Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and ...matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer.
Gene networks are rapidly growing in size and number, raising the question of which networks are most appropriate for particular applications. Here, we evaluate 21 human genome-wide interaction ...networks for their ability to recover 446 disease gene sets identified through literature curation, gene expression profiling, or genome-wide association studies. While all networks have some ability to recover disease genes, we observe a wide range of performance with STRING, ConsensusPathDB, and GIANT networks having the best performance overall. A general tendency is that performance scales with network size, suggesting that new interaction discovery currently outweighs the detrimental effects of false positives. Correcting for size, we find that the DIP network provides the highest efficiency (value per interaction). Based on these results, we create a parsimonious composite network with both high efficiency and performance. This work provides a benchmark for selection of molecular networks in human disease research.
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•Benchmarking of 21 molecular networks in recovering disease gene sets•A composite network (PCNet) has improved performance over any single network•Network performance is driven by increased edge density within disease gene sets
We evaluate 21 human genome-wide interaction networks for their ability to recover 446 disease gene sets. While all networks can recover disease genes, we observe STRING, ConsensusPathDB, and GIANT networks to have the best performance overall. Performance scales with network size, suggesting that comprehensive interaction inclusion outweighs the detrimental effects of false positives. We create a parsimonious composite network with both high efficiency and performance. This work provides a benchmark for selection of molecular networks in human disease research.
Most professional spine societies have enacted formal guidelines for spine surgeons providing expert witness services. However, there is significant heterogeneity in existing recommendations, with ...most societies providing information that is limited in detail and scope.
To provide a review of guidelines published by professional spine societies for spine surgeons serving as expert witnesses.
The Gale Directory Library, PubMed, and the grey literature were queried for national or international professional societies related to spine surgery. The search was focused on societies in the United States and North America, but also included well recognized international organizations in the field of spine surgery. Included societies with publicly available guidelines regarding expert witness services were extracted for 4 domains: (1) qualifications, (2) preparations, (3) testimony, and (4) compensation as well as the presence of a professional compliance program, defined as any official subcommittee aimed toward investigating claims of unethical behavior.
Although most professional spine societies share general themes with respect to expert witness guidelines, important differences exist. Of the 26 societies included, 10 included publicly available guidelines: 4 of which were general neurosurgery societies, 2 general orthopedic surgery, and 4 spine specific. Three societies included the guidelines on all 4 domains (ie, qualifications, preparations, testimony, and compensation), and 2 societies included only 1 of the 4 domains. Eight societies possess a professional compliance program.
There remains a paucity in expert witness guidelines provided by professional spine societies. Although existing recommendations are useful, there is a lack of standardized and comprehensive materials for spine surgeons providing expert witness testimony to reference. Moving forward, joint committees comprising surgeons, attorneys, and patient stakeholders may help improve the guidelines.
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the ...chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.
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•ATAC-seq reveals a chromatin accessibility signature activated by C9orf72 poly(PR)•C9orf72 poly(PR) leads to p53 stabilization and transcription of p53 target genes•p53 ablation protects against neurodegeneration in multiple C9orf72 models
C9orf72 mutations associated with ALS and FTD activate a specific transcriptional program that converges on p53 to drive neurodegeneration in multiple C9orf72 models.
Despite the ubiquitous use of the Glasgow Coma Scale (GCS) worldwide, no study to date has objectively and quantitatively assessed its impact on the scientific literature and clinical practice. ...Therefore, we comprehensively analyzed scientific publications and clinical practice guidelines employing the GCS to gauge its clinical and academic impact, identify research hotspots, and inform future research on the topic.
A cross-sectional bibliometric analysis was performed on Scopus to obtain relevant publications incorporating the GCS from 1974 to 2022. In addition, a systematic review of existing clinical practice guidelines in PubMed, Scopus, Web of Science, and Trip Database was performed. Validated bibliometric parameters including article title, journal, publication year, authors, citation count, country, institution, keywords, impact factor, and references were assessed. When evaluating clinical practice guidelines, the sponsoring organization, country of origin, specialty, and publication year were assessed.
A total of 37,633 articles originating from 3924 different scientific journals spanning 1974–2022 were included in the final analysis. The compound annual growth rate of publications referencing the GCS was 16.7%. Of 104 countries, the United States had the highest total number of publications employing the GCS (n = 8517). World Neurosurgery was the scientific periodical with the highest number of publications on the GCS (n = 798). The top trending author-supplied keyword was “traumatic brain injury” (n = 3408). The 97 included clinical practice guidelines most commonly employed the GCS in the fields of internal medicine (n = 22, 23%), critical care (n = 21, 22%), and neurotrauma (n = 19, 20%).
At the turn of the 50th anniversary of the GCS, we provided a unique and detailed description of the “path to success” of the GCS both in terms of its scientific and clinical impact. These results have not only a historical but also an important didactic value. Ultimately our detailed analysis, which revealed some of the factors that led the GCS to become such a widespread and highly influential score, may assist future researchers in their development of new outcome measures and clinical scores, especially as such tools become increasingly relevant in an evidence-based data-driven age.
The Role of Exercise in Parkinson’s Disease Emig, Mallory; George, Tikku; Zhang, Justin K. ...
Journal of Geriatric Psychiatry and Neurology,
07/2021, Letnik:
34, Številka:
4
Book Review, Journal Article
Recenzirano
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder of the central nervous system. While it primarily affects motor function, patients eventually develop non-motor symptoms ...including depression, anxiety, and eventually dementia. Although there is currently no cure, treatment is aimed largely at improving quality of life though medication or surgical techniques to reduce motor symptoms. However, there is vast evidence of the benefits of physical activity as adjunct therapy for Parkinson’s disease. In this review, we analyze 31 studies or reviews and highlight the role of exercise and rehabilitation in PD treatment. This study serves to provide clinicians with a comprehensive resource of the wide variety of exercises with proven benefit for patients affected by Parkinson’s disease. Specifically, patients report significant improvements in motor function, cognition, mood and sleep habits.
An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains ...unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.
Diffusion basis spectrum imaging (DBSI) is a noninvasive quantitative imaging modality that may improve understanding of cervical spondylotic myelopathy (CSM) pathology through detailed evaluations ...of spinal cord microstructural compartments.
To determine the utility of DBSI as a biomarker of CSM disease severity.
A single-center prospective cohort study enrolled 50 patients with CSM and 20 controls from 2018 to 2020. All patients underwent clinical evaluation and diffusion-weighted MRI, followed by diffusion tensor imaging and DBSI analyses. Diffusion-weighted MRI metrics assessed white matter integrity by fractional anisotropy, axial diffusivity, radial diffusivity, and fiber fraction. In addition, DBSI further evaluates extra-axonal changes by isotropic restricted and nonrestricted fraction. Including an intra-axonal diffusion compartment, DBSI improves estimations of axonal injury through intra-axonal axial diffusivity. Patients were categorized into mild, moderate, and severe CSM using modified Japanese Orthopedic Association classifications. Imaging parameters were compared among patient groups using independent samples t tests and ANOVA.
Twenty controls, 27 mild (modified Japanese Orthopedic Association 15-17), 12 moderate (12-14), and 11 severe (0-11) patients with CSM were enrolled. Diffusion tensor imaging and DBSI fractional anisotropy, axial diffusivity, and radial diffusivity were significantly different between control and patients with CSM ( P < .05). DBSI fiber fraction, restricted fraction, and nonrestricted fraction were significantly different between groups ( P < .01). DBSI intra-axonal axial diffusivity was lower in mild compared with moderate (mean difference 95% CI: 1.1 0.3-2.1, P < .01) and severe (1.9 1.3-2.4, P < .001) CSM.
DBSI offers granular data on white matter tract integrity in CSM that provide novel insights into disease pathology, supporting its potential utility as a biomarker of CSM disease progression.
Prospective cohort study.
The aim was to assess the association between diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) measures and cervical spondylotic myelopathy (CSM) ...clinical assessments at baseline and two-year follow-up.
Despite advancements in diffusion-weighted imaging, few studies have examined associations between diffusion magnetic resonance imaging (MRI) markers and CSM-specific clinical domains at baseline and long-term follow-up.
A single-center prospective cohort study enrolled 50 CSM patients who underwent surgical decompression and 20 controls from 2018 to 2020. At initial evaluation, all patients underwent diffusion-weighted MRI acquisition, followed by DTI and DBSI analyses. Diffusion-weighted MRI metrics assessed white matter integrity by fractional anisotropy, axial diffusivity, radial diffusivity, and fiber fraction. To improve estimations of intra-axonal anisotropic diffusion, DBSI measures intra-/extra-axonal fraction and intra-axonal axial diffusivity. DBSI also evaluates extra-axonal isotropic diffusion by restricted and nonrestricted fraction. Clinical assessments were performed at baseline and two-year follow-up and included the modified Japanese Orthopedic Association (mJOA); 36-Item Short Form Survey physical component summary (SF-36 PCS); SF-36 mental component summary; neck disability index; myelopathy disability index; and disability of the arm, shoulder, and hand. Pearson correlation coefficients were computed to compare associations between DTI/DBSI and clinical measures. A False Discovery Rate correction was applied for multiple comparisons testing.
At baseline presentation, of 36 correlations analyzed between DTI metrics and CSM clinical measures, only DTI fractional anisotropy showed a positive correlation with SF-36 PCS ( r =0.36, P =0.02). In comparison, there were 30/81 (37%) significant correlations among DBSI and clinical measures. Increased DBSI axial diffusivity, intra-axonal axial diffusivity, intra-axonal fraction, restricted fraction, and extra-axonal anisotropic fraction were associated with worse clinical presentation (decreased mJOA; SF-36 PCS/mental component summary; and increased neck disability index; myelopathy disability index; disability of the arm, shoulder, and hand). At latest follow-up, increased preoperative DBSI intra-axonal axial diffusivity and extra-axonal anisotropic fraction were significantly correlated with improved mJOA.
This findings demonstrate that DBSI measures may reflect baseline disease burden and long-term prognosis of CSM as compared with DTI. With further validation, DBSI may serve as a noninvasive biomarker following decompressive surgery.
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