ETV5 promotes lupus pathogenesis and follicular helper T cell differentiation by inducing osteopontin expression.

Follicular helper T (TFH) cells mediate germinal center reactions to generate high affinity antibodies against specific pathogens, and their excessive production is associated with the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). ETV5, a member of the ETS transcription factor family, promotes TFH cell differentiation in mice. In this study, we examined the role of ETV5 in the pathogenesis of lupus in mice and humans. T cell-specific deletion of Etv5 alleles ameliorated TFH cell differentiation and autoimmune phenotypes in lupus mouse models. Further, we identified SPP1 as an ETV5 target that promotes TFH cell differentiation in both mice and humans. Notably, extracellular osteopontin (OPN) encoded by SPP1 enhances TFH cell differentiation by activating the CD44-AKT signaling pathway. Furthermore, ETV5 and SPP1 levels were increased in CD4+ T cells from patients with SLE and were positively correlated with disease activity. Taken together, our findings demonstrate that ETV5 is a lupus-promoting transcription factor, and secreted OPN promotes TFH cell differentiation.

Identifying subgroups of eating behavior traits unrelated to obesity using functional connectivity and feature representation learning.

Eating behavior is highly heterogeneous across individuals and cannot be fully explained using only the degree of obesity. We utilized unsupervised machine learning and functional connectivity measures to explore the heterogeneity of eating behaviors measured by a self-assessment instrument using 424 healthy adults (mean ± standard deviation [SD] age = 47.07 ± 18.89 years; 67% female). We generated low-dimensional representations of functional connectivity using resting-state functional magnetic resonance imaging and estimated latent features using the feature representation capabilities of an autoencoder by nonlinearly compressing the functional connectivity information. The clustering approaches applied to latent features identified three distinct subgroups. The subgroups exhibited different levels of hunger traits, while their body mass indices were comparable. The results were replicated in an independent dataset consisting of 212 participants (mean ± SD age = 38.97 ± 19.80 years; 35% female). The model interpretation technique of integrated gradients revealed that the between-group differences in the integrated gradient maps were associated with functional reorganization in heteromodal association and limbic cortices and reward-related subcortical structures such as the accumbens, amygdala, and caudate. The cognitive decoding analysis revealed that these systems are associated with reward- and emotion-related systems. Our findings provide insights into the macroscopic brain organization of eating behavior-related subgroups independent of obesity.

Tracking antigen-specific TCR clonotypes in SARS-CoV-2 infection reveals distinct severity trajectories.

Despite the importance of antigen-specific T cells in infectious disease, characterizing and tracking clonally amplified T cells during the progression of a patient's symptoms remain unclear. Here, we performed a longitudinal, in-depth single-cell multiomics analysis of samples from asymptomatic, mild, usual severe, and delayed severe patients of SARS-CoV-2 infection. Our in-depth analysis revealed that hyperactive or improper T-cell responses were more aggressive in delayed severe patients. Interestingly, tracking of antigen-specific T-cell receptor (TCR) clonotypes along the developmental trajectory indicated an attenuation in functional T cells upon severity. In addition, increased glycolysis and interleukin-6 signaling in the cytotoxic T cells were markedly distinct in delayed severe patients compared to usual severe patients, particularly in the middle and late stages of infection. Tracking B-cell receptor clonotypes also revealed distinct transitions and somatic hypermutations within B cells across different levels of disease severity. Our results suggest that single-cell TCR clonotype tracking can distinguish the severity of patients through immunological hallmarks, leading to a better understanding of the severity differences in and improving the management of infectious diseases by analyzing the dynamics of immune responses over time.

FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.

Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.

Workplace Violence Experienced by Community Mental Health Workers.

A cross-sectional online survey was conducted to 1) investigate the prevalence of workplace violence and workers' emotional distress, 2) explore factors associated with workplace violence, and 3) assess workers' needs for preventive measures. A total of 763 community mental health workers participated in Korea. Among them, 85.85% of workers experienced workplace violence, including verbal (74.31%), emotional (66.45%), infectious (47.44%), informational (42.60%), sexual (32.50%), and physical (23.72%) abuse. Binary logistic regression analysis indicated that sex, occupation, certification, and working institution were significantly associated with workplace violence. Workplace violence affects workers' depression, anger, and anxiety negatively. The most-needed preventive measure is a two-person home visit.

Diagnosis-informed connectivity subtyping discovers subgroups of autism with reproducible symptom profiles.

Clinical heterogeneity has been one of the main barriers to develop effective biomarkers and therapeutic strategies in autism spectrum disorder (ASD). Recognizing this challenge, much effort has been made in recent neuroimaging studies to find biologically more homogeneous subgroups (called 'neurosubtypes') in autism. However, most approaches have rarely evaluated how much the employed features in subtyping represent the core anomalies of ASD, obscuring its utility in actual clinical diagnosis. To address this, we combined two data-driven methods, 'connectome-based gradient' and 'functional random forest', collectively allowing to discover reproducible neurosubtypes based on resting-state functional connectivity profiles that are specific to ASD. Indeed, the former technique provides the features (as input for subtyping) that effectively summarize whole-brain connectome variations in both normal and ASD conditions, while the latter leverages a supervised random forest algorithm to inform diagnostic labels to clustering, which makes neurosubtyping driven by the features of ASD core anomalies. Applying this framework to the open-sharing Autism Brain Imaging Data Exchange repository data (discovery, n = 103/108 for ASD/typically developing [TD]; replication, n = 44/42 for ASD/TD), we found three dominant subtypes of functional gradients in ASD and three subtypes in TD. The subtypes in ASD revealed distinct connectome profiles in multiple brain areas, which are associated with different Neurosynth-derived cognitive functions previously implicated in autism studies. Moreover, these subtypes showed different symptom severity, which degree co-varies with the extent of functional gradient changes observed across the groups. The subtypes in the discovery and replication datasets showed similar symptom profiles in social interaction and communication domains, confirming a largely reproducible brain-behavior relationship. Finally, the connectome gradients in ASD subtypes present both common and distinct patterns compared to those in TD, reflecting their potential overlap and divergence in terms of developmental mechanisms involved in the manifestation of large-scale functional networks. Our study demonstrated a potential of the diagnosis-informed subtyping approach in developing a clinically useful brain-based classification system for future ASD research.

Distribution of cellular remnants of melanocytes in the nail plate: Clue to the diagnosis of subungual melanoma.

BACKGROUND: Previous studies reported that cellular remnants in the nail plate could be a diagnostic clue for subungual melanoma (SUM). We sought to characterize the histopathologic features of cellular remnants in the nail plates of SUM patients. METHODS: A retrospective case-control study was conducted in a single tertiary center from 2012 to 2019. Twenty-three patients with pathologically diagnosed SUM and eight nail matrix nevi (NMN) patients were recruited. The analysis of the nail plate specimens focused on large cellular remnants of melanocytes (LCRMs). Longitudinal linear density and vertical distribution pattern of the LCRMs were scrutinized for possible features distinguishing SUM from NMN. RESULTS: The median linear density of the LCRMs was significantly higher in the SUM samples than in the NMN samples. LCRMs in the SUM samples were more dorsally distributed than those in the NMN samples. In invasive SUM, LCRMs were more likely to be found in the dorsal part of the nail plate compared to SUM in situ. CONCLUSION: Nail plate specimens should not be overlooked in the histopathological examination of melanonychia. High-density LCRMs with more dispersion to the dorsal side might be suggestive of SUM.

Hutchinson Sign: Biopsy May Assist in Diagnosis of Subungual Melanoma in Situ.

BACKGROUND: Early and accurate diagnosis of subungual melanoma (SUM) through histopathologic examination is critical, but lack of clinical suspicion leads to delays in diagnosis. Hutchinson sign (HS) can be one of the important clinical indicators for diagnosing SUM. OBJECTIVE: To evaluate the diagnostic value of small biopsies of HS for detecting SUM in situ. METHODS: We retrospectively evaluated 12 patients who were diagnosed as SUM in situ and underwent punch biopsy at HS areas. Clinical features, dermoscopic findings, and histopathologic findings in HS regions were analyzed. RESULTS: In most cases, HS was seen in hyponychium (11/12, 91.7%) with 1 case found in proximal nail fold, and 1 case in both the hyponychium and proximal nail fold. Dermoscopic features of HS showed irregular diffuse pigmentation (12/12, 100%) and parallel ridge pattern (7/12, 58.3%). Histopathologically, all cases showed irregularly scattered atypical melanocytes with hyperchromatic nuclei. Two cases showed subtle changes in melanocytes with little nuclear atypia, but additional section specimen showed more definitive findings of SUM in situ. CONCLUSION: We present a supplementary biopsy technique for diagnosing SUM. Biopsy of HS may help in the diagnosis of SUM.

Anti-pollution skincare: Research on effective ways to protect skin from particulate matter.

While there is increasing interest in anti-pollution care to particulate matter (PM), there has been no research evaluating the efficacy of skin care products in a real-world setting. Our objective was to find effective ways to protect skin from PM. In total, 64 volunteers whose skin was classified as reactive to PM concentration in the previous study were enrolled. Through split-face study, different combinations of skin care products (barrier cream, barrier cream/micellar water, antioxidant, and antioxidant/micellar water) were applied for 4 weeks during the high-PM period. The biophysical properties were measured, and a facial analysis system was used to evaluate skin condition at days 0, 14, and 28. The concentrations of PM and daily events that may affect skin conditions were also recorded. The mean concentration levels of PM10 and PM2.5 from days 0 to 14 were higher in the barrier cream group than in the antioxidant group. For each group, aside from skin tone in the antioxidant/micellar water group, there were no statistically significant differences in skin measurements before and after the application, which reflects no aggravation in skin condition during high-PM periods. Intergroup analysis showed no differences in skin measurements among the four groups from day 0 to day 14, from day 14 to day 28, and from day 0 to 28. For anti-pollution care, maintaining skin barrier function using barrier cream seems to be sufficient in individuals sensitive to PM.

Clinical characteristics and pathological depths of syringomas in 94 Korean patients.

BACKGROUND: Syringoma is a common benign tumor with eccrine origin that typically occurs on the face of middle-aged women. Laser ablation with CO2 laser or Er:YAG laser has been widely used in the clinical field, often leading to scars due to its deep location. This study aimed to investigate clinical characteristics and pathological depths of the lesions in syringoma patients. MATERIALS AND METHODS: Syringoma patients, pathologically confirmed at Samsung medical center (Seoul, Korea) from January 1996 to March 2019, were analyzed. Clinical characteristics such as the location of lesion, age, and sex, and pathological depths of the lesions were investigated, and univariable and multivariable analyses were done for these factors. RESULTS: Of total 94 syringomas, 17.0% were located on periocular area, 10.6% on forehead, 34.0% on head and neck areas excluding periocular area and forehead, and 38.3% on trunk and extremities. The mean depth of syringoma from the surface including stratum corneum to the deepest stromal location was 1174.14 ± 1142.95 µm for periocular area, 1055.93 ± 247.76 µm for forehead, 1488.06 ± 1217.36 µm for other areas of head and neck including scalp, and 1169.53 ± 349.2 for the lesions located at trunk and extremities including external genitalia. No significant correlation was observed from univariable analysis and multivariable analysis by age, sex, and site of lesion. CONCLUSION: Our findings offer valuable information of the mean depth of syringoma at different sites, which can be taken into consideration for successful treatment without adverse events such as scarring.

Melanocytic nevi on the hyponychium with dermoscopic features of longitudinal brush pigmentation in children.

The dermoscopic features of longitudinally aligned pigmentation on the hyponychium were previously described in pediatric patients with longitudinal melanonychia. We report four cases of biopsy-proven acral melanocytic nevi on the hyponychium with a longitudinal brush pigmentation (LBP) pattern in dermoscopy. This LBP pattern on the hyponychium may be a counterpart of the fibrillar pattern of acral melanocytic nevi. Therefore, the LBP pattern in dermoscopy may provide a useful clue for distinguishing benign melanocytic nevi from melanoma in pediatric patients.

Hospital Nurses' Willingness to Respond in a Disaster.

OBJECTIVE: This study examined the factors associated with nurses' willingness to respond in a disaster. BACKGROUND: Nurses are key personnel in case of disasters, and therefore, understanding factors associated with willingness to respond is important. METHODS: Questionnaires were distributed to 200 nurses recruited from 2 public hospitals in Seoul, Korea. Data were collected in January and February 2018 and 181 responses were analyzed. RESULTS: Factors predicting willingness to respond in a disaster among public hospital nurses were level of education, self-efficacy, and disaster management competency. CONCLUSIONS: Providing well-organized disaster preparedness and response training programs would enhance nurses' level of knowledge about disasters. In addition, training could improve nurses' self-efficacy and disaster management competency, which should enhance willingness to respond in a disaster.

Animal-Assisted Therapy as an Intervention for Older Adults: A Systematic Review and Meta-Analysis to Guide Evidence-Based Practice.

BACKGROUND: Animal-assisted therapy (AAT) can ameliorate diverse health problems in older adults. However, applications of AAT have been limited because of the lack of intervention guidelines for older adults. AIMS: This study aimed to explore applications of AAT to older adults, analyze its health effects, and provide evidence for future interventions. METHODS: A systematic review and meta-analysis were conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Data were analyzed based on both a narrative synthesis and a meta-analysis specifically for depression. RESULTS: A total of 47 studies were selected for analysis. About 45% focused on older adults with diseases such as dementia, and 57.4% selected dog(s) as an intervention animal. About 34.0% delivered interventions once a week, and the behavioral outcome domain was the most frequently investigated. The meta-analysis showed that the effect sizes of the AAT group were -1.310 (95% CI [-1.900, -.721]). LINKING EVIDENCE TO ACTION: This review provides evidence for AAT as an intervention in the physiological, psychosocial, cognitive, and behavioral domains of older adults. When planning interventions for older adults, nurses should consider intended health outcomes, appropriate therapeutic animals, and the consequent intervention contents.

PDX models of human lung squamous cell carcinoma: consideration of factors in preclinical and co-clinical applications.

BACKGROUND: Treatment of human lung squamous cell carcinoma (LUSC) using current targeted therapies is limited because of their diverse somatic mutations without any specific dominant driver mutations. These mutational diversities preventing the use of common targeted therapies or the combination of available therapeutic modalities would require a preclinical animal model of this tumor to acquire improved clinical responses. Patient-derived xenograft (PDX) models have been recognized as a potentially useful preclinical model for personalized precision medicine. However, whether the use of LUSC PDX models would be appropriate enough for clinical application is still controversial. METHODS: In the process of developing PDX models from Korean patients with LUSC, the authors investigated the factors influencing the successful initial engraftment of tumors in NOD scid gamma mice and the retainability of the pathological and genomic characteristics of the parental patient tumors in PDX tumors. CONCLUSIONS: The authors have developed 62 LUSC PDX models that retained the pathological and genomic features of parental patient tumors, which could be used in preclinical and co-clinical studies. Trial registration Tumor samples were obtained from 139 patients with LUSC between November 2014 and January 2019. All the patients provided signed informed consents. This study was approved by the institutional review board (IRB) of Samsung Medical Center (2018-03-110).

Capicua suppresses colorectal cancer progression via repression of ETV4 expression.

BACKGROUND: Although major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined. METHODS: Databases for gene expression profile in CRC patient samples were used to evaluate the association of the levels of CIC and Polyoma enhancer activator 3 (PEA3) group genes (ETS translocation variant 1 (ETV1), ETV4, and ETV5), the best-characterized CIC targets in terms of CIC functions, with clinicopathological features of CRC. CIC and ETV4 protein levels were also examined in CRC patient tissue samples. Gain- and loss-of function experiments in cell lines and mouse xenograft models were performed to investigate regulatory functions of CIC and ETV4 in CRC cell growth and invasion. qRT-PCR and western blot analyses were performed to verify the CIC regulation of ETV4 expression in CRC cells. Rescue experiments were conducted using siRNA against ETV4 and CIC-deficient CRC cell lines. RESULTS: CIC expression was decreased in the tissue samples of CRC patients. Cell invasion, migration, and proliferation were enhanced in CIC-deficient CRC cells and suppressed in CIC-overexpressing cells. Among PEA3 group genes, ETV4 levels were most dramatically upregulated and inversely correlated with the CIC levels in CRC patient samples. Furthermore, derepression of ETV4 was more prominent in CIC-deficient CRC cells, when compared with that observed for ETV1 and ETV5. The enhanced cell proliferative and invasive capabilities in CIC-deficient CRC cells were completely recovered by knockdown of ETV4. CONCLUSION: Collectively, the CIC-ETV4 axis is not only a key module that controls CRC progression but also a novel therapeutic and/or diagnostic target for CRC.

Liver disease-associated keratin 8 and 18 mutations modulate keratin acetylation and methylation.

Keratin 8 (K8) and keratin 18 (K18) are the intermediate filament proteins whose phosphorylation/transamidation associate with their aggregation in Mallory-Denk bodies found in patients with various liver diseases. However, the functions of other post-translational modifications in keratins related to liver diseases have not been fully elucidated. Here, using a site-specific mutation assay combined with nano-liquid chromatography-tandem mass spectrometry, we identified K8-Lys108 and K18-Lys187/426 as acetylation sites, and K8-Arg47 and K18-Arg55 as methylation sites. Keratin mutation (Arg-to-Lys/Ala) at the methylation sites, but not the acetylation sites, led to decreased stability of the keratin protein. We compared keratin acetylation/methylation in liver disease-associated keratin variants. The acetylation of K8 variants increased or decreased to various extents, whereas the methylation of K18-del65-72 and K18-I150V variants increased. Notably, the highly acetylated/methylated K18-I150V variant was less soluble and exhibited unusually prolonged protein stability, which suggests that additional acetylation of highly methylated keratins has a synergistic effect on prolonged stability. Therefore, the different levels of acetylation/methylation of the liver disease-associated variants regulate keratin protein stability. These findings extend our understanding of how disease-associated mutations in keratins modulate keratin acetylation and methylation, which may contribute to disease pathogenesis.-Jang, K.-H., Yoon, H.-N., Lee, J., Yi, H., Park, S.-Y., Lee, S.-Y., Lim, Y., Lee, H.-J., Cho, J.-W., Paik, Y.-K., Hancock, W. S., Ku, N.-O. Liver disease-associated keratin 8 and 18 mutations modulate keratin acetylation and methylation.

The association of genetic polymorphisms with nonalcoholic fatty liver disease in a longitudinal study.

BACKGROUND: Several genetic variants are known to be associated with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the longitudinal associations between genetic variants and NAFLD. METHODS: We performed a genome-wide association study (GWAS) in Korean individuals who underwent repeated health check-ups. NAFLD was defined by ultrasonography and exclusion of secondary causes. RESULTS: The subjects had a median age of 50.0 years, and 54.8% were male. The median follow-up duration was 39 months. Among the 3905 subjects without NAFLD at baseline, 874 (22.4%) subjects developed NAFLD, and among the 1818 subjects with NAFLD at baseline, NAFLD regressed in 336 (18.5%) subjects during the follow-up period. After adjusting for age, sex and body mass index, no single-nucleotide polymorphism (SNP) passed Bonferroni correction for genome-wide significance in the development or regression of NAFLD. Among the SNPs that passed the genome-wide suggestiveness threshold (p = 1E-04) in the discovery set in the GWAS, only 1 SNP (rs4906353) showed an association with the development of NAFLD, with marginal significance in the validation set (p-value, discovery set = 9.68E-5 and validation set = 0.00531). CONCLUSIONS: This exploratory study suggests that longitudinal changes in NAFLD are not associated with genetic variants in the Korean population. These findings provide new insight into genetic mechanisms in the pathogenesis of NAFLD.

End-of-life care needs for noncancer patients who want to die at home in South Korea.

AIM: The awareness for the need for end-of-life care has increased among noncancer patients. However, studies on the topic have rarely targeted the needs of noncancer patients who want to die at home. This study assessed the end-of-life care needs of noncancer patients who were receiving care and wanted to die at home. METHODS: A cross-sectional study design was used and involved 200 participants who were diagnosed as noncancer patients and receiving home care nursing. Data were collected on demographics, disease, Palliative Performance Scale (PPS) scores, and end-of-life care needs, in April and May, 2016. RESULTS: Among the six areas of care, "supporting fundamental needs" of patients required the most care, followed by "coordination among family or relatives." Multivariate analysis revealed that the duration of home care nursing held a significant association with end-of-life care needs. CONCLUSION: By reflecting on the comprehensive care needs of patients with chronic illnesses and including them in the care process, it will be possible to provide better quality palliative care to patients at home in the end-of-life stages.

Bereaved Families' Experiences of End-of-Life Care at Home for Older Adults with Non-Cancer in South Korea.

The aim of this study was to gain an understanding of the experiences of families who care for older adults with non-cancer diseases at the end of their lives. The data accrued through in-depth interviews, analyzed using Giorgi's phenomenological method: caregiving burden; situational responsibility; consolation by support; and mourning for the deceased. In Korean culture, adult children had the responsibility of caring for their aged parents as a burden of caregiving and as a main motive for caregiving. Educational and psychological support programs for caregivers should aim to boost confidence, rather than merely focusing on their burden.

Effects of Sexual Media Literacy Education for School Nurses in South Korea.

This study aimed to examine the effects of a sexual education program (SEP) focused on sexual media literacy (SML) for school nurses. A quasi-experimental, pre-/posttest design was used to examine SML knowledge, awareness, reinterpretation skill, and self-efficacy. A total of 66 school nurses participated. The experimental group (n = 35) participated in an 18-hr SEP that focused on SML, while the control group (n = 31) did not. The experimental group showed significant improvement in knowledge (t = 6.47, d = 1.62, p < .001), awareness (t = 5.08, d = 1.19, p < .001), reinterpretation skill (t = 4.81, d = 2.28, p < .001), and self-efficacy (t = 8.29, d = 1.38, p < .001) as compared to the control group. The SEP developed in this study may be an effective educational intervention for school nurses.