Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by ...massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF
and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA ...sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.
Post-traumatic stress disorder (PTSD) is associated with abnormalities in the processing and regulation of emotion as well as cognitive deficits. This study evaluated the differential brain ...activation patterns associated with cognitive and emotional distractors during working memory (WM) maintenance for human faces between patients with PTSD and healthy controls (HCs) and assessed the relationship between changes in the activation patterns by the opposing effects of distraction types and gray matter volume (GMV). Twenty-two patients with PTSD and twenty-two HCs underwent T1-weighted magnetic resonance imaging (MRI) and event-related functional MRI (fMRI), respectively. Event-related fMRI data were recorded while subjects performed a delayed-response WM task with human face and trauma-related distractors. Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the inferior frontal gyrus (IFG) (p < 0.05, FWE-corrected). For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus and IFG compared with HCs (p < 0.05, FWE-corrected). The patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG during the trauma-related distractor trial was observed (p < 0.05, FWE-corrected). Such differential brain activation patterns associated with the effects of distraction in PTSD patients may be linked to neural mechanisms associated with impairments in both cognitive control for confusable distractors and the ability to control emotional distraction.
•Reduced volume of inferior frontal gyrus (IFG) in patients with PTSD.•This abnormality correlated with CAPS scores, symptoms of PTSD.•IFG was also less activated during WM maintenance with face distractors.•Increased activity in STG during trauma-related distractor trial was observed.•These findings may represent dissociation between cognition and emotion regulation in PTSD.
Background
Mild behavioural impairment (MBI) is an emergent and persistent neuropsychiatric symptom (NPS) in subjects aged 50 and older who are at risk for cognitive decline. We examined the ...prevalence of MBI across the spectrum from cognitively normal (CN), mild cognitive impairment (MCI), to dementia, and further investigated the association between the MBI domain and cognitive and functional impairment.
Method
MBI was assessed in 2337 elderly patients in the Alzheimer's Disease Neuroimaging Initiative database (mean age, 73.04 years; 52.8% male). Among the subjects, 868 (37.1%) had normal cognition, 1066 (45.6%) had MCI, and 403 (17.2%) had mild Alzheimer's dementia (AD). MBI was evaluated in accordance with the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment diagnostic criteria for MBI, utilising the Neuropsychiatric Inventory. We compared the prevalence of the MBI domain with CN using multinominal logistic regression analysis and further quantified the magnitude of the association between MCI/AD and the MBI domains by calculating the population attributable risk (PAR). We assessed the association between the MBI domains and cognitive and functional impairment using simultaneous linear regression analysis.
Results
The most common MBI domains in each diagnostic group were affective dysregulation followed by impulse dyscontrol, decreased motivation, social inappropriateness, and abnormal perception or thought content. The PARs for MBI domains in subjects with MCI or AD were respectively: 16.60% and 24.34% for affective dysregulation; 3.72% and 18.06% for impulse dyscontrol; 4.78% and 14.13% for decreased motivation, 1.91% and 2.29% for social inappropriateness; and 0.68% and 3.85% for abnormal perception or thought content. All MBI domains except for social inappropriateness were significantly associated with a higher 11‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale total score. All MBI domains were significantly associated with a higher Functional Activities Questionnaire total score.
Conclusion
Our findings show that MBI is highly prevalent across subjects with CN, MCI, and AD and is associated with cognitive and functional decline. MBI could be a crucial clinical phenotype relevant to the risk of cognitive and functional impairment, and provides a useful dimension pertinent to diagnostic approaches.
Although RNA-guided genome editing via the CRISPR-Cas9 system is now widely used in biomedical research, genome-wide target specificities of Cas9 nucleases remain controversial. Here we present ...Digenome-seq, in vitro Cas9-digested whole-genome sequencing, to profile genome-wide Cas9 off-target effects in human cells. This in vitro digest yields sequence reads with the same 5' ends at cleavage sites that can be computationally identified. We validated off-target sites at which insertions or deletions were induced with frequencies below 0.1%, near the detection limit of targeted deep sequencing. We also showed that Cas9 nucleases can be highly specific, inducing off-target mutations at merely several, rather than thousands of, sites in the entire genome and that Cas9 off-target effects can be avoided by replacing 'promiscuous' single guide RNAs (sgRNAs) with modified sgRNAs. Digenome-seq is a robust, sensitive, unbiased and cost-effective method for profiling genome-wide off-target effects of programmable nucleases including Cas9.
A new type of interface using a conduction hot spot reflecting the user's intention is presented. Conventional methods using fingertips to generate conduction hot points cannot be applied to those ...who have difficulty using their hands or cold hands. In order to overcome this problem, an exhaling interaction using a hollow rod is proposed and extensively analyzed in this paper. A preliminary study on exhaling interaction demonstrated the possibility of the method. This paper is an attempt to develop and extend the concept and provide the necessary information for properly implementing the interaction method. We have repeatedly performed conduction hot-point-generation experiments on various materials that can replace walls or screens to make wide use of the proposed interfaces. Furthermore, a lot of experiments have been conducted in different seasons, considering that the surface temperature of objects also changes depending on the season. Based on the results of an extensive amount of experiments, we provide key observations on important factors such as material, season, and user condition, which should be considered for realizing contactless exhaling interfaces.
It is a crucial disease that descending necrotizing mediastinitis need to be treated promptly with proper antibiotics and drainage. The characteristics of its symptoms such as chest pain are ...difficult to distinguish from acute myocardial infarction.
An 80-year-old female presented with severe squeezing chest pain. The cardiac marker was elevated. And coronary angiography showed the significant coronary stenosis. Although the revascularization through percutaneous coronary intervention was completed successfully, the patient still presented chest pain. Computed tomography of neck revealed that hypodense heterogeneous lesions with clear and distinguishable margin extended from the deep neck to mediastinum diffusely.
The patient was diagnosed with descending necrotizing mediastinitis.
Percutaneous catheter insertion to patient's abscess lesion at was performed.
Catheter drainage of descending necrotizing mediastinitis led to an improvement in the patient's condition.
Descending necrotizing mediastinitis made chest paint with elevated cardiac enzyme mimicked myocardial infarction.
All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the ...first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches.
Background:Extended dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is frequently used for high-risk patients in real-world practice. However, there are limited data ...about the long-term efficacy of extended DAPT after percutaneous coronary intervention (PCI).Methods and Results:This study investigated 1,470 patients who underwent PCI. The study population was divided into 2 groups based on DAPT duration: guideline-based DAPT (G-DAPT; DAPT ≤12 months after PCI; n=747) and extended DAPT (E-DAPT; DAPT >12 months after PCI; n=723). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as cardiac death, myocardial infarction (MI), repeat target vessel revascularization, or stroke. The median follow-up duration was 80.8 months (interquartile range 60.6–97.1 months). The incidence of MACCE was similar in the G-DAPT and E-DAPT groups (21.0% vs. 18.3%, respectively; P=0.111). However, the E-DAPT group had a lower incidence of non-fatal MI (hazard ratio HR 0.535; 95% confidence interval CI 0.329–0.869; P=0.011), and target lesion revascularization (HR 0.490; 95% CI 0.304–0.792; P=0.004), and stent thrombosis (HR 0.291; 95% CI 0.123–0.688; P=0.005). The incidence of bleeding complications, including major bleeding, was similar between the 2 groups (5.2% vs. 6.3%, respectively; P=0.471).Conclusions:Although E-DAPT after DES implantation was not associated with a reduced rate of MACCE, it was associated with a significantly lower incidence of non-fatal MI, TLR, and stent thrombosis.
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