The precise, temporal order of gene expression during development is critical to ensure proper lineage commitment, cell fate determination, and ultimately, organogenesis. Epigenetic regulation of ...chromatin structure is fundamental to the activation or repression of genes during embryonic development. In recent years, there has been an explosion of research relating to various modes of epigenetic regulation, such as DNA methylation, post-translational histone tail modifications, noncoding RNA control of chromatin structure, and nucleosome remodeling. Technological advances in genome-wide epigenetic profiling and pluripotent stem cell differentiation have been primary drivers for elucidating the epigenetic control of cellular identity during development and nuclear reprogramming. Not only do epigenetic mechanisms regulate transcriptional states in a cell-type-specific manner but also they establish higher order genomic topology and nuclear architecture. Here, we review the epigenetic control of pluripotency and changes associated with pluripotent stem cell differentiation. We focus on DNA methylation, DNA demethylation, and common histone tail modifications. Finally, we briefly discuss epigenetic heterogeneity among pluripotent stem cell lines and the influence of epigenetic patterns on genome topology.
BACKGROUND AND OBJECTIVES
The detection of a simple and reliable prognostic biomarker for colorectal cancer (CRC) outcomes remains a significant challenge. The use of neutrophil‐to‐lymphocyte ratio ...(NLR), has been reported to predict surgical and survival outcomes. The aim of our review was to assess the predictive value of pre‐operative NLR in predicting post‐operative outcomes in CRC.
METHODS
A systematic review of the available studies on NLR in CRC was performed. Primarily, we assessed its ability to predict survival outcomes, and highlight values that would help adjuvant therapy choices.
RESULTS
19 studies comprising 10 259 patients were included. Eleven and eight studies reported on patients with localized CRC and colorectal liver metastasis, respectively. Five‐year survival for those with localized CRC was 77.2% in patients with a “low” pre‐operative NLR versus 50.8% in those with a “high” pre‐operative NLR value. Alternatively, for patients with colorectal liver metastasis, patients with a “high” pre‐operative NLR value had a 5‐year survival of 27%.
CONCLUSION
Elevated pre‐operative NLR>5 is associated with poorer long‐term survival in both patients with localized CRC and those with liver metastasis. NLR is a useful biomarker in delineating those patients with poorer prognosis and whom may benefit from adjuvant therapies.
A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect ...on the balance between health and disease
. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units
), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches
to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry
. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.
Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in ...overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.
Mammographic screening programmes have increased detection rates of non-palpable breast cancers. In these cases, wire-guided localization (WGL) is the most common approach used to guide breast ...conserving surgery (BCS). Several RCTs have compared WGL to a range of novel localization techniques. We aimed to perform a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing methods of non-palpable breast cancer localization.
A NMA was performed according to PRISMA-NMA guidelines. Analysis was performed using R packages and Shiny.
24 RCTs assessing 9 tumour localization methods in 4236 breasts were included. Margin positivity and reoperation rates were 16.9% (714/4236) and 14.3% (409/2870) respectively. Cryo-assisted localization had the highest margin positivity (28.2%, 58/206) and reoperation (18.9%, 39/206) rates. Compared to WGL (n = 2045 from 24 RCTs) only ultrasound guided localization (USGL) (n = 316 from 3 RCTs) significantly lowered margin positivity (odds ratio (OR): 0.192, 95% confidence interval (CI): 0.079–0.450) and reoperation rates (OR: 0.182, 95%CI: 0.069–0.434). Anchor-guided localization (n = 52, 1 RCT) significantly lowered margin positivity (OR: 0.229, 95%CI: 0.050–0.938) and magnetic-marker localization improved patient satisfaction (OR: 0.021, 95%CI: 0.001–0.548). There was no difference in operation duration, overall complications, haematoma, seroma, surgical site infection rates, or specimen size/vol/wt between methods.
USGL and AGL are non-inferior to WGL for the localization of non-palpable breast cancers. The reported data suggests that these techniques confer reduced margin positivity rates and requirement for re-operation. However, caution when interpreting results relating to RCTs with small sample sizes and further validation is required in larger prospective, randomized studies.
•Ultrasound-guided (USGL) and anchor-guided (AGL) localization had optimal outcomes.•These methods significantly lowered margin positivity (odds ratio: 0.192 & 0.229).•However, small sample sizes in trials evaluating USGL and AGL limit these results.•Operation duration, complications, or specimen data were comparable for all methods.
Here we present an open-source R package 'meaRtools' that provides a platform for analyzing neuronal networks recorded on Microelectrode Arrays (MEAs). Cultured neuronal networks monitored with MEAs ...are now being widely used to characterize in vitro models of neurological disorders and to evaluate pharmaceutical compounds. meaRtools provides core algorithms for MEA spike train analysis, feature extraction, statistical analysis and plotting of multiple MEA recordings with multiple genotypes and treatments. meaRtools functionality covers novel solutions for spike train analysis, including algorithms to assess electrode cross-correlation using the spike train tiling coefficient (STTC), mutual information, synchronized bursts and entropy within cultured wells. Also integrated is a solution to account for bursts variability originating from mixed-cell neuronal cultures. The package provides a statistical platform built specifically for MEA data that can combine multiple MEA recordings and compare extracted features between different genetic models or treatments. We demonstrate the utilization of meaRtools to successfully identify epilepsy-like phenotypes in neuronal networks from Celf4 knockout mice. The package is freely available under the GPL license (GPL> = 3) and is updated frequently on the CRAN web-server repository. The package, along with full documentation can be downloaded from: https://cran.r-project.org/web/packages/meaRtools/.
•Radiomic analysis of breast imaging is plausible in molecular subtyping.•Radiomics successfully differentiates luminal, triple negative and HER2+ disease.•Refinement of radiomic techniques are ...necessary before implementation into practice.•Although these results are promising, core biopsy will remain the gold standard.
Breast cancer has four distinct molecular subtypes which are discriminated using gene expression profiling following biopsy. Radiogenomics is an emerging field which utilises diagnostic imaging to reveal genomic properties of disease. We aimed to perform a systematic review of the current literature to evaluate the value radiomics in differentiating breast cancers into their molecular subtypes using diagnostic imaging.
A systematic review was performed as per PRISMA guidelines. Studies assessing radiomictumour analysis in differentiatingbreast cancer molecular subtypeswere included. Quality was assessed using the radiomics quality score (RQS). Diagnostic sensitivity and specificity of radiomic analyses were included for meta-analysis; Study specific sensitivity and specificity were retrieved and summary ROC analysis were performed to compile pooled sensitivities and specificities.
Forty-one studies were included. Overall, there were 10,090 female patients (mean age of 47.6 ± 11.7 years, range: 21–93) and molecular subtypewas reported in 7,693 of cases, with Luminal A (LABC), Luminal B (LBBC), Human Epidermal Growth Factor Receptor-2 overexpressing (HER2+), and Triple Negative (TNBC) breast cancers representing 51.3%, 19.9%, 12.3% and 16.3% of tumour respectively. Seven studies provided radiomic analysis to determine molecular subtypes using mammography to differentiateTNBCvs.others (sensitivity: 0.82,specificity:0.79). Thirty-five studies reported on radiomic analysis of magnetic resonance imaging (MRI); LABC versus others(sensitivity:0.78,specificity:0.83),HER2+versusothers(sensitivity:0.87,specificity:0.88), andLBBCversusTNBC (sensitivity: 0.79,specificity:0.88) respectively.
Radiomic tumour assessment of contemporary breast imaging provide a novel option in determining breast cancer molecular subtypes. However, amelioration of such techniques are required and genetic expression assessment will remain the gold standard.
Intraoperative parathyroid hormone (ioPTH) is a surgical adjunct that has been increasingly used during minimally invasive parathyroidectomy (MIP). Despite its growing popularity, to our knowledge a ...meta-analysis comparing MIP with ioPTH vs MIP without ioPTH has not yet been conducted.
To evaluate the safety and efficacy of MIP with ioPTH for treatment of primary hyperparathyroidism.
A systematic search of the databases PubMed, Embase, Scopus, Web of Science, and Cochrane Collaboration was performed to identify studies that compared MIP with and without ioPTH. Data were analyzed between August and September 2019.
Inclusion criteria consisted of randomized clinical trials and observational studies with a retrospective/prospective design, comparing MIP using ioPTH vs MIP not using ioPTH for treatment of primary hyperparathyroidism. Eligible studies had to present odds ratio (OR), risk ratio, or hazard ratio estimates (with 95% CI), standard errors, or number of events necessary to calculate these for the outcome of interest rate. Studies involving patients with secondary or tertiary hyperparathyroidism or those with multiple endocrine neoplasia syndrome were excluded.
Two reviewers independently reviewed the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Dichotomous variables were pooled as ORs while continuous variables were compared using weighted mean differences. Quality assessment was performed using the Newcastle-Ottawa Scale.
The primary outcome was rate of cure. Secondary outcomes included need for reoperation, need for bilateral neck exploration, morbidity, and length of surgery.
A total of 12 studies, involving 2290 patients with primary hyperparathyroidism, were eligible for inclusion. The median (SD) age of participants was 60.1 (11.8) years and 77.3% of participants were women. The median Newcastle-Ottawa score was 7. Patients who underwent MIP with ioPTH had higher cure rates (OR, 3.88; 95% CI, 2.12-7.10; P < .001). There was a greater need for reoperation in the group of patients who had surgery without ioPTH (OR, 0.40; 95% CI, 0.19-0.86; P = .02). There was a trend toward longer operating times/increased duration of surgery in the ioPTH group; however, this did not reach statistical significance (weighted mean difference, 21.62 minutes; 95% CI, -0.93 to 44.17 minutes; P = .06). The use of ioPTH was associated with higher rates of bilateral neck exploration (OR, 3.55; 95% CI, 1.27-9.92; P = .02).
Use of ioPTH is associated with higher cure rates for patients with primary hyperparathyroidism undergoing MIP. Minimally invasive parathyroidectomy performed without ioPTH is associated with less conversion to bilateral neck exploration at initial surgery but with lower cure rates and an increased risk for reoperation.
PROSPERO identifier: CRD42020148588.
Somatic mutation in neurons is linked to neurologic disease and implicated in cell-type diversification. However, the origin, extent, and patterns of genomic mutation in neurons remain unknown. We ...established a nuclear transfer method to clonally amplify the genomes of neurons from adult mice for whole-genome sequencing. Comprehensive mutation detection and independent validation revealed that individual neurons harbor ∼100 unique mutations from all classes but lack recurrent rearrangements. Most neurons contain at least one gene-disrupting mutation and rare (0–2) mobile element insertions. The frequency and gene bias of neuronal mutations differ from other lineages, potentially due to novel mechanisms governing postmitotic mutation. Fertile mice were cloned from several neurons, establishing the compatibility of mutated adult neuronal genomes with reprogramming to pluripotency and development.
•Reprogramming neurons by cloning enables high-fidelity whole-genome sequencing•Neurons harbor ∼100 unique mutations but lack recurrent DNA rearrangements•Neuronal mutations impact expressed genes and exhibit unique molecular signatures•Mature adult neurons can generate fertile adult mouse clones
Hazen et al. use cloning to amplify and perform complete genome sequence analyses on adult neurons. They discover unique characteristics of neuronal genomes consistent with postmitotic mutation and further establish neuronal genomic integrity by generating fertile mice from these neurons.
Introduction
The primary objective of this research was to evaluate the psychometric properties of a questionnaire designed to assess perceive injustice associated with injury.
Methods
In Study 1, ...the 12-item Injustice Experience Questionnaire (IEQ) was administered to 226 individuals with musculoskeletal conditions. A subsample of 85 individuals were interviewed 1-year later about their ongoing symptoms and return to work status. In Study 2, the IEQ and other pain-related measures were administered on two separate occasions to 70 pain patients participating in a functional restoration rehabilitation program.
Results—Study 1
Principal components analysis yielded a two-component solution with eigenvalues greater 1. Item content of the two components reflected elements of blame and irreparability of loss. In cross sectional analyses, the IEQ was significantly correlated with measures of catastrophic thinking,
r
= .75,
P
< .01, fear of movement/re-injury,
r
= .58,
P
< .01, depression,
r
= .66,
P
< .01, and pain severity,
r
= .54,
P
< .01. Cross-sectional regression analyses revealed that the IEQ, β = .44,
P
< .01, and the PCS, β = .18,
P
< .05, each contributed significant unique variance to the prediction of pain severity. The IEQ prospectively predicted return to work status, OR = .75, 95% CI = .58–.99, but not pain severity.
Results—Study 2
Analyses supported the test re-test reliability of the IEQ,
r
= .90,
P
< .01. Treatment-related changes in the IEQ were significantly correlated with an objective index of improved physical function,
r
= .51,
P
< .01.
Conclusions
The findings of these two studies support the construct validity of the IEQ and suggest that this measure might be a useful complement to psychosocial assessment of individuals with persistent pain conditions. Discussion addresses the processes through which perceived injustice might impact on disability and rehabilitation outcomes.
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