While there is growing evidence that many epigenetically silenced genes in cancer are tumour suppressor candidates, their significance in cancer biology remains unclear. Here, we identify human ...Neuralized (NEURL), which acts as a novel tumour suppressor targeting oncogenic Wnt/β‐catenin signalling in human cancers. The expression of NEURL is epigenetically regulated and markedly suppressed in human colorectal cancer. We, therefore, considered NEURL to be a bona fide tumour suppressor in colorectal cancer and demonstrate that this tumour suppressive function depends on NEURL‐mediated oncogenic β‐catenin degradation. We find that NEURL acts as an E3 ubiquitin ligase, interacting directly with oncogenic β‐catenin, and reducing its cytoplasmic levels in a GSK3β‐ and β‐TrCP‐independent manner, indicating that NEURL‐β‐catenin interactions can lead to a disruption of the canonical Wnt/β‐catenin pathway. This study suggests that NEURL is a therapeutic target against human cancers and that it acts by regulating oncogenic Wnt/β‐catenin signalling.
Synopsis
Neuralized (NEURL) is a novel tumour suppressor targeting the oncogenic Wnt/β‐catenin pathway in colorectal cancer by promoting β‐catenin degradation independent of GSK3β and β‐TrCP.
NEURL hypermethylation is associated with poor outcomes in patients with colon cancer.
NEURL acts as a tumour suppressor in colon cancer by inhibiting cell proliferation and interrupting tumorigenesis.
NEURL targets β‐catenin as an E3 ubiquitin ligase impairing oncogenic WNT signalling in colorectal cancer.
Neuralized (NEURL) is a novel tumour suppressor targeting the oncogenic Wnt/β‐catenin pathway in colorectal cancer by promoting β‐catenin degradation independent of GSK3β and β‐TrCP.
Nuclear factor-κB (NF-κB) is a transcription factor that plays a crucial role in various biological processes, including immune response, inflammation, cell growth and survival, and development. ...NF-κB is critical for human health, and aberrant NF-κB activation contributes to development of various autoimmune, inflammatory and malignant disorders including rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, multiple sclerosis and malignant tumors. Thus, inhibiting NF-κB signaling has potential therapeutic applications in cancer and inflammatory diseases.
Neuromorphic computing targets the hardware embodiment of neural network, and device implementation of individual neuron and synapse has attracted considerable attention. The emulation of synaptic ...plasticity has shown promising results after the advent of memristors. However, neuronal intrinsic plasticity, which involves in learning process through interactions with synaptic plasticity, has been rarely demonstrated. Synaptic and intrinsic plasticity occur concomitantly in learning process, suggesting the need of the simultaneous implementation. Here, we report a neurosynaptic device that mimics synaptic and intrinsic plasticity concomitantly in a single cell. Threshold switch and phase change memory are merged in threshold switch-phase change memory device. Neuronal intrinsic plasticity is demonstrated based on bottom threshold switch layer, which resembles the modulation of firing frequency in biological neuron. Synaptic plasticity is also introduced through the nonvolatile switching of top phase change layer. Intrinsic and synaptic plasticity are simultaneously emulated in a single cell to establish the positive feedback between them. A positive feedback learning loop which mimics the retraining process in biological system is implemented in threshold switch-phase change memory array for accelerated training.
Current treatments for wound healing engage in passive healing processes and rarely participate in stimulating skin cell behaviors for active wound healing. Electric potential difference‐derived ...electrical fields (EFs) are known to modulate skin cell behaviors. Here, a piezoelectric dermal patch is developed that can be applied on skin wound site and EF is generated to promote wound healing. The one‐directionally aligned zinc oxide nanorod‐based piezoelectric patch generates piezoelectric potential upon mechanical deformations induced by animal motion, and induces EF at the wound bed. In vitro and in vivo data demonstrate that the piezoelectric patch promotes the wound healing process through enhanced cellular metabolism, migration, and protein synthesis. This modality may lead to a clinically relevant piezoelectric dermal patch therapy for active wound healing.
A piezoelectric patch that can be applied on skin wounds and generate electric fields (EFs) to promote wound healing is developed. The zinc oxide nanorod‐based patch generates piezoelectric potential upon skin movements, and induces EF at the wound bed. In vitro and in vivo data suggest the patch promotes skin regeneration through enhanced cellular metabolism, migration, and protein synthesis.
Objective
To evaluate the efficacy of prednisolone in the treatment of medication‐overuse headache (MOH) using data from a multicenter prospective registry (Registry for Load and Management of ...Medication Overuse Headache RELEASE).
Background
The treatment of MOH is challenging, especially when withdrawal headache manifests during the cessation of overused medication. Although systemic corticosteroids have been empirically used to reduce withdrawal headaches, their efficacy on the long‐term outcomes of MOH has not been documented.
Methods
This was a post hoc analysis of the RELEASE study. The RELEASE is an ongoing multicenter observational cohort study in which patients with MOH have been recruited from seven hospitals in Korea since April 2020. Clinical characteristics, disease profiles, treatments, and outcomes were assessed at baseline and specific time points. We analyzed the effect of prednisolone on MOH reversal at 3 months.
Results
Among the 309 patients enrolled during the study period, prednisolone was prescribed to 59/309 (19.1%) patients at a dose ranging from 10 to 40 mg/day for 5–14 days; 228/309 patients (73.8%) completed the 3‐month follow‐up period. The MOH reversal rates at 3 months after baseline were 76% (31/41) in the prednisolone group and 57.8% (108/187) in the non‐prednisolone group (p = 0.034). The effect of steroids remained significant (adjusted odds ratio 2.78, 95% confidence interval 1.27–6.1, p = 0.010) after adjusting for the number of monthly headache days at baseline, mode of discontinuation of overused medication, use of early preventive medications, and the number of preventive medications combined.
Conclusions
Although our observational study could not draw a definitive conclusion, prednisolone may be effective in the treatment of MOH.
We report the chloroplast (cp) genome sequence of tartary buckwheat (Fagopyrum tataricum) obtained by next-generation sequencing technology and compared this with the previously reported common ...buckwheat (F. esculentum ssp. ancestrale) cp genome. The cp genome of F. tataricum has a total sequence length of 159,272 bp, which is 327 bp shorter than the common buckwheat cp genome. The cp gene content, order, and orientation are similar to those of common buckwheat, but with some structural variation at tandem and palindromic repeat frequencies and junction areas. A total of seven InDels (around 100 bp) were found within the intergenic sequences and the ycf1 gene. Copy number variation of the 21-bp tandem repeat varied in F. tataricum (four repeats) and F. esculentum (one repeat), and the InDel of the ycf1 gene was 63 bp long. Nucleotide and amino acid have highly conserved coding sequence with about 98% homology and four genes--rpoC2, ycf3, accD, and clpP--have high synonymous (Ks) value. PCR based InDel markers were applied to diverse genetic resources of F. tataricum and F. esculentum, and the amplicon size was identical to that expected in silico. Therefore, these InDel markers are informative biomarkers to practically distinguish raw or processed buckwheat products derived from F. tataricum and F. esculentum.
Tg2576 transgenic mice for Alzheimer's disease (AD) exhibited significant phenotypes for neuropathological constipation, but no research has been conducted on the association of the fecal microbiota ...with dysbiosis. The correlation between fecal microbiota composition and neuropathological constipation in Tg2576 mice was investigated by examining the profile of fecal microbiota and fecal microbiota transplantation (FMT) in 9-10-month-old Tg2576 mice with the AD phenotypes and constipation. Several constipation phenotypes, including stool parameters, colon length, and histopathological structures, were observed prominently in Tg2576 mice compared to the wild-type (WT) mice. The fecal microbiota of Tg2576 mice showed decreases in Bacteroidetes and increases in the Firmicutes and Proteobacteria populations at the phylum level. The FMT study showed that stool parameters, including weight, water content, and morphology, decreased remarkably in the FMT group transplanted with a fecal suspension of Tg2576 mice (TgFMT) compared to the FMT group transplanted with a fecal suspension of WT mice (WFMT). The distribution of myenteric neurons and the interstitial cells of Cajal (ICC), as well as the enteric nervous system (ENS) function, remained lower in the TgFMT group. These results suggest that the neuropathological constipation phenotypes of Tg2576 mice may be tightly linked to the dysbiosis of the fecal microbiota.
Gamma-glutamyl transferase (GGT) is related to inflammation, osteoporosis, and vascular diseases. Recently, changes in metabolic parameters have been proposed as osteoporosis biomarkers. We aimed to ...assess longitudinally the association of GGT variability with osteoporotic fractures.
From the National Health Insurance Service-Health Screening Cohort database, participants who underwent three or more health examinations between 2003 and 2008 were included (n = 1,072,432). Variability indexes were as follows: (1) coefficient of variation (CV), (2) standard deviation (SD), and (3) variability independent of the mean (VIM). The primary outcome was occurrence of osteoporotic fracture, defined as identification of one of the following international classification of diseases-10 codes: vertebral fractures (S22.0, S22.1, S32.0, S32.7, T08, M48.4, M48.5, M49.5), hip fractures (S72.0, S72.1), distal radius fractures (S52.5, S52.6), or humerus fractures (S42.2, S42.3).
During a median of 12.3 years (interquartile range 12.1-12.6), osteoporotic fractures occurred in 49,677 (4.6%) participants. In multivariable analysis, GGT variability based on CV positively correlated with the occurrence of osteoporotic fracture (adjusted hazard ratio HR of the highest quartile compared with the lowest quartile 1.15, 95% confidence interval CI 1.12-1.18, P < 0.001). These results were consistent even when GGT variability was defined by SD (adjusted HR 1.22, 95% CI 1.19-1.25, P < 0.001) and VIM (adjusted HR 1.12, 95% CI 1.09-1.15, P < 0.001).
Increased GGT variability is associated with an increased risk of osteoporotic fractures in the Korean population. Maintaining constant and stable GGT level may help reduce the risk of osteoporotic fractures.
Objective
To characterize the clinical features of patients with medication‐overuse headache (MOH) according to the class of acute medications being overused.
Background
MOH is a common global health ...problem, severely disabling the majority of the patients affected. Although various medications can cause MOH, whether clinical features differ according to the overused medication type remains unclear.
Methods
We analyzed data from a multicenter cross‐sectional study in neurology clinics in Korea from April 2020 to June 2021.
Results
Among 229 eligible patients, MOH was documented in patients who overused multiple drug classes (69/229, 30.1%; most frequent occurrence), triptans (50/229, 21.8%), non‐opioid analgesics (48/229, 21.0%), and combination‐analgesics (40/229, 17.4%). Patients who overused multiple drug classes reported more frequent use of acute medications (median 25th–75th percentiles: 25.0 15.0–30.0 vs. 17.5 10.0–25.5 days/month, p = 0.029) and fewer crystal‐clear days (0.0 0.0–9.5 vs. 9.0 0.0–10.0 days/month, p = 0.048) than those who overused triptans. Patients who overused multiple drug classes also reported shorter intervals from chronic daily headache to the onset of MOH than patients who overused combination‐analgesics (0.6 0.2–1.9 vs. 2.4 0.7–5.4 years, p = 0.001) or non‐opioid analgesics (1.5 0.6–4.3 years, p = 0.004). Patients who overused multiple drug classes reported more emergency room visits (1.0 0.0–1.0 visits/year) than those who overused combination‐analgesics (0.0 0.0–1.0, p = 0.024) or non‐opioid analgesics (0.0 0.0–1.0, p = 0.030). Patients who overused triptans reported fewer headache days (21.0 20.0–30.0 vs. 30.0 20.5–30.0 days/month, p = 0.008) and fewer severe headache days (7.0 4.0–10.0 vs. 10.0 5.0–15.0 days/month, p = 0.017) than those who overused non‐opioid analgesics.
Conclusions
Some clinical characteristics of MOH significantly differed according to the class of overused medications. The findings from this study may contribute to the understanding of the clinical characteristics and pathophysiology of MOH.
Introduction/Aims
There are limited studies on the association of COVID‐19 vaccination with neuralgic amyotrophy (NA). Therefore, we evaluated the association between COVID‐19 vaccination and the ...occurrence of NA.
Methods
We explored unexpected safety signals for NA related to COVID‐19 vaccination through disproportionality analysis using VigiBase, the World Health Organization's pharmacovigilance database.
Results
On October 15, 2021, 335 cases of NA were identified in the database. The median time to onset of NA after vaccination was around 2 weeks. A significant signal of disproportionality of NA was observed for the ChAdOx1 nCoV‐19 vaccine (AstraZeneca) (information component IC025 = 0.33, reporting odds ratio ROR025 = 1.30) and two mRNA‐based COVID‐19 vaccines (BNT162b2 Pfizer and BioNTech and mRNA‐1273 Moderna) (IC025 = 1.74, ROR025 = 3.82) compared with the entire database. However, when compared with influenza vaccines, we did not detect any signal of disproportionality of NA for both the ChAdOx1 nCoV‐19 vaccine (IC025 = −2.71, ROR025 = 0.05) and mRNA‐based COVID‐19 vaccines (IC025 = −1.38, ROR025 = 0.13).
Discussion
A weak association was observed between NA and COVID‐19 vaccines. However, the risk did not surpass that of influenza vaccines.
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