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Objective: Impaired skeletal muscle glycogen synthesis contributes to insulin resistance (IR). Aerobic exercise reported to ameliorate IR by augmenting insulin signaling, however the detailed mechanism behind this improvement remains unclear. This study investigated whether aerobic exercise enhances glycogen anabolism and insulin sensitivity via EGR-1/PTP1B signaling pathway in skeletal muscle of rats., Methods: Sprague-Dawley rats fed a high-fat diet (HFD), and performed treadmill exercise training for 6-week. Oral glucose tolerance test was conducted to confirm the IR. Periodic Acid-Schiff (PAS) staining and anthrone colorimetry were used to assess the skeletal muscle glycogen. RT-qPCR, western blot, and immunofluorescence were used to detect the EGR-1/PTP1B pathway and associated signaling molecules., Results: We found that exercise training significantly decreased blood glucose, insulin, and homeostasis model assessment for IR (HOMA-IR) against HFD-induced elevation. Decreased muscle glycogen content due to HFD was significantly restored after exercise training. Exercise training promoted mRNA expressions of Irs1, Akt, and Glut4, while inhibited Gsk-3β expression against HFD. Next, the decreased IRS1 (phosphorylated/total), AKT (phosphorylated/total), and GLUT4, and increased GSK-3β proteins with HFD were significantly reversed by exercise. Furthermore, HFD-induced overexpression of EGR-1 and PTP1B evidenced by mRNA, protein, and immunofluorescence intensity, were substantially inhibited by exercise, which may contribute to promote insulin sensitivity and glycogen anabolism., Conclusions: Aerobic exercise training promotes insulin sensitivity and skeletal muscle glycogen synthesis in HFD-fed rats. The beneficial effects of exercise might be mediated by EGR-1/PTP1B signaling pathway in skeletal muscle, however further studies are necessary to confirm this mechanism., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Choline alfoscerate, a cholinergic precursor with limited evidence of efficacy in dementia management, has been used for various cognitive impairments in Korea. Partly due to its insurance coverage, this agent appears to incur significant expense for the insurance system. Thus, we aimed to describe choline alfoscerate prescription patterns and analyze their long-term effects in an older adult cohort with dementia., Methods: This observational study used the National Health Insurance Service Senior Cohort Dataset. Choline alfoscerate -naïve patients who were diagnosed with dementia between 2003 and 2014 with at least 12 months of follow-up were selected. Time-dependent Cox regression was employed to estimate the association between drug exposure and the risk of treatment failure events., Results: There were 11,463 eligible participants, of whom approximately 73% were female, and 19% had been exposed to choline alfoscerate. According to the main regression survival analysis, the association between longitudinal choline alfoscerate use and the risk of progression events related to treatment failure was unclear. However, a significant decrease of nearly 20% in the risk of all-cause mortality was associated with choline alfoscerate exposure, and a slight reduction in progression regarding treatment failure was observed with CA use only during the early stages of diagnosis. Age, sex, insurance premiums, several comorbidities and concurrent medications were significantly associated with the probability of the events according to the multivariate models., Conclusions: Further analyses are needed to confirm the early-stage and long-term effectiveness of choline alfoscerate in specific populations, which will help in considering its reimbursement., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. Ethical approval was granted by the Research Ethics Committee of Chungnam National University (Date March 11, 2021/ No. 202102-SB-020-01). Consent to participate: Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The dissemination of Klebsiella spp. producing multiple carbapenemases has been increasingly recognized. Between July 2019 and August 2021, ten patients were found to carry Klebsiella spp. co-harboring bla KPC-4 and bla VIM-1 across multiple wards at a Korean hospital, and one isolate was recovered from a hand-washing sink, more than a year after the outbreak. This study aimed to investigate the outbreak and conduct a genomic study of these isolates., Methods: Whole-genome sequencing, including long-read sequencing, was performed to analyze plasmid structures and mobile genetic elements (MGEs). Bioinformatics analyses were performed to trace clonal transmission chains and horizontal gene transfer., Results: The findings suggested that the inter-ward spread of Klebsiella spp. seemed to be facilitated by healthcare worker contact or patient movement. Of the nine isolates collected (eight clinical and one environmental), seven (including the environmental isolate) were identified as K. pneumoniae (ST3680) and two were K. variicola (single-locus variant of ST5252). These isolates showed high genetic relatedness within their species and harbored the IncHI5B plasmid carrying both bla KPC-4 and bla VIM-1 (pKPCVIM.1). On this plasmid, bla VIM-1 was located in the Class 1 integron associated with IS1326::IS1353 (In2), and Tn4401b carrying bla KPC-4 was inserted into IS1326::IS1353, creating a novel MGE construct (In2_bla VIM-1 -Tn4401b_bla KPC-4 )., Conclusion: The hospital-wide spread of bla KPC-4 and bla VIM-1 was facilitated by clonal spread and horizontal plasmid transfer. The persistence of this strain in the hospital sink suggests a potential reservoir of the strain. Understanding the transmission mechanisms of persistent pathogens is important for improving infection control strategies in hospitals., (© 2024. The Author(s).)

Background: As ethical conflicts increase in the ever-changing healthcare field, nursing task performance, which is the overall ability of a nurse's professional knowledge, attitude, and skills, is important for patient health and safety, the provision of quality nursing care, and the appropriate resolution of nursing ethical problems. This study aimed to evaluate the mediating effect of critical thinking disposition on the relationship between hospital ethical climate and nursing task performance., Methods: A cross-sectional study was conducted. A total of a convenience sample of 200 clinical nurses from two Korean cities were recruited between November and December 2021. Direct questionnaires and online surveys were used to collect the data. The study variables were analyzed using descriptive statistics, correlations, and a model tested using the Hayes PROCESS macro (Model 4) mediation model., Results: The mean scores for hospital ethical climate, critical thinking disposition, and nursing task performance were 91.86 ± 11.29, 97.74 ± 10.70, and 138.58 ± 14.95, respectively. Hospital ethical climate and critical thinking disposition were positively correlated with nursing task performance. In the mediation test model, hospital ethical climate was found to be positively and significantly associated with nursing task performance (ß = 0.46, p < .001) with the mediation of critical thinking disposition (ß = 0.70, p < .001)., Conclusions: Hospital ethical climate and critical thinking disposition may be important determinants of task performance among clinical nurses. Hospital administrators should make efforts to create a more positive ethical climate in hospitals and conduct education and campaigns on a positive hospital ethical climate for hospital staff to improve nurses' performance., (© 2024. The Author(s).)

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions., (© 2024. The Author(s).)

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level., (© 2024. The Author(s).)

Background: Acute kidney injury (AKI) has a complex pathophysiology and imposes serious health concerns worldwide. Extracellular vesicles (EVs) derived from induced mesenchymal stem cells (iMSCs) have been recognized as novel cell-free therapeutics for various inflammatory and degenerative disorders. In this study, we investigated whether iMSCs stimulated with a pan-peroxisome proliferator-activated receptor (PPAR) agonist could enhance the therapeutic efficacy of EVs against AKI., Methods: Human iMSCs were primed with or without lanifibranor, a PPAR agonist for 24 h, and EVs were collected after an additional 24 h. The basic characteristics of EVs were evaluated using cryo-transmission electron microscopy imaging, immunoblot detection of EV markers, nanoparticle tracking analysis, and localization in AKI kidneys. In vitro, the potential of the EVs to promote the growth and survival of HK-2 cells undergoing cisplatin-induced apoptosis and anti-inflammatory effects in M1-polarized THP-1 was compared. Subsequently, AKI was induced in BALB/c mice using cisplatin. After 8 and 24 h of cisplatin treatment, iMSC-EVs or pan-PPAR-iMSC-EVs were injected intravascularly. At 96 h after cisplatin administration, the renoprotective effects of iMSC-EVs or pan-PPAR-iMSC-EVs in inhibiting inflammation and apoptosis were compared using serum biochemistry, histology, immunohistochemistry, and gene expression analysis by qPCR., Results: Both EV types expressed EV markers and had typical EV morphology, and their localization in the renal tissue was confirmed. The proliferation and survival of HK-2 cells were higher in pan-PPAR-iMSC-EVs than those in iMSC-EVs. In M1-polarized THP-1 cells, the reduction in the mRNA expression of inflammatory cytokines was more significant in pan-PPAR-iMSC-EVs than that in iMSC-EVs. In the mouse model of cisplatin-induced AKI, pan-PPAR-iMSC-EVs markedly enhanced renoprotective effects compared to iMSC-EVs. Specifically, pan-PPAR-iMSC-EVs reduced tissue inflammation, immune cell infiltration, and apoptosis. Pan-PPAR-iMSC-EVs also increased renal capillary density., Conclusion: Priming iMSCs with a PPAR agonist significantly improved the therapeutic potential of EVs by reducing inflammation and apoptosis. The reported strategy may contribute to the development of a novel cell-free option for AKI treatment., Trial Registration: Not applicable., (© 2023. The Author(s).)

Background: Rectal microbicides (RM) are biomedical HIV prevention products that aim to prevent or reduce the transmission of HIV and other sexually transmitted infections (STIs). RM modalities may be beneficial for populations who have complex lifestyles, difficulties adhering to pre-exposure prophylaxis (PrEP) regimens, and/or have limited access to care. MTN-035 (DESIRE; Developing and Evaluating Short-Acting Innovations for Rectal Use), a randomized crossover trial, aimed to evaluate the safety and acceptability of, and adherence to, three placebo RM modalities (douche, insert, and suppository) prior to receptive anal intercourse., Methods: We conducted latent trajectory analysis to identify clusters of individuals who shared similar trajectories in acceptability and adherence for each product (douche, insert, and suppository) over time. We analyzed weekly short messaging service (SMS) use reports for each modality as reported by enrolled sexual and gender minority (SGM) participants., Results: Two trajectories for each product were identified: a "protocol compliant" trajectory (i.e., at least one product use occasion per week) and "high use" trajectory (i.e., more than three product use occasions per week). Participants with high use were more likely to lack access to PrEP and have higher intentions to utilize RM modalities compared to those who were protocol compliant., Conclusions: This study highlighted high adherence to RM modalities among SGM. As research into viable HIV prevention modalities continues to evolve, tailored intervention strategies are needed to support the uptake of and adherence to alternative prevention modalities that are behaviorally congruent with targeted users., Trial Registration: NCT03671239 (14/09/2018)., (© 2023. The Author(s).)

Background: Single-person households constitute over 40% of all households in the Republic of Korea and are more vulnerable to food insecurity and depression than multi-person households. There is a lack of research on examining whether regional characteristics are associated with the degree of food insecurity and depression among single-person households. This study aimed to examine the regional disparities in food security and depression among single-person households in the Republic of Korea., Methods: A total of 227,873 adults from the 2019 Korean Community Health Survey was included in the analysis. According to population density and poverty rate, the residence of the participants was classified into four regions: metropolitan areas with high population density were classified into areas with low poverty rates (Region 1) and high poverty rates (Region 2), and provinces with low population density were classified into areas with low poverty rates (Region 3) and high poverty rates (Region 4). Using a single item of household food security, those who had experienced a lack of food due to financial difficulties over the past year were classified as food insecure. Depression was measured using the Patient Health Questionnaire-9. Odds ratios and 95% confidence intervals (CI) for the risk of food insecurity and depression according to regional characteristics were calculated after adjusting for potential confounding variables., Results: After adjusting for confounding variables, single-person households in regions with high population density, Regions 1 and 2, had 1.16 times (95% CI = 1.04-1.30) and 1.43 times (95% CI = 1.27-1.61) higher odds of food insecurity, respectively, compared to those in Region 4. Single-person households in regions with low poverty rates, Regions 1 and 3, had 1.54 times (95% CI = 1.34-1.77) and 1.21 times (95% CI = 1.01-1.46) higher odds of depression, respectively, than those in Region 4. Among those who lived alone, the middle-aged, having low income, receiving livelihood benefits, or having a low educational attainment had higher odds of experiencing both food insecurity and depression than their counterparts., Conclusions: As the risk of food insecurity and depression in single-person households differs according to regional characteristics, local governments need to implement policies for single-person households in consideration of these distinct characteristics., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Achondroplasia is an autosomal dominant disorder mainly affecting bony growth, typically resulting in markedly short stature. From a neurosurgical viewpoint, patients sometimes develop spinal cord compression at the narrowed foramen magnum and hydrocephalus. This study aims to construct growth references for height, weight, and head circumference (HC) of young achondroplasia patients in Korea and to evaluate the predictability of the necessity and timing of neurosurgical procedures through growth patterns., Methods: Growth data were collected from achondroplasia patients who visited our institution between January 2002 and August 2022. First, we constructed percentile growth curves of height, weight, and HC for the patients under 3 years of age with the generalized additive model for location, scale, and shape (GAMLSS). Second, the growth patterns of the patients with hydrocephalus who underwent neurosurgical procedures such as foramen magnum decompression (FMD) and ventriculoperitoneal (VP) shunt were analyzed., Results: There were 125 achondroplasia patients, including 67 males and 58 females. Among 125 patients, 46 underwent FMD, and 5 underwent VP shunt. As short stature and macrocephaly were typical characteristics of achondroplasia, the height of achondroplasia was lower than that of the general population, and HC in achondroplasia showed accelerated growth postnatally. There were no significant changes in HC in hydrocephalus patients before they underwent neurosurgical procedures. The influence of hydrocephalus on the growth patterns of HC in achondroplasia seemed insignificant., Conclusion: Growth references for height, weight, and HC in young achondroplasia patients were constructed. It is the first report of growth patterns of achondroplasia in Korea. Unlike other pediatric patients, the diagnosis of hydrocephalus and the necessity of neurosurgical procedures are hard to be predicted with HC in achondroplasia. Neuroimaging should be considered for achondroplasia patients with neurological symptoms., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Background: To evaluate the feasibility of creating flanges using an optic piercing technique with a 6 - 0 polypropylene monofilament for scleral fixation of dislocated one-piece diffractive multifocal intraocular lenses (IOLs)., Study Design: Experimental study and case series., Subjects: Optical bench test and eyes with IOL dislocation., Methods: Two separate 6 - 0 polypropylenes were penetrated twice at the opposite peripheral optic of the TECNIS Synergy IOL (Johnson & Johnson Vision). The root mean square of the modulation transfer function (MTF RMS ), at between + 1.00 and - 4.00 D of defocus, was measured in the TECNIS Synergy IOL both with and without optic piercing in the optical bench study. This case series included three eyes from two patients who underwent scleral-fixation of multifocal IOLs using the four-flanged polypropylene optic piercing technique. The postoperative corrected distance visual acuity (CDVA) at 4 m, the uncorrected near visual acuity (UNVA) at 40 cm, and IOL centration were evaluated., Results: The optical bench test showed no differences in MTF RMS values measured in the TECNIS Synergy IOL, either with or without optic piercing at all defocuses. In all three case series, the postoperative CDVA at 4 m was 20/20 and UNVA at 40 cm was J1. Postoperative anterior segment photographs showed good centration of IOLs in all cases., Conclusion: The four-flanged polypropylene optic piercing technique for multifocal IOL scleral fixation can provide excellent clinical outcomes and IOL stability after surgery without diminishing the performance of the multifocal IOLs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrP Sc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrP Sc types, with T2 being the predominant type ("MV2-1"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrP Sc types, with T1 significantly exceeding T2 ("MV1-2"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel "C-PL" histotypes are distinct entities rather than intermediate forms between "C" and "C-K" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Carbapenemase-producing Enterobacterales (CPE) poses a significant challenge to infection control in healthcare settings. Active screening is recommended to prevent intra-hospital CPE transmission., Methods: CPE screening was initiated at a 660-bed hospital in South Korea in September 2018, targeting patients previously colonized/infected or admitted to outside healthcare facilities (HCFs) within 1 month. Universal intensive care unit (ICU) screening was performed at the time of admission. After a hospital-wide CPE outbreak in July-September 2019, the screening program was enhanced by extending the indications (admission to any HCF within 6 months, receipt of hemodialysis) with weekly screening of ICU patients. The initial screening method was changed from screening cultures to the Xpert Carba-R assay. The impact was assessed by comparing the CPE incidence per 1000 admissions before (phase 1, September 2018-August 2019) and after instituting the enhanced screening program (phase 2, September 2019-December 2020)., Results: A total of 13,962 (2,149 and 11,813 in each phase) were screened as indicated, among 49,490 inpatients, and monthly screening compliance increased from 18.3 to 93.5%. Compared to phase 1, the incidence of screening positive patients increased from 1.2 to 2.3 per 1,000 admissions (P = 0.005) during phase 2. The incidence of newly detected CPE patients was similar (3.1 vs. 3.4, P = 0.613) between two phases, but the incidence of hospital-onset CPE patients decreased (1.9 vs. 1.1, P = 0.018). A significant decrease was observed (0.5 to 0.1, P = 0.014) in the incidence of patients who first confirmed CPE positive through clinical cultures without a preceding positive screening. Compared to phase 1, the median exposure duration and number of CPE contacts were also markedly reduced in phase 2: 10.8 days vs. 1 day (P < 0.001) and 11 contacts vs. 1 contact (P < 0.001), respectively. During phase 2, 42 additional patients were identified by extending the admission screening indications (n = 30) and weekly in-ICU screening (n = 12)., Conclusions: The enhanced screening program enabled us to identify previously unrecognized CPE patients in a rapid manner and curtailed a hospital-wide CPE outbreak. As CPE prevalence increases, risk factors for CPE colonization can broaden, and hospital prevention strategies should be tailored to the changing local CPE epidemiology., (© 2023. The Author(s).)

Background: This study was performed to develop therapeutic targets of osteoarthritis (OA) that can be targeted to alleviate OA development (i.e., cartilage destruction) and relieve the OA-associated joint pain., Methods: The candidate molecule, STING (stimulator of interferon genes, encoded by Sting1), was identified by microarray analysis of OA-like mouse chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). STING functions in OA and hindpaw mechanical allodynia were evaluated by gain-of-function (intra-articular injection of a STING agonist) and loss-of-function (Sting1-/- mice) approaches., Results: DNA damage was observed in OA-like chondrocytes. Cytosolic DNA sensors, STING and its upstream molecule, cGAS (cyclic GMP-AMP synthase), were upregulated in OA chondrocytes and cartilage of mouse and human. Genetic ablation of STING in mice (Sting1-/-) alleviated OA manifestations (cartilage destruction and subchondral bone sclerosis) and hindpaw mechanical allodynia. In contrast, stimulation of STING signaling in joint tissues by intra-articular injection of cGAMP exacerbated OA manifestations and mechanical sensitization. Mechanistic studies on the regulation of hindpaw mechanical allodynia revealed that STING regulates the expression of peripheral sensitization molecules in the synovium and meniscus of mouse knee joints., Conclusion: Our results indicated that STING, which senses damaged cytosolic DNA and accordingly activates the innate immune response, regulates OA pathogenesis and hindpaw mechanical allodynia. Therefore, inhibition of STING could be a therapeutic approach to inhibit OA cartilage destruction and relieve the associated mechanical sensitization in model mice., (© 2023. The Author(s).)

Background: Sensitivity to inhibitors derived from the pretreatment of plant biomass is a barrier to the consolidated bioprocessing of these complex substrates to fuels and chemicals by microbes. Spermidine is a low molecular weight aliphatic nitrogen compound ubiquitous in microorganisms, plants, and animals and is often associated with tolerance to stress. We recently showed that overexpression of the endogenous spermidine synthase enhanced tolerance of the Gram-positive bacterium, Clostridium thermocellum to the furan derivatives furfural and HMF., Results: Here we show that co-expression with an NADPH-dependent heat-stable butanol dehydrogenase from Thermoanaerobacter pseudethanolicus further enhanced tolerance to furans and acetic acid and most strikingly resulted in an increase in thermotolerance at 65 °C., Conclusions: Tolerance to fermentation inhibitors will facilitate the use of plant biomass substrates by thermophiles in general and this organism in particular. The ability to grow C. thermocellum at 65 °C has profound implications for metabolic engineering., (© 2023. The Author(s).)

Background: Recent studies have demonstrated that the distal forearm dual-energy X-ray absorptiometry (DEXA) scan might be a better method for screening bone mineral density (BMD) and the risk of a distal forearm fracture, compared with a central DEXA scan. Therefore, the purpose of this study was to determine the effectiveness of a distal forearm DEXA scan for predicting the occurrence of a distal radius fracture (DRF) in elderly females who were not initially diagnosed with osteoporosis after a central DEXA scan., Methods: Among the female patients who visited our institutes and who were over 50 years old and underwent DEXA scans at 3 sites (lumbar spine, proximal femur, and distal forearm), 228 patients with DRF (group 1) and 228 propensity score-matched patients without fractures (group 2) were included in this study. The patients' general characteristics, BMD, and T-scores were compared. The odds ratios (OR) of each measurement and correlation ratio among BMD values of the different sites were evaluated., Results: The distal forearm T-score of the elderly females with DRF (group 1) was significantly lower than that of the control group (group 2) (p < 0.001 for the one-third radius and ultradistal radius measurements). BMD measured during the distal forearm DEXA scan was a better predictor of DRF risk than BMD measured during the central DEXA (OR = 2.33; p = 0.031 for the one-third radius, and OR = 3.98; p < 0.001 for the ultradistal radius). The distal one-third radius BMD was correlated with hip BMD, rather than lumbar BMD (p < 0.05 in each group)., Conclusion: Performing a distal forearm DEXA scan in addition to a central DEXA scan appears to be clinically significant for detecting the low BMD in the distal radius, which is associated with osteoporotic DRF in elderly females., Level of Evidence: III; case-control study., (© 2023. The Author(s).)

Background: The objectives of this study were to use a digital camera to measure the discoloration of orthodontic elastomeric chains in various immersion solutions over different time periods and to determine the valid acceptability tolerances for color changes in orthodontic elastomeric chains by surveying digital photographs., Methods: Orthodontic elastomeric chains were applied to the maxillary anterior teeth of nine typodont models. The models were divided into three groups and immersed in the curry, coffee, and wine solutions. The digital images of the elastomeric modules were captured and processed using commercial software after 30 min of immersion, thrice a day, for 28 days. The differences in color changes ([Formula: see text]), depending on the type of immersion solution and period, were analyzed using a repeated-measures analysis of variance (ANOVA) test. A web-based survey questionnaire was randomly distributed to 50 respondents for a visual analysis of the elastomeric chain discoloration. The relationship between the surveying score and [Formula: see text] value was analyzed using Spearman's correlation coefficient. The perceptibility and acceptability of elastomeric chain discoloration ([Formula: see text]) based on the type of immersion solutions and periods were analyzed using a regression model., Results: Significant differences were observed in the discoloration of the elastomeric power chain depending on the immersion solution and period. The amount of discoloration was highest in curry, followed by coffee and wine (P < 0.05). The mean discoloration ([Formula: see text]) continued to increase over the entire immersion period. There was a significant correlation between visual scoring and discoloration ([Formula: see text]) over the entire period, especially in the early stages compared to the later stages (r = 0.918, P < 0.05). In 50% of the respondents, the predicted clinically unacceptable discoloration was between 4.46 and 9.98 and in 90% of the respondents, it was between 16.52 and 19.85., Conclusions: The amount of discoloration was the highest for curry, followed by coffee and wine, and continued to gradually increase during the observation period. Significant differences were found between the color measurements obtained and the visual assessment by observers. The observers varied in their tolerance for perceptibility and acceptability for elastomeric chain discoloration based on the type of dietary media., (© 2023. The Author(s).)

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, pruritus, and abnormal epidermal barrier function. Compared with conventional mesenchymal stem cell (MSC), induced pluripotent stem cell (iPSC)-derived mesenchymal stem cell (iMSC) is recognized as a unique source for producing extracellular vesicles (EVs) because it can be obtained in a scalable manner with an enhanced homogeneity. Stimulation of iMSCs with inflammatory cytokines can improve the immune-regulatory, anti-inflammatory, and tissue-repairing potential of iMSC-derived EVs., Results: Proteome analysis showed that IFN-γ-iMSC-EVs are enriched with protein sets that are involved in regulating interferon responses and inflammatory pathways. In AD mice, expression of interleukin receptors for Th2 cytokines (IL-4Rα/13Rα1/31Rα) and activation of their corresponding intracellular signaling molecules was reduced. IFN-γ-iMSC-EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and thymic stromal lymphopoietin and NF-kB activation; and recovered impaired skin barrier, as evidenced by upregulation of key genes of epidermal differentiation and lipid synthesis., Conclusions: IFN-γ-iMSC-EVs inhibit Th2-induced immune responses, suppress inflammation, and facilitate skin barrier restoration, contributing to AD improvement., (© 2022. The Author(s).)

Purpose: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method., Methods: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made., Results: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results., Conclusions: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field., (© 2022. The Author(s).)

Background: Taking facial and intraoral clinical photos is one of the essential parts of orthodontic diagnosis and treatment planning. Among the diagnostic procedures, classification of the shuffled clinical photos with their orientations will be the initial step while it was not easy for a machine to classify photos with a variety of facial and dental situations. This article presents a convolutional neural networks (CNNs) deep learning technique to classify orthodontic clinical photos according to their orientations., Methods: To build an automated classification system, CNNs models of facial and intraoral categories were constructed, and the clinical photos that are routinely taken for orthodontic diagnosis were used to train the models with data augmentation. Prediction procedures were evaluated with separate photos whose purpose was only for prediction., Results: Overall, a 98.0% valid prediction rate resulted for both facial and intraoral photo classification. The highest prediction rate was 100% for facial lateral profile, intraoral upper, and lower photos., Conclusion: An artificial intelligence system that utilizes deep learning with proper training models can successfully classify orthodontic facial and intraoral photos automatically. This technique can be used for the first step of a fully automated orthodontic diagnostic system in the future., (© 2022. The Author(s).)

Background: The activation of the telomere maintenance mechanism (TMM) is one of the critical drivers of cancer cell immortality. In gliomas, TERT expression and TERT promoter mutation are considered to reliably indicate telomerase activation, while ATRX mutation and/or loss indicates an alternative lengthening of telomeres (ALT). However, these relationships have not been extensively validated in tumor tissues., Methods: Telomerase repeated amplification protocol (TRAP) and C-circle assays were used to profile and characterize the TMM cross-sectionally (n = 412) and temporally (n = 133) across glioma samples. WES, RNA-seq, and NanoString analyses were performed to identify and validate the genetic characteristics of the TMM groups., Results: We show through the direct measurement of telomerase activity and ALT in a large set of glioma samples that the TMM in glioma cannot be defined solely by the combination of telomerase activity and ALT, regardless of TERT expression, TERT promoter mutation, and ATRX loss. Moreover, we observed that a considerable proportion of gliomas lacked both telomerase activity and ALT. This telomerase activation-negative and ALT negative group exhibited evidence of slow growth potential. By analyzing a set of longitudinal samples from a separate cohort of glioma patients, we discovered that the TMM is not fixed and can change with glioma progression., Conclusions: This study suggests that the TMM is dynamic and reflects the plasticity and oncogenicity of tumor cells. Direct measurement of telomerase enzyme activity and evidence of ALT should be considered when defining TMM. An accurate understanding of the TMM in glioma is expected to provide important information for establishing cancer management strategies., (© 2022. The Author(s).)

Background: Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid-polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD., Results: Gb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old male B6;129-Gla tm1Kul /J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved., Conclusions: PEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease., (© 2022. The Author(s).)

Background: The inferior alveolar nerve (IAN) innervates and regulates the sensation of the mandibular teeth and lower lip. The position of the IAN should be monitored prior to surgery. Therefore, a study using artificial intelligence (AI) was planned to image and track the position of the IAN automatically for a quicker and safer surgery., Methods: A total of 138 cone-beam computed tomography datasets (Internal: 98, External: 40) collected from multiple centers (three hospitals) were used in the study. A customized 3D nnU-Net was used for image segmentation. Active learning, which consists of three steps, was carried out in iterations for 83 datasets with cumulative additions after each step. Subsequently, the accuracy of the model for IAN segmentation was evaluated using the 50 datasets. The accuracy by deriving the dice similarity coefficient (DSC) value and the segmentation time for each learning step were compared. In addition, visual scoring was considered to comparatively evaluate the manual and automatic segmentation., Results: After learning, the DSC gradually increased to 0.48 ± 0.11 to 0.50 ± 0.11, and 0.58 ± 0.08. The DSC for the external dataset was 0.49 ± 0.12. The times required for segmentation were 124.8, 143.4, and 86.4 s, showing a large decrease at the final stage. In visual scoring, the accuracy of manual segmentation was found to be higher than that of automatic segmentation., Conclusions: The deep active learning framework can serve as a fast, accurate, and robust clinical tool for demarcating IAN location., (© 2021. The Author(s).)

Background: Extracellular vesicles (EVs) are recognized as novel cell-free therapeutics. Non-alcoholic steatohepatitis (NASH) remains a critical health problem. Herein, we show that EVs from pan peroxisome proliferator-activated receptor agonist-primed induced mesenchymal stem cell (pan PPAR-iMSC-EVs) has unique cargo protein signatures, and demonstrate its therapeutic function in NASH., Results: A unique protein signatures were identified in pan PPAR-iMSC-EVs against those from non-stimulated iMSC-EVs. NASH mice receiving pan PPAR-iMSC-EVs showed reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation. Moreover, pan PPAR-iMSC-EVs promoted liver regeneration via inhibiting apoptosis and enhancing proliferation., Conclusions: We conclude that our strategy for enriching unique cargo proteins in EVs may facilitate the development of novel therapeutic option for NASH., (© 2021. The Author(s).)

Background: Scabies causes considerable morbidity in disadvantaged populations. The International Alliance for the Control of Scabies (IACS) published consensus criteria in 2020 to standardize scabies diagnosis. However, these criteria are complex, and a WHO informal consultation proposed simplified criteria for mapping, to identify regions of high prevalence as targets for mass drug administration. We aimed to investigate the accuracy of simplified criteria in determining scabies prevalence, compared to the 2020 IACS criteria., Methods: We obtained data relating to demographics, relevant history and skin lesions from all-age prevalence surveys from Fiji (n = 3365) and Solomon Islands (n = 5239), as well as school-aged children in Timor-Leste (n = 1043). We calculated prevalence using the 2020 IACS criteria and simplified criteria and compared these disease estimates., Results: There was no significant difference in the pooled prevalence using the two methods (2020 IACS criteria: 16.6%; simplified criteria: 15.6%; difference = 0.9, [95% CI -0.1, 2.0]). In Timor-Leste, the prevalence using simplified criteria was lower (26.5% vs 33.8%). Simplified criteria had a sensitivity of 82.3% (95% CI 80.2, 84.2) and specificity of 97.6% (95% CI 97.2, 97.9) compared to the 2020 IACS criteria., Conclusions: The scabies prevalence estimation using simplified criteria was similar to using the 2020 IACS criteria in high prevalence, tropical countries. The prevalence estimation was lower in the school-based survey in Timor-Leste. Mapping using simplified criteria may be a feasible and effective public health tool to identify priority regions for scabies control. Further work assessing use of simplified criteria for mapping in a field setting should be conducted., (© 2021. The Author(s).)

Background: To compare clinical outcomes and optical performance of a new monofocal with enhanced intermediate function intraocular lenses (IOLs) with that of conventional monofocal IOLs., Methods: Sixty eyes of 30 patients who underwent phacoemulsification with bilateral implantation of the ICB00 (15 patients) or ZCB00 (15 patients) IOLs were enrolled. Binocular corrected distance visual acuity (CDVA), distance corrected near visual acuity (DCNVA), and distance corrected intermediate visual acuity (DCIVA) were measured at 4 weeks after surgery. Patient satisfaction for overall, near, intermediate, and distance vision were assessed. The binocular defocus curves were measured. The root mean square of modulation transfer function (MTF RMS ) was measured in the optical bench study., Results: The mean binocular DCIVA was significantly better in the ICB00 group (0.01 logMAR) compared to the ZCB00 group (0.13 logMAR), but CDVA and DCNVA were not. The patient satisfaction for near and intermediate vision was significantly higher in the ICB00 group compared to the ZCB00. However, there was no difference in patient satisfaction for overall and distance vision between two groups. The defocus curves showed that mean visual acuity of the ICB00 group was significantly better than that of the ZCB00 group at between - 1.00 D to - 3.00 D of defocus. The ICB00 IOL had higher MTF RMS values at between - 0.50 D to - 2.00 D of defocus compared to the ZCB00 IOL., Conclusions: The ICB00 IOL provides better binocular intermediate vision and higher satisfaction for near and intermediate vision than the ZCB00 IOL while maintaining excellent distance vision., (© 2021. The Author(s).)

Background: Sjogren's syndrome (SS) is a heterogenous disease with various phenotypes. We aimed to provide a relevant subclassification based on symptom-based clustering for patients with primary (p) SS., Methods: Data from patients in a prospective pSS cohort in Korea were analysed. Latent class analysis (LCA) was performed using patient reported outcomes, including pain, fatigue, dryness, and anxiety/depression. Clinical and laboratory differences between the classes were analysed. Latent transition analysis (LTA) was applied to the longitudinal data (annually for up to 5 years) to assess temporal stability of the classifications., Results: LCA identified three classes among 341 patients with pSS (i.e., 'high symptom burden', 'dryness dominant', 'low symptom burden'). Each group had distinct laboratory and clinical phenotypes. LTA revealed that class membership remained stable over time. Baseline class predicted future salivary gland function and damage accrual represented by a Sjogren's syndrome disease damage index., Conclusion: Symptom-based clustering of heterogenous patients with primary Sjogren's syndrome provided a relevant classification supported by temporal stability over time and distinct phenotypes between the classes. This clustering strategy may provide more homogenous groups of pSS patients for novel treatment development and predict future phenotypic evolvement., (© 2021. The Author(s).)

Background: Self-expanding nitinol stent (SENS) implantation is commonly oversized in the superficial femoral artery (SFA), and leads to chronic outward force (COF) and in-stent restenosis (ISR). This study aimed to investigate the impact of COF of oversizing SENS on ISR of SFA., Methods: In patients with implanted SENS in SFA, intimal hyperplasia especially between proximal segment and distal segment was evaluated by quantitative angiography, and the impact of COF on mid-term angiographic outcomes was investigated. In addition, porcine model with implanted SENS was used to evaluate the impact of COF on angiographic and histopathologic outcomes at 1 month. Excised stented arteries were evaluated by histopathologic analysis., Results: We analyzed 65 SENS in 61 patients with follow-up angiography at 6 months to 1 year. The baseline diameter was 6.8 ± 0.71 mm and length were 97.0 ± 33.8 mm for the SENS. The ratio of the diameter of the stent to the reference vessel was 1.3 ± 0.24 at the proximal portion and 1.53 ± 0.27 at the distal portion (P < 0.001). In the long SFA stent, stent-to-vessel ratio was significantly higher in the distal stent than in the proximal stent (1.3 ± 0.2 vs. 1.55 ± 0.25, P = 0.001). ISR incidence was higher at the distal stent (37.3% vs 52.6%, P = 0.029). All 11 pigs survived for 4 weeks after SENS implantation. The vessel diameter was 4.04 ± 0.40 mm (control group) vs 4.45 ± 0.63 mm (oversized group), and the implanted stent diameter was 5.27 ± 0.46 mm vs. 7.18 ± 0.4 mm (P = 0.001). The stent-to-vessel diameter ratio was 1.31 ± 0.12 versus 1.63 ± 0.20 (P < 0.001). After 4 weeks, restenosis % was 29.5 ± 12.9% versus 46.8 ± 21.5% (P = 0.016). The neointimal area was 5.37 ± 1.15 mm 2 vs. 8.53 ± 5.18 mm 2 (P = 0.05). The restenosis % was 39.34 ± 8.53% versus 63.97 ± 17.1% (P = 0.001)., Conclusions: COF is an important cause of restenosis in the distal portion of the SFA stent. Optimal sizing of the SFA stent is important to reduce the incidence of restenosis. Therefore, COF was an important factor of restenosis following distal SFA stenting.

Background: Atopic dermatitis (AD) is a chronic allergic inflammatory skin disease characterized by complex pathogenesis including skin barrier dysfunction, immune-redox disturbances, and pruritus. Prolonged topical treatment with medications such as corticosteroids, calcineurin inhibitors, and T-cell inhibitors may have some potential side-effects. To this end, many researchers have explored numerous alternative therapies using natural products and mineral compounds with antioxidant or immunomodulatory effects to minimize toxicity and adverse-effects. In the current study, we investigated the effects of mineral complex material (MCM) treatment on 2, 4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in SKH-1 hairless mice., Methods: Animals were divided into four groups; normal control (NC), negative control treated with DNCB only (DNCB only), positive control treated with DNCB and tacrolimus ointment (PC) and experimental group treated with DNCB and MCM patch (MCM). Skin inflammation and lesion severity were investigated through analyses of skin parameters (barrier score and strength, moisture and trans-epidermal water loss level), histopathology, immunoglobulin E, and cytokines. In addition, reactive oxygen species (ROS), nitric oxide (NO), glutathione peroxidase (GPx), and catalase (CAT) levels were measured in both serum and skin lysate., Results: Our results demonstrates that MCM patch improved the progression of AD-like skin lesions by significantly increasing skin barrier strength and decreasing trans-epidermal water loss. Additionally, dermal administration of MCM patch significantly reduced epidermal thickness, ROS, and NO levels in skin lysate. Furthermore, we found that MCM suppressed the levels of AD-involved (Th 1 and Th 2 ) cytokines such as IL-2, IFN-γ, and IL-4 in blood. In addition, the levels of other Th 1, and Th 2 and inflammatory cytokines such as IL-1β, TNF-α, IL-6, IL-12(p70) and IL-10 were found lowest in the MCM group than in the DNCB only and PC groups. Moreover, we found total serum IgE level significantly increased after DNCB treatment, but decreased in the PC and MCM groups., Conclusion: Taken together, our findings suggest that MCM application may have beneficial effects either systemic or regional on DNCB-induced AD lesional skin via regulation of the skin barrier function and immune-redox response.

Background: Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (T FH ) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to T FH cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of T FH cells in two murine models of lupus., Methods: 10-week-old MRL/lpr mice were orally administered with 100 mg/kg of niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization., Results: Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, niclosamide inhibited the proportion of T FH cells and PCs in the spleens of these animals, and effectively suppressed differentiation of T FH -like cells and expression of associated genes in vitro., Conclusions: Niclosamide exerted therapeutic effects on murine lupus models by suppressing T FH cells and plasma cells through STAT3 inhibition.

Background: Preterm birth (PTB) is one of major causes of perinatal mortality and neonatal morbidity, but knowledge of its complex etiology is still limited. Here we present cervicovaginal fluid (CVF) protein profiles of pregnant women who subsequently delivered at spontaneous preterm or term, aiming to identify differentially expressed CVF proteins in PTB and term birth., Methods: The CVF proteome of women who sequentially delivered at preterm and term was analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional nanoflow liquid chromatography-tandem mass spectrometry (2D-nLC-MS/MS). We compared the CVF proteome of PTB (n = 5) and control subjects (term birth, n = 7) using pooled control CVF (term birth, n = 20) as spike-in standard., Results: We identified 1294 CVF proteins, of which 605 were newly identified proteins. Of 990 proteins quantified in both PTB and term birth, 52 proteins were significantly up/down-regulated in PTB compared to term birth. The differentially expressed proteins were functionally associated to immune response, endopeptidase inhibitors and structural constituent of cytoskeleton. Finally, we confirm the down-regulation of SERPINB7 (a serine-type protease inhibitor) in PTB compared to control by Western blot., Conclusions: Taken together, our study provide quantitative CVF proteome profiles of pregnant women who ultimately delivered at preterm and term. These promising results could help to improve the understanding of PTB etiology and to discover biomarkers for asymptomatic PTB.

Background: Cervical myelopathy and hydrocephalus occasionally occur in young children with achondroplasia. However, these conditions are not evaluated in a timely manner in many cases. The current study presents significant predictors for cervical myelopathy and hydrocephalus in young children with achondroplasia., Methods: A retrospective analysis of 65 patients with achondroplasia who visited Seoul National University Children's Hospital since 2012 was performed. The patients were divided into groups according to the presence of cervical myelopathy and hydrocephalus, and differences in foramen magnum parameters and ventricular parameters by magnetic resonance imaging between groups were analyzed. Predictors for cervical myelopathy and hydrocephalus were analyzed, and the cut-off points for significant ones were calculated., Results: The group with cervical myelopathy showed foramen magnum parameters that indicated significantly lower cord thickness than in the group without cervical myelopathy, and the group with hydrocephalus showed significantly higher ventricular parameters and 'Posterior indentation' grade than the group without hydrocephalus. 'Cord constriction ratio' (OR 5199.90, p = 0.001) for cervical myelopathy and 'Frontal horn width' (OR 1.14, p = 0.001) and 'Posterior indentation' grade (grade 1: OR 9.25, p = 0.06; grade 2: OR 18.50, p = 0.01) for hydrocephalus were significant predictors. The cut-off points for cervical myelopathy were 'Cord constriction ratio' of 0.25 and 'FM AP' of 8 mm (AUC 0.821 and 0.862, respectively) and 'Frontal horn width' of 50 mm and 'Posterior indentation' grade of 0 (AUC 0.788 and 0.758, respectively) for hydrocephalus., Conclusion: 'Cord constriction ratio' for cervical myelopathy and 'Frontal horn width' and 'Posterior indentation' grade for hydrocephalus were significant predictors and may be used as useful parameters for management. 'Posterior indentation' grade may also be used to determine the treatment method for hydrocephalus.

Mitochondrial movement in neurons is finely regulated to meet the local demand for energy and calcium buffering. Elaborate transport machinery including motor complexes is required to deliver and localize mitochondria to appropriate positions. Defects in mitochondrial transport are associated with various neurological disorders without a detailed mechanistic information. In this study, we present evidence that dystrobrevin-binding protein 1 (dysbindin), a schizophrenia-associated factor, plays a critical role in axonal mitochondrial movement. We observed that mitochondrial movement was impaired in dysbindin knockout mouse neurons. Reduced mitochondrial motility caused by dysbindin deficiency decreased the density of mitochondria in the distal part of axons. Moreover, the transport and distribution of mitochondria were regulated by the association between dysbindin and p150 glued . Furthermore, altered mitochondrial distribution in axons led to disrupted calcium dynamics, showing abnormal calcium influx in presynaptic terminals. These data collectively suggest that dysbindin forms a functional complex with p150 glued that regulates axonal mitochondrial transport, thereby affecting presynaptic calcium homeostasis.

Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting., Methods: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis., Results: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset., Conclusions: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.

Background: Extracellular vesicles (EVs) secreted by tumours, including exosomes, are important factors that regulate cell-cell interactions in oncogenesis. Although EV studies are ongoing, the biological understanding of EV-miRNAs derived from brain tumour spheroid-forming cells (BTSCs) of medulloblastoma is poor., Purposes: We explored the specific cellular miRNAs and EV-miRNAs in medulloblastoma BTSCs to determine their potential biological function., Methods: Bulk tumor cells (BTCs) and BTSCs were cultured under different conditions from medulloblastoma tissues (N = 10)., Results: Twenty-four miRNAs were simultaneously increased in both cells and EVs derived from BTSCs in comparison to BTCs. After inhibition of miR-135b or miR135a which were the most significantly increased in BTSCs, cell viability, self-renewal and stem cell marker expression decreased remarkably. Through integrated analysis of mRNAs and miRNAs data, we found that angiomotin-like 2 (AMOTL2), which was significantly decreased, was targeted by both miR-135b and miR-135a. STAT6 and GPX8 were targeted only by miR-135a. Importantly, low expression of AMOTL2 was significantly associated with overall poor survival in paediatric Group 3 and Group 4 medulloblastoma patients., Conclusion: Our results indicated that inhibition of miR-135b or miR-135a leads to suppress stemness of BTSC through modulation of AMOTL2.

Background: Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy., Methods: We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children's Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients' choice., Results: The median age at diagnosis was 11.9 (range, 3.8-25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy., Conclusion: The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.

Background: While ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically., Methods: We reviewed nine NTRK fusion-positive pediatric sarcomas confirmed by fluorescence in situ hybridization and/or next-generation sequencing from Seoul National University Hospital between 2002 and 2020., Results: One case of TPR-NTRK1 fusion-positive intracranial, extra-axial, high-grade undifferentiated sarcoma (12-year-old boy), one case of LMNA-NTRK1 fusion-positive low-grade infantile fibrosarcoma of the forehead (3-year-old boy), one case of ETV6-NTRK3 fusion-positive inflammatory myofibroblastic tumor (IMT) (3-months-old girl), and six cases of ETV6-NTRK3 fusion-positive infantile fibrosarcoma (median age: 2.6 months, range: 1.6-5.6 months, M: F = 5:1) were reviewed. The Trk immunopositivity patterns were distinct, depending on what fusion genes were present. We observed nuclear positivity in TPR-NTRK1 fusion-positive sarcoma, nuclear membrane positivity in LMNA-NTRK1 fusion-positive sarcoma, and both cytoplasmic and nuclear positivity in ETV6-NTRK3 fusion-positive IMT and infantile fibrosarcomas. Also, the TPR-NTRK1 fusion-positive sarcoma showed robust positivity for CD34/nestin, and also showed high mitotic rate. The LMNA-NTRK1 fusion-positive sarcoma revealed CD34/S100 protein/nestin/CD10 coexpression, and a low mitotic rate. The IMT with ETV6-NTRK3 fusion expressed SMA. Six infantile fibrosarcomas with ETV6-NTRK3 fusion showed variable coexpression of nestin (6/6)/CD10 (4/5)/ S100 protein (3/6)., Conclusions: All cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

Background: Rheumatoid arthritis (RA) is a long-term autoimmune disorder that mostly affects the joints and leads to the destruction of cartilage. An RA model in non-human primates is especially useful because of their close phylogenetic relationship to humans in terms of cross-reactivity to compounds developed using modern drug technologies., Methods: We used a collagen-induced arthritis (CIA) model in Macaca fascicularis. CIA was induced by the immunization of chicken type II collagen. Swelling was measured as the longitudinal and transverse axes of 16 proximal interphalangeal joints., Results: A new system for visual evaluation was created, with a perfect score of 16. Individual behavioral analysis was also conducted. Serum was collected once a week after the first immunization. Blood chemistry and inflammatory cytokine parameters were higher in the CIA group than in the wild type group., Conclusion: In conclusion, we established CIA in M. fascicularis, and the results can be used for drug evaluation models.

Background: Sjögren's syndrome (SS) is an autoimmune disease mediated by lymphocytic infiltration into exocrine glands, resulting in progressive lacrimal and salivary destruction and dysfunctional glandular secretion. Metabolic syndrome influences the immune system. To investigate its relationship with metabolic abnormalities, we evaluated the pathogenesis of SS and the immune cell populations in non-obese diabetic NOD/ShiLtJ mice with type 1 diabetes (T1D)., Methods: To induce metabolic abnormalities, streptozotocin (STZ)-a glucosamine-nitrosourea compound that destroys pancreatic β cells, resulting in T1D-was injected into NOD/ShiLtJ mice. The blood glucose level was measured to evaluate induction of T1D. The severity of SS was assessed by determining the body weight, salivary flow rate, and histologic parameters. The expression levels of proinflammatory factors in the salivary glands, lacrimal gland, and spleen were quantified by real-time PCR. The populations of various T- and B-cell subtypes in the peripheral blood, spleen, and salivary glands were assessed by flow cytometry., Results: Induction of T1D in NOD/ShiLtJ mice increased both the severity of SS and the levels of proinflammatory cytokines in the salivary glands compared to the controls. Furthermore, the number of interleukin-17-producing immune cells in the peripheral blood, spleen, and salivary glands was increased in STZ- compared to vehicle-treated NOD/ShiLtJ mice., Conclusions: Metabolic abnormalities play an important role in the development of SS.

Background: Ulnar neuropathy is a common reason for referral to hand surgeons, and 10 to 30% of cubital tunnel syndrome (CuTS) is idiopathic. We hypothesized that the cause of idiopathic CuTS is in the bony structure., Methods: We analyzed 79 elbows (39 idiopathic CuTS and 40 without CuTS symptom) using computed tomography and Materialize Mimics software to compare the differences between the two groups. We proposed a new bony cubital tunnel with a new boundary that could play a role in ulnar nerve compression symptom., Results: The mean cubital tunnel volume was 1245.6 mm 3 in all patients, 1180.6 mm 3 in CuTS patients, and 1282.3 mm 3 in the control group. A significant difference (p = 0.015) between two groups was found. Bony cubital tunnel cross-sectional area, cubital tunnel depth, and cubital tunnel angle also showed significant differences., Conclusion: The shape of the bony cubital tunnel is an important cause of CuTS, and the normal variation of the volume and cross-sectional area of the cubital tunnel and cubital tunnel angle could influence the occurrence of idiopathic CuTS.

Background: The aim of this study is to investigate the composition of microbiota in biliary tract cancer patients and healthy adults by metagenome analysis and evaluate its potential values as biomarkers for biliary tract cancer., Methods: Patients who were diagnosed with biliary tract cancer or benign inflammation were enrolled in this study. The control group consisted of healthy adults who presented with no history of significant medical issues. We isolated bacteria-derived extracellular vesicles in the plasma. The microbiome composition was investigated with 16S rDNA metagenome analysis. We evaluated each microbiome to ensure suitability for the biliary tract cancer prediction model., Results: A total of 155 patients were included in this study: 24 patients with diagnosed biliary tract cancers, 43 diagnosed with cholecystitis or cholangitis, and 88 healthy adults. The microbiome composition pattern of the biliary tract cancer differed from the microbiome composition pattern seen in healthy adult group in beta diversity analysis. The percent composition of microbiota was found to be different from the phylum to genus level. Differences in the composition of the Bifidobacteriaceae and Pseudomonaceae families and Corynebacteriaceae Corynebacterium, Oxalobacteraceae Ralstonia and Comamonadaceae Comamonas species may be used to develop predictive models for biliary tract cancer., Conclusion: Biliary tract cancer patients have altered microbiome composition, which represents a promising biomarker to differentiate malignant biliary tract disease from normal control group.

Background: This study investigated the dose-response relationship between alcohol consumption and CVD incidence, conducting a meta-analysis of studies focusing on residents from local communities. Further, we examined whether light to moderate alcohol consumption had a protective effect on CVD incidence through a sub-group analysis., Methods: This study conducted a meta-analysis of the relationship between alcohol consumption and CVD incidence, selecting journals published up to December 2017. The alcohol consumption level was classified into non-consumers, light (0.01-10.0 g/day), light to moderate (10.1-20.0 g/day), moderate (20.1-40.0 g/day), moderate to high (40.1-60.0 g/day), and high (> 60.0 g/day) groups. The sub-group analysis was conducted according to the number of comorbidities and age., Results: Seven articles were selected in total for the meta-analysis. The mean Newcastle-Ottawa scale score was 8.14 points, suggesting studies were of high quality. There was a J-shaped dose-response relationship between alcohol consumption level and CVD incidence only in men. In general, light to moderate and moderate consumption lowered CVD incidence (Relative risk (RR) [95% confidence interval (CI)] was 0.68 [0.57-0.81] and 0.72 [0.58-0.90], respectively). In men with 3-4 comorbidities, there were no protective effects of light to moderate and moderate consumption on CVD incidence. In either groups of only men or men and women there were protective effects of light to moderate and moderate consumption on CVD incidence only in those aged between 41 and 65., Discussion: We found that light to moderate and moderate alcohol consumption had a protective effect on CVD incidence, there was no protective effect either in those with at least three comorbidities or people aged 40 or younger., Conclusions: We conclude that not all local community residents experience a protective effect of light to moderate consumption on CVD incidence. As such, it is necessary to recommend a moderate amount of drinking or less for each individual.

Background: The antibody-dependent cellular cytotoxicity (ADCC) is a cell-mediated immune defense mechanism in which effector immune cells actively lyse antibody-coated target cells. The ADCC of tumor cells is employed in the treatment of various cancers overexpressing unique antigens, and only natural killer (NK) cells are known to be major effectors of antibody mediated ADCC activity. Canine NK cells are still defined as non-B, non-T large granular lymphocytes because of the lack of information regarding the NK cell-restricted specific marker in dogs, and it has never been demonstrated that canine NK cells have ADCC ability against tumor cells. In the present study, we investigated whether canine non-B, non-T NK cells have ADCC ability against target antibody-coated tumor cells, using cetuximab and trastuzumab, the only human antibodies reported binding to canine cancer cells., Results: Activated canine non-B, non-T NK cells (CD3 - CD21 - CD5 - TCRαβ - TCRγδ - ) for 13~17 days ex vivo showed ADCC ability against trastuzumab- or cetuximab-coated target tumor cells expressing various levels of human epidermal growth factor receptor 2 (HER-2) and epidermal growth factor receptor (EGFR). Trastuzumab and cetuximab induced significant ADCC responses of canine NK cells even in CMT-U334 and CF41.Mg cells expressing low levels of HER-2 and/or EGFR, as well as in SKBR3 and DU145 cells overexpressing HER-2 and/or EGFR. The trastuzumab-mediated ADCC activity of NK cells was significantly enhanced by treatment with rcIL-21., Conclusions: The results of this study suggest that canine non-B, non-T NK lymphocytes have a potential ADCC function and that combinational strategies of monoclonal antibodies with either cytokines, which activate NK cells in vivo, or adoptive transfer of NK cells may be a feasible method for amplifying the efficacy of immunotherapy against malignant cancers even with very low expression of target molecules in dogs.

Background: Radioiodine (RI) treatments can destroy the cellular components of salivary glands (SG) and disrupt their function. This study investigated whether fucoidan could attenuate radioiodine-induced SG dysfunction in a mouse model., Methods: Female C57BL/6 mice (n = 36) were classified into three groups; i) a normal (control) group, ii) an RI-treated group (0.2 mCi/20 g mouse, administered orally), and iii) a fucoidan and RI-treated group. Mice in each group were classified into three subgroups and sacrificed at 2, 4, and 12 weeks after RI treatment. The measurements of salivary flow rates and lag times and histomorphologic examinations were performed, and apoptotic assays were conducted. Changes in salivary 99m Technetium (Tc)-pertechnetate parameters using single-photon emission computed tomography were followed., Results: Salivary flow rates and lag times in the fucoidan group were improved compared to the RI-treated group. Histologic examinations of SGs in the fucoidan group showed mucin-rich parenchymal areas and reduced periductal fibrosis as compared to the RI-treated group. Moreover, compared with the RI-treated group, fucoidan-treated groups showed evidence of cytoprotection, with a greater number of salivary epithelial cells and myoepithelial cells being observed. Fewer apoptotic cells were observed in the fucoidan group as compared to the RI group. The extent of 99m Tc pertechnetate excretion in the fucoidan group was similar to that of the control group., Conclusion: Our results demonstrate that fucoidan administration before RI treatment could attenuate RI-induced SG damage and provides a possible candidate for preventing SG damage induced by RI.

Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets., Methods: Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines., Results: WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNA-Seq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells., Conclusions: We propose that NPM1 is a novel therapeutic target for AT/RTs.

Background: The purpose of the present study was to demonstrate whether alcohol consumption could predict spinal structural damage in axial spondyloarthritis (axSpA) in a prospective cohort study., Methods: AxSpA patients were enrolled from a single tertiary hospital in a prospective cohort. Baseline data were collected, and 2-year follow-up radiographic data were collected. We analyzed the progression of spinal structural damage in 278 axSpA patients and grouped them into alcohol drinkers and non-drinkers. Baseline and follow-up characteristics were compared between the two groups. Univariable and multivariable logistic regression analyses were performed to reveal predictors of spinal structural damage., Results: Changes in modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and syndesmophyte count over the 2-year period were more prominent in the alcohol drinker group than in the non-drinker group (2.7 ± 3.6 vs 1.5 ± 2.8, P = 0.007, 0.9 ± 1.3 vs 0.4 ± 1.2, P = 0.003). The alcohol drinker group showed more frequent significant mSASSS changes (≥ 2 units for 2 years follow-up) and new syndesmophyte/progression of pre-existing syndesmophytes than the non-drinker group (60.7% vs 29.2%, P < 0.001, 51.5% vs 26.4%, P < 0.001, respectively). On univariable and multivariable regression analyses, drinking alcohol showed a significant relationship with the progression of spinal structural damage for both mSASSS and syndesmophyte progression., Conclusion: The present study showed the association between alcohol consumption and spinal structural progression in axSpA patients for the first time.

Background: Using a pathway-focused approach, we aimed to provide a subgroup-specific basis for finding novel therapeutic strategies and further refinement of the risk stratification in pediatric medulloblastoma., Method: Based on genome-wide Cox regression and Gene Set Enrichment Analysis, we investigated prognosis-related signaling pathways and core genes in pediatric medulloblastoma subgroups using 530 patient data from Medulloblastoma Advanced Genomic International Consortium (MAGIC) project. We further examined the relationship between expression of the prognostic core genes and frequent chromosome aberrations using broad range copy number change data., Results: In SHH subgroup, relatively high expression of the core genes involved in p53, PLK1, FOXM1, and Aurora B signaling pathways are associated with poor prognosis, and their average expression synergistically increases with co-occurrence of losses of 17p, 14q, or 10q, or gain of 17q. In Group 3, in addition to high MYC expression, relatively elevated expression of PDGFRA, IGF1R, and FGF2 and their downstream genes in PI3K/AKT and MAPK/ERK pathways are related to poor survival outcome, and their average expression is increased with the presence of isochromosome 17q [i(17q)] and synergistically down-regulated with simultaneous losses of 16p, 8q, or 4q. In Group 4, up-regulation of the genes encoding various immune receptors and those involved in NOTCH, NF-κB, PI3K/AKT, or RHOA signaling pathways are associated with worse prognosis. Additionally, the expressions of Notch genes correlate with those of the prognostic immune receptors. Besides the Group 4 patients with previously known prognostic aberration, loss of chromosome 11, those with loss of 8q but without i(17q) show excellent survival outcomes and low average expression of the prognostic core genes whereas those harboring 10q loss, 1q gain, or 12q gain accompanied by i(17q) show bad outcomes. Finally, several metabolic pathways known to be reprogrammed in cancer cells are detected as prognostic pathways including glutamate metabolism in SHH subgroup, pentose phosphate pathway and TCA cycle in Group 3, and folate-mediated one carbon-metabolism in Group 4., Conclusions: The results underscore several subgroup-specific pathways for potential therapeutic interventions: SHH-GLI-FOXM1 pathway in SHH subgroup, receptor tyrosine kinases and their downstream pathways in Group 3, and immune and inflammatory pathways in Group 4.

Background: Activated T and B cells participate in the development and progression of Sjögren's syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS., Methods: Metformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4 + T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay., Results: Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells., Conclusion: Metformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.

Background: Warfarin is evidence-based therapy for the prevention of cardioembolic stroke, but has not been studied for its effects on whole blood viscosity (WBV). This study investigated the effect of warfarin versus aspirin on WBV in patients presenting with non-valvular atrial fibrillation (NVAF) and acute cardioembolic stroke., Methods: We enrolled patients with acute cerebral infarction, aged 56-90 years who had NVAF, CHADS 2 score ≥ 2, presenting with mild-to-moderate stroke (National Institute of Health Stroke Scale (NIHSS) score < 20 and modified Rankin Scale (2mRS) score < 4) in a single center. The patients were alternately assigned to warfarin or aspirin groups. Post-treatment WBV was assessed after international normalized ratio (INR) reached target range [2, 3] for patients in the warfarin group, and 5 days after baseline in the aspirin group., Results: Total 67 patients were included, and 56 completed this study (33 warfarin and 23 aspirin). Compared to baseline values, warfarin reduced post-treatment BV at all shear rates. The BV reductions greater than 1 cP measured at shear rates of 300, 150, 5, and 1 s - 1 were independently and significantly associated with warfarin treatment compared to aspirin after adjusting for age, sex, CHA 2 DS 2 -VASc scores, and baseline hematocrit., Conclusions: Warfarin confers greater reductions in BV than aspirin in patients with acute cardioembolic stroke. BV could be a useful method to estimate thrombotic risk in patients receiving warfarin., Trial Registration: KCT0001291 , Date of Registration: 2014-12-01.