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MicroRNAs are short non-coding RNAs that regulate gene expression by RNA interference. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. miR-146a has been reported to regulate Toll-like receptors and cytokine signaling, which are both crucial for inflammation and oncogenesis. This study identifies that areca nut extract, TNF[alpha] and TGF[beta] up-regulates miR-146a in OSCC cells. The increased expression of miR-146a enhanced the oncogenicity of OSCC cells. In addition, a G to C polymorphism (rs2910164), which is located in the pre-miR-146a and has been associated with functional alterations in miR-146a, was significantly more prevalent among OSCC patients having more advanced nodal involvement. Our analysis also suggested a higher miR-146a expression in OSCC tissues of patients carrying C polymorphism. The present study concluded a higher prevalence of the pre-mir-146a C-variant was associated with OSCC progression in patients with this disease. [ABSTRACT FROM AUTHOR]

Network connectivity, as mapped by the whole brain connectome, plays a crucial role in regulating auditory function. Auditory deprivation such as unilateral hearing loss might alter structural network connectivity; however, these potential alterations are poorly understood. Thirty-seven acoustic neuroma patients with unilateral hearing loss (19 left-sided and 18 right-sided) and 19 healthy controls underwent diffusion-weighted and T1-weighted imaging to assess edge strength, node strength, and global efficiency of the structural connectome. Edge strength was estimated by pair-wise normalized streamline density from tractography and connectomics. Node strength and global efficiency were calculated through graph theory analysis of the connectome. Pure-tone audiometry and word recognition scores were used to correlate the degree and duration of unilateral hearing loss with node strength and global efficiency. We demonstrate significantly stronger edge strength and node strength through the visual network, weaker edge strength and node strength in the somatomotor network, and stronger global efficiency in the unilateral hearing loss patients. No discernible correlations were observed between the degree and duration of unilateral hearing loss and the measures of node strength or global efficiency. These findings contribute to our understanding of the role of structural connectivity in hearing by facilitating visual network upregulation and somatomotor network downregulation after unilateral hearing loss., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Patients with chronic pain frequently report cognitive symptoms that affect memory and attention, which are functions attributed to the hippocampus. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder characterized by paroxysmal attacks of unilateral orofacial pain. Given the stereotypical nature of TN pain and lack of negative symptoms including sensory loss, TN provides a unique model to investigate the hippocampal implications of chronic pain. Recent evidence demonstrated that TN is associated with macrostructural hippocampal abnormalities indicated by reduced subfield volumes; however, there is a paucity in our understanding of hippocampal microstructural abnormalities associated with TN., Objectives: To explore diffusivity metrics within the hippocampus, along with its functional and structural subfields, in patients with TN., Methods: To examine hippocampal microstructure, we utilized diffusion tensor imaging in 31 patients with TN and 21 controls. T1-weighted magnetic resonance images were segmented into hippocampal subfields and registered into diffusion-weighted imaging space. Fractional anisotropy (FA) and mean diffusivity were extracted for hippocampal subfields and longitudinal axis segmentations., Results: Patients with TN demonstrated reduced FA in bilateral whole hippocampi and hippocampal body and contralateral subregions CA2/3 and CA4, indicating microstructural hippocampal abnormalities. Notably, patients with TN showed significant correlation between age and hippocampal FA, while controls did not exhibit this correlation. These effects were driven chiefly by female patients with TN., Conclusion: This study demonstrates that TN is associated with microstructural hippocampal abnormalities, which may precede and potentially be temporally linked to volumetric hippocampal alterations demonstrated previously. These findings provide further evidence for the role of the hippocampus in chronic pain and suggest the potential for targeted interventions to mitigate cognitive symptoms in patients with chronic pain., Competing Interests: The authors have no conflict of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Pulp inflammation is complex interactions between different types of cells and cytokines. To mimic the interactions of different types of cells in inflamed dental pulp tissues, dental pulp cells (DPCs) were cocultured with different ratios of macrophages (THP-1) or LPS treatment., Methods: DPCs were cocultured with various ratios of THP-1, then photographed cell morphology and determined cell viability by MTT assay at preset times. Total RNA was also extracted to measure the inflammation marker-IL-6 and IL-8 expressions by RT-Q-PCR. The DPCs and THP-1 were treated with 0.01 - 1μg/ml lipopolysaccharide (LPS) and extract RNA at preset times, and detected IL-6 and IL-8 expression. DPCs were cocultured with various ratios of THP-1 with 0.1 μg/mL LPS, and detected IL-6 and IL-8 expression after 24 and 48 h. The data were analyzed by unpaired t-test or Mann-Whitney test. Differences were considered statistically significant when p < 0.05., Results: THP-1 and DPCs coculture models did not suppress the viability of DPCs and THP-1. Cocultured with various ratios of THP-1 could increase IL-6 and IL-8 expressions of DPCs (p = 0.0056 - p < 0.0001). The expressions of IL-6 and IL-8 were stronger in higher ratio groups (p = 0.0062 - p < 0.0001). LPS treatment also induced IL-6 and IL-8 expressions of DPCs and THP-1 (p = 0.0179 - p < 0.0001 and p = 0.0189 - p < 0.0001, separately). Under the presence of 0.1 μg/mL LPS, DPCs cocultured with THP-1 for 24 h also enhanced IL-6 and IL-8 expression (p = 0.0022). After cocultured with a higher ratio of THP-1 for 48 h, IL-6 and IL-8 expressions were even stronger in the presence of LPS (p = 0.0260)., Conclusions: Coculturing dental pulp cells and macrophages under LPS treatment aggravate the inflammatory process. The responses of our models were more severe than traditional inflamed dental models and better represented what happened in the real dental pulp. Utilizing our models to explore the repair and regeneration in endodontics will be future goals., (© 2023. The Author(s).)

Advances in neuroimaging have permitted the non-invasive examination of the human brain in pain. However, a persisting challenge is in the objective differentiation of neuropathic facial pain subtypes, as diagnosis is based on patients' symptom descriptions. We use artificial intelligence (AI) models with neuroimaging data to distinguish subtypes of neuropathic facial pain and differentiate them from healthy controls. We conducted a retrospective analysis of diffusion tensor and T1-weighted imaging data using random forest and logistic regression AI models on 371 adults with trigeminal pain (265 classical trigeminal neuralgia (CTN), 106 trigeminal neuropathic pain (TNP)) and 108 healthy controls (HC). These models distinguished CTN from HC with up to 95% accuracy, and TNP from HC with up to 91% accuracy. Both classifiers identified gray and white matter-based predictive metrics (gray matter thickness, surface area, and volume; white matter diffusivity metrics) that significantly differed across groups. Classification of TNP and CTN did not show significant accuracy (51%) but highlighted two structures that differed between pain groups-the insula and orbitofrontal cortex. Our work demonstrates that AI models with brain imaging data alone can differentiate neuropathic facial pain subtypes from healthy data and identify regional structural indicates of pain., (© 2023. The Author(s).)

Objectives: To explore the inflammatory and differentiation response in inflamed dental pulp cells (DPCs) induced by lipopolysaccharide (LPS) under different conditions with Biodentine and mineral trioxide aggregate (MTA) treatment., Materials and Methods: DPCs were treated with 0.001-1 µg/mL LPS for different periods to induce inflammation. Normal and inflamed DPCs were further treated with 0.14 mg/mL Biodentine or 0.13 mg/mL MTA for different periods. mRNA expression level of IL-6, IL-8 and ALP were analysed by qPCR. DSPP protein expression was detected by western blot. The data were analysed by the Mann-Whitney test, unpaired t test or two-way ANOVA., Results: After treatment for different times and with different concentrations of LPS, different severity of pulp inflammation was revealed by the expressions of IL-6 and IL-8. Higher concentrations of LPS induced higher IL-6 and IL-8 expressions, and these expressions first increased and then decreased (p < 0.0001). At 96 and 192 h, Biodentine significantly suppressed IL-6 expression in both normal and inflamed DPCs (p < 0.05). At 48 and 96 h, Biodentine suppressed ALP expression in both normal and inflamed DPCs (p < 0.05). At 48 and 96 h, Biodentine induced DSPP expressions in both normal and inflamed DPCs (p < 0.05)., Conclusion: Biodentine enhanced more DSPP differentiation of both normal and inflamed DPCs under different treatment durations than MTA., Clinical Relevance: The prognosis of vital pulp therapy may depend on the severity of pulp inflammation which is difficult to be determined in clinical settings. Therefore, Biodentine may enhance odontogenic differentiation in different severity of pulp inflammation imply its clinical indications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Trigeminal neuralgia (TN) is an orofacial pain disorder that is more prevalent in females than males. Although an increasing number of studies point to sex differences in chronic pain, how sex impacts TN patients' journeys to care has not been previously addressed. This study sought to investigate sex differences in patients' journeys to diagnosis, referral, and treatment of TN within a large national context., Methods: Patients with classic TN (n = 100; 50 females and 50 males) were randomly selected through chart reviews at the largest surgical treatment center for TN in Canada for a cross-sectional study. Statistical tests, including Welch's t-test, the chi-square test, Pearson's correlations, and analyses of covariance, were conducted with Python., Results: Key discrepancies between sexes in access to care were identified. Females had a significantly longer referral time interval (average 53.2 months vs 20.4 months, median 27.5 months vs 11.0 months, p = 0.018) and total time interval (average 121.1 months vs 67.8 months, median 78.0 months vs 45.2 months, p = 0.018) than males, despite reporting higher pain intensity at referral. Although medically intolerant patients had a significantly shorter referral time interval than medically tolerant patients (average 13.0 months vs 41.0 months, median 6.0 months vs 17.0 months, p < 0.001), medically tolerant females had a significantly longer referral time interval than medically tolerant males (average 59.9 months vs 21.7 months, median 30.0 months vs 12.0 months, p = 0.017). No statistically significant differences were detected between the sexes for diagnostic time interval (average 63.3 months vs 43.0 months, median 24.0 months vs 24.0 months, p = 0.263) or treatment time interval (average 4.6 months vs 4.7 months, median 4.0 months vs 3.0 months, p = 0.986)., Conclusions: Critical sex differences in patients' journeys to TN surgical treatment were identified, with females enduring considerably longer referral timelines and expressing significantly greater pain intensity than males at referral. Taken together, our findings suggest the presence of unconscious bias and discrimination against females and highlight the need for expediting TN treatment referral for female TN patients.

Introduction: Although driver gene mutations have been believed to be mutually exclusive, some patients with NSCLC and concomitant EGFR mutations and EML4-ALK rearrangements have been reported. In this study, we reported a case of a patient with lung cancer who harbored both EGFR mutation and the EML4-ALK rearrangement after acquiring resistance to the EGFR tyrosine kinase inhibitor treatment. EGFR -mutant and ALK fusion proteins were detected in the same tumor cells through immunohistochemical analysis. Investigation of the molecular mechanisms of concomitant EGFR mutation and the EML4-ALK rearrangement in the same tumor cell can help discover an appropriate treatment for these patients., Methods: PC-9 cells, expressing EGFR exon 19 deletion, were transfected with EML4-ALK variant 3a (v3a) and variant 3b (v3b) separately and selected, and the effect of EGFR and ALK inhibitors was evaluated in vitro and in vivo., Results: PC-9&#95;v3a-gef and PC-9&#95;v3b-gef cells were resistant to gefitinib and ALK inhibitors alone, but ALK inhibitors enhanced gefitinib-induced cytotoxicity. In animal studies, gefitinib completely inhibited the tumor growth in PC-9&#95;vector cells but not in PC-9&#95;v3a-gef and PC-9&#95;v3b-gef cells. A combination of ALK inhibitor and gefitinib was found to be more potent than gefitinib alone in PC-9&#95;v3a-gef and PC-9&#95;v3b-gef cells. Furthermore, combination treatment with osimertinib and ceritinib caused a decrease in liver tumor size of the patient with liver metastases., Conclusions: Our data suggest that combination treatment with EGFR and ALK inhibitors can be a therapeutic strategy for treating NSCLC with concomitant EGFR mutation and EML4-ALK rearrangement., (© 2022 The Authors.)

Abstract: Chronic pain has widespread, detrimental effects on the human nervous system and its prevalence and burden increase with age. Machine learning techniques have been applied on brain images to produce statistical models of brain aging. Specifically, the Gaussian process regression is particularly effective at predicting chronological age from neuroimaging data which permits the calculation of a brain age gap estimate (brain-AGE). Pathological biological processes such as chronic pain can influence brain-AGE. Because chronic pain disorders can differ in etiology, severity, pain frequency, and sex-linked prevalence, we hypothesize that the expression of brain-AGE may be pain specific and differ between discrete chronic pain disorders. We built a machine learning model using T1-weighted anatomical MRI from 812 healthy controls to extract brain-AGE for 45 trigeminal neuralgia (TN), 52 osteoarthritis (OA), and 50 chronic low back pain (BP) subjects. False discovery rate corrected Welch t tests were conducted to detect significant differences in brain-AGE between each discrete pain cohort and age-matched and sex-matched controls. Trigeminal neuralgia and OA, but not BP subjects, have significantly larger brain-AGE. Across all 3 pain groups, we observed female-driven elevation in brain-AGE. Furthermore, in TN, a significantly larger brain-AGE is associated with response to Gamma Knife radiosurgery for TN pain and is inversely correlated with the age at diagnosis. As brain-AGE expression differs across distinct pain disorders with a pronounced sex effect for female subjects. Younger women with TN may therefore represent a vulnerable subpopulation requiring expedited chronic pain intervention. To this end, brain-AGE holds promise as an effective biomarker of pain treatment response., (Copyright © 2022 International Association for the Study of Pain.)

In this study, we established an explainable and personalized risk prediction model for in-hospital mortality after continuous renal replacement therapy (CRRT) initiation. This retrospective cohort study was conducted at Changhua Christian Hospital (CCH). A total of 2932 consecutive intensive care unit patients receiving CRRT between 1 January 2010, and 30 April 2021, were identified from the CCH Clinical Research Database and were included in this study. The recursive feature elimination method with 10-fold cross-validation was used and repeated five times to select the optimal subset of features for the development of machine learning (ML) models to predict in-hospital mortality after CRRT initiation. An explainable approach based on ML and the SHapley Additive exPlanation (SHAP) and a local explanation method were used to evaluate the risk of in-hospital mortality and help clinicians understand the results of ML models. The extreme gradient boosting and gradient boosting machine models exhibited a higher discrimination ability (area under curve [AUC] = 0.806, 95% CI = 0.770-0.843 and AUC = 0.823, 95% CI = 0.788-0.858, respectively). The SHAP model revealed that the Acute Physiology and Chronic Health Evaluation II score, albumin level, and the timing of CRRT initiation were the most crucial features, followed by age, potassium and creatinine levels, SPO2, mean arterial pressure, international normalized ratio, and vasopressor support use. ML models combined with SHAP and local interpretation can provide the visual interpretation of individual risk predictions, which can help clinicians understand the effect of critical features and make informed decisions for preventing in-hospital deaths.

Serum potassium (K+) levels between 3.5 and 5.0 mmol/L are considered safe for patients. The optimal serum K+ level for critically ill patients with acute kidney injury undergoing continuous renal replacement therapy (CRRT) remains unclear. This retrospective study investigated the association between ICU mortality and K+ levels and their variability. Patients aged >20 years with a minimum of two serum K+ levels recorded during CRRT who were admitted to the ICU in a tertiary hospital in central Taiwan between January 01, 2010, and April 30, 2021 were eligible for inclusion. Patients were categorized into different groups based on their mean K+ levels: <3.0, 3.0 to <3.5, 3.5 to <4.0, 4.0 to <4.5, 4.5 to <5.0, and ≥5.0 mmol/L; K+ variability was divided by the quartiles of the average real variation. We analyzed the association between the particular groups and in-hospital mortality by using Cox proportional hazard models. We studied 1991 CRRT patients with 9891 serum K+ values recorded within 24 h after the initiation of CRRT. A J-shaped association was observed between serum K+ levels and mortality, and the lowest mortality was observed in the patients with mean K+ levels between 3.0 and 4.0 mmol/L. The risk of in-hospital death was significantly increased in those with the highest variability (HR and 95% CI = 1.61 [1.13−2.29] for 72 h mortality; 1.39 [1.06−1.82] for 28-day mortality; 1.43 [1.11−1.83] for 90-day mortality, and 1.31 [1.03−1.65] for in-hospital mortality, respectively). Patients receiving CRRT may benefit from a lower serum K+ level and its tighter control. During CRRT, progressively increased mortality was noted in the patients with increasing K+ variability. Thus, the careful and timely correction of dyskalemia among these patients is crucial.

In this study, an unmanned aerial vehicle (UAV) with a camera and laser ranging module was developed to inspect bridge cracks. Four laser ranging units were installed adjacent to the camera to measure the distance from the camera to the object to calculate the object's projection plane and overcome the limitation of vertical photography. The image processing method was adopted to extract crack information and calculate crack sizes. The developed UAV was used in outdoor bridge crack inspection tests; for images taken at a distance of 2.5 m, we measured the crack length, and the error between the result and the real length was less than 0.8%. The developed UAV has a dual-lens design, where one lens is used for bridge inspections and the other lens is used for flight control. The camera of the developed UAV can be rotated from the horizontal level to the zenith according to user requirements; thus, this UAV achieves high safety and efficiency in bridge inspections.

Surface-enhanced Raman scattering (SERS) has been a useful sensing technique, in which inelastic light scattering can be significantly enhanced by absorbing molecules onto rough metal surfaces or nanoparticles. Although many methods have been developed to prepare SERS substrates, it is still highly desirable and challenging to design SERS substrates, especially with highly ordered and controlled three-dimensional (3D) structures. In this work, we develop novel SERS substrates with regular volcano-shaped polymer structures using the versatile solvent on-film annealing method. Polystyrene (PS) nanospheres are first synthesized by surfactant-free emulsion polymerization and assembled on poly(methyl methacrylate) (PMMA) films. After annealing in acetic acid vapors, PMMA chains are selectively swollen and wet the surfaces of the PS nanospheres. By selectively removing the PS nanospheres using cyclohexane, volcano-shaped PMMA films can be obtained. Compared with flat PMMA films with water contact angles of ∼74°, volcano-shaped PMMA films exhibit higher water contact angles of ∼110° due to the sharp features and rough surfaces. The volcano-shaped PMMA films are then coated with gold nanoparticles (AuNPs) as SERS substrates. Using rhodamine 6G as the probe molecules, the SERS results show that the Raman signals of the volcano-shaped PMMA/AuNP hybrid substrates are much higher than those of the pristine PMMA films and PMMA films with AuNPs. For the volcano-shaped PMMA/AuNP hybrid substrates using 400 nm PS nanospheres, a high enhancement factor (EF) value of ∼1.12 × 10 5 with a detection limit of 10 -8 M is obtained in a short integration time of 1 s. A linear calibration line with an R 2 value of 0.918 is also established, demonstrating the ability to determine the concentrations of the analytes. This work offers significant insight into developing novel SERS substrates, which is crucial for improving the detection limits of analytes.

Chronic pain patients frequently report memory and concentration difficulties. Objective testing in this population points to poor performance on memory and cognitive tests, and increased comorbid anxiety and depression. Recent evidence has suggested convergence between chronic pain and memory deficits onto the hippocampus. The hippocampus consists of heterogenous subfields involved in memory consolidation, behavior regulation, and stress modulation. Despite significant studies outlining hippocampal changes in human and chronic pain animal models, the effect of pain relief on hippocampal abnormalities remains unknown. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder which is highly amenable to surgical interventions, providing a unique opportunity to investigate the effect of pain relief. This study investigates the effect of pain relief on hippocampal subfields in TN. Anatomical MR images of 61 TN patients were examined before and 6 months after surgery. Treatment responders (n = 47) reported 95% pain relief, whereas non-responders (n = 14) reported 40% change in pain on average. At baseline, patients had smaller hippocampal volumes, compared to controls. After surgery, responders' hippocampal volumes normalized, largely driven by CA2/3, CA4, and dentate gyrus, which are involved in memory consolidation and neurogenesis. We propose that hippocampal atrophy in TN is pain-driven and successful treatment normalizes such abnormalities. PERSPECTIVE: Chronic pain patients have structural abnormalities in the hippocampus and its subfields. Pain relief normalizes these structural abnormalities and impacts patients in a sex-dependent manner., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Vestibular schwannomas are common cerebellopontine angle tumors arising from the vestibulocochlear nerve and can result in cranial nerve dysfunction. Conventional MR imaging does not provide information that could correlate with cranial nerve compression symptoms of hearing loss or imbalance. We used multitensor tractography to evaluate the relationship between the WM microstructural properties of cranial nerves and tumor volume in a cohort of patients with vestibular schwannomas., Materials and Methods: A retrospective study was performed in 258 patients with vestibular schwannomas treated at the Gamma Knife clinic at Toronto Western Hospital between 2014 and 2018. 3T MR images were analyzed in 160 surgically naïve patients with unilateral vestibular schwannomas. Multitensor tractography was used to extract DTI-derived metrics (fractional anisotropy and radial, axial, and mean diffusivities of the bilateral facial and vestibulocochlear nerves [cranial nerves VII/VIII]). ROIs were placed in the transition between cisternal and intracanalicular segments, and images were analyzed using the eXtended Streamline Tractography reconstruction method. Diffusion metrics were correlated with 3D tumor volume derived from the Gamma Knife clinic., Results: DTI analyses revealed significantly higher fractional anisotropy values and a reduction in axial diffusivity, radial diffusivity, and mean diffusivity (all P < .001) within the affected cranial nerves VII and VIII compared with unaffected side. All specific diffusivities (axial, radial, and mean diffusivity) demonstrated an inverse correlation with tumor volume (axial, radial, and mean diffusivity, P < .01)., Conclusions: Multitensor tractography allows the quantification of cranial nerve VII and VIII WM microstructural alterations in patients with vestibular schwannomas. Our findings support the hypothesis that tumor volume may cause microstructural alterations of the affected cranial nerves VII and VIII. This type of advanced imaging may represent a possible avenue to correlate diffusivities with cranial nerve function., (© 2021 by American Journal of Neuroradiology.)

Aim: To explore the proliferation, adhesion and differentiation response and the underlying mechanisms that occur in lipopolysaccharide (LPS)-induced inflamed dental pulp cells (DPCs) in contact with Biodentine and mineral trioxide aggregate (MTA)., Methodology: The DPCs were isolated from three healthy donors and named DPC-H1 to DPC-H3. The DPCs were pre-cultured with 2 or 5 μg mL -1 LPS for 24 h to induce inflammation. The expression of inflammation marker miR-146a was detected by q-PCR. The normal and LPS-induced DPCs were further treated with 0.14 mg mL -1 Biodentine or 0.13 mg mL -1 MTA for 24 h. MTT assay and adhesion assay were used to analyse the changes of cell phenotypes. DSPP, AKT and ERK expressions were detected by Western blotting. The data were analysed by Mann-Whitney test or two-way anova. Differences were considered statistically significant when P < 0.05., Results: In LPS-induced DPCs, Biodentine and MTA treatment neither induced nor aggravated LPS-induced inflammation, but their presence did increase the expression of the odontogenic differentiation marker DSPP. Under 2 or 5 μg mL -1 LPS-induced inflammation, Biodentine and MTA promoted the proliferation of DPC cells, and significantly in DPC-H2 (P < 0.0001 for both reagents). With the treatment of 2 μg mL -1 LPS, the cell adhesion of DPCs on the fibronectin-coated culture plates was increased significantly by Biodentine (P = 0.0413) and MTA (P < 0.0001). Biodentine and MTA regulated cell adhesion on the fibronectin-coated culture plates (P < 0.0001 for both reagents) and proliferation (P < 0.0001 for both reagents) via the AKT pathway. However, the AKT pathway was not involved in the expression of DSPP induced by Biodentine and MTA., Conclusion: Biodentine and MTA enhanced the proliferation, adhesion and differentiation of LPS-induced DPCs. The proliferation and adhesion process induced by Biodentine and MTA was via the AKT pathway. However, the cellular differentiation process might not use the same pathway, and this needs to be explored in future studies., (© 2021 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Abstract: Men and women can exhibit different pain sensitivities, and many chronic pain conditions are more prevalent in one sex. Although there is evidence of sex differences in the brain, it is not known whether there are sex differences in the organization of large-scale functional brain networks in chronic pain. Here, we used graph theory with modular analysis and machine-learning of resting-state-functional magnetic resonance imaging data from 220 participants: 155 healthy controls and 65 individuals with chronic low back pain due to ankylosing spondylitis, a form of arthritis. We found an extensive overlap in the graph partitions with the major brain intrinsic systems (ie, default mode, central, visual, and sensorimotor modules), but also sex-specific network topological characteristics in healthy people and those with chronic pain. People with chronic pain exhibited higher cross-network connectivity, and sex-specific nodal graph properties changes (ie, hub disruption), some of which were associated with the severity of the chronic pain condition. Females exhibited atypically higher functional segregation in the mid cingulate cortex and subgenual anterior cingulate cortex and lower connectivity in the network with the default mode and frontoparietal modules, whereas males exhibited stronger connectivity with the sensorimotor module. Classification models on nodal graph metrics could classify an individual's sex and whether they have chronic pain with high accuracies (77%-92%). These findings highlight the organizational abnormalities of resting-state-brain networks in people with chronic pain and provide a framework to consider sex-specific pain therapeutics., (Copyright © 2020 International Association for the Study of Pain.)

Aim: A previous study revealed that PPARγ agonists have anti-inflammatory effects in rheumatoid arthritis (RA). Furthermore, some studies have shown that type 2 diabetes mellitus (T2DM) may elicit the development of RA. In this study, we aimed to investigate whether the use of thiazolidinediones (TZDs) is associated with a lower risk of developing RA in patients with T2DM., Methods: Based on the Taiwan National Health Insurance Research Database, we conducted a nationwide case-control study. The selected cases were patients with T2DM who were diagnosed with RA between 2000 and 2013. The controls were retrieved at a ratio of 1:4 by propensity score matching. Logistic regression was conducted to evaluate whether TZD use lowers the risk of RA in patients with T2DM. The dose-response effect was examined according to the total TZD dose, within 2 years before the index date (the first diagnosis date of RA), and TZD doses were divided into four groups by cumulative Defined Daily Dose (cDDD): <30, 31-90, 91-365, and >365 cDDDs., Results: A total of 3605 cases and 14 420 controls were included in this study. After adjusting for age, sex, baseline comorbidities, the results demonstrated that TZD use did not significantly reduce the risk of RA in patients with T2DM (adjusted OR = 0.91, 95% CI 0.81-1.02). In the subgroup analysis by total TZD exposure dose within 2 years, 91-365 cDDDs of TZD had a lower risk of RA development, aOR = 0.87 (95% CI 0.71-1.06) and >365 cDDDs of TZD, aOR = 0.85 (95% CI 0.73-1.01). In the trend test, P was <.05., Conclusions: TZD use might reduce the risk of RA in patients with T2DM, but it was non-statistically significant. Further research is necessary to assess this association., (© 2020 John Wiley & Sons Ltd.)

Background: Trigeminal neuralgia, a severe chronic neuropathic pain disorder, is widely believed to be amenable to surgical treatments. Nearly 20% of patients, however, do not have adequate pain relief after surgery. Objective tools for personalized pre-treatment prognostication of pain relief following surgical interventions can minimize unnecessary surgeries and thus are of substantial benefit for patients and clinicians., Purpose: To determine if pre-treatment regional brain morphology-based machine learning models can prognosticate 1 year response to Gamma Knife radiosurgery for trigeminal neuralgia., Methods: We used a data-driven approach that combined retrospective structural neuroimaging data and support vector machine-based machine learning to produce robust multivariate prediction models of pain relief following Gamma Knife radiosurgery for trigeminal neuralgia. Surgical response was defined as ≥ 75% pain relief 1 year post-treatment. We created two prediction models using pre-treatment regional brain gray matter morphology (cortical thickness or surface area) to distinguish responders from non-responders to radiosurgery. Feature selection was performed through sequential backwards selection algorithm. Model out-of-sample generalizability was estimated via stratified 10-fold cross-validation procedure and permutation testing., Results: In 51 trigeminal neuralgia patients (35 responders, 16 non-responders), machine learning models based on pre-treatment regional brain gray matter morphology (14 regional surface areas or 13 regional cortical thicknesses) provided robust a priori prediction of surgical response. Cross-validation revealed the regional surface area model was 96.7% accurate, 100.0% sensitive, and 89.1% specific while the regional cortical thickness model was 90.5% accurate, 93.5% sensitive, and 83.7% specific. Permutation testing revealed that both models performed beyond pure chance (p < 0.001). The best predictor for regional surface area model and regional cortical thickness model was contralateral superior frontal gyrus and contralateral isthmus cingulate gyrus, respectively., Conclusions: Our findings support the use of machine learning techniques in subsequent investigations of chronic neuropathic pain. Furthermore, our multivariate framework provides foundation for future development of generalizable, artificial intelligence-driven tools for chronic neuropathic pain treatments., (Copyright © 2021. Published by Elsevier Inc.)

Background: Novel magnetic resonance (MR) imaging techniques have led to the development of T1-w/T2-w ratio images or "myelin-sensitive maps (MMs)" to estimate and compare myelin content in vivo. Currently, raw image intensities in conventional MR images are unstandardized, preventing meaningful quantitative comparisons. We propose an improved workflow to standardize the MMs, which was applied to patients with classic trigeminal neuralgia (CTN) and trigeminal neuralgia secondary to multiple sclerosis (MSTN), to assess the validity and feasibility of this clinical tool., Methods: T1-w and T2-w images were obtained for 17 CTN patients and 17 MSTN patients using a 3 T scanner. Template images were obtained from ICBM152. Multiple sclerosis (MS) plaques in the pons were labelled in MSTN patients. For each patient image, a Gaussian curve was fitted to the histogram of its intensity distribution, and transformed to match the Gaussian curve of its template image., Results: After standardization, the structural contrast of the patient image and its histogram more closely resembled the ICBM152 template. Moreover, there was reduced variability in the histogram peaks of the gray and white matter between patients after standardization (p < 0.001). MM intensities were decreased within MS plaques, compared to normal-appearing white matter (NAWM) in MSTN patients (p < 0.001) and its corresponding regions in CTN patients (p < 0.001)., Conclusions: Images intensities are calibrated according to a mathematic relationship between the intensities of the patient image and its template. Reduced variability among histogram peaks allows for interpretation of tissue-specific intensity and facilitates quantitative analysis. The resultant MMs facilitate comparisons of myelin content between different regions of the brain and between different patients in vivo. MM analysis revealed reduced myelin content in MS plaques compared to its corresponding regions in CTN patients and its surrounding NAWM in MSTN patients. Thus, the standardized MM serves as a non-invasive, easily-automated tool that can be feasibly applied to clinical populations for quantitative analyses of myelin content., (Copyright © 2021. Published by Elsevier Inc.)

Background: Gamma Knife radiosurgery (GKRS) is a minimally invasive procedure for trigeminal neuralgia secondary to multiple sclerosis (MS-TN). Patients with MS-TN experience suboptimal response rates to treatment, and the relationship between trigeminal microstructure and treatment outcome is poorly understood., Objective: To characterize imaging features of MS-TN pain and GKRS response., Methods: 3 T diffusion-weighted imaging (DWI), T1-w, T2-w, and fluid-attenuated inversion recovery (FLAIR) sequences were acquired for 18 MS-TN patients undergoing GKRS. Brainstem plaques were standardized into a common space to determine plaque distribution. Ratio of T1-w/T2-w or "myelin maps (MM)" was generated. Multi-tensor tractography was used to delineate the radiosurgical target (RT), root entry zone (REZ), and proximal pontine segment (PPS) of the trigeminal nerves., Results: Laterality of MS-TN is associated with increased axial diffusivity at the PPS, whereas decreased MM at the PPS correlated with poor GKRS response. Preoperatively, GKRS responders have higher fractional anisotropy at the RT, higher axial diffusivity at the REZ, and higher MM intensities at the PPS., Conclusion: This study demonstrates that diffusivities and MM intensities are important correlates of pain and treatment response, respectively. Overall, preoperative multimodal assessment of the central trigeminal pathway is a better indicator of GKRS response than postoperative assessment of the reduction in fractional anisotropy peripherally.

We demonstrate the fabrication of free-standing inverse opals with gradient pores via a combination of electrophoresis and electroplating techniques. Our processing scheme starts with the preparation of multilayer colloidal crystals by conducting sequential electrophoresis with polystyrene (PS) microspheres in different sizes (300, 600, and 1000 nm). The critical factors affecting the stacking of individual colloidal crystals are discussed and relevant electrophoresis parameters are identified so the larger PS microspheres are assembled successively atop of smaller ones in an orderly manner. In total, we construct multilayer colloidal crystals with vertical stacking of microspheres in 300/600, 300/1000, and 300/600/1000 nm sequences. The inverse opals with gradient pores are produced by galvanostatic plating of Ni, followed by the selective removal of colloidal template. Images from scanning electron microscopy exhibit ideal multilayer close-packed structures with well-defined boundaries among different layers. Results from porometer analysis reveal the size of bottlenecks consistent with those of interconnected pore channels from inverse opals of smallest PS microspheres. Mechanical properties determined by nanoindentation tests indicate significant improvements for multilayer inverse opals as compared to those of conventional single-layer inverse opals.

In this paper, an effective approach is demonstrated for the fabrication of IrO 2 -decorated polystyrene@functionalized polypyrrole (core@shell; PS@PPyNH 2 ) microspheres. The synthesis begins with the preparation of monodispersive PS microspheres with a diameter of 490 nm, by a process of emulsifier-free emulsion polymerization, followed by a copolymerization process involving pyrrole and PyNH 2 monomers in a PS microsphere aqueous suspension, to produce uniform PS@PPyNH 2 microspheres with a diameter of 536 nm. The loading of 2 nm IrO 2 nanoparticles onto the PS@PPyNH 2 microspheres can be easily adjusted by tuning the pH value of the IrO 2 colloidal solution and the PS@PPyNH 2 suspension. At pH 4, we successfully obtain IrO 2 -decorated PS@PPyNH 2 microspheres via electrostatic attraction and hydrogen bonding simultaneously between the negatively-charged IrO 2 nanoparticles and the positively-charged PS@PPyNH 2 microspheres. These IrO 2 -decorated PS@PPyNH 2 microspheres exhibit a characteristic cyclic voltammetric profile, similar to that of an IrO 2 thin film. The charge storage capacity is 5.19 mA cm -2 , a value almost five times greater than that of PS@PPyNH 2 microspheres. In addition, these IrO 2 -decorated PS@PPyNH 2 microspheres exhibit excellent cell viability and biocompatibility.

We demonstrate a water-based synthetic route to fabricate composite inverse opals for simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA). Our process involves the conformal deposition of poly(3,4-ethylenedioxythiophene) (PEDOT) and PEDOT/Au on the skeletons of Ni inverse opals via cyclic voltammetric scans (CV) to initiate the electropolymerization of 3,4-ethylenedioxythiophene (EDOT) monomers. The resulting samples, Ni@PEDOT, and Ni@PEDOT/Au inverse opals, exhibit a three-dimensional ordered macroporous platform with a large surface area and interconnected pore channels, desirable attributes for facile mass transfer and strong reaction for analytes. Structural characterization and material/chemical analysis including scanning electron microscope, X-ray photoelectron spectroscopy, and Raman spectroscopy are carried out. The sensing performances of Ni@PEDOT and Ni@PEDOT/Au inverse opals are explored by conducting CV scans with various concentrations of AA, DA, and UA. By leveraging the structural advantages of inverse opals and the selection of PEDOT/Au composite, the Ni@PEDOT/Au inverse opals reveal improved sensing performances over those of conventional PEDOT-based nanostructured sensors.

Conventional magnetic resonance imaging of patients with trigeminal neuralgia (TN) does not typically reveal associated brain lesions. Here, we identify a unique group of TN patients who present with a single brainstem lesion, who do not fulfill diagnostic criteria for multiple sclerosis (MS). We aim to define this new clinical syndrome, which we term TN associated with solitary pontine lesion (SPL-TN), using a clinical and neuroimaging approach. We identified 24 cases of SPL-TN, 18 of which had clinical follow-up for assessment of treatment response. Lesion mapping was performed to determine the exact location of the lesions and site of maximum overlap across patients. Diffusion tensor imaging was used to assess the white-matter microstructural properties of the lesions. Diffusivity metrics were extracted from the (1) SPL-TN lesions, (2) contralateral, unaffected side, (3) MS brainstem plaques from 17 patients with TN secondary to MS, (4) and healthy controls. We found that 17/18 patients were nonresponders to surgical treatment. The lesions were uniformly located along the affected trigeminal pontine pathway, where the site of maximum overlap across patients was in the area of the trigeminal nucleus. The lesions demonstrated abnormal white-matter microstructure, characterized by lower fractional anisotropy, and higher mean, radial, and axial diffusivities compared with the unaffected side. The brainstem trigeminal fiber microstructure within a lesion highlighted the difference between SPL-TN lesions and MS plaques. In conclusion, SPL-TN patients have identical clinical features to TN but have a single pontine lesion not in keeping with MS and are refractory to surgical management.

The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRAS G12V /KRAS G12D mutations and inhibited the KRAS G12V mediated metastasis by Wnt inhibitor. First, we found that KRAS G12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRAS G12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRAS G12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRAS G12D cells. The restored activation of Wnt/β-catenin in H838KRAS G12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRAS G12V -induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRAS G12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRAS G12V /KRAS G12D is distinct.

Background/aim: Cervical cancer is one of the most common cancers worldwide and a major cause of cancer-related mortality among women. Previous studies have reported that microRNA-miR-187*, which is one of the non-coding parts of the genome producing small conserved ribonucleic acids, is associated with various cancers. In this study, we explored the function of miR-187* in cervical cancer cells., Materials and Methods: miR-187* mimic, WWOX reporter constructs, siRNA and overexpression constructs were transfected into SiHa cells to investigate the function and regulatory mechanisms of miR-187*., Results: Exogenous miR-187* was found to increase the oncogenic phenotypes of SiHa cells. The tumor suppressor gene WWOX is a novel target of miR-187* in SiHa cells. WWOX siRNA suppressed endogenous WWOX expression and increased the oncogenic phenotypes of SiHa cells. Exogenous WWOX expression was able to suppress the oncogenic phenotypes of SiHa cells and rescue cells from miR-187*-induced migration., Conclusion: miR-187* seems to enhance SiHa cervical cancer cell oncogenicity via suppression of the WWOX pathway., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Trigeminal Neuralgia (TN) is a chronic neuropathic pain syndrome characterized by paroxysmal unilateral shock-like pains in the trigeminal territory most frequently attributed to neurovascular compression of the trigeminal nerve at its root entry zone. Recent advances in the study of TN suggest a possible central nervous system (CNS) role in modulation and maintenance of pain. TN and other chronic pain patients commonly experience alterations in cognition and affect, as well as abnormalities in CNS volume and microstructure in regions associated with pain perception, emotional modulation, and memory consolidation. However, the microstructural changes in the hippocampus, an important structure within the limbic system, have not been previously studied in TN patients. Here, we use grey matter analysis to assess whether TN pain is associated with altered hippocampal subfield volume in patients with classic TN. Anatomical magnetic resonance (MR) images of twenty-two right-sided TN patients and matched healthy controls underwent automated segmentation of hippocampal subfields using FreeSurfer v6.0. Right-sided TN patients had significant volumetric reductions in ipsilateral cornu ammois 1 (CA1), CA4, dentate gyrus, molecular layer, and hippocampus-amygdala transition area - resulting in decreased whole ipsilateral hippocampal volume, compared to healthy controls. Overall, we demonstrate selective hippocampal subfield volume reduction in patients with classic TN. These changes occur in subfields implicated as neural circuits for chronic pain processing. Selective subfield volume reduction suggests aberrant processes and circuitry reorganization, which may contribute to development and/or maintenance of TN symptoms., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interest in the neuroimaging of pain has highlighted changes in the root entry zone in TN, but also group-level central nervous system gray and white matter (WM) abnormalities. Group differences in neuroimaging data are frequently evaluated with univariate statistics; however, this approach is limited because it is based on single, or clusters of, voxels. By contrast, multivariate pattern analyses consider all the model's neuroanatomical features to capture a specific distributed spatial pattern. This approach has potential use as a prediction tool at the individual level. We hypothesized that a multivariate pattern classification method can distinguish specific patterns of abnormal WM connectivity of classic TN from healthy controls (HCs). Diffusion-weighted scans in 23 right-sided TN and matched controls were processed to extract whole-brain interregional streamlines. We used a linear support vector machine algorithm to differentiate interregional normalized streamline count between TN and HC. This algorithm successfully differentiated between TN and HC with an accuracy of 88%. The structural pattern emphasized WM connectivity of regions that subserve sensory, affective, and cognitive dimensions of pain, including the insula, precuneus, inferior and superior parietal lobules, and inferior and medial orbital frontal gyri. Normalized streamline counts were associated with longer pain duration and WM metric abnormality between the connections. This study demonstrates that machine-learning algorithms can detect characteristic patterns of structural alterations in TN and highlights the role of structural brain imaging for identification of neuroanatomical features associated with neuropathic pain disorders.

Objective: Gamma Knife radiosurgery (GKRS) is an important treatment modality for trigeminal neuralgia (TN). Current longitudinal assessment after GKRS relies primarily on clinical diagnostic measures, which are highly limited in the prediction of long-term clinical benefit. An objective, noninvasive, predictive tool would be of great utility to advance the clinical management of patients. Using diffusion tensor imaging (DTI), the authors' aim was to determine whether early (6 months post-GKRS) target diffusivity metrics can be used to prognosticate long-term pain relief in patients with TN., Methods: Thirty-seven patients with TN treated with GKRS underwent 3T MRI scans at 6 months posttreatment. Diffusivity metrics of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were extracted bilaterally from the radiosurgical target of the affected trigeminal nerve and its contralateral, unaffected nerve. Early (6 months post-GKRS) diffusivity metrics were compared with long-term clinical outcome. Patients were identified as long-term responders if they achieved at least 75% reduction in preoperative pain for 12 months or longer following GKRS., Results: Trigeminal nerve diffusivity at 6 months post-GKRS was predictive of long-term clinical effectiveness, where long-term responders (n = 19) showed significantly lower fractional anisotropy at the radiosurgical target of their affected nerve compared to their contralateral, unaffected nerve and to nonresponders. Radial diffusivity and mean diffusivity, correlates of myelin alterations and inflammation, were also significantly higher in the affected nerve of long-term responders compared to their unaffected nerve. Nonresponders (n = 18) did not exhibit any characteristic diffusivity changes after GKRS., Conclusions: The authors demonstrate that early postsurgical target diffusivity metrics have a translational, clinical value and permit prediction of long-term pain relief in patients with TN treated with GKRS. Importantly, an association was found between the footprint of radiation and clinical effectiveness, where a sufficient level of microstructural change at the radiosurgical target is necessary for long-lasting pain relief. DTI can provide prognostic information that supplements clinical measures, and thus may better guide the postoperative assessment and clinical decision-making for patients with TN.

Ovatodiolide was isolated from the traditional Chinese medicinal herb Anisomeles indica, possesses anti-bacterial and anti-inflammatory properties; however, the anti-cancer activity and its mechanisms have been limitedly reported. This study aimed to examine the effect and molecular action of ovatodiolide in lung cancer cells. Cell cycle distribution and reactive oxygen species (ROS) generation were measured by flow cytometry. Apoptosis was detected by propidium iodide/annexin V staining and TUNEL assay. DNA damage was investigated by comet assay and γ-H2AX staining. Caspase activity was determined using caspase fluorometric kits. Moreover, protein levels were examined by western blot. Ovatodiolide provoked reactive oxygen species generation and DNA damage, as well as inhibited cell growth and induced apoptosis in human lung cancer A549 and H1299 cell lines. DNA damage-related molecules, ATM/ATR and CHK1/CHK2 were activated by ovatodiolide. Moreover, ovatodiolide-mediated G2/M arrest was associated with the decrease of Cyclin B1 and CDC25C levels, and increase of p21 WAF1/CIP1 expression. Additionally, ovatodiolide-triggered apoptosis was through both intrinsic and extrinsic pathways characterized by the elevating PUMA, Bax, and DR5 proteins, decreasing Bcl-2 and Mcl-1, and activating caspase-8, caspase-9 and caspase-3. Caffeine, an ATM/ATR inhibitor, rescued ovatodiolide-mediated cell cycle arrest and apoptosis, but not reactive oxygen species generation. Nevertheless, antioxidant N-acetyl-cysteine completely blocked ovatodiolide-mediated molecular events, G2/M arrest, and apoptosis. These observations suggest that ovatodiolide stimulates reactive oxygen species generation, causes oxidative stress and DNA damage; subsequently, provokes DNA damage signaling pathways, eventually leads to block cell cycle at G2/M phase and trigger apoptosis in lung cancer A549 and H1299 cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to surgery. A proportion of patients, however, do not benefit and suffer ongoing pain. There are currently no imaging tools that permit the prediction of treatment response. To address this paucity, we used diffusion tensor imaging (DTI) to determine whether pre-surgical trigeminal nerve microstructural diffusivities can prognosticate response to TN treatment. In 31 TN patients and 16 healthy controls, multi-tensor tractography was used to extract DTI-derived metrics-axial (AD), radial (RD), mean diffusivity (MD), and fractional anisotropy (FA)-from the cisternal segment, root entry zone and pontine segment of trigeminal nerves for false discovery rate-corrected Student's t -tests. Ipsilateral diffusivities were bootstrap resampled to visualize group-level diffusivity thresholds of long-term response. To obtain an individual-level statistical classifier of surgical response, we conducted discriminant function analysis (DFA) with the type of surgery chosen alongside ipsilateral measurements and ipsilateral/contralateral ratios of AD and RD from all regions of interest as prediction variables. Abnormal diffusivity in the trigeminal pontine fibers, demonstrated by increased AD, highlighted non-responders (n = 14) compared to controls. Bootstrap resampling revealed three ipsilateral diffusivity thresholds of response-pontine AD, MD, cisternal FA-separating 85% of non-responders from responders. DFA produced an 83.9% (71.0% using leave-one-out-cross-validation) accurate prognosticator of response that successfully identified 12/14 non-responders. Our study demonstrates that pre-surgical DTI metrics can serve as a highly predictive, individualized tool to prognosticate surgical response. We further highlight abnormal pontine segment diffusivities as key features of treatment non-response and confirm the axiom that central pain does not commonly benefit from peripheral treatments.

Gastric carcinoma is highly prevalent throughout the world. Understanding the pathogenesis of this disease will benefit diagnosis and resolution. Studies show that miRNAs are involved in the tumorigenesis of gastric carcinoma. An initial screening followed by subsequent validation identified that miR-376c is up-regulated in gastric carcinoma tissue and the plasma of patients with the disease. In addition, the urinary level of miR-376c is also significantly increased in gastric carcinoma patients. The plasma miR-376c level was validated as a biomarker for gastric carcinoma, including early stage tumors. The induction of miR-376c was found to enrich the proliferation, migration and anchorage-independent growth of carcinoma cells and, furthermore, the repression of the expression of endogenous miR-376c was able to reduce such oncogenic phenotypes. ARID4A gene is a direct target of miR-376c. Knockdown of endogenous ARID4A increased the oncogenicity of carcinoma cells, while ARID4A was found to be drastically down-regulated in tumor tissue. Thus, expression levels of miR-376c and ARID4A mRNA tended to be opposing in tumor tissue. Our results demonstrate that miR-376c functions by suppressing ARID4A expression, which in turn enhances the oncogenicity of gastric carcinoma cells. It seems likely that the level of miR-376c in plasma and urine could act as invaluable markers for the detection of gastric carcinoma.

Introduction: Tractography analysis in group-based studies across large populations has been difficult to implement. We propose Selective Automated Group Integrated Tractography (SAGIT), an automated group tractography software platform that incorporates multiple diffusion magnetic resonance imaging (dMRI) practices which will allow great accessibility to group-wise dMRI. We use a merged tractography approach that permits evaluation of tractography datasets at the group level. We also introduce an image normalized overlap score (NOS) that measures the quality of the group tractography results. We deploy SAGIT to evaluate deterministic and probabilistic constrained spherical deconvolution (CST det , CST prob ) tractography, eXtended Streamline Tractography (XST), and diffusion tensor tractography (DTT) in their ability to delineate different neuroanatomy, as well as validating NOS across these different brain regions. Materials and methods: Magnetic resonance sequences were acquired from 42 healthy adults. Anatomical and group registrations were performed using Automated Normalization Tools. Cortical segmentation was performed using FreeSurfer. Four tractography algorithms were used to delineate six sets of neuroanatomy: fornix, facial/vestibular-cochlear cranial nerve complex, vagus nerve, rubral-cerebellar decussation, optic radiation, and auditory radiation. The tracts were generated both with and without region of interest filters. The generated visual reports were then evaluated by five neuroscientists. Results: At a group level, merged tractography demonstrated that different methods have different fiber distribution characteristics. CST prob is prone to false-positives, and thereby suitable in anatomy with strong priors. CST det and XST are more conservative, but have greater difficulty resolving hemispherical decussation and distant crossing projections. DTT consistently shows the worst reproducibility across the anatomies. Linear regression of rater scores against NOS shows significant ( p < 0.05) correlation of the two sets of scores in filtered tractography. However, correlations are not significant ( p > 0.05) for unfiltered tractography. Conclusion: The tractography results demonstrated reliable and consistent performance of SAGIT across multiple subjects and techniques. Through SAGIT, we quantifiably demonstrated that different algorithms showed different strengths and weaknesses at a group level. While no single algorithm seems to be suitable for all anatomical tasks, it is useful to consider the use of a mix of algorithms for different anatomical segments. SAGIT appears to be a promising group-wise tractography analysis approach for this purpose.

Purpose: The purpose was to study the effect of introducing intracameral cefuroxime, which was compounded by a hospital pharmacy, on postoperative endophthalmitis in a tertiary eye centre in Hong Kong., Methods: All cases that underwent cataract surgeries over a 12-year period (January 2004 to December 2015) were included. The routine use of intracameral cefuroxime at the end of cataract surgery was introduced at our centre after April 2010. All cefuroxime aliquots were prepared by the hospital pharmacy using an aseptic compounding technique. The rates of postoperative endophthalmitis before April 2010 (Group 1, no intracameral cefuroxime) and after April 2010 (Group 2, routine use of intracameral cefuroxime) were compared., Results: A total of 30,428 eyes (7,332 in Group 1 and 23,096 in Group 2) were studied. Eight cases developed postoperative endophthalmitis (1.09 in 1000; 0.11 %) in Group 1 whereas no cases developed endophthalmitis (0 %) in Group 2. The rate of reduction was statistically significant (p < 0.0001). Seven out of eight cases of endophthalmitis were confirmed by positive culture. Organisms identified were Group G Streptococcus (two cases), Group B Streptococcus, Staphylococcus aureus, Serratia marcescens, and coagulase-negative Staphylococcus (two cases). Antibiotic susceptibility testing results were available in six cases. Four out of six organisms were susceptible to the penicillin group. No adverse events related to the use of intracameral cefuroxime were encountered., Conclusions: The use of intracameral cefuroxime could significantly reduce the rate of postoperative endophthalmitis in a tertiary centre in Hong Kong. The use of aseptic compounding to prepare cefuroxime aliquots by hospital pharmacy appeared to be safe and efficacious.

The International Agency for Research on Cancer lists the principal component of betel quid (BQ), the areca nut, and that of cigarette smoke, benzo[a]pyrene (BaP), as Group 1 carcinogens. Epidemiological studies have shown that coexposure of BQ and cigarette smoke markedly increases the risk of cancer. We previously demonstrated that arecoline, the most abundant alkaloid in the areca nut, inhibits nucleotide excision repair through the repression of p53 activity. To investigate the combined potency of arecoline and BaP in carcinogenesis, we treated human epithelial HEp-2 cells with subcytotoxic doses of arecoline and BaP, alone or in combination, and examined the effects on DNA damage and repair. When exposed for 24h, BaP enhanced DNA repair and p53 transactivation activity. However, these enhancements were suppressed through concurrent treatment of the cells with arecoline. Using a Comet assay, we found that extended exposure to arecoline and BaP caused moderate-to-severe DNA damage in 60% of the cells. Expression of the XPD helicase was transcriptionally suppressed by 1 week of treatment with BaP. Our studies have revealed potential targets in the DNA repair pathway that are affected by BQ and tobacco components, as well as the effect of these components on carcinogenesis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This was a two-phase prospective intervention study in the cardiology intensive care unit (CICU) and medical intensive care unit (MICU) and of a public 1800-bed medical centre in Taiwan. In phase I, cleaning efficacy was monitored by ATP bioluminescence after daily morning cleaning, and only 43.9% of 221 tested surfaces passed. The baseline data were used to define an intervention consisting of a new cleaning protocol as well as a new education/training programme. In phase II, following the intervention, 88.1% of 270 surfaces were found to be clean. The combined infection rate in the CICU and MICU showed a statistically significant decrease of 49.7%., (Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial for tumorigenesis. Previously, we have identified that miR-31 is frequently upregulated in OSCC and that this miR-31 increase, together with downstream effector modulation, enhances oral carcinogenesis. We have identified higher levels of miR-31 expression in oral potential malignant disorder (OPMD) tissues compared with normal oral mucosa. Exogenous miR-31 and human telomerase reverse transcriptase (hTERT) expression were introduced into cultured normal oral keratinocytes (NOKs), which led to the immortalization; these lines were designated M31OK1 and M31OK3. These immortalized lines maintained the capability to undergo squamous differentiation. In addition, migration by both cell lines was attenuated by hTERT and miR-31 knockdown. M31OK1 carries a p53 gene mutation at codon 273. A serum-tolerant subline, M31OK1-D, exhibits potent anchorage-independent growth that is attenuated by knockdown of both hTERT and miR-31. miR-31-targeted factors inhibiting HIF (FIH), which upregulated vascular endothelial growth factor (VEGF), was found crucial for oral tumorigenesis. The proliferation, migration and epithelial-mesenchymal transition of M31OK1-D are associated with downregulation of FIH and upregulation of VEGF, which require miR-31 expression. High miR-31 expression is correlated with higher VEGF expression and lower E-cadherin expression in OPMD tissue. It can be concluded that miR-31 collaborates with hTERT to immortalize NOKs and that this may contribute to early stage oral carcinogenesis. The targeting of downstream factors by miR-31 may further advance the neoplastic progression of immortalized NOKs, allowing them to become malignant.

MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial to tumorigenesis. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. Up-regulation of miR-146 has been identified in OSCC tissues. However, the roles of miR-146 in carcinogenesis are controversial as it is suppressive in many other malignancies. The present study investigated the pathogenic implications of miR-146a in oral carcinogenesis. Microdissected OSCC exhibits higher levels of miR-146a expression than matched adjacent mucosal cells. The plasma miR-146a levels of patients are significantly higher than those of control subjects; these levels decrease drastically after tumor resection. miR-146a levels in tumors and in patients' plasma can be used to classify OSCC and non-disease status (sensitivity: >0.72). Exogenous miR-146a expression is significantly increased in vitro oncogenic phenotypes as well as during xenograft tumorigenesis and OSCC metastasis. The plasma miR-146a levels of these mice parallel the xenograft tumor burdens of the mice. A miR-146a blocker abrogates the growth of xenograft tumors. miR-146a oncogenic activity is associated with down-regulation of IRAK1, TRAF6 and NUMB expression. Furthermore, miR-146a directly targets the 3'UTR of NUMB and a region within the NUMB coding sequence when suppressing NUMB expression. Exogenous NUMB expression attenuates OSCC oncogenicity. Double knockdown of IRAK1 and TRAF6, and of TRAF6 and NUMB, enhance the oncogenic phenotypes of OSCC cells. Oncogenic enhancement modulated by miR-146a expression is attenuated by exogenous IRAK1 or NUMB expression. This study shows that miR-146a expression contributes to oral carcinogenesis by targeting the IRAK1, TRAF6 and NUMB genes.

Mesenchymal stromal cells (MSCs) hold great potential in skeletal tissue engineering and regenerative medicine. However, conventional methods that are used in molecular biology to evaluate osteogenic differentiation of MSCs require a relatively large amount of cells. Cell lysis and cell fixation are also required and all these steps are time-consuming. Therefore, it is imperative to develop a facile technique which can provide real-time information with high sensitivity and selectivity to detect the osteogenic maturation of MSCs. In this study, we use Raman spectroscopy as a biosensor to monitor the production of mineralized matrices during osteogenic induction of MSCs. In summary, Raman spectroscopy is an excellent biosensor to detect the extent of maturation level during MSCs-osteoblast differentiation with a non-disruptive, real-time and label free manner. We expect that this study will promote further investigation of stem cell research and clinical applications.

Introduction: MicroRNAs are small noncoding RNAs that play crucial roles in regulating normal and pathologic functions. Bacterial lipopolysaccharide (LPS) is one of the key regulators of pulpal pathogenesis. This study investigated how LPS regulates microRNA expression and affects the phenotype of human dental pulp cells (DPCs)., Methods: Primary DPCs were established and immortalized to achieve immortalized DPCs (I-DPCs). DPCs and I-DPCs were treated with LPS and examined to identify changes in microRNA expression, cell proliferation, and cell migration. Quantitative reverse-transcriptase polymerase chain reaction was used to detect changes in gene expression. Exogenous miR-146a expression was performed transfection with pre-mir-146a mimic. Knockdown of interleukin receptor-associated kinase (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) expression was performed by small interference oligonucleotide transfection. Western blot analysis was used to detect changes in the expression of the IRAK1 and TRAF6 proteins., Results: The differentiation of DPCs was induced by osteogenic medium. I-DPCs had a higher level of human telomerase reverse transcriptase gene than the parental DPCs. Up-regulation of miR-146a expression and an increase in migration was induced by LPS treatment of DPCs and I-DPCs. Exogenous miR-146a expression increased the migration of DPCs and I-DPCs and down-regulated the expression of IRAK1 and TRAF6. Knockdown of IRAK1 and/or TRAF6 increased the migration of DPCs., Conclusions: The results suggested that LPS is able to increase the migration of DPCs by modulating the miR-146a-TRAF6/IRAK1 regulatory cascade., (Copyright © 2012 American Association of Endodontists. All rights reserved.)

MicroRNAs (miRNAs) are endogenous non-coding RNAs that are known to be involved in the pathogenesis of tumors. Gastric carcinoma (GC) is a common malignancy worldwide. The aim of this study was the identification of the expression signature and functional roles of aberrant miRNAs in GC. Initial screening established a profile of aberrantly expressed miRNAs in tumors. miR-370 was confirmed to be overexpressed in GC tissues. Higher expression of miR-370 in GC tissues was associated with more advanced nodal metastasis and a higher clinical stage compared with controls. In addition, significantly higher level of miR-370 was noted in the plasma of GC patients compared with controls. Patients having more invasive or advanced tumors also exhibited a higher plasma level of miR-370. In vitro assays indicated that exogenous miR-370 expression enhanced the oncogenic potential of GC cells. The AGS-GFPM2 cells with exogenous miR-370 expression also exhibited enhanced abdominal metastatic dissemination in nude mice. Reporter assays confirmed that miR-370 targeted predicted sites in 3'UTR of transforming growth factor-β receptor II (TGFβ-RII) gene. The exogenous miR-370 expression decreased TGFβ-RII expression and the phosphorylation of Smad3 elicited by TGFβ1. The TGFβ1-mediated repression in cell migration was reverted by exogenous miR-370 expression. A reverse correlation between miR-370 and TGFβ-RII expression was noted in GC tissues. This study concludes that miR-370 is a miRNA that is associated with GC progression by downregulating TGFβ-RII. The miRNA expression profile described in this study should contribute to future studies on the role of miRNAs in GC.

Background: Oral squamous cell carcinoma (OSCC) is an important malignant disease around the world. Aberrant expression of MicroRNAs (miRNAs) has been implicated in carcinogenesis of various cancers. In previous studies, up-regulation of miR-181 was observed when OSCC progressed from leukoplakia, dysplasia to invasive carcinoma. However, the function of miR-181 in oral tumorigenesis remains unclear., Materials and Methods: The expression levels of miR-181 in the tissue and plasma of OSCC patients were measured by quantitative RT-PCR. The correlation between miR-181 level and multiple clinical variables were then checked by Mann-Whitney test and Wilcoxon matched pairs test. To study the functional meaning of up-regulated miR-181, migration assay and invasion assay by transwells and colony forming assay were applied to analyze the tumorigenic phenotypes of OSCC cells with ectopical expression of miR-181., Results: Among different clinical variables, over-expression of miR-181 was correlated with lymph-node metastasis, vascular invasion, and a poor survival. Functional assays revealed ectopically over-expressed miR-181 would enhance cell migration and invasion, but not the ability of anchorage-independent growth of OSCC cells. In addition, the up-regulation of miR-181 could be detected both in tumor tissues and plasma., Conclusion: miR-181 may enhance lymph-node metastasis through regulating migration, which could potentially be exploited as a putative biomarker for patients with OSCC., (© 2011 John Wiley & Sons A/S.)

Objectives: Osteoporosis is one of the recognized features of AS. It is known that RANK ligand (RANKL), which binds to RANK, can cause the activation of bone resorption. Osteoprotegerin (OPG) also competes with RANK by binding to RANKL and inhibiting bone absorption. Therefore, we designed a case-control study to evaluate the association between occurrence and clinical features of AS and RANK, RANKL and OPG genetic polymorphisms., Methods: A total of 330 AS patients and 330 age- and gender-matched controls were recruited. PCR-restriction fragment length polymorphism was applied to identify RANK C575T, RANKL C-290T and OPG G1181C genotypes., Results: OPG GG genotype carriers had an elevated risk of AS compared with those with the GC and CC genotypes (matched odds ratio 1.74; 95% CI 1.26, 2.40). Age of symptom onset and frequency of peripheral arthritis significantly differed among AS patients by OPG G1181C genotypes. HLA-B27(+) patients with the OPG C allele had the earliest age of symptom onset [mean (s.d.) 26.6 (9.6) years], followed by HLA-B27(+) patients with the OPG G allele [32.6 (12.2) years], HLA-B27(-) patients with the OPG G allele [38.1 (13.6) years] and HLA-B27(-) patients with the OPG C allele [38.6 (9.8) years]. CONCLUSION. OPG G1181C polymorphism may be associated with AS development and clinical manifestations.

Backgrounds: The chromosome 3q26 locus is a hotspot region carrying oncogenes that frequently altered in neoplasms. ZASC1 is a zinc finger protein transcription factor localized on 3q26. Our previous study showed the frequent amplification of 3q26, including the ZASC1 gene, in oral squamous cell carcinoma (OSCC). This study investigated the copy number changes of ZASC1 gene from primary to recurrent OSCC and the functions of ZASC1 in OSCC cells., Materials and Methods: A total of 27 OSCC patients with primary and recurrent tumors were examined for ZASC1 and TERC copy number changes using Quantitative PCR analysis. Exogenous expression and knockdown of ZASC1 were carried out to specify the oncogenic potential of ZASC1 in OSCC cells., Results: A ZASC1 copy number that has increased from primary to recurrent tumor counterparts in tissue pairs suggested the importance of ZASC1 in tumor progression. The increase of ZASC1 gene copy number in recurrent tumors was associated with the consumption of betel quid in patients. OSCC cells expressing ZASC1-FLAG fusion protein showed increased proliferation. After the knockdown of endogenous ZASC1 expression using small interference RNA, the growth and colony formation of SAS OSCC cells decreased., Conclusions: The findings support the hypothesis that ZASC1 localized on 3q26 contributes to the recurrence of OSCC., (© 2010 John Wiley & Sons A/S.)

Curcumin is a common food ingredient derived from the plant Curcuma longa and is a potent drug against tumorigenesis. Both insulin-like growth factor binding protein-5 (IGFBP-5) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) are suppressors of head and neck carcinogenesis. We identified curcumin as an inducer of IGFBP-5 expression in multiple types of oral keratinocytes; furthermore, curcumin induces IGFBP-5 promoter activity in SAS oral cancer cells. Promoter deletion mapping identified a region (nt -71 to nt -59 relative to the transcription start site) as containing a C/EBPalpha-binding element that is indispensable for curcumin-mediated IGFBP-5 upregulation. Chromatin immunoprecipitation assays revealed that in vivo binding of C/EBPalpha to this region was remarkably increased in the presence of curcumin. Curcumin increased nuclear C/EBPalpha expression and IGFBP-5 expression through p38 activation and this was abrogated by SB203580 treatment. Furthermore, MKK6 expression activated p38 and C/EBPalpha, increasing IGFBP-5 promoter activity and expression. Finally, curcumin-induced IGFBP-5 expression is associated with the suppression of xenograft tumorigenesis in mice due to oral cancer cells. We conclude that curcumin activates p38, which, in turn, activates the C/EBPalpha transactivator by interacting with binding elements in the IGFBP-5 promoter. The consequential upregulation of C/EBPalpha and IGFBP-5 by curcumin is crucial to the suppression of oral carcinogenesis.

Differentiation of periodontal ligament (PDL) cells occurs under specific induction; furthermore, NF-kappaB signaling is important for regulation of bone differentiation. MicroRNAs are small non-coding RNAs that repress the translation of target genes and modulate cellular processes. miR-146a has been reported to modulate NF-kappaB signaling. This study hypothesized that miR-146a has a regulatory role in PDL differentiation by affecting NF-kappaB signaling. Immortalized PDL (I-PDL) cell lines were established by exogenous telomerase expression. The genesis of alkaline phosphatase and the up-regulation of miR-146a were induced by ascorbic acid in the I-PDL cells and primary PDL cells. I-PDL cells with exogenous miR-146a expression showed attenuation of NF-kappaB activity and exhibited higher differentiation relative to the controls. Exogenous NF-kappaB expression decreased the expression of differentiation markers, while the inactivation of endogenous NF-kappaB increased alkaline phosphatase in I-PDL cells. This study concludes that miR-146a promotes the differentiation in PDL cells through the down-regulation of NF-kappaB signaling.

MicroRNAs (miRNAs) play important roles in neoplastic process. miR-24 is localized on chromosome 9q22 and 19p13, regions frequently altered in oral squamous cell carcinoma (OSCC). This study showed that miR-24 was up-regulated in OSCC tissues relative to control samples. In addition, the plasma levels of miR-24 in OSCC patients were significantly higher than in control individuals. miR-24 expression was also higher in OSCC cell lines relative to normal oral keratinocytes. Experiments blocking miR-24 and using exogenous miR-24 expression indicated that miR-24 contributes to the growth of OSCC cells and that miR-24 may target p57. This study suggests that miR-24 is involved in the regulation of OSCC growth and that the miR-24's level in plasma may be validatable as a tumor marker for OSCC patients., ((c) 2010 Elsevier Ltd. All rights reserved.)