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Background and Objectives : This study investigated whether there is an association between elderly frailty and asthma. Material Methods : We examined 9745 elderly participants who did not have asthma and 275 elderly patients who had asthma diagnosed by a doctor from the 2020 Survey of Living Conditions and Welfare Needs of Korean Older Persons Survey. Study Selections: The Korean version of the fatigue, resistance, ambulation, illnesses, and loss of weight (K-FRAIL) scale was used to determine their level of frailty. The relationship between frailty and geriatric asthma was examined using multiple logistic regression analysis, which was adjusted for a number of confounding variables (socioeconomic, health behavior, psychological characteristics, and functional status). Results : Frailty as defined by the K-FRAIL scale was significantly higher in the asthma group (7.6%) than the non-asthma group (4.9%). The frailty phenotype component showed that resistance, ambulation, and illness severity were more severe in the asthma group than the non-asthma group. After adjusting, asthma was significantly associated with an increased risk of frailty (OR 1.45; 95% confidence interval [CI] 1.01-2.09) compared to the non-asthma group. Conclusions : Frailty might be associated with elderly asthma in patients from the Korean population. Frailty may not only be associated with asthma, but also with other diseases. So, more evidence is needed to establish this association.

Subxiphoid thymectomy is a novel alternative to the transthoracic approach and sternotomy, with potential benefits, such as reduced postoperative pain and faster recovery. We previously reported the initial experience with subxiphoid single-port robotic-assisted thoracic surgery (SRATS) thymectomy using the single-port robotic system (SPS). However, the efficacy of this technique remains unknown. Thus, this study examined the multi-institutional experience with SRATS thymectomy and compared the perioperative outcomes of this technique to those of subxiphoid single-port video-assisted thoracic surgery (SVATS) thymectomy. The data of patients who underwent subxiphoid SRATS and SVATS thymectomy, performed by three thoracic surgeons at three institutions between September 2018 and May 2024, were retrospectively collected. In total, 110 patients were included, with 85 and 25 undergoing SRATS and SVATS thymectomy, respectively. After propensity score matching, 25 patients were included in each group. The SRATS group was associated with a lower conversion rate to multi-port surgery (0% vs. 20%, p = 0.05), shorter chest tube drainage duration (1.32 ± 0.75 vs. 2.00 ± 1.29 days, p = 0.003), and a shorter postoperative hospital stay (2.52 ± 1.00 vs. 5.08 ± 5.20 days, p = 0.003). Subxiphoid SRATS thymectomy using the SPS is feasible and is a good alternative to conventional thymectomy. Further studies are necessary to confirm its benefits.

This study aimed to identify the clinical manifestation and implications according to the grading of tumor spread through air spaces in early-stage small (≤2 cm) pathological stage I non-mucinous lung adenocarcinomas. Medical records of patients with pathological stage I tumors sized ≤2 cm were retrospectively reviewed and analyzed. The furthest distance of the spread through air spaces from the tumor margin was measured on a standard-length scale (mm). Enrolled patients were categorized into spread through air spaces (STAS) (-) and STAS (+), and STAS (+) was subdivided according to its furthest distance as follows: STAS (+)-L (<2 mm) and STAS (+)-H (≥2 mm). Risk factors for STAS (+) included papillary predominant subtype ( p = 0.027), presence of micropapillary patterns ( p < 0.001), and EGFR ( p = 0.039). The overall survival of the three groups did not differ significantly ( p = 0.565). The recurrence-free survival of STAS (+)-H groups was significantly lower than those of STAS (-) and STAS (+)-L ( p < 0.001 and p = 0.039, respectively). A number of alveolar spaces were definite risk factors for STAS (+)-H groups ( p < 0.001), and male gender could be one ( p = 0.054). In the patient group with small (≤2 cm) pathological stage I lung adenocarcinomas, the presence of STAS ≥ 2 mm was related to significantly lower recurrence-free survival. For identifying definite risk factors for the presence of farther STAS, more precise analysis from a larger study population should be undertaken.

Polyetheretherketone (PEEK), an organic thermoplastic polymer, has gained interest in dentistry due to its excellent mechanical strength, flexibility, and biocompatibility. Furthermore, the ability to utilize CAD/CAM in the fabrication of PEEK enhances accuracy, reliability, and efficiency while also saving time. Hence, several orthodontic studies have explored the utilization of PEEK in various applications, such as archwires, brackets, fixed lingual retainers, palatal expansion devices, transpalatal arches, Tübingen palatal plates, different types of space maintainers, mini-implant insertion guides, and more. However, a complete systematic review of the available data comparing the performance of PEEK with traditional orthodontic materials has not yet been conducted. Therefore, this systematic review seeks to assess if PEEK material meets the required mechanical criteria to serve as an alternative to conventional orthodontic appliances. To ensure clarity and precision, this review will specifically concentrate on fixed appliances. This systemic review followed the PRISMA guidelines and utilized databases including PubMed/MEDLINE, Embase, Springer, Web of Science, and Wiley. Searches were restricted to English language articles from January 2013 to February 2024. Keywords such as "Polyetheretherketone" or "PEEK" and "Orthodontic" or "Orthodontic device" or "Orthodontic materials" were employed across all databases. Nine studies were incorporated, covering orthodontic archwires, brackets, and fixed lingual retainers. Based on the reviewed literature, PEEK demonstrates promising potential in orthodontic fixed appliances, offering advantages in force delivery, friction reduction, and aesthetic appeal. Further research is needed to fully explore its capabilities and optimize its application in clinical practice.

Heat shock protein 47 (HSP47), also known as SERPINH1 , functions as a collagen-specific molecular chaperone protein essential for the formation and stabilization of the collagen triple helix. Here, we delved into the regulatory pathways governed by HSP47, shedding light on collagen homeostasis. Our investigation revealed a significant reduction in HSP47 mRNA levels in the skin tissue of older mice as compared to their younger counterparts. The augmented expression of HSP47 employing lentivirus infection in fibroblasts resulted in an increased secretion of type I collagen. Intriguingly, the elevated expression of HSP47 in fibroblasts correlated with increased protein and mRNA levels of type I collagen. The exposure of fibroblasts to IRE1α RNase inhibitors resulted in the reduced manifestation of HSP47-induced type I collagen secretion and expression. Notably, HSP47-overexpressing fibroblasts exhibited increased XBP1 mRNA splicing. The overexpression of HSP47 or spliced XBP1 facilitated the nuclear translocation of β-catenin and transactivated a reporter harboring TCF binding sites on the promoter. Furthermore, the overexpression of HSP47 or spliced XBP1 or the augmentation of nuclear β-catenin through Wnt3a induced the expression of type I collagen. Our findings substantiate that HSP47 enhances type I collagen expression and secretion in fibroblasts by orchestrating a mechanism that involves an increase in nuclear β-catenin through IRE1α activation and XBP1 splicing. This study therefore presents potential avenues for an anti-skin-aging strategy targeting HSP47-mediated processes.

Skin-based wearable devices have gained significant attention due to advancements in soft materials and thin-film technologies. Nevertheless, traditional wearable electronics often entail expensive and intricate manufacturing processes and rely on metal-based substrates that are susceptible to corrosion and lack flexibility. In response to these challenges, this paper has emerged with an alternative substrate for wearable electrodes due to its cost-effectiveness and scalability in manufacturing. Paper-based electrodes offer an attractive solution with their inherent properties of high breathability, flexibility, biocompatibility, and tunability. In this study, we introduce carbon nanotube-based paper composites (CPC) electrodes designed for the continuous detection of biopotential signals, such as electrooculography (EOG), electrocardiogram (ECG), and electroencephalogram (EEG). To prevent direct skin contact with carbon nanotubes, we apply various packaging materials, including polydimethylsiloxane (PDMS), Eco-flex, polyimide (PI), and polyurethane (PU). We conduct a comparative analysis of their signal-to-noise ratios in comparison to conventional gel electrodes. Our system demonstrates real-time biopotential monitoring for continuous health tracking, utilizing CPC in conjunction with a portable data acquisition system. The collected data are analyzed to provide accurate heart rates, respiratory rates, and heart rate variability metrics. Additionally, we explore the feasibility using CPC for sleep monitoring by collecting EEG signals.

Recently, proton beam therapy (PBT) has gathered attention for improving outcomes and reducing toxicities in various cancers; however, the evidence for esophageal squamous cell carcinoma (ESCC) is lacking. Our study retrospectively evaluated the outcomes of PBT for ESCC patients at a single institute. The patients treated with PBT between November 2015 and February 2022 were included in the study, excluding those with distant metastases or those that had undertaken prior treatment for esophageal cancer (EC). The 3 year overall survival (OS) and progression-free survival (PFS) rates were calculated based on stage grouping. The patterns of failure, salvage treatment outcomes, and toxicity profiles were analyzed. The median follow-up was 35.1 months, and 132 patients were analyzed. The 3 year OS and PFS rates for the stages I, II, and III disease cases were 81.0%, 62.9%, and 51.3%; and 70.6%, 71.8%, and 39.8%, respectively. Nineteen patients presented isolated local progression, ten patients underwent appropriate salvage procedures, and nine were successfully salvaged. One patient with isolated regional progression was also salvaged. No cases of grade ≥ 4 lymphopenia were observed. One patient had grade 4 pericardial effusion and esophageal fistula. For the patients with ESCC, PBT is an effective treatment in terms of the survival outcomes and toxicities.

Three-dimensional bioprinting represents an innovative platform for fabricating intricate, three-dimensional (3D) tissue structures that closely resemble natural tissues. The development of hybrid bioinks is an actionable strategy for integrating desirable characteristics of components. In this study, cellulose recovered from plum seed was processed to synthesize carboxymethyl cellulose (CMC) for 3D bioprinting. The plum seeds were initially subjected to α-cellulose recovery, followed by the synthesis and characterization of plum seed-derived carboxymethyl cellulose (PCMC). Then, hybrid bioinks composed of PCMC and sodium alginate were fabricated, and their suitability for extrusion-based bioprinting was explored. The PCMC bioinks exhibit a remarkable shear-thinning property, enabling effortless extrusion through the nozzle and maintaining excellent initial shape fidelity. This bioink was then used to print muscle-mimetic 3D structures containing C2C12 cells. Subsequently, the cytotoxicity of PCMC was evaluated at different concentrations to determine the maximum acceptable concentration. As a result, cytotoxicity was not observed in hydrogels containing a suitable concentration of PCMC. Cell viability was also evaluated after printing PCMC-containing bioinks, and it was observed that the bioprinting process caused minimal damage to the cells. This suggests that PCMC/alginate hybrid bioink can be used as a very attractive material for bioprinting applications.

Three-dimensional (3D) printed calcium phosphate cement (CPC) scaffolds are increasingly being used for bone tissue repair. Traditional materials used for CPC scaffolds, such as bovine and porcine bone, generally contain low amounts of calcium phosphate compounds, resulting in reduced production rates of CPC scaffolds. On the other hand, cockle shells contain more than 99% CaCO 3 in the form of amorphous aragonite with excellent biocompatibility, which is expected to increase the CPC production rate. In this study, 3D-printed cockle shell powder-based CPC (CSP-CPC) scaffolds were developed by the material extrusion method. Lactic acid and hyaluronic acid were used to promote the printability. The characterization of CSP-CPC scaffolds was performed using Fourier transform infrared spectra, X-ray diffraction patterns, and scanning electron microscopy. The biocompatibility of CSP-CPC scaffolds was evaluated using cell viability, Live/Dead, and alkaline phosphatase assays. In addition, CSP-CPC scaffolds were implanted into the mouse calvarial defect model to confirm bone regeneration. This study provides an opportunity to create high value added in fishing villages by recycling natural products from marine waste.

Three-dimensional (3D) bioprinting holds great promise for tissue engineering, allowing cells to thrive in a 3D environment. However, the applicability of natural polymers such as silk fibroin (SF) in 3D bioprinting faces hurdles due to limited mechanical strength and printability. SF, derived from the silkworm Bombyx mori, is emerging as a potential bioink due to its inherent physical gelling properties. However, research on inducing thermosensitive behavior in SF-based bioinks and tailoring their mechanical properties to specific tissue requirements is notably lacking. This study addresses these gaps through the development of silk fibroin-based thermosensitive bioinks (SF-TPBs). Precise modulation of gelation time and mechanical robustness is achieved by manipulating glycerol content without recourse to cross-linkers. Chemical analysis confirms β-sheet conformation in SF-TPBs independent of glycerol concentration. Increased glycerol content improves gelation kinetics and results in rheological properties suitable for 3D printing. Overall, SF-TPBs offer promising prospects for realizing the potential of 3D bioprinting using natural polymers.

Ionic wind, which is generated by a corona discharge, is a promising field that offers significant advantages by directly converting electrical energy into kinetic energy. Because of the electrical characteristics of ionic wind, most studies aiming to improve the performance of ionic wind generators have focused on modifying the geometry of electrode configurations. A mesh-type electrode is one of the electrodes used as a collecting electrode in an ionic wind generator. Using a mesh electrode results in decreased momentum of the ionic wind and increased pressure drop due to frictional loss of the flow. In this study, to minimize the reduction in momentum, a mesh electrode with a central hole was proposed and investigated. Experiments were conducted with the configuration of a needle and mesh with the central hole. These experiments analyzed the effect of the central hole diameter and the distance between the needle and the mesh electrodes on the electrical and physical characteristics of the ionic wind. The addition of the central hole led to a higher average velocity and lower current, thus resulting in increased energy conversion efficiency. The presented configuration offers a simple geometry without electrical and physical interference from complex configurations, and it is considered to have the potential to improve energy conversion efficiency and optimize ionic wind flow.

Leucine-rich alpha-2-glycoprotein 1 (LRG1) mediates skin repair and fibrosis by stimulating the transforming growth factor-beta (TGF-β) signaling pathway. In the present study, we investigated the effect of LRG1 on extracellular matrix (ECM) integrity in fibroblasts, as well as on skin aging. The treatment of dermal fibroblasts with purified recombinant human LRG1 increased type I collagen secretion and decreased matrix metalloproteinase-1 secretion. Additionally, LRG1 promoted SMAD2/SMAD3 phosphorylation in a pattern similar to that of TGF-β1 treatment. An inhibitor of TGF-β receptor 1 abolished LRG1-induced SMAD2 phosphorylation. RNA sequencing identified "extracellular region", "extracellular space", and "extracellular matrix" as the main Gene Ontology terms in the differentially expressed genes of fibroblasts treated with or without LRG1. LRG1 increased TGF-β1 mRNA levels, suggesting that LRG1 partially transactivates the expression of TGF-β1. Furthermore, an increased expression of type I collagen was also observed in fibroblasts grown in three-dimensional cultures on a collagen gel mimicking the dermis. LRG1 mRNA and protein levels were significantly reduced in elderly human skin tissues with weakened ECM integrity compared to in young human skin tissues. Taken together, our results suggest that LRG1 could retard skin aging by activating the TGF-β signaling pathway, increasing ECM deposition while decreasing its degradation.

The matricellular secreted protein acidic and rich in cysteine (SPARC; also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis, cell-ECM interactions, and bone mineralization. We found decreased SPARC expression in aged skin. Incubating foreskin fibroblasts with recombinant human SPARC led to increased type I collagen production and decreased matrix metalloproteinase-1 (MMP-1) secretion at the protein and mRNA levels. In a three-dimensional culture of foreskin fibroblasts mimicking the dermis, SPARC significantly increased the synthesis of type I collagen and decreased its degradation. In addition, SPARC also induced receptor-regulated SMAD (R-SMAD) phosphorylation. An inhibitor of transforming growth factor-beta (TGF-β) receptor type 1 reversed the SPARC-induced increase in type I collagen and decrease in MMP-1, and decreased SPARC-induced R-SMAD phosphorylation. Transcriptome analysis revealed that SPARC modulated expression of genes involved in ECM synthesis and regulation in fibroblasts. RT-qPCR confirmed that a subset of differentially expressed genes is induced by SPARC. These results indicated that SPARC enhanced ECM integrity by activating the TGF-β signaling pathway in fibroblasts. We inferred that the decline in SPARC expression in aged skin contributes to process of skin aging by negatively affecting ECM integrity in fibroblasts.

Vacuolar ATPases (V-ATPases) are multi-subunit ATP-dependent proton pumps necessary for cellular functions, including pH regulation and membrane fusion. The evidence suggests that the V-ATPase a-subunit's interaction with the membrane signaling lipid phosphatidylinositol (PIPs) regulates the recruitment of V-ATPase complexes to specific membranes. We generated a homology model of the N-terminal domain of the human a4 isoform (a4NT) using Phyre2.0 and propose a lipid binding domain within the distal lobe of the a4NT. We identified a basic motif, K 234 IKK 237 , critical for interaction with phosphoinositides (PIP), and found similar basic residue motifs in all four mammalian and both yeast a-isoforms. We tested PIP binding of wildtype and mutant a4 NT in vitro. In protein lipid overlay assays, the double mutation K234A/K237A and the autosomal recessive distal renal tubular-causing mutation K237del reduced both PIP binding and association with liposomes enriched with PI(4,5)P 2 , a PIP enriched within plasma membranes. Circular dichroism spectra of the mutant protein were comparable to wildtype, indicating that mutations affected lipid binding, not protein structure. When expressed in HEK293, wildtype a4NT localized to the plasma membrane in fluorescence microscopy and co-purified with the microsomal membrane fraction in cellular fractionation experiments. a4NT mutants showed reduced membrane association and decreased plasma membrane localization. Depletion of PI(4,5)P 2 by ionomycin caused reduced membrane association of the WT a4NT protein. Our data suggest that information contained within the soluble a4NT is sufficient for membrane association and that PI(4,5)P 2 binding capacity is involved in a4 V-ATPase plasma membrane retention.

The purpose of this study was to determine the prognostic impact of fat loss after immune checkpoint inhibitor (ICI) treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). Data from 60 patients treated with ICI therapy for metastatic ccRCC were retrospectively analyzed. Changes in cross-sectional areas of subcutaneous fat (SF) between the pre-treatment and post-treatment abdominal computed tomography (CT) images were expressed as percentages and were divided by the interval between the CT scans to calculate ΔSF (%/month). SF loss was defined as ΔSF < -5%/month. Survival analyses for overall survival (OS) and progression-free survival (PFS) were performed. Patients with SF loss had shorter OS (median, 9.5 months vs. not reached; p < 0.001) and PFS (median, 2.6 months vs. 33.5 months; p < 0.001) than patients without SF loss. ΔSF was independently associated with OS (adjusted hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.07-2.07; p = 0.020) and PFS (adjusted HR, 1.57; 95% CI, 1.17-2.12; p = 0.003), with a 5%/month decrease in SF increasing the risk of death and progression by 49% and 57%, respectively. In conclusion, Loss of SF after treatment initiation is a significant and independent poor prognostic factor for OS and PFS in patients with metastatic ccRCC who receive ICI therapy.

Computational modeling can provide a mechanistic and quantitative framework for describing intracellular spatial heterogeneity of solutes such as oxygen partial pressure (pO 2 ). This study develops and evaluates a finite-element model of oxygen-consuming mitochondrial bioenergetics using the COMSOL Multiphysics program. The model derives steady-state oxygen (O 2 ) distributions from Fickian diffusion and Michaelis-Menten consumption kinetics in the mitochondria and cytoplasm. Intrinsic model parameters such as diffusivity and maximum consumption rate were estimated from previously published values for isolated and intact mitochondria. The model was compared with experimental data collected for the intracellular and mitochondrial pO 2 levels in human cervical cancer cells (HeLa) in different respiratory states and under different levels of imposed pO 2 . Experimental pO 2 gradients were measured using lifetime imaging of a Förster resonance energy transfer (FRET)-based O 2 sensor, Myoglobin-mCherry, which offers in situ real-time and noninvasive measurements of subcellular pO 2 in living cells. On the basis of these results, the model qualitatively predicted (1) the integrated experimental data from mitochondria under diverse experimental conditions, and (2) the impact of changes in one or more mitochondrial processes on overall bioenergetics.

Conventional irreversible electroporation (IRE) with low-frequency pulsed electric field (LF-PEF) is used to induce cell death; however, it has several disadvantages including a long procedure time and severe muscle contraction due to high-voltage electric field. This study investigates a novel IRE protocol with high-frequency pulsed electric field (HF-PEF) of 500 Hz repetition to ablate the prostate tissue in beagles for treatment of prostate cancer. A finite element analysis was performed to validate optimal electrical field strength for the procedure. In total, 12 beagles received HF-PEF of 500 Hz and were sacrificed at 4 h, 4 days, and 28 days (3 each). The remaining three beagles underwent sham procedure. The outcomes of HF-PEF were assessed by histological responses. HF-PEF successfully decellularized the prostate tissues 4 h after the treatment. The prostate glands, duct, and urethra were well preserved after IRE with HF-PEF. The ablated prostatic tissues were gradually regenerated and appeared similar to the original tissues 28 d after IRE with HF-PEF. Moreover, electrocardiography and hematology demonstrated that IRE with HF-PEF did not seriously affect the cardiac tissue. HF-PEF was effective and safe in the beagle prostate and effectively induced the ablation and gradually recovered with cellular regeneration.

The risk of prostate cancer (PCa) in prostate imaging reporting and data system version 2 (PI-RADSv2) score-3 lesions is equivocal; it is regarded as an intermediate status of presented PCa. In this study, we evaluated the clinical utility of the prostate health index (PHI) for the diagnosis of PCa and clinically significant PCa (csPCa) in patients with PI-RADSv2 score-3 lesions. The study cohort included patients who underwent a transrectal ultrasound (TRUS)-guided, cognitive-targeted biopsy for PI-RADSv2 score-3 lesions between November 2018 and April 2021. Before prostate biopsy, the prostate-specific antigen (PSA) derivatives, such as total PSA (tPSA), [-2] proPSA (p2PSA) and free PSA (fPSA) were determined. The calculation equation of PHI is as follows: [(p2PSA/fPSA) × tPSA ½]. Using a receiver operating characteristic (ROC) curve analysis, the values of PSA derivatives measured by the area under the ROC curve (AUC) were compared. For this study, csPCa was defined as Gleason grade 2 or higher. Of the 392 patients with PI-RADSv2 score-3 lesions, PCa was confirmed in 121 (30.9%) patients, including 59 (15.1%) confirmed to have csPCa. Of all the PSA derivatives, PHI and PSA density (PSAD) showed better performance in predicting overall PCa and csPCa, compared with PSA (all p < 0.05). The AUC of the PHI for predicting overall PCa and csPCa were 0.807 (95% confidence interval (CI): 0.710−0.906, p = 0.001) and 0.819 (95% CI: 0.723−0.922, p < 0.001), respectively. By the threshold of 30, PHI was 91.7% sensitive and 46.1% specific for overall PCa, and was 100% sensitive for csPCa. Using 30 as a threshold for PHI, 34.4% of unnecessary biopsies could have been avoided, at the cost of 8.3% of overall PCa, but would include all csPCa.

To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were expressed in the eyelid, conjunctiva and skin in wild-type (WT) mice, whereas their mRNA and protein levels were downregulated in Fut1 knock-out (KO) mice. We then evaluated age-dependent changes in the total and acinar areas of MG, meibocyte differentiation, lipid synthesis, and eyelid inflammation and oxidative stress in Fut1 KO and WT mice. Results show that both the total and acinar areas of MG were smaller in Fut1 KO mice than in WT mice in all evaluated age groups. Meibocyte differentiation, lipid-producing capacities and the enzyme levels responsible for lipid synthesis were reduced in Fut1 KO mice, compared to WT controls. The levels of pro-inflammatory cytokines and oxidative-stress-related markers were elevated in the eyelids and MG of FUT1 KO mice. These findings demonstrate the physiologic function of FUT1-mediated fucosylation in MG development and function, and indicate its potential role in ocular surface homeostasis.

Purpose: To compare the perioperative outcomes and oncological results of open, laparoscopic, and robotic radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC) and to analyze trends in the utilization of RNU. Methods: From 2017 to 2020, the records of 61, 185, and 119 patients who underwent open, laparoscopic, and robotic RNU, respectively, were reviewed. Results: Baseline characteristics were not significantly different among the three groups. Robotic RNU has recently started to increase from 9% in 2017 to 67% in 2021. Operation time, blood loss, length of hospital stay, and 90-day complications were not different between the three groups. The three-year overall survival (OS) rates for open, laparoscopic, and robotic RNU were 91.8%, 90.4%, and 92.1%, respectively (p > 0.05). No differences in the progression-free survival (PFS), cancer-specific survival (CSS), and OS were observed according to the surgical approach in the Kaplan−Meier survival analysis. Multivariate analysis showed that surgical approach was not an independent predictor of PFS, CSS, and OS. Conclusion: The use of robotic RNU in patients with UTUC has been starting to increase and replace open and laparoscopic RNU. Perioperative outcomes, 90-day complications, and oncological outcomes of robotic RNU were not inferior to those of open and laparoscopic RNU.

Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1 , a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing ( n = 60) and whole transcriptomic sequencing (WTS) ( n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.

Parkinson's disease (PD) is a progressive neurodegenerative motor disorder without an available therapeutic to halt the formation of Lewy bodies for preventing dopaminergic neuronal loss in the nigrostriatal pathway. Since oxidative-stress-mediated damage has been commonly reported as one of the main pathological mechanisms in PD, we assessed the efficacy of a novel NOX inhibitor from AptaBio Therapeutics (C-6) in dopaminergic cells and PD mouse models. The compound reduced the cytotoxicity and enhanced the cell viability at various concentrations against MPP+ and α-synuclein preformed fibrils (PFFs). Further, the levels of ROS and protein aggregation were significantly reduced at the optimal concentration (1 µM). Using two different mouse models, we gavaged C-6 at two different doses to the PD sign-displaying transgenic mice for 2 weeks and stereotaxically PFF-injected mice for 5 weeks. Our results demonstrated that both C-6-treated mouse models showed alleviated motor deficits in pole test, hindlimb clasping, crossbeam, rotarod, grooming, and nesting analyses. We also confirmed that the compound treatment reduced the levels of protein aggregation, along with phosphorylated-α-synuclein, in the striatum and ventral midbrain and further dopaminergic neuronal loss. Taken together, our results strongly suggest that NOX inhibition can be a potential therapeutic target for PD.

The clinical value of sarcopenia has not been determined yet in metastatic hormone-sensitive prostate cancer (mHSPC). We retrospectively evaluated data of 70 consecutive patients with mHSPC receiving treatment with either early docetaxel ( n = 42) or abiraterone acetate ( n = 28) between July 2018 and April 2021. Skeletal muscle index was calculated from cross-sectional areas of skeletal muscle on baseline computed tomography (CT), defining sarcopenia as a skeletal muscle index of ≤52.4 cm 2 /m 2 . Failure-free survival (FFS), radiographic progression-free survival, and time to prostate-specific antigen (PSA) progression were estimated using the Kaplan-Meier method, and differences in survival probability were compared using the log-rank test. Cox proportional hazards regression analysis was conducted to identify the predictors of clinical outcomes. Patients with sarcopenia ( n = 47) had shorter FFS than those without sarcopenia ( n = 23) (median, 20.1 months vs. not reached; log-rank p < 0.001). Sarcopenia was independently associated with shorter FFS (hazard ratio (HR), 6.69; 95% confidence interval (CI), 1.57-28.49; p = 0.010) and time to PSA progression (HR, 12.91; 95% CI, 1.08-153.85; p = 0.043). In conclusion, sarcopenia is an independent prognostic factor for poor FFS and time to PSA progression in patients with mHSPC who receive early docetaxel or abiraterone acetate treatment.

Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes ( ACSL5 and SERINC2 ) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.

The lymph node ratio (LNR) has been investigated as a prognostic factor in many different types of cancers, including differentiated thyroid cancer; however, reports regarding medullary thyroid cancer (MTC) are limited. Therefore, this study aims to evaluate LNR as a risk factor for structural recurrence in patients with MTC. Medical records of patients treated for MTC in a single tertiary center between 1995 and 2017 were retrospectively reviewed. LNR is defined as the number of metastatic lymph nodes or lymph node metastases (LNM) divided by the number of retrieved lymph nodes or lymph node yield (LNY). In the survival analysis, recurrence-free survival was defined as the time from the date of total thyroidectomy to recurrence or last follow-up. To identify risk factors influencing structural recurrence, univariable and multivariable Cox proportional hazard models were used. A total of 132 patients were enrolled. The mean age of study participants was 49.7 years, and 86 patients (65%) were women. Structural recurrence was identified in 39 patients at the end of the study period, and the median follow-up period was 8.7 years. In univariable analyses, gross extra thyroidal extension, N stage, postoperative serum calcitonin and carcinoembryonic antigen (CEA) levels, and LNR were significant ( p < 0.05) predictors of structural recurrence. In multivariable analysis, postoperative serum calcitonin, postoperative serum CEA, and LNR were identified as a predictor of disease-free survival ( p < 0.05). LNR can potentially predict structural recurrence as a quantitative evaluation tool for lymph node metastasis in patients with MTC.

The biological behavior of sebaceous carcinoma (SeC) is relatively indolent; however, local invasion or distant metastasis is sometimes reported. Nevertheless, a lack of understanding of the genetic background of SeC makes it difficult to apply effective systemic therapy. This study was designed to investigate major genetic alterations in SeCs in Korean patients. A total of 29 samples, including 20 ocular SeCs (SeC-Os) and 9 extraocular SeCs (SeC-EOs), were examined. Targeted next-generation sequencing tests including 171 cancer-related genes were performed. TP53 and PIK3CA genes were frequently mutated in both SeC-Os and SeC-EOs with slight predominance in SeC-Os, whereas the NOTCH1 gene was more commonly mutated in SeC-EOs. In clinical correlation, mutations in RUNX1 and ATM were associated with development of distant metastases, and alterations in MSH6 and BRCA1 were associated with inferior progression-free survival (all p < 0.05). In conclusion, our study revealed distinct genetic alterations between SeC-Os and SeC-EOs and some important prognostic molecular markers. Mutations in potentially actionable genes, including EGFR , ERBB2 , and mismatch repair genes, were noted, suggesting consideration of a clinical trial in intractable cases.

Distant metastasis is a poor prognostic factor in medullary thyroid carcinoma (MTC), but the significance of differentiating the characteristics according to the site of distant metastasis remains unclear. This study aimed to evaluate the clinical characteristics and long-term oncologic outcomes in MTC patients with distant metastasis. We identified 46 MTC patients with distant metastasis between 1994 and 2019. Clinical characteristics were compared based on the timing of the detection of distant metastasis. Additionally, survival rates following the detection of distant metastasis were evaluated to compare the clinical significance of metastatic site. The detailed causes of death were also investigated. Of the 46 patients, 15 patients (32.6%) had synchronous distant metastasis and 31 patients (67.4%) had metachronous distant metastasis. There was no clinical difference between these two groups except regarding initial surgical extent. The lung (52.2%) was the most common metastatic site, followed by the bone (28.3%), mediastinum (19.6%), liver (17.4%), adrenal gland (4.3%), brain (4.3%), kidney (2.2%), and pancreas (2.2%). Patients with bone metastasis and multisite metastasis had significantly worse prognoses than those with lung metastasis (hazard ratio: 5.42; p = 0.044 and hazard ratio: 6.11; p = 0.006). Complications due to the progression of distant metastasis, airway obstruction due to tracheal invasion, and complications related to chemotherapy were leading causes of death. In conclusion, there was no difference in clinical characteristics according to the timing of distant metastasis. Oncological outcomes differed by metastatic site.

The purpose of this study was to evaluate the structural performance of composite deck slabs containing macro-synthetic fibers. after a fire by proposing a deflection estimation method for non-fireproof structural decks. Therefore, this study evaluated the fire resistance performance and deflection of deck slabs mixed with macro-synthetic fibers. Afterward, the deflection estimation method considering the thermal characteristics of concrete and deck plates was proposed. A material test was first conducted to evaluate the mechanical properties of concrete mixed with macro-synthetic fibers. This test found that the compressive strength and elasticity modulus of concrete mixed with macro-synthetic fibers was greater than that of general concrete. A flexural tensile test confirmed that residual strength was maintained after the maximum strength was achieved. The fire resistance of the deck slab was adequate even when a fire-resistant coating was not applied. The internal temperature was lowest for the specimen with macro-synthetic fibers. Deflection was evaluated using previously published equations and standards. The deflection evaluation confirmed that the temperature distribution should be applied differently in the estimation method that uses the thermal load of the deck slab.

The use of bone graft materials is required for the treatment of bone defects damaged beyond the critical defect; therefore, injectable calcium phosphate cement (CPC) is actively used after surgery. The application of various polymers to improve injectability, mechanical strength, and biological function of injection-type CPC is encouraged. We previously developed a chitosan-PEG conjugate (CS/PEG) by a sulfur (VI) fluoride exchange reaction, and the resulting chitosan derivative showed high solubility at a neutral pH. We have demonstrated the CPC incorporated with a poly (ethylene glycol) (PEG)-grafted chitosan (CS/PEG) and developed CS/PEG CPC. The characterization of CS/PEG CPC was conducted using Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD). The initial properties of CS/PEG CPCs, such as the pH, porosity, mechanical strength, zeta potential, and in vitro biocompatibility using the WST-1 assay, were also investigated. Moreover, osteocompatibility of CS/PEG CPCs was carried out via Alizarin Red S staining, immunocytochemistry, and Western blot analysis. CS/PEG CPC has enhanced mechanical strength compared to CPC, and the cohesion test also demonstrated in vivo stability. Furthermore, we determined whether CS/PEG CPC is a suitable candidate for promoting the osteogenic ability of Dental Pulp Stem Cells (DPSC). The elution of CS/PEG CPC entraps more calcium ion than CPC, as confirmed through the zeta potential test. Accordingly, the ion trapping effect of CS/PEG is considered to have played a role in promoting osteogenic differentiation of DPSCs. The results strongly suggested that CS/PEG could be used as suitable additives for improving osteogenic induction of bone substitute materials.

Skullcapflavone II (SFII), a flavonoid derived from Scutellaria baicalensis , has been reported to have anti-inflammatory properties. However, its therapeutic potential for skin inflammatory diseases and its mechanism are unknown. Therefore, this study aimed to investigate the effect of SFII on TNF-α/IFN-γ-induced atopic dermatitis (AD)-associated cytokines, such as thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC). Co-stimulation with TNF-α/IFN-γ in HaCaT cells is a well-established model for induction of pro-inflammatory cytokines. We treated cells with SFII prior to TNF-α/IFN-γ-stimulation and confirmed that it significantly inhibited TARC and MDC expression at the mRNA and protein levels. Additionally, SFII also inhibited the expression of cathepsin S (CTSS), which is associated with itching in patients with AD. Using specific inhibitors, we demonstrated that STAT1, NF-κB, and p38 MAPK mediate TNF-α/IFN-γ-induced TARC and MDC, as well as CTSS expression. Finally, we confirmed that SFII significantly suppressed TNF-α/IFN-γ-induced phosphorylation of STAT1, NF-κB, and p38 MAPK. Taken together, our study indicates that SFII inhibits TNF-α/IFN-γ-induced TARC, MDC, and CTSS expression by regulating STAT1, NF-κB, and p38 MAPK signaling pathways.

The role of telomerase reverse transcriptase ( TERT ) promoter mutations as an independent poor prognostic factor in differentiated thyroid cancer (DTC) patients is well known, but there is no prognostic system that combines the TERT promoter mutation status with tumor-node-metastasis (TNM) stage to predict cancer-specific survival (CSS). A total of 393 patients with pathologically confirmed DTC after thyroidectomy were enrolled. After incorporating wild-type TERT and mutant TERT with stages I, II, and III/IV of the AJCC TNM system 8th edition (TNM-8), we generated six combinations and calculated 10-year and 15-year CSS and adjusted hazard ratios (HRs) for cancer-related death using Cox regression. Then, a new mortality prediction model termed TNM-8T was derived based on the CSS and HR of each combination in the four groups. Of the 393 patients, there were 27 (6.9%) thyroid cancer-related deaths during a median follow-up of 14 years. Patients with a more advanced stage had a lower survival rate (10-year CSS for TNM-8T stage 1, 2, 3, and 4: 98.7%, 93.5%, 77.3%, and 63.0%, respectively; p < 0.001). TNM-8T showed a better spread of CSS ( p < 0.001) than TNM-8 ( p = 0.002) in the adjusted survival curves. The C-index for mortality risk predictability was 0.880 (95% CI, 0.665-0.957) in TNM-8T and 0.827 (95% CI, 0.622-0.930) in TNM-8 ( p < 0.001). TNM-8T, a new prognostic system that incorporates the TERT mutational status into TNM-8, showed superior predictability to TNM-8 in the long-term survival of DTC patients.

Endoscopic submucosal dissection (ESD) is a surgical procedure to remove early neoplastic lesions in the gastrointestinal tract with the critical issue of perforation. A submucosal fluid cushion, such as normal saline, is used as a cushioning agent to prevent perforation; however, its cushioning maintenance is insufficient for surgery. In this study, we introduce an injectable thermosensitive chitosan solution (CS) with β -glycerophosphate ( β -GP) as a submucosal injection agent for ESD. The CS/ β -GP system with optimal β -GP concentration showed drastic viscosity change near body temperature while other commercial products did not. Additionally, the injectability of the solution was similar to or greater than other commercial products. The solution with low β -GP concentration showed low cytotoxicity similar to other products. An in vivo preclinical study illustrated maintenance of the high cushioning of the thermosensitive solutions. These results indicate that a CS/ β -GP system with optimal β -GP concentration might be used as a submucosal injection agent in ESD, and further studies are needed to validate the effectiveness of the solutions in vivo.

To identify cancer/testis (CT) antigens and immunogenic proteins, immunoscreening of testicular and small-cell lung cancer cell line NCI-H889 cDNA libraries was performed using serum obtained from a small-cell lung cancer (SCLC) patient. We obtained 113 positive cDNA clones comprised of 74 different genes, designated KP-SCLC-1 through KP-SCLC-74. Of these genes, 59 genes were found to be related to cancers by EMBASE analysis. Three of these antigens, including KP-SCLC-29 (NOL4), KP-SCLC-59 (CCDC83), and KP-SCLC-69 (KIF20B), were CT antigens. RT-PCR and western blot analysis showed that NOL4 was frequently present in small-cell lung cancer cell lines (8/9, 8/9). In addition, NOL4 mRNA was weakly, or at a low frequency, or not detected in various cancer cell lines. Our results reveal that NOL4 was expressed at protein levels in small-cell lung cancer tissues (10/10) but not detected in lung adenocarcinoma and squamous cell carcinoma by immunohistochemical analysis. Serological response to NOL4 was also evaluated by western blot assay using NOL4 recombinant protein. A humoral response against NOL4 proteins was detected in 75% (33/44) of small-cell lung cancer patients and in 65% (13/20) of healthy donors by a serological western blot assay. These data suggest that NOL4 is a specific target that may be useful for diagnosis and immunotherapy in SCLC.

Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed SREBP1 promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.

We compared American Thyroid Association (ATA) guidelines, Korean (K)-Thyroid Imaging, Reporting and Data Systems (TIRADS), EU-TIRADS, and American College of Radiology (ACR) TIRADS in diagnosing malignancy for thyroid nodules with nondiagnostic/unsatisfactory cytology. Among 1143 nondiagnostic/unsatisfactory aspirations from April 2011 to March 2016, malignancy was detected in 39 of 89 excised nodules. The minimum malignancy rate was 7.82% in EU-TIRADS 5 and 1.87-3.00% in EU-TIRADS 3-4. In the other systems, the minimum malignancy rate was 14.29-16.19% in category 5 and ≤3% in the remaining categories. Although the EU-TIRADS category ≥ 5 exhibited the highest positive likelihood ratio (LR) of only 2.214, category ≥ 5 in the other systems yielded the highest positive LR of >5. Receiver operating characteristic (ROC) curves of all systems to predict malignancy were located statistically above the diagonal nondiscrimination line (P for ROC curve: EU-TIRADS, 0.0022; all others, 0.0001). The areas under the ROC curve (AUCs) were not significantly different among the four systems. The ATA guidelines, K-TIRADS, and ACR TIRADS may be useful to guide management for nondiagnostic/unsatisfactory nodules. The EU-TIRADS, although also useful, exhibited inferior performance in predicting malignancy for nondiagnostic/unsatisfactory nodules in Korea, an iodine-sufficient area.

The neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammation, and its elevation has recently been associated with poor survival in many solid cancers. Leukocyte elevation and lymphocyte reduction are associated with a poor response to radiotherapy (RT). This study aimed to assess the prognostic value of NLR before and after RT for anaplastic thyroid carcinoma (ATC). This retrospective study analyzed 40 patients with ATC who received RT with available complete blood cell count data from November 1995 through May 2020 at Samsung Medical Center (Seoul, Korea). Patients were classified into two groups according to the NLR before and after RT. The median overall survival (OS) was 8.9 months (range, 3.5-18.2) in the low NLR group (<3.47) and 5.2 months (range, 2.7-7.5) months in the high NLR group (≥3.47). The association between NLR and OS was also observed in multivariable Cox regression analysis (hazard ratio, 3.18; 95% confidence interval, 1.15-8.85; p = 0.026). The OS curves differed significantly according to post-RT NLR ( p = 0.036). A high NLR before and after RT may be significantly associated with poor OS in patients with ATC who receive RT.

There is controversy over the usefulness of prostate-specific antigen (PSA) as a prostate cancer (PCa) biomarker. This controversy arises when there are differences in the results of PSA assay modalities. In this study, which aimed to evaluate a proper validation between the two PSA assay modalities, the agreement between the results of the two modalities was analyzed. PSA examinations were conducted using two PSA assay modalities in 4810 patients. The intra-class correlation coefficient (ICC) and weighted kappa analysis were used to evaluate the agreement between the two assay modalities. A linear regression was performed to evaluate the association between the two assay modalities. According to ICC values (ICC: 0.999, p < 0.001) and weighted kappa analysis values (kappa: 0.951, alpha's standard error (ASE): 0.001, p < 0.0001), the agreement between the assay modalities was rated as excellent. However, the strength of agreement was poor in the following PSA sub-groups: 0.05-0.1 ng/mL (ICC: 0.281, p = 0.0860); 0.15-0.2 ng/mL (ICC: 0.288, p = 0.0036); 1.5-2.0 ng/mL (ICC: 0.360, p = 0.0860); and 2.0-2.5 ng/mL (ICC: 0.303, p = 0.0868). In linear regression analysis, when modality B PSA yielded a value of 0.2 ng/mL, the expected value for modality A was 0.258 ng/mL (95% CI: 0.255-0.260), and when modality B PSA yielded a value of 4 ng/mL, the expected value for modality A was 3.192 ng/mL (95% CI: 3.150-3.235). The difference in the PSA values between the two PSA assay modalities is confirmed, and this difference may be clinically meaningful.

Periodontal diseases occur through bacterial infection in the oral cavity, which can cause alveolar bone loss. Several efforts have been made to reconstruct alveolar bone, such as grafting bone substitutes and 3D-printed scaffolds. Poly(ε-caprolactone) (PCL) is biocompatible and biodegradable, thus demonstrating its potential as a biomaterial substitute; however, it is difficult for cells to adhere to PCL because of its strong hydrophobicity. Therefore, its use as a biomaterial has limitations. In this study, we used graphene oxide (GO) as a coating material to promote the osteogenic differentiation ability of PCL scaffolds. First, 3D-printed PCL scaffolds were fabricated, and the oxygen plasma treatment and coating conditions were established according to the concentration of GO. The physical and chemical properties of the prepared scaffolds were evaluated through water contact angle analysis, Raman spectroscopy, and image analysis. In addition, the adhesion and proliferation of periodontal ligament stem cells (PDLSCs) on the GO scaffolds were assessed via the water-soluble tetrazolium salt-1 (WST-1) assay, and the osteogenic differentiation ability was evaluated through alizarin red S staining. The results confirmed that the cell proliferation and osteogenic differentiation of the PDLSCs were enhanced in the scaffolds coated with oxygen plasma and GO. In conclusion, the plasma-treated GO-coating method that we developed can be used to promote the cell proliferation and osteogenic differentiation of the scaffolds.

Histone deacetylases (HDACs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins and play a crucial role in epigenetic regulation. Previously, we showed that histone acetylation is implicated in ultraviolet (UV)-induced inflammation and matrix impairment. To elucidate the histone acetylation status and specific HDACs involved in skin aging, we examined the changes in histone acetylation, global HDAC activity, and the expression of HDACs and sirtuins (SIRTs) in intrinsically aged and photoaged human skin as well as in UV-irradiated human skin in vivo. Following acute UV irradiation, the acetylated histone H3 (AcH3) level was increased, but HDAC activity and the expression levels of HDAC4, HDAC11, and SIRT4 were significantly decreased. In intrinsically aged skin, AcH3 levels were increased, but HDAC activity and the expression levels of HDAC4, HDAC5, HDAC10, HDAC11, SIRT6, and SIRT7 were significantly decreased. However, histone acetylation and HDAC expression in photoaged skin were not significantly different from those in intrinsically aged skin. Collectively, HDAC4 and HDAC11 were decreased in both UV-irradiated and intrinsically aged skin, suggesting that they may play a universal role in increased histone acetylation associated with skin aging.

Our research group has previously shown that the presence of TERT promoter mutations is an independent prognostic factor, by applying the TERT mutation status to the variables of the AJCC 7th edition. This study aimed to determine if TERT mutations could be independent predictors of thyroid cancer-specific mortality based on the AJCC TNM 8th edition, with long-term follow-up. This was a retrospective study of 393 patients with pathologically confirmed differentiated thyroid carcinoma (DTC) after thyroidectomy at a tertiary Korean hospital from 1994 to 2004. The thyroid cancer-specific mortality rate was 6.9% (5.2% for papillary and 15.2% for follicular cancers). TERT promoter mutations were identified in 10.9% (43/393) of DTC cases (9.8% of papillary and 16.7% of follicular cancer) and were associated with older age ( p < 0.001), the presence of extrathyroidal invasion ( p < 0.001), distant metastasis ( p = 0.001), and advanced stage at diagnosis ( p < 0.001). The 10-year survival rate in mutant TERT was 67.4% for DTC patients (vs. 98% for wild-type; adjusted hazard ratio (HR) of 9.93, (95% CI: 3.67-26.90)) and 75% for patients with papillary cancer (vs. 99%; 18.55 (4.83-71.18)). In addition, TERT promoter mutations were related to poor prognosis regardless of histologic type ( p < 0.001 for both papillary and follicular cancer) or initial stage ( p < 0.001, p = 0.004, and p = 0.086 for stages I, II, and III and IV, respectively). TERT promoter mutations comprise an independent poor prognostic factor after adjusting for the clinicopathological risk factors of the AJCC TNM 8th edition, histologic type, and each stage at diagnosis, which could increase prognostic predictability for patients with DTC.

Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and decorin, have been reported to decrease as skin ages. Insulin-like growth factor-1 (IGF-1) is important in various physiological functions such as cell survival, growth, and apoptosis. It is well known that the serum level of IGF-1 decreases with age. Therefore, we investigated whether and how IGF-1 affects biglycan and decorin. When primary cultured normal human dermal fibroblasts (NHDFs) were treated with IGF-1, protein levels of biglycan and decorin increased, despite no difference in mRNA expression. This increase was not inhibited by transcription blockade using actinomycin D, suggesting that it is mediated by IGF-1-induced enhanced translation. Additionally, both mRNA and protein expression of ADAMTS5, a PG-degrading enzyme, were decreased in IGF-1-treated NHDFs. Knockdown of ADAMTS5 via RNA interference increased protein expression of biglycan and decorin. Moreover, mRNA and protein expression of ADAMTS5 increased in aged human skin tissues compared to young tissue. Overall, IGF-1 increases biglycan and decorin, which is achieved by improving protein translation to increase synthesis and preventing ADAMTS5-mediated degradation. This suggests a new role of IGF-1 as a regulator for biglycan and decorin in skin aging process.

Activin A receptor type 1C (ACVR1C), a type I transforming growth factor-β (TGF-β) receptor, has been implicated in sensitive skin and psoriasis and is involved in the regulation of metabolic homeostasis as well as cell proliferation and differentiation. In this study, we identified a novel role of ACVR1C in the ultraviolet (UV)-irradiation-induced reduction of epidermal lipogenesis in human skin. UV irradiation decreased ACVR1C expression and epidermal triglyceride (TG) synthesis in human skin in vivo and in primary normal human epidermal keratinocytes (NHEK) in vitro. Lipogenic genes, including genes encoding acetyl-CoA carboxylase (ACC) and sterol regulatory element binding protein-1 (SREBP1), were significantly downregulated in UV-irradiated NHEK. ACVR1C knockdown by shRNA resulted in greater decreases in SREBP1 and ACC in response to UV irradiation. Conversely, the overexpression of ACVR1C attenuated the UV-induced decreases in SREBP1 and ACC. Further mechanistic study revealed that SMAD2 phosphorylation mediated the ACVR1C-induced lipogenic gene modulation. Taken together, a decrease in ACVR1C may cause UV-induced reductions in SREBP1 and ACC as well as epidermal TG synthesis via the suppression of SMAD2 phosphorylation. ACVR1C may be a target for preventing or treating UV-induced disruptions in lipid metabolism and associated skin disorders.

The 3D-printed bioactive ceramic incorporated Poly(ε-caprolactone) (PCL) scaffolds show great promise as synthetic bone graft substitutes. However, 3D-printed scaffolds still lack adequate surface properties for cells to be attached to them. In this study, we modified the surface characteristics of 3D-printed poly(ε-caprolactone)/hydroxyapatite scaffolds using O2 plasma and sodium hydroxide. The surface property of the alkaline hydrolyzed and O2 plasma-treated PCL/HA scaffolds were evaluated using field-emission scanning microscopy (FE-SEM), Alizarin Red S (ARS) staining, and water contact angle analysis, respectively. The in vitro behavior of the scaffolds was investigated using human dental pulp-derived stem cells (hDPSCs). Cell proliferation of hDPSCs on the scaffolds was evaluated via immunocytochemistry (ICC) and water-soluble tetrazolium salt (WST-1) assay. Osteogenic differentiation of hDPSCs on the scaffolds was further investigated using ARS staining and Western blot analysis. The result of this study shows that alkaline treatment is beneficial for exposing hydroxyapatite particles embedded in the scaffolds compared to O2 plasma treatment, which promotes cell proliferation and differentiation of hDPSCs.

Auditory attention detection (AAD) is the tracking of a sound source to which a listener is attending based on neural signals. Despite expectation for the applicability of AAD in real-life, most AAD research has been conducted on recorded electroencephalograms (EEGs), which is far from online implementation. In the present study, we attempted to propose an online AAD model and to implement it on a streaming EEG. The proposed model was devised by introducing a sliding window into the linear decoder model and was simulated using two datasets obtained from separate experiments to evaluate the feasibility. After simulation, the online model was constructed and evaluated based on the streaming EEG of an individual, acquired during a dichotomous listening experiment. Our model was able to detect the transient direction of a participant's attention on the order of one second during the experiment and showed up to 70% average detection accuracy. We expect that the proposed online model could be applied to develop adaptive hearing aids or neurofeedback training for auditory attention and speech perception.

Post-surgery failure of dental implants due to alveolar bone loss is currently critical, disturbing the quality of life of senior dental patients. To overcome this problem, bioceramic or bone graft material is loaded into the defect. However, connective tissue invasion instead of osteogenic tissue limits bone tissue regeneration. The guided bone regeneration concept was adapted to solve this problem and still has room for improvements, such as biochemical similarity or oriented structure. In this article, an aligned electrospun-guided bone regeneration barrier with xenograft equine bone-derived nano hydroxyapatite (EBNH-RB) was fabricated by electrospinning EBNH/PCL solution on high-speed rotating drum collector and fiber characterization, viability and differentiation enhancing properties of mesenchymal dental pulp stem cell on the barrier was determined. EBNH-RB showed biochemical and structural similarity to natural bone tissue electron microscopy image analysis and x-ray diffractometer analysis, and had a significantly better effect in promoting osteogenesis based on the increased bioceramic content by promoting cell viability, calcium deposition and osteogenic marker expression, suggesting that they can be successfully applied to regenerate alveolar bone as a guided bone regeneration barrier.

P21-activated kinases (PAKs) are serine/threonine protein kinases that contribute to several cellular processes. Here, we aimed to determine the prognostic value of PAK1 and its correlation with the clinicopathological characteristics and five-year survival rates in patients with non-small cell lung cancer (NSCLC). We evaluated PAK1 mRNA and protein expression in NSCLC cells and resected tumor specimens, as well as in healthy human bronchial epithelial cells and adjacent healthy lung tissues, respectively, for effective comparison. Immunohistochemical tissue microarray analysis of 201 NSCLC specimens showed the correlation of PAK1 expression with clinicopathological characteristics. The mRNA and protein expression of PAK1 were 2.9- and 4.3-fold higher in six of seven NSCLC cell types and human tumors (both, p < 0.001) than in healthy human bronchial epithelial BEAS-2B cells and adjacent healthy lung tissues, respectively. Decreased survival was significantly associated with PAK1 overexpression in the entire cohort (χ 2 = 8.48, p = 0.0036), men (χ 2 = 17.1, p < 0.0001), and current and former smokers (χ 2 = 19.2, p < 0.0001). Notably, epidermal growth factor receptor (EGFR) mutation-positive lung cancer patients with high PAK1 expression showed higher mortality rates than those with low PAK1 expression (91.3% vs. 62.5%, p = 0.02). Therefore, PAK1 overexpression could serve as a molecular target for the treatment of EGFR mutation-positive lung cancer, especially among male patients and current/former smokers.

Tenascin C (TNC) is an element of the extracellular matrix (ECM) of various tissues, including the skin, and is involved in modulating ECM integrity and cell physiology. Although skin aging is apparently associated with changes in the ECM, little is known about the role of TNC in skin aging. In this study, we found that the Tnc mRNA level was significantly reduced in the skin tissues of aged mice compared with young mice, consistent with reduced TNC protein expression in aged human skin. TNC-large (TNC-L; 330-kDa) and -small (TNC-S; 240-kDa) polypeptides were observed in conditional media from primary dermal fibroblasts. Both recombinant TNC polypeptides, corresponding to TNC-L and TNC-S, increased the expression of type I collagen and reduced the expression of matrix metalloproteinase-1 in fibroblasts. Treatment of fibroblasts with a recombinant TNC polypeptide, corresponding to TNC-L, induced phosphorylation of SMAD2 and SMAD3. TNC increased the level of transforming growth factor-β1 ( TGF-β1 ) mRNA and upregulated the expression of type I collagen by activating the TGF-β signaling pathway. In addition, TNC also promoted the expression of type I collagen in fibroblasts embedded in a three-dimensional collagen matrix. Our findings suggest that TNC contributes to the integrity of ECM in young skin and to prevention of skin aging.