IntroductionWith the advent of next generation sequencing of whole exomes and whole genomes, we can now obtain a comprehensive view of the somatic mutations that are present in tumours. Using latent ...variable discovery approaches such as non-negative matrix factorisation (NMF), recurrent somatic mutational patterns, called mutational signatures, have been identified, some of which have been attributed to mutational processes, such as sunlight exposure or homologous recombination deficiency. As more cancer whole genomes are available, the identification of new signatures and disambiguation of known signatures become possible. We can now begin to ask new questions, such as whether the same mutational process may induce different, organ-specific, mutational signatures.Material and methodsWe used somatic mutations from 2577 tumours from the PCAWG dataset, organised in 21 organs. We then performed 21 independent local organ-specific signature extractions and one global signature extraction with all the samples. Extraction is performed using NMF. The optimal number of signatures for each extraction is determined by the clustering properties of repeated NMF runs. Cluster analysis based on cosine similarity was performed to determine similarity of signatures across organs.Results and discussionsSeveral of the mutational signatures obtained from organ-specific extractions resemble known COSMIC mutational signatures. COSMIC signature 1 can be found in almost all organs, with the exception of the Liver. Other signatures, such as COSMIC signatures 2, 3, 13, 17 and 18, are independently obtained from multiple organs. All the signatures that are found in multiple organs present organ-specificity. Further investigation is required to determine how much of this specificity is biological and how much is due to a dataset bias.ConclusionOur work is the first attempt to determine the variability of mutational signatures across different organs. It reveals that some mutational signatures are more robust than others, and that the same mutational process may induce slightly different mutational signatures in different organs, though part of these differences may be attributed to a dataset bias. The use of organ-specific mutational signatures may be critical for the correct assignment of mutations in a tumour to signatures and, in turn, the correct identification of mutational processes that are at work in a tumour.
Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency ...of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within ...clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
Non-analytical reasoning is thought to play a key role in dermatology diagnosis. Considering its potential importance, surprisingly little work has been done to research whether similar ...identification processes can be supported in non-experts. We describe here a prototype diagnostic support software, which we have used to examine the ability of medical students (at the beginning and end of a dermatology attachment) and lay volunteers, to diagnose 12 images of common skin lesions. Overall, the non-experts using the software had a diagnostic accuracy of 98% (923/936) compared with 33% for the control group (215/648) (Wilcoxon p < 0.0001). We have demonstrated, within the constraints of a simplified clinical model, that novices' diagnostic scores are significantly increased by the use of a structured image database coupled with matching of index and referent images. The novices achieve this high degree of accuracy without any use of explicit definitions of likeness or rule-based strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk ...for Alzheimer's disease is less well understood.
To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly.
Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device.
We found that severity of OSA indices (AHIall F
= 4.26; P < 0.05 and AHI4% F
= 4.36; P < 0.05) were associated with annual rate of change of cerebrospinal fluid amyloid β
using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in AD
-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F
= 2.96, P = 0.09; and F
= 2.32, not significant, respectively).
In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.
Based on associations between sleep spindles, cognition, and sleep-dependent memory processing, here we evaluated potential relationships between levels of CSF Aβ
, P-tau, and T-tau with sleep ...spindle density and other biophysical properties of sleep spindles in a sample of cognitively normal elderly individuals.
One-night in-lab nocturnal polysomnography (NPSG) and morning to early afternoon CSF collection were performed to measure CSF Aβ
, P-tau and T-tau. Seven days of actigraphy were collected to assess habitual total sleep time.
Spindle density during NREM stage 2 (N2) sleep was negatively correlated with CSF Aβ
, P-tau and T-tau. From the three, CSF T-tau was the most significantly associated with spindle density, after adjusting for age, sex and ApoE4. Spindle duration, count and fast spindle density were also negatively correlated with T-tau levels. Sleep duration and other measures of sleep quality were not correlated with spindle characteristics and did not modify the associations between sleep spindle characteristics and the CSF biomarkers of AD.
Reduced spindles during N2 sleep may represent an early dysfunction related to tau, possibly reflecting axonal damage or altered neuronal tau secretion, rendering it a potentially novel biomarker for early neuronal dysfunction. Given their putative role in memory consolidation and neuroplasticity, sleep spindles may represent a mechanism by which tau impairs memory consolidation, as well as a possible target for therapeutic interventions in cognitive decline.
Abstract Objectives To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Methods A baseline and ...2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau231 ), amyloid beta (Aβ) Aβ42 /Aβ40 ratio, isoprostane (IP) as well as P-tau231 /Aβ42/40 and T-tau/Aβ42/40 ratios. Results At baseline and at follow-up MCI-AD showed higher levels P-tau231 , T-tau, IP, P-tau231 /Aβ42/40 and T-tau/Aβ42/40 ratios and lower Aβ42 /Aβ40 than MCI-MCI or NL-NL. Baseline P-tau231 best predicted MCI-AD (80%, p < 0.001) followed in accuracy by P-tau231 /Aβ42/40 and T-tau/Aβ42/40 ratios (both 75%, p 's < 0.001), T-tau (74%, p < 0.001), Aβ42 /Aβ40 (69%, p < 0.01), and IP (68%, p < 0.01). Only IP showed longitudinal effects ( p < 0.05). Conclusions P-tau231 is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.
Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical ...cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aβ), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.
The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP ...enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation.
We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using
C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation.
Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation.
Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans.
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