old age.

Overview of retrospective data harmonisation in the MINDMAP project: process and results.

BACKGROUND: The MINDMAP project implemented a multinational data infrastructure to investigate the direct and interactive effects of urban environments and individual determinants of mental well-being and cognitive function in ageing populations. Using a rigorous process involving multiple teams of experts, longitudinal data from six cohort studies were harmonised to serve MINDMAP objectives. This article documents the retrospective data harmonisation process achieved based on the Maelstrom Research approach and provides a descriptive analysis of the harmonised data generated. METHODS: A list of core variables (the DataSchema) to be generated across cohorts was first defined, and the potential for cohort-specific data sets to generate the DataSchema variables was assessed. Where relevant, algorithms were developed to process cohort-specific data into DataSchema format, and information to be provided to data users was documented. Procedures and harmonisation decisions were thoroughly documented. RESULTS: The MINDMAP DataSchema (v2.0, April 2020) comprised a total of 2841 variables (993 on individual determinants and outcomes, 1848 on environmental exposures) distributed across up to seven data collection events. The harmonised data set included 220 621 participants from six cohorts (10 subpopulations). Harmonisation potential, participant distributions and missing values varied across data sets and variable domains. CONCLUSION: The MINDMAP project implemented a collaborative and transparent process to generate a rich integrated data set for research in ageing, mental well-being and the urban environment. The harmonised data set supports a range of research activities and will continue to be updated to serve ongoing and future MINDMAP research needs.

Can early neurological improvement after mechanical thrombectomy be used as a surrogate for final stroke outcome?

BACKGROUND AND PURPOSE: We aimed to identify the best definition of early neurological improvement (ENI) at 2 and 24 hours after mechanical thrombectomy (MT) and determine its ability to predict a good functional outcome at 3 months. METHODS: This retrospective analysis was based on a prospectively collected registry of patients treated by MT for ischemic stroke from May 2010 to March 2017. We included patients treated with stent-retrievers with National Institute of Health Stroke Scale (NIHSS) score before treatment and at 2 and/or 24 hours after treatment and modified Rankin Score (mRS) at 3 months. Receiver operating characteristic curve analysis was performed to estimate optimal thresholds for ENI at 2 and 24 hours. The relationship between optimal ENI definitions and good outcome at 3 months (mRS 0-2) was assessed by logistic regression. RESULTS: The analysis included 246 patients. At 2 hours, the optimal threshold to predict a good outcome at 3 months was improvementin the NIHSS score of >1 point (AUC 0.83,95% CI 0.77 to 0.87), with sensitivity and specificity 78.3% (62.2-85.7%) and 84.6% (77.2-90.3%), respectively, and OR 12.67 (95% CI 4.69 to 31.10, p<0.0001). At 24 hours, the optimal threshold was an improvementin the NIHSS score of >4 points (AUC 0.93, 95% CI 0.89 to 0.96), with sensitivity and specificity 93.8% (87.7-97.5%) and 83.2% (75.7-89.2%), respectively, and OR 391.32 (95% CI 44.43 to 3448.35, p<0.0001). CONCLUSIONS: ENI 24 hours after thrombectomy appears to be a straightforward surrogate of long-term endpoints and may have value in future research.

18F-FDG PET/CT Evaluation of Ceritinib Therapy in Metastatic ALK-Positive Non-small Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLC) account for 3% to 7% of all NSCLC and require a standard treatment by crizotinib. However, crizotinib resistance is frequent within the first 12 months of treatment. Ceritinib is a novel tyrosine kinase inhibitor of ALK recently introduced in France for metastatic or locally advanced crizotinib-resistant ALK NSCLC. We report the first use of ceritinib in our institution with a spectacular tumoral response after only 3 months of treatment. This case demonstrates the major role of F-FDG PET/CT for monitoring the effectiveness of this new treatment.

The ABCG transporter PEC1/ABCG32 is required for the formation of the developing leaf cuticle in Arabidopsis.

The cuticle is an essential diffusion barrier on aerial surfaces of land plants whose structural component is the polyester cutin. The PERMEABLE CUTICLE1/ABCG32 (PEC1) transporter is involved in plant cuticle formation in Arabidopsis. The gpat6 pec1 and gpat4 gapt8 pec1 double and triple mutants are characterized. Their PEC1-specific contributions to aliphatic cutin composition and cuticle formation during plant development are revealed by gas chromatography/mass spectrometry and Fourier-transform infrared spectroscopy. The composition of cutin changes during rosette leaf expansion in Arabidopsis. C16:0 monomers are in higher abundance in expanding than in fully expanded leaves. The atypical cutin monomer C18:2 dicarboxylic acid is more prominent in fully expanded leaves. Findings point to differences in the regulation of several pathways of cutin precursor synthesis. PEC1 plays an essential role during expansion of the rosette leaf cuticle. The reduction of C16 monomers in the pec1 mutant during leaf expansion is unlikely to cause permeability of the leaf cuticle because the gpat6 mutant with even fewer C16:0 monomers forms a functional rosette leaf cuticle at all stages of development. PEC1/ABCG32 transport activity affects cutin composition and cuticle structure in a specific and non-redundant fashion.

A member of the PLEIOTROPIC DRUG RESISTANCE family of ATP binding cassette transporters is required for the formation of a functional cuticle in Arabidopsis.

Although the multilayered structure of the plant cuticle was discovered many years ago, the molecular basis of its formation and the functional relevance of the layers are not understood. Here, we present the permeable cuticle1 (pec1) mutant of Arabidopsis thaliana, which displays features associated with a highly permeable cuticle in several organs. In pec1 flowers, typical cutin monomers, such as ω-hydroxylated fatty acids and 10,16-dihydroxypalmitate, are reduced to 40% of wild-type levels and are accompanied by the appearance of lipidic inclusions within the epidermal cell. The cuticular layer of the cell wall, rather than the cuticle proper, is structurally altered in pec1 petals. Therefore, a significant role for the formation of the diffusion barrier in petals can be attributed to this layer. Thus, pec1 defines a new class of mutants. The phenotypes of the pec1 mutant are caused by the knockout of ATP BINDING CASSETTEG32 (ABCG32), an ABC transporter from the PLEIOTROPIC DRUG RESISTANCE family that is localized at the plasma membrane of epidermal cells in a polar manner toward the surface of the organs. Our results suggest that ABCG32 is involved in the formation of the cuticular layer of the cell wall, most likely by exporting particular cutin precursors from the epidermal cell.