KinScan: AI-based rapid profiling of activity across the kinome.

Kinases play a vital role in regulating essential cellular processes, including cell cycle progression, growth, apoptosis, and metabolism, by catalyzing the transfer of phosphate groups from adenosing triphosphate to substrates. Their dysregulation has been closely associated with numerous diseases, including cancer development, making them attractive targets for drug discovery. However, accurately predicting the binding affinity between chemical compounds and kinase targets remains challenging due to the highly conserved structural similarities across the kinome. To address this limitation, we present KinScan, a novel computational approach that leverages large-scale bioactivity data and integrates the Multi-Scale Context Aware Transformer framework to construct a virtual profiling model encompassing 391 protein kinases. The developed model demonstrates exceptional prediction capability, distinguishing between kinases by utilizing structurally aligned kinase binding site features derived from multiple sequence alignment for fast and accurate predictions. Through extensive validation and benchmarking, KinScan demonstrated its robust predictive power and generalizability for large-scale kinome-wide profiling and selectivity, uncovering associations with specific diseases and providing valuable insights into kinase activity profiles of compounds. Furthermore, we deployed a web platform for end-to-end profiling and selectivity analysis, accessible at https://kinscan.drugonix.com/softwares/kinscan.

Diagnostic Utility of Restriction Spectrum Imaging in Head and Neck Tumors: A Pilot Study.

OBJECTIVE: Imaging is crucial in the assessment of head and neck cancers for site, extension, and enlarged lymph nodes. Restriction spectrum imaging (RSI) is a new diffusion-weighted magnetic resonance imaging (MRI) technique that enhances the ability to differentiate aggressive cancer from low-grade or benign tumors and helps guide treatment and biopsy. Its contribution to imaging of brain and prostate tumors has been previously published. However, there are no prior studies using RSI sequence in head and neck tumors. The purpose of this study was to evaluate the feasibility of performing RSI in head and neck cancer. METHODS: An additional RSI sequence was added in the routine MRI neck protocol for 13 patients diagnosed with head and neck cancer between November 2018 and April 2019. Restriction spectrum imaging sequence was performed with b values of 0, 500, 1500, and 3000 s/mm 2 and 29 directions on 1.5T magnetic resonance scanners.Diffusion-weighted imaging (DWI) images and RSI images were compared according to their ability to detect the primary malignancy and possible metastatic lymph nodes. RESULTS: In 71% of the patients, RSI outperformed DWI in detecting the primary malignancy and possible metastatic lymph nodes, whereas in the remaining cases, the 2 were comparable. In 66% of the patients, RSI detected malignant lymph nodes that DWI/apparent diffusion coefficient failed to detect. CONCLUSIONS: This is the first study of RSI in head and neck imaging and showed its superiority over the conventional DWI sequence. Because of its ability to differentiate benign and malignant lymph nodes in some cases, the addition of RSI to routine head and neck MRI should be considered.

Identification of Hit Compounds Using Artificial Intelligence for the Management of Allergic Diseases.

This study aimed to identify and evaluate drug candidates targeting the kinase inhibitory region of suppressor of cytokine signaling (SOCS) 3 for the treatment of allergic rhinitis (AR). Utilizing an artificial intelligence (AI)-based new drug development platform, virtual screening was conducted to identify compounds inhibiting the SH2 domain binding of SOCS3. Luminescence assays assessed the ability of these compounds to restore JAK-2 activity diminished by SOCS3. Jurkat T and BEAS-2B cells were utilized to investigate changes in SOCS3 and STAT3 expression, along with STAT3 phosphorylation in response to the identified compounds. In an OVA-induced allergic rhinitis mouse model, we measured serum levels of total IgE and OVA-specific IgE, performed real-time PCR on nasal mucosa samples to quantify Th2 cytokines and IFN-γ expression, and conducted immunohistochemistry to analyze eosinophil levels. Screening identified 20 hit compounds with robust binding affinities. As the concentration of SOCS3 increased, a corresponding decrease in JAK2 activity was observed. Compounds 5 and 8 exhibited significant efficacy in restoring JAK2 activity without toxicity. Treatment with these compounds resulted in reduced SOCS3 expression and the reinstatement of STAT3 phosphorylation in Jurkat T and BEAS-2B cells. In the OVA-induced allergic rhinitis mouse model, compounds 5 and 8 effectively alleviated nasal symptoms and demonstrated lower levels of immune markers compared to the allergy group. This study underscores the promising nonclinical efficacy of compounds identified through the AI-based drug development platform. These findings introduce innovative strategies for the treatment of AR and highlight the potential therapeutic value of targeting SOCS3 in managing AR.

Experimental study of endurance characteristics of Al-doped HfO2ferroelectric capacitor.

In this work, the endurance characteristics of Al-doped HfO2(HAO)-based metal-ferroelectric-metal (MFM) capacitors (which were annealed at 1000 °C) with various doping concentrations were investigated. The doping concentration was optimized for the high annealing temperature (1000 °C) process. To investigate the impact of cycling pulses on the endurance characteristics of HAO-based MFM capacitor, the rise/fall time (tr/f) and hold time (th) for the cycling pulses were varied. Moreover, by adopting the recoverable fatigue process, the endurance characteristics under repetitive wake-up/fatigue processes were studied. The HAO capacitors achieved the remnant polarization (2Pr) of 23.767µC cm-2at pristine state under the high annealing temperature. Furthermore, it was demonstrated that the endurance characteristics (∼108cycles) of the HAO capacitors were comparable to them of other HfO2-based ferroelectric capacitors. Lastly but not least, it turned out that the amount of oxygen and oxygen vacancies in the HAO thin film was dependent of doping concentrations for the film. The impact of oxygen and oxygen vacancies was quantitatively analyzed, in detail, with TEM, XPS and GIXRD analysis.

Deep learning reconstruction allows for usage of contrast agent of lower concentration for coronary CTA than filtered back projection and hybrid iterative reconstruction.

BACKGROUND: The demand for homogeneous and higher vascular contrast enhancement is critical to provide an appropriate interpretation of abnormal vascular findings in coronary computed tomography angiography (CTA). PURPOSE: To evaluate the effect of various contrast media concentrations (Iohexol-370, Iohexol-300, Iohexol-240) and image reconstructions (filtered back projection [FBP], hybrid iterative reconstruction [IR], and deep learning reconstruction [DLR]) on coronary CTA. MATERIAL AND METHODS: A total of 63 patients referred for coronary CTA between July and October 2021 were enrolled in this prospective study, and they randomly received one of three contrast media. CTA images were reconstructed with FBP, hybrid IR, and DLR. The CT attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated for all three images. The images were subjectively evaluated by two radiologists in terms of overall image quality, artifacts, image noise, and vessel wall delineation on a 5-point Likert scale. RESULTS: The application of DLR resulted in significantly lower image noise; higher CT attenuation, SNR, and CNR; and better subjective analysis among the three different concentrations of contrast media groups (P < 0.001). There was no significant difference in the CT attenuation of the left ventricle (P = 0.089) and coronary arteries (P = 0.072) between hybrid IR at Iohexol-300 and DLR at Iohexol-240. Furthermore, application of DLR to the Iohexol-240 significantly improved SNR and CNR; it achieved higher subjective scores compared with hybrid IR at Iohexol-300 (P < 0.001). CONCLUSION: We suggest that using DLR with Iohexol-240 contrast media is preferable to hybrid IR with Iohexol-300 contrast media in coronary CTA.

USP13 regulates HMGB1 stability and secretion through its deubiquitinase activity.

BACKGROUND: High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that plays a central role in innate immunity. HMGB1 acts as a late mediator of inflammation when actively secreted in response to inflammatory stimuli. Several post-translational modifications (PTMs), including acetylation, phosphorylation, and oxidation, are involved in HMGB1 secretion. However, the E3 ligases of HMGB1 and the mechanism by which DUBs regulate HMGB1 deubiquitination are not well known. METHODS: LC-MS/MS, proximity ligation assay, immunoprecipitation were used to identify ubiquitin-specific protease 13 (USP13) as a binding partner of HMGB1 and to investigate ubiquitination of HMGB1. USP13 domain mutant was constructed for domain study and Spautin-1 was treated for inhibition of USP13. Confocal microscopy image showed localization of HMGB1 by USP13 overexpression. The data were analyzed using one-way analysis of variance with Tukey's honestly significant difference post-hoc test for multiple comparisons or a two-tailed Student's t-test. RESULTS: We identified ubiquitin-specific protease 13 (USP13) as a novel binding partner of HMGB1 and demonstrated that USP13 plays a role in stabilizing HMGB1 from ubiquitin-mediated degradation. USP13 overexpression increased nucleocytoplasmic translocation of HMGB1 and promoted its secretion, which was inhibited by treatment with Spautin-1, a selective inhibitor of USP13. CONCLUSION: Taken together, we suggest that USP13 is a novel deubiquitinase of HMGB1 that regulates the stability and secretion of HMGB1.

Impact of Chamber/Annealing Temperature on the Endurance Characteristic of Zr:HfO2 Ferroelectric Capacitor.

The endurance characteristic of Zr-doped HfO2 (HZO)-based metal-ferroelectric-metal (MFM) capacitors fabricated under various deposition/annealing temperatures in the atomic layer deposition (ALD) process was investigated. The chamber temperature in the ALD process was set to 120 °C, 200 °C, or 250 °C, and the annealing temperature was set to 400 °C, 500 °C, 600 °C, or 700 °C. For the given annealing temperature of 700 °C, the remnant polarization (2Pr) was 17.21 µC/cm2, 26.37 µC/cm2, and 31.8 µC/cm2 at the chamber temperatures of 120 °C, 200 °C, and 250 °C, respectively. For the given/identical annealing temperature, the largest remnant polarization (Pr) was achieved when using the chamber temperature of 250 °C. At a higher annealing temperature, the grain size in the HZO layer becomes smaller, and thereby, it enables to boost up Pr. It was observed that the endurance characteristics for the capacitors fabricated under various annealing/chamber temperatures were quite different. The different endurance characteristics are due to the oxygen and oxygen vacancies in ferroelectric films, which affects the wakeup/fatigue behaviors. However, in common, all the capacitors showed no breakdown for an externally applied pulse (up to 108 cycles of the pulse).

DNMTs Are Involved in TGF-ß1-Induced Epithelial-Mesenchymal Transitions in Airway Epithelial Cells.

Chronic rhinosinusitis (CRS) pathogenesis is closely related to tissue remodeling, including epithelial-mesenchymal transition (EMT). Epigenetic mechanisms play key roles in EMT. DNA methylation, mediated by DNA methyltransferases (DNMTs), is an epigenetic marker that is critical to EMT. The goal of this study was to determine whether DNMTs were involved in TGF-ß1-induced EMT and elucidate the underlying mechanisms in nasal epithelial cells and air-liquid interface cultures. Global DNA methylation and DNMT activity were quantified. DNMT expression was measured using real-time PCR (qRT-PCR) in human CRS tissues. mRNA and protein levels of DNMTs, E-cadherin, vimentin, α-SMA, and fibronectin were determined using RT-PCR and Western blotting, respectively. DNMT1, DNMT3A, and DNMT3B gene expression were knocked down using siRNA transfection. MAPK phosphorylation and EMT-related transcription factor levels were determined using Western blotting. Signaling pathways were analyzed using specific inhibitors of MAPK. We demonstrated these data in primary nasal epithelial cells and air-liquid interface cultures. Global DNA methylation, DNMT activity, and DNMT expression increased in CRS tissues. DNMT expression was positively correlated with Lund-McKay CT scores. TGF-ß1 dose-dependently induced DNMT expression. Further, 5-Aza inhibited TGF-ß1-induced DNMT, Snail, and Slug expression related to EMT, as well as p38 and JNK phosphorylation in A549 cells and TGF-ß1-induced DNMT expression and EMT in primary nasal epithelial cells and air-liquid interface cultures. TGF-ß1-induced DNMT expression leads to DNA methylation and EMT via p38, JNK, Snail, and Slug signaling pathways. Inhibition of DNMT suppressed the EMT process and therefore is potentially a CRS therapeutic strategy.

Risk Model Establishment of Endoscopic Sinus Surgery for Patients with Chronic Rhinosinusitis: a Multicenter Study in Korea.

BACKGROUND: Endoscopic sinus surgery (ESS) is the mainstay treatment for refractory chronic rhinosinusitis (CRS). Since various factors may contribute to the surgical outcome, it is challenging for physicians to predict surgical outcomes. The aim of study was to analyze the prognostic factors of postoperative outcomes and to establish the prediction model with the risk factors that impact the postoperative outcomes. METHODS: Medical records of CRS patients who underwent ESS at 9 institutions in 2005, 2010, and 2016 were retrospectively reviewed. We classified the patients into 2 groups based on postoperative objective endoscopic outcomes. Demographics, nose-specific symptoms, olfactory function, eosinophil counts in blood (EoB) and nasal tissue (EoT), and Lund-Mackay CT score (LMS) were collected. Univariate and multivariate analyses were performed and established a prediction equation for postoperative endoscopic objective outcomes. RESULTS: In total (n = 1,249), 27.0% were not satisfied under postoperative endoscopic examination. Of 10 variables, LMS (> 5), sinus dominancy (maxillary sinus and ethmoid sinus), EoB (> 210), and EoT (> 100) were statistically significant in univariate analysis (P < 0.05, all). In multivariate analysis, EoT (> 100) and LMS (> 5) were significantly associated with poor postoperative outcome. Furthermore, 5 significant variables were employed to establish the risk model of postoperative outcomes and P (the value of prediction probability) = 1 / (1 + exp [-0.392 + 1.088 × EoT (> 100) + 0.123 × mean LMS (> 5) - 0.366 × sinus dominancy (maxillary) + 0.064 × sinus dominancy (similar) + 0.200 × EoB (4%) + 0.344 × EoB (> 210)] was developed. CONCLUSION: Tissue eosinophil count and radiographic severity predispose to a poorer outcome of ESS and the risk model established may be helpful to predict postoperative outcomes of ESS.

miR-29b Regulates TGF-ß1-Induced Epithelial-Mesenchymal Transition by Inhibiting Heat Shock Protein 47 Expression in Airway Epithelial Cells.

Tissue remodeling contributes to ongoing inflammation and refractoriness of chronic rhinosinusitis (CRS). During this process, epithelial-mesenchymal transition (EMT) plays an important role in dysregulated remodeling and both microRNA (miR)-29b and heat shock protein 47 (HSP47) may be engaged in the pathophysiology of CRS. This study aimed to determine the role of miR-29b and HSP47 in modulating transforming growth factor (TGF)-ß1-induced EMT and migration in airway epithelial cells. Expression levels of miR-29b, HSP47, E-cadherin, α-smooth muscle actin (α-SMA), vimentin and fibronectin were assessed through real-time PCR, Western blotting, and immunofluorescence staining. Small interfering RNA (siRNA) targeted against miR-29b and HSP47 were transfected to regulate the expression of EMT-related markers. Cell migration was evaluated with wound scratch and transwell migration assay. miR-29b mimic significantly inhibited the expression of HSP47 and TGF-ß1-induced EMT-related markers in A549 cells. However, the miR-29b inhibitor more greatly induced the expression of them. HSP47 knockout suppressed TGF-ß1-induced EMT marker levels. Functional studies indicated that TGF-ß1-induced EMT was regulated by miR-29b and HSP47 in A549 cells. These findings were further verified in primary nasal epithelial cells. miR-29b modulated TGF-ß1-induced EMT-related markers and migration via HSP47 expression modulation in A549 and primary nasal epithelial cells. These results suggested the importance of miR-29b and HSP47 in pathologic tissue remodeling progression in CRS.

Denoising of diffusion MRI improves peripheral nerve conspicuity and reproducibility.

BACKGROUND: Quantitative diffusion MRI is a promising technique for evaluating peripheral nerve integrity but low signal-to-noise ratio (SNR) can impede measurement accuracy. PURPOSE: To evaluate principal component analysis (PCA) and generalized spherical deconvolution (genSD) denoising techniques to improve within-subject reproducibility and peripheral nerve conspicuity. STUDY TYPE: Prospective. SUBJECTS: Seven healthy volunteers and three peripheral neuropathy patients. FIELD STRENGTH/SEQUENCE: 3T/multiband single-shot echo planar diffusion sequence using multishell 55-direction scheme. ASSESSMENT: Images were processed using four methods: "original" (no denoising), "average" (10 repetitions), "PCA-only," and "PCA + genSD." Tibial and common peroneal nerve segmentations and masks were generated from volunteer diffusion data. Quantitative (SNR and contrast-to-noise ratio [CNR]) values were calculated. Three radiologists qualitatively evaluated nerve conspicuity for each method. The two denoising methods were also performed in three patients with peripheral neuropathies. STATISTICAL TESTS: For healthy volunteers, calculations included SNR and CNRFA (computed using FA values). Coefficient of variation (CV%) of CNRFA quantified within-subject reproducibility. Groups were compared with two-sample t-tests (significance P < 0.05; two-tailed, Bonferroni-corrected). Odds ratios (ORs) quantified the relative rates of each of three radiologists confidently identifying a nerve, per slice, for the four methods. RESULTS: "PCA + genSD" yielded the highest SNR (meanoverall = 14.83 ± 1.99) and tibial and common peroneal nerve CNRFA (meantibial = 3.45, meanperoneal = 2.34) compared to "original" (P SNR < 0.001; P CNR = 0.011) and "PCA-only" (P SNR < 0.001, P CNR < 0.001). "PCA + genSD" had higher within-subject reproducibility (low CV%) for tibial (6.04 ± 1.98) and common peroneal nerves (8.27 ± 2.75) compared to "original" and "PCA-only." The mean FA was higher for "original" than "average" (P < 0.001), but did not differ significantly between "average" and "PCA + genSD" (P = 0.14). "PCA + genSD" had higher tibial and common peroneal nerve conspicuity than "PCA-only" (ORtibial = 2.50, P < 0.001; ORperoneal = 1.86, P < 0.001) and "original" (ORtibial = 2.73, P < 0.001; ORperoneal = 2.43, P < 0.001). DATA CONCLUSION: PCA + genSD denoising method improved SNR, CNRFA , and within-subject reproducibility (CV%) without biasing FA and nerve conspicuity. This technique holds promise for facilitating more reliable, unbiased diffusion measurements of peripheral nerves. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1128-1137.

Clinicopathologic characteristics of paranasal sinus fungus ball: retrospective, multicenter study in Korea.

PURPOSE: Fungus ball (FB) is the most common type of fungal rhinosinusitis and the prevalence of FB has increased over the past 10 years. The aim of this study was to compare the clinical characteristics of Korean adult patients with FB and chronic rhinosinusitis (CRS) without FB. METHODS: We retrospectively analyzed data on 1362 patients (147 FB and 1215 CRS) who underwent endoscopic sinus surgery at nine Korean medical centers in 2005, 2010, and 2016. We evaluated the prevalence of FB and compared the clinical characteristics of FB and CRS. Medical records, computed tomography (CT) findings, atopic status, concomitant diseases, tissue, and blood eosinophil count were assessed. RESULTS: The prevalence of FB was significantly higher in 2016 (15.9%) than in the other years (7.8% in 2005 and 7.5% in 2010). The FB patients were more likely to be female, older, have unilateral disease and less likely to have allergy compared to the CRS patients. The most common main complaint related to CRS and FB was nasal obstruction. CT determined that unilateral disease and maxillary sinus dominancy were common in patients with FB. The incidence of concomitant diseases was much higher in FB, with lower tissue and blood eosinophilia. CONCLUSION: FB is commonly encountered in older women with the increased prevalence. FB had a different clinical presentation, radiological findings, and prognosis than CRS. Further studies are needed to understand the pathophysiologic mechanisms underlying the development of FB.

Position Tracking Techniques Using Multiple Receivers for Anti-Drone Systems.

The need for drone traffic control management has emerged as the demand for drones increased. Particularly, in order to control unauthorized drones, the systems to detect and track drones have to be developed. In this paper, we propose the drone position tracking system using multiple Bluetooth low energy (BLE) receivers. The proposed system first estimates the target's location, which consists of the distance and angle, while using the received signal strength indication (RSSI) signals at four BLE receivers and gradually tracks the target based on the estimated distance and angle. We propose two tracking algorithms, depending on the estimation method and also apply the memory process, improving the tracking performance by using stored previous movement information. We evaluate the proposed system's performance in terms of the average number of movements that are required to track and the tracking success rate.

Impact of Ferroelectric Capacitor's Electrode Area on the Performance of Negative Capacitance Field Effect Transistor.

To overcome the Boltzmann limit of Metal Oxide Semiconductor Field Effect Transistor (MOSFET), negative (differential) capacitance FET (NCFET) has been under development since 2008. NCFET enables to implement the internal amplification of gate voltage, resulting in a high on/off-current ratio, and good compatibility with current CMOS technology. The hysteresis window of NCFET, however, is the conspicuous obstacle for its commercialization (especially, for CMOS logic device application). It is well known that there are various factors, which affect the hysteresis window of NCFET, such as the thickness of ferroelectric capacitor, the kinds of ferroelectric material, etc. While the thickness of ferroelectric capacitor and the kinds of ferroelectric material have been widely studied, the impact of ferroelectric capacitor's electrode area on the performance of NCFET has never been investigated. In this work, the aforementioned impact is analyzed with preliminary experiment data.

Steep Slope Silicon-on-Insulator Field Effect Transistor with Negative Capacitance: Analysis on Hysteresis.

In recent 10 years, many studies have investigated/considered negative capacitance field effect transistor (NCFET) as future low-power device. In addition to the experimental demonstration of NC planar bulk MOSFET, the state-of-the-art 14 nm FinFET technology has adopted the benefits of using negative capacitance and therefore, the NC-FinFET is expected to be available in market. However, there is a lack of experimental study on NC Silicon-on-Insulator (SOI) FET, which should be another candidate for ultra-low-power device. To complement the lack of such studies, in this work, the experimental study on NCSOI device (e.g., the degree of hysteresis, steep switching characteristic, and so on) has been done with reliable 10 nm hafnium-based ferroelectric capacitor.

Quasi-periodic patterns of intrinsic brain activity in individuals and their relationship to global signal.

Quasiperiodic patterns (QPPs) as reported by Majeed et al., 2011 are prominent features of the brain's intrinsic activity that involve important large-scale networks (default mode, DMN; task positive, TPN) and are likely to be major contributors to widely used measures of functional connectivity. We examined the variability of these patterns in 470 individuals from the Human Connectome Project resting state functional MRI dataset. The QPPs from individuals can be coarsely categorized into two types: one where strong anti-correlation between the DMN and TPN is present, and another where most areas are strongly correlated. QPP type could be predicted by an individual's global signal, with lower global signal corresponding to QPPs with strong anti-correlation. After regression of global signal, all QPPs showed strong anti-correlation between DMN and TPN. QPP occurrence and type was similar between a subgroup of individuals with extremely low motion and the rest of the sample, which shows that motion is not a major contributor to the QPPs. After regression of estimates of slow respiratory and cardiac induced signal fluctuations, more QPPs showed strong anti-correlation between DMN and TPN, an indication that while physiological noise influences the QPP type, it is not the primary source of the QPP itself. QPPs were more similar for the same subjects scanned on different days than for different subjects. These results provide the first assessment of the variability in individual QPPs and their relationship to physiological parameters.

Glucocorticoids ameliorate periostin-induced tissue remodeling in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Periostin plays an important role in the development of chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP). Glucocorticoids (GCs) are anti-inflammatory drugs used to treat CRS, but the mechanism for inhibiting periostin-induced tissue remodeling is still unclear. We sought to investigate the expression of periostin, α-SMA, and extracellular matrix (ECM) components in sinonasal tissues and to evaluate the inhibitory mechanism of GCs in nasal fibroblasts and mucosa. METHODS: We measured the expression of periostin, α-SMA and ECM components in sinonasal tissues. Correlation of CRS severity and periostin was evaluated by the Lund-Mackey score. Fibroblasts and ex vivo culture of the inferior turbinate were used to investigate the effects of GCs on periostin-induced alterations using real-time PCR, western blot, and immunostaining. Wound healing, transwell invasion, and collagen gel contraction were performed to evaluate migration and collagen contraction. RESULTS: Periostin was highly expressed in eosinophilic CRSwNP and correlated with the Lund-Mackay score. In nasal fibroblasts, periostin increased tissue remodeling involved protein. GCs suppressed the alterations of periostin. In addition, periostin induced activation of Src/AKT/mTOR, which was inhibited by GCs. GCs also inhibited periostin-induced migration, invasion, and collagen gel contraction. CONCLUSION: We suggest that GCs are therapeutic agents for CRSwNP by inhibiting tissue remodeling through their inhibitory effect on Src/Akt/mTOR signaling pathway. This article is protected by copyright. All rights reserved.

Problematic alcohol use associates with sodium channel and clathrin linker 1 (SCLT1) in trauma-exposed populations.

Excessive alcohol use is extremely prevalent in the United States, particularly among trauma-exposed individuals. While several studies have examined genetic influences on alcohol use and related problems, this has not been studied in the context of trauma-exposed populations. We report results from a genome-wide association study of alcohol consumption and associated problems as measured by the alcohol use disorders identification test (AUDIT) in a trauma-exposed cohort. Results indicate a genome-wide significant association between total AUDIT score and rs1433375 [N = 1036, P = 2.61 × 10-8 (dominant model), P = 7.76 × 10-8 (additive model)], an intergenic single-nucleotide polymorphism located 323 kb upstream of the sodium channel and clathrin linker 1 (SCLT1) at 4q28. rs1433375 was also significant in a meta-analysis of two similar, but independent, cohorts (N = 1394, P = 0.0004), the Marine Resiliency Study and Systems Biology PTSD Biomarkers Consortium. Functional analysis indicated that rs1433375 was associated with SCLT1 gene expression and cortical-cerebellar functional connectivity measured via resting state functional magnetic resonance imaging. Together, findings suggest a role for sodium channel regulation and cerebellar functioning in alcohol use behavior. Identifying mechanisms underlying risk for problematic alcohol use in trauma-exposed populations is critical for future treatment and prevention efforts.

Chemical Chaperone of Endoplasmic Reticulum Stress Inhibits Epithelial-Mesenchymal Transition Induced by TGF-ß1 in Airway Epithelium via the c-Src Pathway.

Epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells to assume a mesenchymal cell phenotype. EMT is considered as a therapeutic target for several persistent inflammatory airway diseases related to tissue remodeling. Herein, we investigated the role of endoplasmic reticulum (ER) stress and c-Src in TGF-ß1-induced EMT. A549 cells, primary nasal epithelial cells (PNECs), and inferior nasal turbinate organ cultures were exposed to 4-phenylbutylic acid (4PBA) or PP2 and then stimulated with TGF-ß1. We found that E-cadherin, vimentin, fibronectin, and α-SMA expression was increased in nasal polyps compared to inferior turbinates. TGF-ß1 increased the expression of EMT markers such as E-cadherin, fibronectin, vimentin, and α-SMA and ER stress markers (XBP-1s and GRP78), an effect that was blocked by PBA or PP2 treatment. 4-PBA and PP2 also blocked the effect of TGF-ß1 on migration of A549 cells and suppressed TGF-ß1-induced expression of EMT markers in PNECs and organ cultures of inferior turbinate. In conclusion, we demonstrated that 4PBA inhibits TGF-ß1-induced EMT via the c-Src pathway in A549 cells, PNECs, and inferior turbinate organ cultures. These results suggest an important role for ER stress and a diverse role for TGF-ß1 in upper airway chronic inflammatory disease such as CRS.

Efficacy of hyaluronic acid and hydroxyethyl starch in preventing adhesion following endoscopic sinus surgery.

Adhesion is a major complication of endoscopic sinus surgery that may lead to recurrence of chronic rhinosinusitis, necessitating revision surgery. The purpose of this study was to evaluate the effect of hyaluronic acid and hydroxyethyl starch (HA-HES) relative to hyaluronic acid and carboxymethylcellulose (HA-CMC) with regard to anti-adhesion effect. In this multi-center, prospective, single-blind, randomized controlled study, 77 consecutive patients who underwent bilateral endoscopic sinus surgery were enrolled between March 2014 and March 2015. HA-HES and HA-CMC were applied to randomly assigned ethmoidectomized cavities after the removal of middle meatal packing. At the 1st, 2nd and 4th weeks after surgery, the presence and grades of adhesion, edema, and infection were, respectively, examined via endoscopy by a blinded assessor. The incidence and grades of adhesion at the 2-week follow-up were significantly less in the HA-CMC group than in the HA-HES group (p < 0.05). However, with the exception of week 2, there were no significant differences in the incidence or grades of adhesion, edema, and infection between the two groups. When the primary endpoint-the presence of adhesion at the 4-week follow-up-was compared between two groups, the incidence of adhesion in HA-HES group at the 4-week follow-up was 32% and in HA-CMC was 41.3%, indicating that HA-HES was not inferior to HA-CMC in terms of anti-adhesive effect. No severe adverse reactions were noted during the study period. In conclusion, HA-HES is a safe substitutional anti-adhesion agent that has equivalent effect as HA-CMC after endoscopic sinus surgery.