Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Aims:Coronavirus disease 2019 caused by SARS-CoV-2 has rapidly evolved into a sweeping pandemic. While its major manifestation is in the respiratory tract, the general extent of organ involvement as well as microscopic changes in the lungs remain insufficiently characterised. Autopsies are essential to elucidate COVID-19-associated organ alterations.Methods: This study reports autopsy findings of 21 COVID-19 patients hospitalised at the University Hospital Basel and at the Cantonal Hospital Baselland, Switzerland. An in-corpore technique was performed to ensure optimal staff safety. Results:The primary cause of death was respiratory failure with exudative diffuse alveolar damage with massive capillary congestion often accompanied by microthrombi despite anticoagulation. Ten cases showed superimposed bronchopneumonia. Further findings included pulmonary embolisms (n=4), alveolar haemorrhage (n=3) and vasculitis (n=1). Pathologies in other organ systems were predominantly attributable to shock; three patients showed signs of generalised thrombotic microangiopathy. Six patients were diagnosed with senile cardiac amyloidosis upon autopsy. Most patients suffered from one or more comorbidities (hypertension, obesity, cardiovascular diseases, diabetes mellitus). Additionally, there was an overall predominance of males and individuals with blood group A (81% and 65%, respectively). All relevant histological slides are linked as open-source scans in supplementary files. Conclusions:This study provides an overview of post-mortem findings in COVID-19 cases, implying that hypertensive, elderly, obese, male individuals with severe cardiovascular comorbidities as well as those with blood group A may have a lower threshold of tolerance for COVID-19. This provides a pathophysiological explanation for higher mortality rates amongst these patients.

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease 1. In the disease process neuronal tau inclusions first appear in transentorhinal cortex, from where they appear to spread to hippocampal formation and neocortex 2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. Abundant tau inclusions, in the absence of β-amyloid deposits, define Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases 1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia 3-5. Thus, transgenic mice expressing mutant (e.g. P301S) human tau in nerve cells exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein 6,7. In contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or display neurodegeneration 7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that the injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces the assembly of wild-type human tau into filaments and the spreading of pathology from the site of injection to neighbouring brain regions.

Introduction and Aims: Chronic kidney disease (CKD) is a major risk factor for atherosclerotic cardiovascular diseases. Recently it has been reported that apoptosis of aortic smooth muscle cells (AoSMCs) may relate to the atherosclerosis with plaque formation or calcification. Therefore, in the present study, we examined the effect of indoxyl sulfate (IS), which is thought to be one of uremic toxin, for apoptosis in cultured rat AoSMCs. Methods: The induction of apoptosis was quantitated by assay of the caspase CPP32, which plays a direct role in the execution of cell death. And the activity of SAPK/JNK and P38 MAP kinase, which is known as apoptosis-inducing signal transduction, was assessed by standard immunoblot using phospho-specific antibodies. Results: Twenty five μg/ml of IS, which is compatible with the concentration of IS in the serum of end-stage renal failure patients, induced 3.9±2.7-fold increase in the caspase CPP32 activity responding to serum withdrawal for 12 hours. The blockade of organic anion transporter (OAT) by 0.5mM probenecid (Pb) abolished the effect of IS on the apoptosis in AoSMCs (relative increase in the caspase CPP32: Pb-, IS-; 1±0.1, Pb-, IS+; 2.4±0.2, Pb+, IS-; 0.9±0.1, Pb+, IS+; 1.2±0.1). Indoxyl sulfate activated SAPK/JNK in AoSMCs that was significantly elevated by 30 minutes and sustained for over 2 hours, although it did not affect the activation of P38 MAP kinase. Conclusions: These results indicate that IS accelerates apoptosis induced by serum withdrawal in rat AoSMCs, which is mediated by cellular transport of IS via the OAT and may also be related to the activation of SAPK/JNK pathway. The induction of apoptosis by the accumulation of IS in blood due to CKD may play an important role in atherosclerotic lesion formation.