Long-term effects of the interruption of the Dutch breast cancer screening program due to COVID-19:A modelling study

Due to COVID-19, the Dutch breast cancer screening program was interrupted for three months with uncertain long-term effects. The aim of this study was to estimate the long-term impact of this interruption on delay in detection, tumour size of screen-detected breast cancers, and interval cancer rate. After validation, the micro-simulation model SiMRiSc was used to calculate the effects of interruption of the breast cancer screening program for three months and for hypothetical interruptions of six and twelve months. A scenario without interruption was used as reference. Outcomes considered were tumour size of screen-detected breast cancers and interval cancer rate. Women of 55–59 and 60–64 years old at time of interruption were considered. Uncertainties were estimated using a sensitivity analysis. The three-month interruption had no clinically relevant long-term effect on the tumour size of screen-detected breast cancers. A 19% increase in interval cancer rate was found between last screening before and first screening after interruption compared to no interruption. Hypothetical interruptions of six and twelve months resulted in larger increases in interval cancer rate of 38% and 78% between last screening before and first screening after interruption, respectively, and an increase in middle-sized tumours in first screening after interruption of 26% and 47%, respectively. In conclusion, the interruption of the Dutch screening program is not expected to result in a long-term delay in detection or clinically relevant change in tumour size of screen-detected cancers, but only affects the interval cancer rate between last screening before and first screening after interruption

Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-beta plaques

BACKGROUND: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression. RESULTS: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. CONCLUSIONS: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease

Axonal Odorant Receptors Mediate Axon Targeting

In mammals, odorant receptors not only detect odors but also define the target in the olfactory bulb, where sensory neurons project to give rise to the sensory map. The odorant receptor is expressed at the cilia, where it binds odorants, and at the axon terminal. The mechanism of activation and function of the odorant receptor at the axon terminal is, however, still unknown. Here, we identify phosphatidylethanolamine- binding protein 1 as a putative ligand that activates the odorant receptor at the axon terminal and affects the turning behavior of sensory axons.Genetic ablation of phosphatidylethanolamine-binding protein 1 in mice results in a strongly disturbed olfactory sensory map. Our data suggest that the odorant receptor at the axon terminal of olfactory neurons acts as an axon guidance cue that responds to molecules originating in the olfactory bulb. The dual function of the odorant receptor links specificity of odor perception and axon targeting

Topographical Organization of Mu and Beta Band Activity Associated with Hand and Foot Movements in Patients with Perirolandic Lesions

To study the topographical organization of mu and beta band event-related desynchronization (ERD) associated with voluntary hand and foot movements, we used magnetoencephalographic (MEG) recordings from 19 patients with perirolandic lesions. Synthetic aperture magnetometry (SAM) was used to detect and localize changes in the mu (7 - 11 Hz) and beta (13 - 30 Hz) frequency bands associated with repetitive movements of the hand and foot and overlaid on individual coregistered magnetic resonance (MR) images. Hand movements showed homotopic and contralateral ERD at the sensorimotor (S/M) cortex in the majority of cases for mu and to a lesser extent for beta rhythms. Foot movements showed an increased heterotopic distribution with bilateral and ipsilateral ERD compared to hand movements. No systematic topographical segregation between mu and beta ERD could be observed. In patients with perirolandic lesions, the mu and beta band spatial characteristics associated with hand movements retain the expected functional-anatomical boundaries to a large extent. Foot movements have altered patterns of mu and beta band ERD, which may give more insight into the differential functional role of oscillatory activity in different voluntary movements

Spherical harmonic decomposition applied to spatial-temporal analysis of human high-density EEG

We demonstrate an application of spherical harmonic decomposition to analysis of the human electroencephalogram (EEG). We implement two methods and discuss issues specific to analysis of hemispherical, irregularly sampled data. Performance of the methods and spatial sampling requirements are quantified using simulated data. The analysis is applied to experimental EEG data, confirming earlier reports of an approximate frequency-wavenumber relationship in some bands.Comment: 12 pages, 8 figures, submitted to Phys. Rev. E, uses APS RevTeX style

Correlation between Pathologic Complete Response in the Breast and Absence of Axillary Lymph Node Metastases after Neoadjuvant Systemic Therapy

Objective:The aim was to investigate whether pathologic complete response (PCR) in the breast is correlated with absence of axillary lymph node metastases at final pathology (ypN0) in patients treated with neoadjuvant systemic therapy (NST) for different breast cancer subtypes.Background:Pathologic complete response rates have improved on account of more effective systemic treatment regimens. Promising results in feasibility trials with percutaneous image-guided tissue sampling for the identification of breast PCR after NST raise the question whether breast surgery is a redundant procedure. Thereby, the need for axillary surgery should be reconsidered as well.Methods:Patients diagnosed with cT1-3N0-1 breast cancer and treated with NST, followed by surgery between 2010 and 2016, were selected from the Netherlands Cancer Registry. Patients were compared according to the pa

Tetraspanin 6: a pivotal protein of the multiple vesicular body determining exosome release and lysosomal degradation of amyloid precursor protein fragments

BACKGROUND: The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase. METHODS: We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo. RESULTS: Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF. CONCLUSIONS: TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover