Predicting Ovarian Cancer Treatment Response in Histopathology using Hierarchical Vision Transformers and Multiple Instance Learning

For many patients, current ovarian cancer treatments offer limited clinical benefit. For some therapies, it is not possible to predict patients' responses, potentially exposing them to the adverse effects of treatment without any therapeutic benefit. As part of the automated prediction of treatment effectiveness in ovarian cancer using histopathological images (ATEC23) challenge, we evaluated the effectiveness of deep learning to predict whether a course of treatment including the antiangiogenic drug bevacizumab could contribute to remission or prevent disease progression for at least 6 months in a set of 282 histopathology whole slide images (WSIs) from 78 ovarian cancer patients. Our approach used a pretrained Hierarchical Image Pyramid Transformer (HIPT) to extract region-level features and an attention-based multiple instance learning (ABMIL) model to aggregate features and classify whole slides. The optimal HIPT-ABMIL model had an internal balanced accuracy of 60.2% +- 2.9% and an AUC of 0.646 +- 0.033. Histopathology-specific model pretraining was found to be beneficial to classification performance, though hierarchical transformers were not, with a ResNet feature extractor achieving similar performance. Due to the dataset being small and highly heterogeneous, performance was variable across 5-fold cross-validation folds, and there were some extreme differences between validation and test set performance within folds. The model did not generalise well to tissue microarrays, with accuracy worse than random chance. It is not yet clear whether ovarian cancer WSIs contain information that can be used to accurately predict treatment response, with further validation using larger, higher-quality datasets required.Comment: Submission to ATEC23 challenge at MICCAI 2023 conferenc

Autoinsertion of soluble oligomers of Alzheimer's Aβ(1–42) peptide into cholesterol-containing membranes is accompanied by relocation of the sterol towards the bilayer surface

BACKGROUND: Soluble Alzheimer's Aβ oligomers autoinsert into neuronal cell membranes, contributing to the pathology of Alzheimer's Disease (AD), and elevated serum cholesterol is a risk factor for AD, but the reason is unknown. We investigated potential connections between these two observations at the membrane level by testing the hypothesis that Aβ(1–42) relocates membrane cholesterol. RESULTS: Oligomers of Aβ(1–42), but not the monomeric peptide, inserted into cholesterol-containing phosphatidylcholine monolayers with an anomalously low molecular insertion area, suggesting concurrent lipid rearrangement. Membrane neutron diffraction, including isomorphous replacement of specific lipid hydrogens with highly-scattering deuterium, showed that Aβ(1–42) insertion was accompanied by outward displacement of membrane cholesterol, towards the polar surfaces of the bilayer. Changes in the generalised polarisation of laurdan confirmed that the structural changes were associated with a functional alteration in membrane lipid order. CONCLUSION: Cholesterol is known to regulate membrane lipid order, and this can affect a wide range of membrane mechanisms, including intercellular signalling. Previously unrecognised Aβ-dependent rearrangement of the membrane sterol could have an important role in AD

Maritime Cultural Heritage and Urbanisation in the Middle East and North Africa

Urbanisation, comprising development, land reclamation and population growth along coastal margins, continues to place significant pressure on the maritime cultural heritage (MCH), particularly in the Middle East and North Africa (MENA) region. Thus, there is a growing need for ascertaining the extent of the affected MCH resource and its condition. One such assessment is being undertaken by the Maritime Endangered Archaeology (MarEA) project, which is generating a unique informed database of the maritime resource in the MENA region. Through a regional overview combined with focused assessment on two case studies – Marsa Matruh (Egypt) and Bahrain – this paper demonstrates the threat urbanisation poses and the damage it has inflicted on MCH. The analyses and documentation that MarEA produces via remote sensing, deskbased and field-based assessments, constitutes a valuable resource that, at the very least, exists in digital perpetuity. It establishes a record that can be drawn upon to formulate targeted strategies and initiatives inclusive of the maritime cultural heritage resource

The effect of stress on the expression of the amyloid precursor protein in rat brain

AbstractThe abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology

Motoneurons secrete angiogenin to induce RNA cleavage in astroglia.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS

VRPassport: Travel the world in Virtual Reality for people with Dementia

The loss of autonomy that comes with being in the care of others has a significant impact on the emotional well-being of people with dementia (PwD). Our research aims to investigate key design factors when creating Virtual Reality (VR) non-pharmacological interventions to improve their emotional wellbeing and enhance their interactions with caregivers. This paper, presents the iterative design and initial evaluation of a VR system aiming to enhance the procedure of admitting VR interventions

The North Atlantic Fish Revolution (ca. AD 1500)

UID/HIS/04666/2013We propose the concept of the “Fish Revolution” to demarcate the dramatic increase in North Atlantic fisheries after AD 1500, which led to a 15-fold increase of cod (Gadus morhua) catch volumes and likely a tripling of fish protein to the European market.We consider three key questions: (1) What were the environmental parameters of the Fish Revolution? (2) What were the globalising effects of the Fish Revolution? (3) What were the consequences of the Fish Revolution for fishing communities? While these questions would have been considered unknowable a decade or two ago, methodological developments in marine environmental history and historical ecology have moved information about both supply and demand into the realm of the discernible. Although much research remains to be done, we conclude that this was a major event in the history of resource extraction from the sea, mediated by forces of climate change and globalisation, and is likely to provide a fruitful agenda for future multidisciplinary research.publishersversionpublishe

Comparative genome and methylome analysis reveals restriction/modification system diversity in the gut commensal Bifidobacterium breve

Bifidobacterium breve represents one of the most abundant bifidobacterial species in the gastrointestinal tract of breast-fed infants, where their presence is believed to exert beneficial effects. In the present study whole genome sequencing, employing the PacBio Single Molecule, Real-Time (SMRT) sequencing platform, combined with comparative genome analysis allowed the most extensive genetic investigation of this taxon. Our findings demonstrate that genes encoding Restriction/Modification (R/M) systems constitute a substantial part of the B. breve variable gene content (or variome). Using the methylome data generated by SMRT sequencing, combined with targeted Illumina bisulfite sequencing (BS-seq) and comparative genome analysis, we were able to detect methylation recognition motifs and assign these to identified B. breve R/M systems, where in several cases such assignments were confirmed by restriction analysis. Furthermore, we show that R/M systems typically impose a very significant barrier to genetic accessibility of B. breve strains, and that cloning of a methyltransferase-encoding gene may overcome such a barrier, thus allowing future functional investigations of members of this species.</p