Molecular pathology and synaptic loss in primary tauopathies: A [18F]AV-1451 and [11C]UCB-J PET study

The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender-matched control participants were recruited from the National Institute for Health Research ‘Join Dementia Research’ platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB-J and [18F]AV-1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer’s pathology – we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB-J and [18F]AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between [11C]UCB-J and [18F]AV-1451 BPND (ß = 0.4, t = 3.6, p = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (ß = - 0.02, t = -2.9, p = 0.007, R = -0.41). Between regions, cortical [18F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher [18F]AV-1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.Cambridge Centre for Parkinson-Plus (RG95450); the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014); the PSP Association (“MAPT-PSP” study), and the Association of British Neurologists, Patrick Berthoud Charitable Trust (RG99368)

Survey of UK histopathology consultants’ attitudes towards academic and molecular pathology

Objective: Academic pathology is facing a crisis; an ongoing decline in academic pathology posts, a paucity of academic pathologist’s in-training and unfilled posts at a time when cellular pathology departments are challenged to deliver increasing numbers of molecular tests. The National Cancer Research Institute initiative in Cellular & Molecular Pathology commissioned a survey to assess attitudes of cellular pathology consultants towards research in order to understand barriers and identify possible solutions to improve this situation. As cellular pathology is encompassing an increasing number of diagnostic molecular tests, we also surveyed the current approach to and extent of training in molecular pathology. Methods: The survey was distributed to all UK-based consultant pathologists via the Pathological Society of Great Britain & Ireland and Royal College of Pathologist networks. Heads of Department were contacted separately to obtain figures for number of academic training and consultant posts. Results: 302 cellular pathologists completed the survey which represents approximately 21% of the total cellular histopathology workforce. Most respondents (89%) had been involved in research at some point; currently, 22% were undertaking research formally, and 41% on an informal basis. Of those previously involved in research, 57% stopped early in their consultant career. The majority of substantive academic posts were Professors of which 60% had been in post for >20 years. Most respondents (84%) used molecular pathology in diagnostic work, independent of where they worked or the length of time in post. Notably, 53% of consultants had not received molecular pathology training, particularly more senior consultants and consultants in district general hospitals. Conclusions: The survey reveals that the academic workforce is skewed towards senior individuals, many of whom are approaching retirement, with a missing cohort of ‘junior consultant’ academic pathologists to replace them. Most pathologists stop formal research activity at the beginning of a consultant career. While molecular pathology is an increasing part of a pathologist’s workload, the majority of consultant cellular pathologists have not received any formal molecular training

The long Tramp from Cellular Pathology to Molecular Pathology

Background: The Charite is a well known and one of the biggest University Hospital in Germany. Its Institute of Pathology was founded in 1831, and took part in all changes and modifications of diagnostic surgical pathology. Herein, it forms the basis to describe the history and development of molecular pathology from its early beginning. The appearance of biological structures at microscopic levels forms its fundament, similar to additional tissue theories which have been derived from cellular pathology. Theories of pathology: Theories of pathology frequently describe reaction patterns, and try to explain the relationship between disease and its visible manifestation. They have entered pathology in the 20th century. To name some of them:  theory of inflammation [Heinrich Schade 1924, [1], pathology of relations [Gustav Ricker (1924), [2], intercellular pathology [Tivadar Huzella (1937), [3]. Derivatives: The observation of principal identity of biological meaningful elements can be agglutinated to a ‘general theory of live’ and its manifestation. All of the investigated elements posses the same regularities, which are altered, destroyed or newly built by external influences such as disease, physical and psychological forces. Not all magnification levels that display with these elements are of the same significance. Already Virchow suggested that ‘smaller elements (molecules) might be responsible for changes that are visible ‘in larger elements’ (at cellular level).  The reflection on these ideas can be associated with the implementation of molecular techniques which has been developed in the 20th century and are still ongoing today. Perspectives: Thus, cellular and molecular pathology can be integrated under one umbrella. This umbrella will lead to newly man-formed structures, such as artificial DNA and gene components or functional chip implantations

Функціональний онкогеном — основа сучасної діагностики та нової стратегії протипухлинної терапії

Проаналізовано сучасні досягнення, у тому числі результати досліджень науковців Інституту експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України (ІЕПОР НАН України), у галузі молекулярної онкобіології та обґрунтовано можливості їх використання у клінічній практиці.Modern achievements in the field of the molecular biology, including results of investigations carried out in Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, were analyzed and evidences of their potential usage in the clinical practice were justified

Global genomic analyses of wheat powdery mildew reveal association of pathogen spread with historical human migration and trade

The fungus Blumeria graminis f. sp. tritici causes wheat powdery mildew disease. Here, we study its spread and evolution by analyzing a global sample of 172 mildew genomes. Our analyses show that B.g. tritici emerged in the Fertile Crescent during wheat domestication. After it spread throughout Eurasia, colonization brought it to America, where it hybridized with unknown grass mildew species. Recent trade brought USA strains to Japan, and European strains to China. In both places, they hybridized with local ancestral strains. Thus, although mildew spreads by wind regionally, our results indicate that humans drove its global spread throughout history and that mildew rapidly evolved through hybridization.Centro de Investigaciones AgropecuariasFil: Sotiropoulos, Alexandros G. University of Zurich. Department of Plant and Microbial Biology; SuizaFil: Arango-Isaza, Epifanía. University of Zurich. Department of Evolutionary Biology and Environmental Studies; SuizaFil: Ban, Tomohiro. Yokohama City University. Kihara Institute for Biological Research; JapónFil: Barbieri, Chiara. University of Zurich. Department of Evolutionary Biology and Environmental Studies; SuizaFil: Barbieri, Chiara. Max Planck Institute for Evolutionary Anthropology. Department of Linguistic and Cultural Evolution; AlemaniaFil: Bourras, Salim. University of Zurich. Department of Plant and Microbial Biology; SuizaFil: Bourras, Salim. University of Agricultural Sciences. Department of Forest Mycology and Plant Pathology; SueciaFil: Cowger, Christina. North Carolina State University; Estados Unidos. USDA-ARS Department of Plant Pathology; Estados UnidosFil: Czembor, Paweł C. National Research Institute. Plant Breeding and Acclimatization Institute; PoloniaFil: Ben-David, Roi. ARO-Volcani Center. Institute of Plant Sciences. Department of Vegetables and Field Crops; IsraelFil: Dinoor, Amos. University of Jerusalem. The Robert H. Smith Faculty of Agriculture, Food & Environment. Department of Plant Pathology and Microbiology; IsraelFil: Ellwood, Simon R. Curtin University. School of Molecular and Life Sciences. Centre for Crop and Disease Management; AustraliaFil: Graf, Johannes. University of Zurich. Department of Plant and Microbial Biology; SuizaFil: Hatta, Koichi. National Agricultural Research Organization. Hokkaido Agricultural Research Center Field Crop Research and Development; JapónFil: Helguera, Marcelo. Instituto Nacional de Tecnología Agropecuaria (INTA). Centro de Investigaciones Agropecuarias; ArgentinaFil: Wicker, Thomas. University of Zurich. Department of Plant and Microbial Biology; Suiz

Roadmap to a Comprehensive Clinical Data Warehouse for Precision Medicine Applications in Oncology

Leading institutions throughout the country have established Precision Medicine programs to support personalized treatment of patients. A cornerstone for these programs is the establishment of enterprise-wide Clinical Data Warehouses. Working shoulder-to-shoulder, a team of physicians, systems biologists, engineers, and scientists at Rutgers Cancer Institute of New Jersey have designed, developed, and implemented the Warehouse with information originating from data sources, including Electronic Medical Records, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology and Pathology archives, and Next Generation Sequencing services. Innovative solutions were implemented to detect and extract unstructured clinical information that was embedded in paper/text documents, including synoptic pathology reports. Supporting important precision medicine use cases, the growing Warehouse enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information of patient tumors individually or as part of large cohorts to identify changes and patterns that may influence treatment decisions and potential outcomes

Assessment of clinical trial protocols for pathology content using the SPIRIT-Path guidelines highlights areas for improvement

The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement provides evidence-based recommendations for the minimum content of clinical trial protocols. The Cellular Molecular Pathology Initiative, hosted by the UK National Cancer Research Institute, developed an extension, SPIRIT-Path, describing how to effectively incorporate pathology support into clinical trial protocols. The current study assessed the inclusion of SPIRIT-Path items in protocols of active clinical trials. Publicly available clinical trial protocols were identified for assessment against the new guidelines using a single UK hospital as the ‘test site’. One hundred and ninety interventional clinical trials were identified as receiving support from the pathology department. However, only 38 had publicly available full trial protocols (20%) and following application of the inclusion/exclusion criteria, 19 were assessed against the SPIRIT-Path guidelines. The reviewed clinical trial protocols showed some areas of compliance and highlighted other items that were inadequately described. The latter lacked information about the individuals responsible for the pathology content of the trial protocol, how pathology activities and roles were organised in the trial, where the laboratory work would be carried out, and the accreditation status of the laboratory. Only one trial had information specific to digital pathology, a technology certain to become more prevalent in the future. Adoption of the SPIRIT-Path checklist will facilitate comprehensive trial protocols that address all the key cellular and molecular pathology aspects of interventional clinical trials. This study highlights once again the lack of public availability of trial protocols. Full trial protocols should be available for scrutiny by the scientific community and the public who participate in the studies, increasing the transparency of clinical trial activity and improving quality

Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits

Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8[superscript +/–] mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8 in adult mice recapitulates improved acquired motor learning behavior found in Chd8[superscript +/–] animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.National Science Foundation (U.S.) (1122374)National Science Foundation (U.S.) (2013169249)National Institute of Mental Health (U.S.) (F31-MH111157)Howard Hughes Medical Institute (NS046789)Simons Foundation Autism Research Initiative (306063)Simons Foundation Autism Research Initiative (6927482)National Institute of Mental Health (U.S.) (5DP1-MH100706)National Institute of Mental Health (U.S.) (1R01-MH110049)Nancy Lurie Marks Family Foundation (6928117)Howard Hughes Medical Institute (NS046789

Time for change: a new training programme for morpho-molecular pathologists?

The evolution of cellular pathology as a specialty has always been driven by technological developments and the clinical relevance of incorporating novel investigations into diagnostic practice. In recent years, the molecular characterisation of cancer has become of crucial relevance in patient treatment both for predictive testing and subclassification of certain tumours. Much of this has become possible due to the availability of next-generation sequencing technologies and the whole-genome sequencing of tumours is now being rolled out into clinical practice in England via the 100 000 Genome Project. The effective integration of cellular pathology reporting and genomic characterisation is crucial to ensure the morphological and genomic data are interpreted in the relevant context, though despite this, in many UK centres molecular testing is entirely detached from cellular pathology departments. The CM-Path initiative recognises there is a genomics knowledge and skills gap within cellular pathology that needs to be bridged through an upskilling of the current workforce and a redesign of pathology training. Bridging this gap will allow the development of an integrated 'morphomolecular pathology' specialty, which can maintain the relevance of cellular pathology at the centre of cancer patient management and allow the pathology community to continue to be a major influence in cancer discovery as well as playing a driving role in the delivery of precision medicine approaches. Here, several alternative models of pathology training, designed to address this challenge, are presented and appraised

Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063)