Association between short- and medium-term exposure to air pollutants and depressive episode using comprehensive air quality index among the population in South Korea.

BACKGROUND: Currently, air pollution is suggested as a risk factor for depressive episodes. Our study aimed to consider multiple air pollutants simultaneously, and continuously evaluate air pollutants using comprehensive air quality index (CAI) with depressive episode risk. METHODS: Using a nationally representative sample survey from South Korea between 2014 and 2020, 20,796 participants who underwent health examination and Patient Depression Questionnaire-9 were included in the study. Six air pollutants (PM10, PM2.5, O3, CO, SO2, NO2) were measured for the analysis. Every air pollutant was standardized by air quality index (AQI) and CAI was calculated for universal representation. Using logistic regression, short- and medium-term exposure by AQI and CAI with the risk of depressive episode was calculated by odds ratio and 95 % confidence interval (CI). Furthermore, consecutive measurements of CAI over 1-month time intervals were evaluated with the risk of depressive episodes. Every analysis was conducted seasonally. RESULTS: There were 950 depressive episodes occurred during the survey. An increase in AQI for short-term exposure (0-30 days) showed higher risk of depressive episode in CO, while medium-term exposure (0-120 days) showed higher risk of depressive episode in CO, SO2, PM2.5, and PM10. During the cold season, the exposure to at least one abnormal CAI within 1-month intervals over 120 days was associated with a 68 % (95 % CI 1.11-2.54) increase in the risk of depressive episode. CONCLUSIONS: Short- and medium-term exposure of air pollution may be associated with an increased risk of depressive episodes, especially for cold season.

Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats.

A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.

TMBIM6-mediated miR-181a expression regulates breast cancer cell migration and invasion via the MAPK/ERK signaling pathway.

Transmembrane Bax Inhibitor Motif-containing 6 (TMBIM6) has been reported to regulate cell death pathways and is overexpressed in several types of cancers. In this study, we investigated whether high expression of TMBIM6 in breast cancer was significantly associated with cancer invasiveness. Knockdown of TMBIM6 reduced proliferation and migration of invasive breast cancer cells through downregulation of the MAPK/ERK signaling pathway. Moreover, we suggested that expression of miR-181a was significantly suppressed upon TMBIM6 knockdown. In contrast, overexpression of TMBIM6 significantly increased cell invasion and migration through up-regulation of mesenchymal markers and matrix metalloproteinase-9 (MMP-9) and enhanced activation of the MAPK/ERK signaling pathway. We also observed that up-regulation of TMBIM6 significantly increased the expression of miR-181a by TMBIM6-mediated pathway. TMBIM6 and miR-181a-mediated ERK activation induced the expression of Snail-1 and Snail-2 in FOSL-1/C-JUN-dependent manner. Overall, our data demonstrated that TMBIM6-induced miR-181a up-regulation plays an important role in the efficient modulation of migration and invasion of breast cancer cells.

Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC Expression are Related to Clinical Outcomes in Various Cancers.

Background and Objectives: MYC, also known as an oncogenic reprogramming factor, is a multifunctional transcription factor that maintains induced pluripotent stem cells (iPSCs). Although MYC is frequently upregulated in various cancers and is correlated with a poor prognosis, MYC is downregulated and correlated with a good prognosis in lung adenocarcinoma. MYC and two other MYC family genes, MYCN and MYCL, have similar structures and could contribute to tumorigenic conversion both in vitro and in vivo. Methods and Results: We systematically investigated whether MYC family genes act as prognostic factors in various human cancers. We first evaluated alterations in the expression of MYC family genes in various cancers using the Oncomine and The Cancer Genome Atlas (TCGA) database and their mutation and copy number alterations using the TCGA database with cBioPortal. Then, we investigated the association between the expression of MYC family genes and the prognosis of cancer patients using various prognosis databases. Multivariate analysis also confirmed that co-expression of MYC/MYCL/MYCN was significantly associated with the prognosis of lung, gastric, liver, and breast cancers. Conclusions: Taken together, our results demonstrate that the MYC family can function not only as an oncogene but also as a tumor suppressor gene in various cancers, which could be used to develop a novel approach to cancer treatment.

Improved Wound Healing and Skin Regeneration Ability of 3,2'-Dihydroxyflavone-Treated Mesenchymal Stem Cell-Derived Extracellular Vesicles.

Flavonoids enhance the self-renewal and differentiation potential of mesenchymal stem cells (MSCs) and have therapeutic activities, including regenerative, anti-oxidative, and anti-inflammatory effects. Recent studies have revealed that MSC-derived extracellular vesicles (MSC-EVs) have therapeutic effects on tissue regeneration and inflammation. To facilitate further research on the therapeutic potential of MSC-EVs derived from flavonoid-treated MSCs, we surveyed the production of EVs and their therapeutic applications in wound regeneration. MSCs treated with flavonoids enhanced EV production twofold compared with naïve MSCs. EVs produced by MSCs treated with flavonoids (Fla-EVs) displayed significant anti-inflammatory and wound-healing effects in vitro. The wound-healing capacity of EVs was mediated by the upregulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Interestingly, the protein level of p-ERK under inhibition of MEK signals was maintained in Fla-EV-treated fibroblasts, suggesting that Fla-EVs have a higher therapeutic potential than naïve MSC-EVs (Cont-EVs) in wound healing. Moreover, the in vivo wound closure effect of the Fla-EVs showed significant improvement compared with that of the flavonoid-only treatment group and the Cont-EVs. This study provides a strategy for the efficient production of EVs with superior therapeutic potential using flavonoids.

Deep learning model to predict Epstein-Barr virus associated gastric cancer in histology.

The detection of Epstein-Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model's performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor.

An automated deep learning method and novel cardiac index to detect canine cardiomegaly from simple radiography.

Since most of degenerative canine heart diseases accompany cardiomegaly, early detection of cardiac enlargement is main priority healthcare issue for dogs. In this study, we developed a new deep learning-based radiographic index quantifying canine heart size using retrospective data. The proposed "adjusted heart volume index" (aHVI) was calculated as the total area of the heart multiplied by the heart's height and divided by the fourth thoracic vertebral body (T4) length from simple lateral X-rays. The algorithms consist of segmentation and measurements. For semantic segmentation, we used 1000 dogs' radiographic images taken between Jan 2018 and Aug 2020 at Seoul National University Veterinary Medicine Teaching Hospital. The tversky loss functions with multiple hyperparameters were used to capture the size-unbalanced regions of heart and T4. The aHVI outperformed the current clinical standard in predicting cardiac enlargement, a common but often fatal health condition for small old dogs.

In Vitro Metabolism of Donepezil in Liver Microsomes Using Non-Targeted Metabolomics.

Donepezil is a reversible acetylcholinesterase inhibitor that is currently the most commonly prescribed drug for the treatment of Alzheimer's disease. In general, donepezil is known as a safe and well-tolerated drug, and it was not associated with liver abnormalities in several clinical trials. However, rare cases of drug-related liver toxicity have been reported since it has become commercially available. Few studies have investigated the metabolic profile of donepezil, and the mechanism of liver damage caused by donepezil has not been elucidated. In this study, the in vitro metabolism of donepezil was investigated using liquid chromatography-tandem mass spectrometry based on a non-targeted metabolomics approach. To identify metabolites, the data were subjected to multivariate data analysis and molecular networking. A total of 21 donepezil metabolites (17 in human liver microsomes, 21 in mice liver microsomes, and 17 in rat liver microsomes) were detected including 14 newly identified metabolites. One potential reactive metabolite was identified in rat liver microsomal incubation samples. Metabolites were formed through four major metabolic pathways: (1) O-demethylation, (2) hydroxylation, (3) N-oxidation, and (4) N-debenzylation. This study indicates that a non-targeted metabolomics approach combined with molecular networking is a reliable tool to identify and detect unknown drug metabolites.

Nontargeted Metabolomics by High-Resolution Mass Spectrometry to Study the In Vitro Metabolism of a Dual Inverse Agonist of Estrogen-Related Receptors ß and γ, DN203368.

DN203368 ((E)-3-[1-(4-[4-isopropylpiperazine-1-yl]phenyl) 3-methyl-2-phenylbut-1-en-1-yl] phenol) is a 4-hydroxy tamoxifen analog that is a dual inverse agonist of estrogen-related receptor ß/γ (ERRß/γ). ERRγ is an orphan nuclear receptor that plays an important role in development and homeostasis and holds potential as a novel therapeutic target in metabolic diseases such as diabetes mellitus, obesity, and cancer. ERRß is also one of the orphan nuclear receptors critical for many biological processes, such as development. We investigated the in vitro metabolism of DN203368 by conventional and metabolomic approaches using high-resolution mass spectrometry. The compound (100 µM) was incubated with rat and human liver microsomes in the presence of NADPH. In the metabolomic approach, the m/z value and retention time information obtained from the sample and heat-inactivated control group were statistically evaluated using principal component analysis and orthogonal partial least-squares discriminant analysis. Significant features responsible for group separation were then identified using tandem mass spectra. Seven metabolites of DN203368 were identified in rat liver microsomes and the metabolic pathways include hydroxylation (M1-3), N-oxidation (M4), N-deisopropylation (M5), N,N-dealkylation (M6), and oxidation and dehydrogenation (M7). Only five metabolites (M2, M3, and M5-M7) were detected in human liver microsomes. In the conventional approach using extracted ion monitoring for values of mass increase or decrease by known metabolic reactions, only five metabolites (M1-M5) were found in rat liver microsomes, whereas three metabolites (M2, M3, and M5) were found in human liver microsomes. This study revealed that nontargeted metabolomics combined with high-resolution mass spectrometry and multivariate analysis could be a more efficient tool for drug metabolite identification than the conventional approach. These results might also be useful for understanding the pharmacokinetics and metabolism of DN203368 in animals and humans.

Antibacterial and antibiofilm activities of cinnamon essential oil nanoemulsion against multi-species oral biofilms.

Cinnamon essential oil (CEO) has antibacterial properties, but its ability to suppress the formation of multi-species oral biofilms has not been fully elucidated. This study evaluated the antibacterial and antibiofilm activities of cinnamon essential oil nanoemulsion (CEON) against oral biofilms formed using a microcosm biofilm model. The biofilms were formed on bovine enamel specimens over a 7-day period, during which all specimens were treated with one of three solutions: 5% CEON (n = 35), 0.5% cocamidopropyl betaine (n = 35), or 0.12% chlorhexidine gluconate (CHX; n = 35). Antibacterial and antibiofilm activities were determined by the red/green ratios (R/G values) of 7-day-old mature biofilms photographed with quantitative light-induced fluorescence-digital, the number of aciduric bacterial colony-forming units (CFUs) within each biofilm, and the absorbance of bacterial suspensions. One-way and repeated-measures analysis of variance were performed to compare differences among the three solutions. R/G values were lowest in the 0.12% CHX group, but not significantly differ from the 5% CEON group. The number of CFUs and absorbance were lowest in the 5% CEON group. This study showed that nanoemulsified CEO inhibited the maturation of multi-species oral biofilms and the growth of oral microorganisms in biofilms, including aciduric bacteria that cause dental caries.

Position-specific oxidation of miR-1 encodes cardiac hypertrophy.

In pathophysiology, reactive oxygen species oxidize biomolecules that contribute to disease phenotypes1. One such modification, 8-oxoguanine2 (o8G), is abundant in RNA3 but its epitranscriptional role has not been investigated for microRNAs (miRNAs). Here we specifically sequence oxidized miRNAs in a rat model of the redox-associated condition cardiac hypertrophy4. We find that position-specific o8G modifications are generated in seed regions (positions 2-8) of selective miRNAs, and function to regulate other mRNAs through o8G•A base pairing. o8G is induced predominantly at position 7 of miR-1 (7o8G-miR-1) by treatment with an adrenergic agonist. Introducing 7o8G-miR-1 or 7U-miR-1 (in which G at position 7 is substituted with U) alone is sufficient to cause cardiac hypertrophy in mice, and the mRNA targets of o8G-miR-1 function in affected phenotypes; the specific inhibition of 7o8G-miR-1 in mouse cardiomyocytes was found to attenuate cardiac hypertrophy. o8G-miR-1 is also implicated in patients with cardiomyopathy. Our findings show that the position-specific oxidation of miRNAs could serve as an epitranscriptional mechanism to coordinate pathophysiological redox-mediated gene expression.

Improved Isolation and Culture of Urine-Derived Stem Cells (USCs) and Enhanced Production of Immune Cells from the USC-Derived Induced Pluripotent Stem Cells.

The availability of autologous adult stem cells is one of the essential prerequisites for human stem cell therapy. Urine-derived stem cells (USCs) are considered as desirable cell sources for cell therapy because donor-specific USCs are easily and non-invasively obtained from urine. Efficient isolation, expansion, and differentiation methods of USCs are necessary to increase their availability. Here, we developed a method for efficient isolation and expansion of USCs using Matrigel, and the rho-associated protein kinase (ROCK) inhibitor, Y-27632. The prepared USCs showed significantly enhanced migration, colony forming capacity, and differentiation into osteogenic or chondrogenic lineage. The USCs were successfully reprogramed into induced pluripotent stem cells (USC-iPSCs) and further differentiated into kidney organoid and hematopoietic progenitor cells (HPCs). Using flavonoid molecules, the isolation efficiency of USCs and the production of HPCs from the USC-iPSCs was increased. Taken together, we present an improved isolation method of USCs utilizing Matrigel, a ROCK inhibitor and flavonoids, and enhanced differentiation of USC-iPSC to HPC by flavonoids. These novel findings could significantly enhance the use of USCs and USC-iPSCs for stem cell research and further application in regenerative stem cell-based therapies.

The effect of indirect vision skills on head and shoulder posture amongst Korean dental hygienists.

OBJECTIVES: This study aimed to investigate the effects of indirect vision skills on head and shoulder posture in dental hygienists. MATERIALS AND METHODS: This cross-sectional study included a total of 100 female clinical dental hygienists. It evaluated musculoskeletal symptoms of the neck, shoulders and back, head and shoulder posture (craniovertebral angle [CVA] and sagittal shoulder posture angle [SSPA]). Indirect vision skills were assessed using the O'Connor tweezer test under indirect vision with a mirror. To analyse factors associated with the CVA and SSPA, an independent t test, one-way ANOVA, and multiple linear regression analysis were conducted, respectively. RESULTS: The body region in which the greatest number of symptoms of work-related musculoskeletal disorders was recognised was the neck (89.0%). In the multiple linear regression model, which adjusted for other factors associated with musculoskeletal disorders, dental hygienists with poor indirect vision skills showed relatively small SSPA value (P < .05). However, indirect vision skills were not associated with the CVA value. CONCLUSIONS: Good indirect vision skills contribute to the prevention of rounded shoulders in dental hygienists. Therefore, where possible, dental hygienists should perform clinical procedures using indirect vision with a dental mirror to maintain a balanced posture and reduce flexion of the back or the neck. A dental hygiene curriculum should include training to improve clinical skills, as well as education regarding dental ergonomics and a monitoring system to determine whether ergonomic principles are well observed.

Systematic expression alteration analysis of master reprogramming factor OCT4 and its three pseudogenes in human cancer and their prognostic outcomes.

OCT4 is a master transcription factor that regulates the pluripotency of pluripotent stem cells and cancer stem cells along with other factors, including SOX2, KLF4, and C-MYC. Three different transcripts, OCT4A, OCT4B, and OCT4B1, are known to be generated by alternative splicing and eight OCT4 pseudogenes have been found in the human genome. Among them, we examined OCT4 and three pseudogenes (POU5F1P1, POU5F1P3, and POU5F1P4) because of their high expression possibility in cancer. In addition, previous studies indicated that OCT4 expression is augmented in cervical cancer and associated with poor prognosis, whereas OCT4 is down-regulated and correlated with good clinical outcomes in breast cancer. Because of these conflicting reports, we systematically evaluated whether expression of OCT4 and its pseudogenes can serve as oncogenic markers in various human cancers using the Oncomine database. Moreover, copy number alterations and mutations in OCT4 gene and its pseudogenes were analyzed using cBioPortal and the relationship between expression of OCT4 and pseudogenes and survival probability of cancer patients were explored using Kaplan-Meier plotter, OncoLnc, PROGgeneV2, and PrognoScan databases. Multivariate survival analysis was further conducted to determine the risk of the expression of the occurrence of OCT4 and its pseudogenes on certain cancer types using data from the Kaplan-Meier plotter. Overall, an association between expression of OCT4 and pseudogenes and cancer prognosis were established, which may serve as a therapeutic target for various human cancers.

Image quality and radiation dose of CT venography with double dose reduction using model based iterative reconstruction: comparison with conventional CT venography using filtered back projection.

Background Computed tomography venography (CTV) at low kVp using model-based iterative reconstruction (MBIR) can enhance vascular enhancement with noise reduction. Purpose To evaluate image qualities and radiation doses of CTV at 80 kVp using MBIR and a small iodine contrast media (CM) dose and to compare these with those of CTV performed using a conventional protocol. Material and Methods Sixty-five patients (mean age = 58.1 ± 7.2 years) that underwent CTV for the evaluation of deep vein thrombosis (DVT) and varicose veins were enrolled in this study. Patients were divided into two groups: Group A (35 patients, 80 kVp, MBIR, automatic tube current modulation, CM = 270 mg/mL, 100 mL) and Group B (30 patients, 100 kVp, filtered back projection [FBP], 120 fixed mA, CM = 370 mg/mL, 120 mL). Objective and subjective image qualities of inferior vena cava (IVC), femoral vein (FV), and popliteal vein (PV) were assessed and radiation doses were recorded. Results Mean vascular enhancement in group A was significantly lower than in group B ( P < 0.01). Noise in group A was significantly lower than in group B except for PV and contrast-to-noise ratio were not significantly different in the two groups ( P > 0.05). In addition, radiation dose in group A was significantly lower than in group B ( P < 0.001). Subjective image quality comparison revealed group A was statistically inferior to group B except for subjective image noise. Conclusion CTV at 80 kVp using MBIR with small iodine contrast dose provided acceptable image quality at a lower radiation dose than conventional CTV using FBP.