The Association of Chronic Periodontitis as a Potential Risk Factor with Rheumatoid Arthritis: A Nested Case-Control Study Using a Korean National Health Screening Cohort.

Growing research has proposed that rheumatoid arthritis (RA) and chronic periodontitis (CP) share similar pathophysiological mechanisms involving inflammation and tissue destruction. However, the potential correlation of CP as a contributing factor for the occurrence of RA warrants validation in the Korean population, where both diseases are prevalent, especially considering the increasingly aging demographic in Korea. This study examined 5139 RA cases and 509,727 matched controls from a Korean national cohort dataset (2002-2019) by carefully employing propensity score matching to ensure comparability between groups. Baseline characteristics were compared using standardized differences, and logistic regression was employed to estimate the impact of CP history on RA likelihood while controlling for covariates. We fully examined medical records documenting CP occurrences within the two-year period leading up to the index date, conducting comprehensive subgroup analyses. While a 1-year history of CP did not show a significant association with likelihood of RA, a 2-year history of CP increased RA likelihood by 12%, particularly among older adults, females, rural residents, and those with certain comorbidities such as hypercholesterolemia. Interestingly, this association persisted even among individuals with non-smoking habits, normal weight, and infrequent alcohol consumption. These findings suggest that chronic CP exposure for at least 2 years may independently elevate RA risk in Korean adults. The association in certain subgroups appears to suggest a predisposition toward genetic susceptibilities over lifestyle and environmental factors. Predicting RA in CP patients may be challenging, emphasizing the importance of regular RA screening, especially in high-risk subgroups.

Investigating the Connection between Chronic Periodontitis and Parkinson's Disease: Findings from a Korean National Cohort Study.

Recent research suggests a potential relevance between chronic periodontitis (CP) and Parkinson's disease (PD), raising concerns about comorbid PD among elderly CP patients. However, the epidemiologic basis for this association remains unclear. Employing a nested case-control design, this study explored the association between CP and subsequent PD occurrences in Korean adults, leveraging a validated national population-based dataset covering the period from 2002 to 2019. It included 8794 PD patients and 35,176 matched control individuals, established through propensity score matching for age, sex, residential area, and income. Baseline characteristics were compared using standardized differences, and logistic regression was employed to assess the impact of CP histories on PD likelihood while controlling for covariates. We performed a thorough examination of CP events within both 1-year and 2-year intervals preceding the index date, incorporating subgroup analyses. Our analysis revealed no statistically significant association between CP history and PD development overall. However, subgroup analysis revealed a slightly increased likelihood of PD development among CP individuals with a high disease burden (Charlson Comorbidity Index score ≥ 2). In conclusion, although our study did not find a significant overall association between CP history and PD development, the elevated likelihood of PD in subgroups with high disease burden may suggest that comorbidities influence PD probability among certain CP patients. Considering comorbid conditions in PD screening for some individuals with CP may be also important.

Associations between Chronic Kidney Disease and Migraine Incidence: Findings from a Korean Longitudinal Big Data Study.

While headaches frequently occur in individuals with chronic kidney disease (CKD), there are few statistical evaluations of their connection to migraines in population-based studies. In this nationwide longitudinal follow-up study of Korean health examination data (2002-2019), a total of 15,443 participants with CKD and 61,772 matched controls were enrolled. We applied overlap-weighted Cox proportional hazard regression models to assess hazard ratios, examining the correlation between CKD and the development of migraines. After accounting for various factors, we observed a modest reduction of approximately 11% in the likelihood of migraine occurrence among CKD patients (95% confidence intervals = 0.81-0.97) during the 16-year monitoring period. Subgroup analysis revealed a significant association among specific demographic and health conditions, including individuals aged 70 or older, females, overweight individuals, nonsmokers, and those without hypertension or diabetes. Our research may indicate a potential relationship between CKD and the onset of migraines in Korean adults, suggesting a slight reduction in the probability of the occurrence of migraines among those with CKD. These findings emphasize the need for attentive follow-up and preventive management in individuals without the identified protective factors, particularly in male CKD patients under the age of 70 with hypertension.

Predicting disease recurrence in limited disease small cell lung cancer using cell-free DNA-based mutation and fragmentome analyses.

Background: Limited disease (LD) small cell lung cancer (SCLC) treated with definitive concurrent chemoradiotherapy (CCRT) potentially experience disease recurrence. We investigated the feasibility of circulating-tumor DNA (ctDNA)-based genomic and fragmentome analyses to assess the risk of recurrence. Methods: Targeted sequencing was conducted using pre-treatment and on-treatment blood samples from definitive CCRT-treated patients with LD-SCLC (n=50). Based on 12-month recurrence-free survival (RFS), patients were categorized into persistent-response (PeR, n=29) and non-PeR (n=21) groups. Fragmentome analysis was conducted using ctDNA fragments of different lengths: P1 (100-155 bp) and P2 (160-180 bp). Results: Patients with TP53 (n=15) and RB1 (n=11) mutation in on-treatment samples demonstrated significantly shorter RFS than patients with wild-type (WT) (P=0.05, P=0.0014, respectively). Fragmentome analysis of all available on-treatment samples (n=26) revealed that the non-PeR group (n=10) had a significantly higher P1 range (P=0.003) and lower P2 range (P=0.002). The areas under the curves for P1, P2, and the fragmentation ratio (P1/P2) in distinguishing the PeR and non-PeR were 0.850, 0.725, and 0.900, respectively. Using optimal cut-off, longer RFSs were found with the low-fragmentation-ratio group than with the high-fragmentation-ratio group (not reached vs. 7.6 months, P=0.002). Patients with both WT RB1 and a low-fragmentation-ratio (n=10) showed better outcomes than patients with both mutated RB1 and a high-fragmentation-ratio (n=10; hazard ratio, 7.55; 95% confidence interval: 2.14-26.6; P=0.002). Conclusions: RB1 mutations and high fragmentation ratios correlated with early disease recurrence. Analyzing ctDNA could help in predicting early treatment failure and making clinical decisions for high-risk patients.

Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis.

Transcriptional coactivators regulate the rate of gene expression in the nucleus. Nuclear receptor coactivator 6 (NCOA6), a coactivator, has been implicated in embryonic development, metabolism, and cancer pathogenesis, but its role in innate immunity and inflammatory diseases remains unclear. Here, we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions. Unexpectedly, nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC, forming cytoplasmic specks. Mechanistically, NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3, promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1ß and active caspase-1. Of note, Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3R258W gain-of-function mutation in macrophages. Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases, folic-induced acute tubular necrosis and crystal-induced arthritis, in mice. Consistent with these findings, NCOA6 was highly expressed in macrophages derived from gout patients, and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results. Conclusively, NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases, including gout.

ACY-241, a histone deacetylase 6 inhibitor, suppresses the epithelial-mesenchymal transition in lung cancer cells by downregulating hypoxia-inducible factor-1 alpha.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1α activity is essential in normal tissues, its presence in the tumor microenvironment represents a significant risk factor as it can induce angiogenesis and confer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1α even under normoxia. In this study, we observed an inclination toward increased normoxic HIF-1α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF-1α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a significant reduction in HIF-1α expression upon HDAC6 inhibition. Moreover, the downregulation of HIF-1α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also demonstrated an inhibitory effect on cell invasion and migration by reducing HIF-1α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer.

An elevated likelihood of stroke, ischemic heart disease, or heart failure in individuals with gout: a longitudinal follow-up study utilizing the National Health Information database in Korea.

Objective: Accumulating evidence from other countries indicates potential associations between gout and cardiovascular diseases; however, the associations of gout with cardiovascular diseases, particularly stroke, ischemic heart disease, and heart failure, remain ambiguous in the Korean population. We hypothesized that individuals with gout are at a higher likelihood of stroke, ischemic heart disease, or heart failure. This study expands upon previous research by ensuring a comparable baseline between patient and control groups and analyzing 16 years of data derived from an extensive healthcare database. Methods: We selected 22,480 patients with gout and 22,480 control individuals from the Korean National Health Insurance Service-Health Screening Cohort database (2002-2019), and matched them at a 1:1 ratio according to sex, age, income, and residence. A Cox proportional hazard model with weighted overlap was employed to examine the relationship between gout and the risk of stroke, ischemic heart disease, or heart failure after adjustment for several covariates. Results: The incidences of stroke, ischemic heart disease, or heart failure in participants with gout were slightly higher than those in controls (stroke: 9.84 vs. 8.41 per 1000 person-years; ischemic heart disease: 9.77 vs. 7.15 per 1000 person-years; heart failure: 2.47 vs. 1.46 per 1000 person-years). After adjustment, the gout group had an 11% (95% confidence interval [CI] = 1.04-1.19), 28% (95% CI = 1.19-1.37), or 64% (95% CI = 1.41-1.91) higher likelihood of experiencing stroke, ischemic heart disease, or heart failure, respectively, than the control group. Conclusion: The present findings suggest that individuals with gout in the Korean population, particularly those aged ≥ 60 years, were more likely to have stroke, ischemic heart disease, or heart failure.

Intracellular Adhesion Molecule-1 Improves Responsiveness to Immune Checkpoint Inhibitor by Activating CD8+ T Cells.

Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non-small cell lung cancer treated with anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule-1 (ICAM-1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM-1 (sICAM-1) is a key molecule that increases the efficacy of anti-PD-1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM-1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM-1-mediated anti-tumor pathway. Using sICAM-1 alone and in combination with anti-PD-1 enhances anti-tumor efficacy in anti-PD-1-responsive tumors in murine models. Notably, combinatorial therapy with sICAM-1 and anti-PD-1 converts anti-PD-1-resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM-1.

Programmed Death-Ligand 1 Copy Number Alteration as an Adjunct Biomarker of Response to Immunotherapy in Advanced NSCLC.

INTRODUCTION: This study aimed to evaluate the value of programmed death-ligand 1 (PD-L1) copy number (CN) alteration as an additional biomarker to standard immunohistochemistry (IHC) in predicting response to immune checkpoint inhibitor (ICI) therapy in advanced NSCLC. METHODS: Before ICI monotherapy, tumor PD-L1 CN alteration (gain, neutral, or loss) was called using whole-exome sequencing data and compared with IHC results (tumor proportion score ≥50, 1-49, or 0). Progression-free survival (PFS) and overall survival were correlated with both biomarkers. In addition, the impact of CN alteration was further evaluated in two independent cohorts using next-generation sequencing panel. RESULTS: A total of 291 patients with advanced-stage NSCLC met the study inclusion criteria. Although the IHC classification distinguished the best responsive group (tumor proportion score ≥ 50), the CN-based classification distinguished the worst responsive group (CN loss) from the others (PFS, p = 0.020; overall survival, p = 0.004). After adjusting for IHC results, CN loss was an independent risk factor for progression (adjusted hazard ratio = 1.32, 95% confidence interval: 1.00-1.73, p = 0.049) and death (adjusted hazard ratio = 1.39, 95% confidence interval: 1.05-1.85, p = 0.022). A risk classification system was developed on the basis of IHC and CN profiles, which outperformed the conventional IHC system. In the validation cohorts, CN loss determined by next-generation sequencing panel was independently associated with worse PFS after ICI treatment, revealing its practical value. CONCLUSIONS: This is the first study to directly compare CN alterations with IHC results and survival outcomes after anti-PD-(L)1 therapy. Tumor PD-L1 CN loss can serve as an adjunct biomarker to predict the lack of response. Prospective studies are required to further validate this biomarker.

Clonal expansion of resident memory T cells in peripheral blood of patients with non-small cell lung cancer during immune checkpoint inhibitor treatment.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an essential treatment for non-small cell lung cancer (NSCLC). Currently, the tumor-related intrinsic factors in response to ICIs have mostly been elucidated in tissue samples. However, tissue immune status and changes in the immune microenvironment can also be reflected and monitored through peripheral blood. METHODS: Single-cell RNA and T cell receptor (scTCR) sequencing were conducted using peripheral blood mononuclear cells (PBMCs) from 60 patients with stage IV NSCLC. Those samples were prospectively acquired from patients treated with anti-PD(L)-1 therapy for advanced lung cancer. Based on the clinical outcomes, samples were classified as durable clinical benefit (DCB) and non-durable clinical benefit (NCB). The samples constituted paired longitudinal samples, consisting of pre-treatment and on-treatment. Additionally, PBMC samples from 60 healthy donors from the Asian Immune Diversity Atlas project were used as a control. RESULTS: The dynamic changes in major cell types between pre-treatment and on-treatment PBMCs were associated with an increase in proliferating T cells and NK cells in both DCB and NCB groups. Among T cell subtypes, effector memory CD8+ T cells (CD8+ TEM_GZMK_PDCD1) were increased after ICI treatment in both DCB and NCB. From the lineage trajectory analysis, effector memory CD8+ T cells resided at the bifurcation point, which has the potential to differentiate into lineages with precursor exhausted CD8+ T cells (CD8+ TCM cells) assumed to be related to the ICI response. From the scTCR-seq, effector memory CD8+ T cells along with T cells recognizing unknown antigen expanded and composed of novel clones skewed toward dysfunctional status, especially in on-treatment samples of the DCB group. The extent of immunophenotype conversion capabilities of the TCR with effector memory CD8+ T cells showed remarkable variation in the on-treatment sample in the DCB group. CONCLUSION: A transitioning T cell subtype identified in PBMCs might be related to the prolonged ICI response. From our study, expansion of effector memory CD8+ T cells with novel TCRs in PBMCs after ICI treatment could contribute to a better clinical outcome in patients with NSCLC. This proof-of-concept research strengthens the use of non-invasive PBMCs in studying systemic changes of immune reactions related to the ICI treatment.

Cellular plasticity and immune microenvironment of malignant pleural effusion are associated with EGFR-TKI resistance in non-small-cell lung carcinoma.

Malignant pleural effusion (MPE) is a complication of lung cancer that can be used as an alternative method for tissue sampling because it is generally simple and minimally invasive. Our study evaluated the diagnostic potential of non-small-cell lung carcinoma (NSCLC)-associated MPE in terms of understanding tumor heterogeneity and identifying response factors for EGFR tyrosine kinase inhibitor (TKI) therapy. We performed a single-cell RNA sequencing analysis of 31,743 cells isolated from the MPEs of 9 patients with NSCLC (5 resistant and 4 sensitive to EGFR TKI) with EGFR mutations. Interestingly, lung epithelial precursor-like cells with upregulated GNB2L1 and CAV1 expression were enriched in the EGFR TKI-resistant group. Moreover, GZMK upregulated transitional effector T cells, and plasmacytoid dendritic cells were significantly enriched in the EGFR TKI-resistant patients. Our results suggest that cellular plasticity and immunosuppressive microenvironment in MPEs are potentially associated with the TKI response of patients with EGFR-mutated NSCLC.

Human Palatine Tonsils Are Linked to Alzheimer's Disease through Function of Reservoir of Amyloid Beta Protein Associated with Bacterial Infection.

Amyloid-ß (Aß)-peptide production or deposition in the neuropathology of Alzheimer's disease (AD) was shown to be caused by chronic inflammation that may be induced by infection, but the role of pathogenic-bacteria-related AD-associated Aß is not yet clearly understood. In this study, we validated the hypothesis that there is a correlation between the Aß-protein load and bacterial infection and that there are effects of bacteria, Staphylococcus aureus (S. aureus), on the Aß load in the inflammatory environment of human tonsils. Here, we detected Aß-peptide deposits in human tonsil tissue as well as tissue similar to tonsilloliths found in the olfactory cleft. Interestingly, we demonstrated for the first time the presence of Staphylococcus aureus (S. aureus) clustered around or embedded in the Aß deposits. Notably, we showed that treatment with S. aureus upregulated the Aß-protein load in cultures of human tonsil organoids and brain organoids, showing the new role of S. aureus in Aß-protein aggregation. These findings suggest that a reservoir of Aß and pathogenic bacteria may be a possible therapeutic target in human tonsils, supporting the treatment of antibiotics to prevent the deposition of Aß peptides via the removal of pathogens in the intervention of AD pathogenesis.

Evaluation of cold atmospheric microwave plasma on skin physiological parameters and tolerability in dogs.

BACKGROUND: Cold atmospheric microwave plasma (CAMP) is a promising therapeutic option for treating skin infections and wounds. Changes in biophysical skin parameters and the tolerability in dogs after applying CAMP is unknown. OBJECTIVE: This study aimed to evaluate the in vivo effects of CAMP on skin biophysical parameters [hydration, transepidermal water loss (TEWL) and surface temperature] and tolerability in dogs. ANIMALS: Twenty client-owned dogs with normal skin. MATERIALS AND METHODS: Cold atmospheric microwave plasma treatment was performed for 30 s and 1, 2 and 4 min, respectively, at different sites of normal canine skin in the inguinal area. Hydration, TEWL and surface temperature were measured five, three and three times, respectively, before and after CAMP application. After treatment, pain and adverse effects were evaluated using a modified Melbourne Pain Scale and the modified short form Glasgow Composite Measure Pain Scale (modified CMPS-SF). RESULTS: Transepidermal water loss values significantly decreased with 4 min of treatment, and hydration decreased significantly with 2 min of treatment. Temperature increased significantly with increasing treatment time. For other parameters, no significant changes were observed. No significant pain response or adverse effects were observed in most dogs, aside from mild erythema in the treatment area after 4 min. CONCLUSION AND CLINICAL SIGNIFICANCE: Cold atmospheric microwave plasma treatment was well-tolerated and did not significantly change canine skin biophysical parameters. CAMP achieves basic recommendations for safe use and is a potential therapeutic option for various skin diseases in dogs.

Contexte - Le CAMP (Cold Atmospheric Microwave Plasma) est une option thérapeutique prometteuse pour le traitement des infections cutanées et des plaies. Les modifications des paramètres biophysiques de la peau et la tolérance chez les chiens après l'application de CAMP sont inconnues. Objectif - Cette étude visait à évaluer les effets in vivo du CAMP sur les paramètres biophysiques de la peau [hydratation, perte d'eau transépidermique (TEWL) et température de surface] et la tolérance chez le chien. Animaux - Vingt chiens de propriétaires à peau normale. Matériels et méthodes - Le traitement CAMP a été effectué pendant 30 s et 1, 2 et 4 min, respectivement, sur différents sites de peau canine normale dans la région inguinale. L'hydratation, la TEWL et la température de surface ont été mesurées cinq, trois et trois fois, respectivement, avant et après l'application de CAMP. Après le traitement, la douleur et les effets indésirables ont été évalués à l'aide d'une échelle de douleur de Melbourne modifiée et de la forme courte modifiée de l'échelle de mesure de la douleur composite de Glasgow (CMPS-SF modifiée). Résultats - Les valeurs de TEWL ont diminué de manière significative après 4 minutes de traitement et l'hydratation a diminué de manière significative après 2 minutes de traitement. La température a augmenté de manière significative avec l'augmentation du temps de traitement. Pour les autres paramètres, aucun changement significatif n'a été observé. Aucune réponse significative à la douleur ni aucun effet indésirable n'ont été observés chez la plupart des chiens, à l'exception d'un léger érythème dans la zone de traitement après 4 minutes. Conclusion et signification clinique - Le traitement CAMP a été bien toléré et n'a pas modifié de manière significative les paramètres biophysiques de la peau canine. CAMP répond aux recommandations de base pour une utilisation sûre et constitue une option thérapeutique potentielle pour diverses maladies de la peau chez les chiens.

Introducción- el plasma de microondas atmosférico frío (CAMP) es una opción terapéutica prometedora para el tratamiento de infecciones y heridas de la piel. Se desconocen los cambios en los parámetros biofísicos de la piel y la tolerabilidad en perros después de aplicar CAMP. Objetivo- este estudio tuvo como objetivo evaluar los efectos in vivo de CAMP en los parámetros biofísicos de la piel [hidratación, pérdida de agua transepidérmica (TEWL) y temperatura superficial] y la tolerabilidad en perros. Animales - Veinte perros de propietarios particulares con piel normal. Materiales y métodos - El tratamiento CAMP se realizó durante 30 s y 1, 2 y 4 min, respectivamente, en diferentes sitios de piel canina normal en el área inguinal. La hidratación, el TEWL y la temperatura superficial se midieron cinco, tres y tres veces, respectivamente, antes y después de la aplicación de CAMP. Después del tratamiento, el dolor y los efectos adversos se evaluaron mediante una escala de dolor de Melbourne modificada y la escala de dolor de medida compuesta de Glasgow de forma abreviada modificada (CMPS-SF modificada). Resultados- los valores de TEWL disminuyeron significativamente con 4 min de tratamiento y la hidratación disminuyó significativamente con 2 min de tratamiento. La temperatura aumentó significativamente con el aumento del tiempo de tratamiento. Para otros parámetros no se observaron cambios significativos. En la mayoría de los perros no se observaron reacciones significativas de dolor ni efectos adversos, aparte de un leve eritema en el área de tratamiento después de 4 min. Conclusión y significado clínico- el tratamiento con CAMP fue bien tolerado y no cambió significativamente los parámetros biofísicos de la piel canina. CAMP obtuvo recomendaciones básicas para un uso seguro y es una opción terapéutica potencial para diversas enfermedades de la piel en perros.

Contexto - O plasma frio atmosférico de micro-ondas (CAMP) é uma opção terapêutica promissora para o tratamento de infecções cutâneas e feridas. Não se sabe a respeito das alterações nos parâmetros biofísicos da pele e a tolerabilidade de cães após a aplicação de CAMP. Objetivo - Este estudo tem como objetivo avaliar os efeitos in vivo de CAMP nos parâmetros biofísicos da pele [hidratação, perda de água transepidérmica (TEWL) e temperatura da superfície] e a tolerabilidade em cães. Materiais e métodos - O tratamento com CAMP foi realizado por 30s e 1, 2 e 4 min, respectivamente, em diferentes locais da pele canina normal na região inguinal. Hidratação, TEWL e temperatura da superfície foram medidas cinco, três e três vezes, respectivamente, antes e após a aplicação do CAMP. Após o tratamento, a dor e os efeitos adversos foram avaliados usando uma escala de dor de Melbourne modificada e a escala de medida composta de dor de Glasgow modificada (CMPS-SF modificada). Resultados - Os valores de TEWL reduziram significativamente com o tratamento de 4 min, e a hidratação reduziu significativamente com dois minutos de tratamento. A temperatura aumentou significativamente com o aumento do tempo de tratamento. Não foram observadas alterações significativas para outros parâmetros. Não se observou uma resposta de dor significativa ou efeitos adversos na maioria dos cães, além de eritema leve na área tratada após 4 min. Conclusão e significância clínica - O tratamento com CAMP foi bem tolerado e não alterou significativamente os parâmetros biofísicos da pele canina. CAMP requer recomendações básicas de segurança na sua utilização e é uma opção terapêutica potencial para várias dermatopatias em cães.

Changes in the Mean of Medical Visits Due to Psychiatric Disease in Korean Children and Adolescents before and during the COVID-19 Pandemic.

The COVID-19 pandemic has been suggested to have adverse impacts on psychiatric disorders. This study aimed to investigate the changes in medical visits due to a wide range of psychiatric disorders in children during the COVID-19 pandemic. The medical visits of all Korean children and adolescents (0−19 years old) due to the 12 following psychiatric disorders were investigated: autism; attention-deficit/hyperactivity disorder (ADHD); depressive disorder; bipolar disorder; primary insomnia; schizophrenia; panic disorder; hypochondriasis; posttraumatic stress disorder (PTSD); anxiety disorder; anorexia nervosa; and adephagia. The mean medical visits before and during the COVID-19 pandemic were compared. The mean number of clinical visits due to autism, ADHD, depressive disorder, bipolar disorder, panic disorder, hypochondriasis, PTSD, anxiety disorder, and anorexia nervosa was higher during the COVID-19 pandemic than before the COVID-19 pandemic (all p < 0.05). The higher mean number of medical visits due to psychiatric disorders was maintained in age and sex subgroups. The female and adolescent groups demonstrated a higher mean number of medical visits due to psychiatric disorders during the COVID-19 pandemic. The medical visits due to many psychiatric disorders were higher during the COVID-19 pandemic than before COVID-19 in children and adolescents in Korea. Women and adolescents were more susceptible to psychiatric disorders during the COVID-19 pandemic.

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux.

Statins, a class of lipid-lowering drugs, are used in drug repositioning for treatment of human cancer. However, the molecular mechanisms underlying statin-induced cancer cell death and autophagy are not clearly defined. In the present study, we showed that pitavastatin could increase apoptosis in a FOXO3a-dependent manner in the oral cancer cell line, SCC15, and the colon cancer cell line, SW480, along with the blockade of autophagy flux. The inhibition of autophagy by silencing the LC3B gene reduced apoptosis, while blockade of autophagy flux using its inhibitor, Bafilomycin A1, further induced apoptosis upon pitavastatin treatment, which suggested that autophagy flux blockage was the cause of apoptosis by pitavastatin. Further, the FOXO3a protein accumulated due to the blockade of autophagy flux which in turn was associated with the induction of ER stress by transcriptional upregulation of PERK-CHOP pathway, subsequently causing apoptosis due to pitavastatin treatment. Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.

Comparative genomic analysis of plasmids encoding metallo-ß-lactamase NDM-5 in Enterobacterales Korean isolates from companion dogs.

Carbapenems are broad-spectrum antibiotics widely used for the treatment of human infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, emerging carbapenemase-producing Enterobacterales (CPE) are rising as a public threat to human and animal health. We screened clinical bacterial isolates from 241 dogs and 18 cats hospitalized at Veterinary Medical Teaching Hospital, Seoul National University, from 2018 to 2020 for carbapenemase production. In our study, 5 strains of metallo-ß-lactamase NDM-5-producing Escherichia coli and Klebsiella pneumoniae were isolated from 4 different dogs. Multilocus sequence typing (MLST) results showed that all E. coli strains were ST410 and all K. pneumoniae strains were ST378. Whole genome analysis of the plasmid showed that blaNDM-5 is carried on a IncX3 plasmid, showing a high concordance rate with plasmids detected worldwide in human and animal isolates. The blaNDM gene was associated with the bleMBL gene and the ISAba125 element, truncated with the IS5 element. The results of this study show that CPE has already become as a threat to both animals and humans in our society, posing the necessity to solve it in terms of "One Health". Therefore, preventive strategies should be developed to prevent the spread of CPE in animal and human societies.

ACY-241, an HDAC6 inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by inducing autophagy.

Histone deacetylase 6 (HDAC6) is a promising target for cancer treatment because it regulates cell mobility, protein trafficking, cell growth, apoptosis, and metastasis. However, the mechanism of HDAC6-induced anticancer drug resistance is unclear. In this study, we evaluated the anticancer effect of ACY-241, an HDAC6-selective inhibitor, on erlotinib-resistant pancreatic cancer cells that overexpress HDAC6. Our data revealed that ACY-241 hyperacetylated the HDAC6 substrate, α-tubulin, leading to a significant reduction in cell viability of erlotinib-resistant pancreatic cells, BxPC3-ER and HPAC-ER. Notably, a synergistic anticancer effect was observed in cells that received combined treatment with ACY-241 and erlotinib. Combined treatment effectively induced autophagy and inhibited autophagy through siLC3B, and siATG5 alleviated ACY-241-mediated cell death, as reflected by the recovery of PARP cleavage and apoptosis rates. In addition, combined ACY-241 and erlotinib treatment induced autophagy and subsequently, cell death by reducing AKT-mTOR activity and increasing phospho-AMPK signaling. Therefore, HDAC6 may be involved in the suppression of autophagy and acquisition of resistance to erlotinib in ER pancreatic cancer cells. ACY-241 to overcome erlotinib resistance could be an effective therapeutic strategy against pancreatic cancer.

Effector Memory CD8+ and CD4+ T Cell Immunity Associated with Metabolic Syndrome in Obese Children.

PURPOSE: We investigated the association of effector memory (EM) CD8+ T cell and CD4+ T cell immunity with metabolic syndrome (MS). METHODS: Surface and intracellular staining of peripheral blood mononuclear cells was performed. Anti-interleukin-7 receptor-alpha (IL-7Rα) and CX3CR1 antibodies were used to stain the subsets of EM CD8+ T cells, while anti-interferon-gamma (IFN-γ), interleukin-17 (IL-17), and forkhead box P3 (FOXP3) antibodies were used for CD4+ T cell subsets. RESULTS: Of the 47 obese children, 11 were female. Children with MS had significantly higher levels of serum insulin (34.8±13.8 vs. 16.4±6.3 µU/mL, p<0.001) and homeostasis model assessment of insulin resistance (8.9±4.1 vs. 3.9±1.5, p<0.001) than children without MS. Children with MS revealed significantly higher frequencies of IL-7Rαlow CD8+ T cells (60.1 ±19.1% vs. 48.4±11.5%, p=0.047) and IL-7RαlowCX3CR1+ CD8+ T cells (53.8±20.1% vs. 41.5 ±11.9%, p=0.036) than children without MS. As the serum triglyceride levels increased, the frequency of IL-7RαlowCX3CR1+ and IL-7RαhighCX3CR1- CD8+ T cells increased and decreased, respectively (r=0.335, p=0.014 and r=-0.350, p=0.010, respectively), in 47 children. However, no CD4+ T cell subset parameters were significantly different between children with and without MS. CONCLUSION: In obese children with MS, the changes in immunity due to changes in EM CD8+ T cells might be related to the morbidity of obesity.

Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.

BACKGROUND: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. METHODS: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. RESULTS: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. CONCLUSIONS: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

Ginseng gintonin attenuates the disruptions of brain microvascular permeability and microvascular endothelium junctional proteins in an APPswe/PSEN-1 double-transgenic mouse model of Αlzheimer's disease.

It has been previously indicated that gintonin, which is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand, restores memory dysfunctions in an APPswe/PSEN-1 double-transgenic mouse model of Alzheimer's disease (AD Tg mice) by attenuating ß-amyloid plaque deposition, recovering cholinergic dysfunctions and upregulating hippocampal neurogenesis in the cortex and hippocampus. Although ß-amyloid plaque depositions in AD is accompanied with disruptions of brain microvessels, including the brain-blood barrier (BBB), it is unknown whether gintonin exerts protective effects on brain microvascular dysfunctions in AD Tg mice. In the present study, the effects of gintonin-enriched fraction (GEF) on the changes in ß-amyloid plaque depositions, brain permeability of Evans blue, and microvascular junctional proteins were investigated in AD Tg mice. Long-term oral administration of GEF reduced ß-amyloid plaque depositions in the cortex and hippocampus of AD Tg mice. GEF treatment also reduced the permeability of Evans blue through BBB and decreased immunoreactivity of platelet endothelial cell adhesion molecule-1 (a marker of BBB disruption) in the cortex and hippocampus of AD Tg mice in a dose-dependent manner. However, GEF elevated the protein expression of occludin, claudin-5 and zonula occludens-1, which are tight-junction proteins. The present results demonstrated that long-term oral GEF treatment not only attenuates ß-amyloid plaque depositions in the brain but also exhibits protective effects against microvascular disruptions in AD Tg mice. Finally, GEF exhibits anti-AD effects through attenuation of ß-amyloid plaque depositions and protection against brain microvascular damage in an AD animal model.