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Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro , B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by skin and internal organ fibrosis and obliterative vasculopathy. Few effective treatments are currently available for fibrosis in SSc, therefore, demand persists for novel therapies. Although use of Ginkgo biloba extract (GBE) has been reported to improve blood circulation and alleviate liver and lung fibrosis, its effect on skin fibrosis in SSc remains unclear. In this study, the effects and underlying mechanisms of GBE on skin fibrosis in bleomycin (BLM)-induced mouse model of SSc was investigated. GBE significantly reduced dermal thickness and protein levels of profibrotic factors in the BLM-induced SSc mouse model. Moreover, GBE inhibited the gene expression of profibrotic factors, such as COL1A1, α-SMA, and connective tissue growth factor (CTGF), in fibroblasts by suppressing transforming growth factor (TGF)-β signaling. Furthermore, GBE inhibited the transdifferentiation of adipocytes into myofibroblasts. Thus, our findings suggest that GBE is a promising therapeutic candidate for the treatment of SSc., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee. ACL reconstruction (ACLR) proves the standard for treating this injury. However, graft choice and method of fixation remain a heavily debated topic. This study investigates the following: bone-patellar tendon-bone (BPTB) vs. hamstring tendon (HT) autograft, single-bundle vs. double-bundle hamstring graft, and metal vs. bioabsorbable screws in ACLR., Methods: A systematic review was performed on PubMed and Google Scholar according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected on patient demographics, complications, and functionality scores including International Knee Documentation Committee (IKDC) and Lysholm scores. A systematic review and meta-analysis were conducted with Review Manager. Outcome measurements were determined using forest plots with significant differences considered p < 0.05., Results: Twenty-five studies were included, accounting for 2,170 patients. No statistically significant difference was appreciated when comparing BPTB to hamstring autografts. Patients who received a double bundle HT autograft exhibited significantly superior outcomes in terms of revision (p = 0.05), failure (p = 0.002), normal pivot shift tests (p = 0.04), and normal IKDC (p = 0.008). When comparing screw types, bioabsorbable screws had a greater Lysholm score (p = 0.01) and lower failure rates for copolymer screws (p = 0.03)., Conclusion: Overall, the data collected suggested that BPTB and HT autografts display similar postoperative results. However, if an HT autograft is used, the data suggest a double-bundle graft improves both functionality and decreases the possible complications. Finally, bioabsorbable screws prove superior to metal screws when looking at both functionality and failure rates. Further research into the superior graft type is still needed., Level of Evidence: Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/B84)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Myosin phosphatase (MP) is an enzyme complex that regulates muscle contraction and plays important roles in various physiological and pathological conditions. Myosin phosphatase targeting subunit (MYPT) 2, a subunit of MP, interacts with protein phosphatase 1c to regulate its phosphatase activity. MYPT2 exists in various isoforms that differ in the composition of essential motifs that contribute to its function. However, regulatory mechanisms underlying these isoforms are poorly understood. Human leukocyte antigen-F adjacent transcript 10 (FAT10) is a ubiquitin-like modifier that not only targets proteins for proteasomal degradation but also stabilizes its interacting proteins. In this study, we investigated the effect of the interaction between FAT10 and MYPT2 isoform a (the canonical full-length form of MYPT2) or MYPT2 isoform f (the natural truncated form of MYPT2). FAT10 interacted with both MYPT2 isoforms a and f; however, only MYPT2 isoform f was increased by FAT10, whereas MYPT2 isoform a remained unaffected by FAT10. We further confirmed that, in contrast to MYPT2 isoform a, MYPT2 isoform f undergoes rapid degradation via the ubiquitin-proteasome pathway and that FAT10 stabilizes MYPT2 isoform f by inhibiting its ubiquitination. Therefore, our findings suggest that the interaction between FAT10 and MYPT2 isoforms leads to distinct stabilization effects on each isoform, potentially modulating MP activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Autoimmune diseases are conditions in which the immune system mistakenly targets and damages healthy tissue in the body. In recent decades, the incidence of autoimmune diseases has increased, resulting in a significant disease burden. The current autoimmune therapies focus on targeting inflammation or inducing immunosuppression rather than addressing the underlying cause of the diseases. The activity of metabolic pathways is elevated in autoimmune diseases, and metabolic changes are increasingly recognized as important pathogenic processes underlying these. Therefore, metabolically targeted therapies may represent an important strategy for treating autoimmune diseases. This review provides a comprehensive overview of the evidence surrounding glucose metabolic reprogramming and its potential applications in drug discovery and development for autoimmune diseases, such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

As our previous study revealed that N -benzyl- N -methyldecan-1-amine (BMDA), a new molecule originated from Allium sativum , exhibits anti-neoplastic activities, we herein explored other functions of the compound and its derivative [decyl-(4-methoxy-benzyl)-methyl-amine; DMMA] including anti-inflammatory and anti-oxidative activities. Pretreatment of THP-1 cells with BMDA or DMMA inhibited tumor necrosis factor (TNF)-α and interleukin (IL)-1β production, and blocked c-jun terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), MAPKAP kinase (MK)2 and NF-κΒ inflammatory signaling during LPS stimulation. Rectal treatment with BMDA or DMMA reduced the severity of colitis in 2,4-dinitrobenzenesulfonic acid (DNBS)-treated rat. Consistently, administration of the compounds decreased myeloperoxidase ( MPO) activity (representing neutrophil infiltration in colonic mucosa), production of inflammatory mediators such as cytokine-induced neutrophil chemoattractant (CINC)-3 and TNF-α, and activation of JNK and p38 MAPK in the colon tissues. In addition, oral administration of these compounds ameliorated collagen-induced rheumatoid arthritis (RA) in mice. The treatment diminished the levels of inflammatory cytokine transcripts, and protected connective tissues through the expression of anti-oxidation proteins such as nuclear factor erythroid-related factor (Nrf)2 and heme oxygenase (HO)1. Additionally, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels did not differ between the BMDA- or DMMA-treated and control animals, indicating that the compounds do not possess liver toxicity. Taken together, these findings propose that BMDA and DMMA could be used as new drugs for curing inflammatory bowel disease (IBD) and RA., Competing Interests: Author I-RC was employed by Hayoung Meditech Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kim, Kang, Budluang, Yawut, Cho, Choi, Kim, Ju, Lee, Sohn, Yim, Lee, Han, Jung, Kang, Park, Jung, Hwang and Chung.)

The WAVE regulatory complex (WRC) is involved in various cellular processes by regulating actin polymerization. The dysregulation of WRC components is associated with cancer development. ABI family member 3 (ABI3)/new molecule including SH3 (NESH) is one of the WRC components and it has been reported that ABI3 phosphorylation can affect WRC function. Although several residues of ABI3 have been reported to be possible phosphorylation sites, it is still unclear which residues are important for the function of ABI3. Furthermore, it is unclear how the phosphorylated form of ABI3 is regulated. Here, we demonstrate that ABI3 is stabilized by its interaction with human leukocyte antigen-F adjacent transcript 10 (FAT10). Using phospho-dead or phospho-mimetic mutants of ABI3, we showed that serine 213 and 216 are important phosphorylation sites of ABI3. In particular, FAT10 has a higher affinity for the phosphorylated form of ABI3 than the non-phosphorylated form, and it stabilizes the phosphorylated form more than the non-phosphorylated form through this differential affinity. The interaction between FAT10 and the phosphorylated form of ABI3 promoted cancer cell migration. Therefore, our results suggest that FAT10 stabilizes the phosphorylated form of ABI3, which may lead to WRC activation, thereby promoting cancer cell migration., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Parkin dysfunction associated with the progression of parkinsonism contributes to a progressive systemic skeletal disease characterized by low bone mineral density. However, the role of parkin in bone remodeling has not yet been elucidated in detail., Result: We observed that decreased parkin in monocytes is linked to osteoclastic bone-resorbing activity. siRNA-mediated knockdown of parkin significantly enhanced the bone-resorbing activity of osteoclasts (OCs) on dentin without any changes in osteoblast differentiation. Moreover, Parkin-deficient mice exhibited an osteoporotic phenotype with a lower bone volume accompanied by increased OC-mediated bone-resorbing capacity displaying increased acetylation of α-tubulin compared to wild-type (WT) mice. Notably, compared to WT mice, the Parkin-deficient mice displayed increased susceptibility to inflammatory arthritis, reflected by a higher arthritis score and a marked bone loss after arthritis induction using K/BxN serum transfer, but not ovariectomy-induced bone loss. Intriguingly, parkin colocalized with microtubules and parkin-depleted-osteoclast precursor cells (Parkin -/- OCPs) displayed augmented ERK-dependent acetylation of α-tubulin due to failure of interaction with histone deacetylase 6 (HDAC6), which was promoted by IL-1β signaling. The ectopic expression of parkin in Parkin -/- OCPs limited the increase in dentin resorption induced by IL-1β, accompanied by the reduced acetylation of α-tubulin and diminished cathepsin K activity., Conclusion: These results indicate that a deficiency in the function of parkin caused by a decrease in parkin expression in OCPs under the inflammatory condition may enhance inflammatory bone erosion by altering microtubule dynamics to maintain OC activity., (© 2023. The Author(s).)

Background: Periodontitis is a major inflammatory disease of the oral mucosa that is not limited to the oral cavity but also has systemic consequences. Although the importance of chronic periodontitis has been emphasized, the systemic immune response induced by periodontitis and its therapeutic effects remain elusive. Here, we report the transcriptomes of peripheral blood mononuclear cells (PBMCs) from patients with periodontitis., Methods: Using single-cell RNA sequencing, we profiled PBMCs from healthy controls and paired pre- and post-treatment patients with periodontitis. We extracted differentially expressed genes and biological pathways for each cell type and calculated activity scores reflecting cellular characteristics. Intercellular crosstalk was classified into therapy-responsive and -nonresponsive pathways., Results: We analyzed pan-cellular differentially expressed genes caused by periodontitis and found that most cell types showed a significant increase in CRIP1, which was further supported by the increased levels of plasma CRIP1 observed in patients with periodontitis. In addition, activated cell type-specific ligand-receptor interactions, including the BTLA, IFN-γ, and RESISTIN pathways, were prominent in patients with periodontitis. Both the BTLA and IFN-γ pathways returned to similar levels in healthy controls after periodontal therapy, whereas the RESISTIN pathway was still activated even after therapy., Conclusion: These data collectively provide insights into the transcriptome changes and molecular interactions that are responsive to periodontal treatment. We identified periodontitis-specific systemic inflammatory indicators and suggest unresolved signals of non-surgical therapy as future therapeutic targets., (© 2022. The Author(s).)

Competing Interests: The author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research ® editors and board members are on file with the publication and can be viewed on request.

Although recent studies have demonstrated a proinflammatory effect of extracellular histones in sepsis via endothelial cytotoxicity, little is known about their contribution to autoimmune arthritis. Therefore, we investigated the role of extracellular histones in autoimmune arthritis and their cytotoxic effect on synoviocytes and macrophages. We measured histones in the synovial fluid of patients with rheumatoid arthritis (RA) and evaluated arthritis severity in a serum-transfer arthritis (STA) mouse model with intraperitoneal histone injection. Histone-induced cytotoxicity was measured using SYTOX green staining in the synoviocyte cell line MH7A and macrophages differentiated from the monocytic cell line THP-1, and the production of damage-associated molecular patterns (DAMPs) was measured by HMGB1 and ATP. Furthermore, we performed RNA-seq analysis of THP-1 cells stimulated with H2B-α1 peptide or with its citrullinated form. The levels of histones were elevated in RA synovial fluid, and histones aggravated arthritis in the STA model. Histones induced cytotoxicity and DAMP production in synoviocytes and macrophages. Chondroitin sulfate reduced histone-induced cytotoxicity, while lipopolysaccharides aggravated cytotoxicity. Moreover, the cytotoxicity decreased when the arginines in H2B-α1 were replaced with citrullines, which demonstrated its electrostatic nature. In transcriptome analysis, H2B-α1 changed the gene expression pattern of THP-1 cells involving chemokines, interleukin-1, -4, -10, -13, and toll-like receptor (TLR) signaling pathways. Extracellular histones were increased in RA synovial fluid and aggravated synovitis in STA. They induced lytic cell death through electrostatic interaction with synoviocytes and macrophages, leading to the secretion of DAMPs. These findings suggest that histones play a central role in autoimmune arthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jung, Lee, Kim, Kim, Jang, Roh, Lee, Robinson, Sohn, Pyun and Song.)

Oxidative stress causes several diseases and dysfunctions in cells, including oocytes. Clearly, oxidative stress influences oocyte quality during in vitro maturation and fertilization. Here we tested the ability of coenzyme Q10 (CoQ10) to reduce reactive oxygen species (ROS) and improve mouse oocyte quality during in vitro culture. Treatment with 50 μM CoQ10 efficiently reduced ROS levels in oocytes cultured in vitro. The fertilizable form of an oocyte usually contains a cortical granule-free domain (CGFD). CoQ10 enhanced the ratio of CGFD-oocytes from 35% to 45%. However, the hardening of the zona pellucida in oocytes was not affected by CoQ10 treatment. The in vitro maturation capacity of oocytes, which was determined by the first polar body extrusion, was enhanced from 48.9% to 75.7% by the addition of CoQ10 to the culture medium. During the parthenogenesis process, the number of two-cell embryos was increased by CoQ10 from 43.5% to 67.3%. Additionally, treatment with CoQ10 increased the expression of Bcl2 and Sirt1 in cumulus cells. These results suggested that CoQ10 had a positive effect on ROS reduction, maturation rate and two-cell embryo formation in mouse oocyte culture.

Introduction: The buccal route has been considered an attractive alternative delivery route for injectable formulations. Cell-penetrating peptides (CPPs) are gaining increased attention for their cellular uptake and tissue permeation effects. This study was aimed to evaluate the in vitro and ex vivo permeation-enhancing effect of penetratin-conjugated liposomes for salmon calcitonin (sCT) in TR146 human buccal cells and porcine buccal tissues., Methods: Penetratin was conjugated to phospholipids through a maleimide-thiol reaction. Liposomes were prepared and sCT was encapsulated using a thin-film hydration method. Physical properties such as particle size, zeta potential, encapsulation efficiency, and morphological images via transmission electron microscopy were obtained. Cellular uptake studies were conducted using flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). A cell permeation study was performed using a Transwell ® assay, and permeation through porcine buccal tissue was evaluated. The amount of sCT permeated was quantified using an ELISA kit and was optically observed using CLSM., Results: The particle size of penetratin-conjugated liposomes was approximately 123.0 nm, their zeta potential was +29.6 mV, and their calcitonin encapsulation efficiency was 18.0%. In the cellular uptake study using FACS and CLSM, stronger fluorescence was observed in penetratin-conjugated liposomes compared with the solution containing free sCT and control liposomes. Likewise, the amount of sCT permeated from penetratin-conjugated liposomes was higher than that from the free sCT solution and control liposomes by 5.8-fold across TR146 cells and 91.5-fold across porcine buccal tissues., Conclusion: Penetratin-conjugated liposomes are considered a good drug delivery strategy for sCT via the buccal route., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Keum et al.)

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Despite the recent advances in the pathogenesis and treatment of SSc, effective therapies for fibrosis caused by SSc have not yet been established. In this study, we investigated the potential role of mirodenafil, a potent phosphodiesterase 5 (PDE5) inhibitor, in the treatment of fibrosis in SSc. We used a bleomycin (BLM)-induced SSc mouse model to mimic the typical features of fibrosis in human SSc and examined the dermal thickness to assess the degree of skin fibrosis after staining with hematoxylin and eosin or Masson's trichrome stains. The effect of mirodenafil on the expression of profibrotic genes was also analyzed by treating fibroblasts with transforming growth factor (TGF)-β and mirodenafil. We showed that mirodenafil ameliorated dermal fibrosis and downregulated the protein levels of fibrosis markers including COL1A1 and α-SMA in the BLM-induced SSc mouse model. Further, using mouse embryonic fibroblasts and human lung fibroblasts, we demonstrated that the expression of collagen and profibrotic genes was reduced by treatment with mirodenafil. Finally, we showed that mirodenafil inhibited TGF-β-induced phosphorylation of Smad2/3 in fibroblasts, which suggested that this drug may ameliorate fibrosis by suppressing the TGF-β/Smad signaling pathway. Our findings suggest that mirodenafil possesses a therapeutic potential for treating fibrosis in SSc., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Case: Combined medial and lateral patellar instability is exceptionally rare with only 3 reported cases to date. Here, we present the case of a 37-year-old White woman with multiple recurrent medial and lateral patellar instability. After failure of conservative care with bracing and therapy, she underwent surgical stabilization with medial and lateral allograft reconstruction., Conclusion: This case provides an example of the condition and successful surgical follow-up., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B634)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by widespread joint inflammation, which leads to joint damage, disability, and mortality. Among the several types of immune cells, myeloid cells such as macrophages are critical for controlling the pathogenesis of RA. Inositol phosphates are water-soluble signaling molecules, which are synthesized by a series of enzymes including inositol phosphate kinases. Previous studies revealed actions of inositol phosphates and their metabolic enzymes in the modulation of inflammation such as Toll-like receptor-triggered innate immunity. However, the physiological roles of inositol polyphosphate (IP) metabolism in the regulation of RA remain largely uncharacterized. Therefore, our study sought to determine the role of inositol polyphosphate multikinase (IPMK), a key enzyme for IP metabolism and various cellular signaling control mechanisms, in mediating RA. Using myeloid cell-specific IPMK knockout (KO) mice, arthritis was induced via intraperitoneal K/BxN serum injection, after which disease severity was evaluated. Both wild-type and IPMK KO mice developed similar RA phenotypes; however, conditional deletion of IPMK in myeloid cells led to elevated arthritis scores during the resolution phase, suggesting that IPMK deficiency in myeloid cells impairs the resolution of inflammation. Bone marrow-derived IPMK KO macrophages exhibited no apparent defects in immunoglobulin Fc receptor (FcR) activation, osteoclast differentiation, or resolvin signaling. Taken together, our findings suggest that myeloid IPMK is a key determinant of RA resolution., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

We investigated decaying post-seismic deformation observed on the Korean Peninsula associated with the 2011 Mw 9.0 Tohoku-Oki earthquake using Global Navigation Satellite System (GNSS). The GNSS velocity vectors were estimated in five periods from 2005 to 2019. A co-seismic offset of the Korean Peninsula caused by the 2011 earthquake was inversely proportional to epicentral distances. According to the temporal variations of two components (magnitude and direction) of the GNSS velocity vector with the epicentral distance, the difference between the eastern and western regions for the two components becomes smaller over time. For approximately nine years after the 2011 event, the direction for the crustal movement in South Korea showed a recovery pattern returning to the pre-earthquake motion. In addition, the recovery patterns of the crustal movement were observed differently with the regional geologic structure (e.g., the crustal thickness) and each period. Our estimates of the decay in post-seismic deformation of the Korean Peninsula suggest that post-seismic relaxation will be complete within 5-20 years after the 2011 earthquake. The results suggest that the crustal movement on the Korean Peninsula is gradually recovering to its pre-earthquake motion.

We examined whether it is possible to directly detect citrullinated antigens in the serum of rheumatoid arthritis (RA) patients using a monoclonal antibody (mAb) designed to be specific for citrullinated peptides. In order to confirm the potential of the mAb as a direct arthritis-inducing substance through experimental model of RA, a monoclonal antibody (mAb) 12G1 was generated using by immunization of mice with a challenging cyclic citrullinated peptide. Immunohistochemical analysis of RA-affected synovial tissue showed that our mAb 12G1 could indeed detect citrullinated proteins in target tissues. Subsequently, serum levels of citrullinated type II collagen and filaggrin were measured in healthy volunteers, patients with RA, ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) using a 12G1-based sandwich ELISA. This showed that citrullinated filaggrin showed 78.9% sensitivity and 85.9% specificity for RA diagnosis with a cutoff optical density (OD) value of 1.013, comparable with the results from a second-generation anti-citrullinated protein antibody (ACPA) test. Circulating citrullinated collagen and filaggrin were detected even in sera of RA patients who were negative for both rheumatoid factor (RF) and ACPA. ELISA results also showed that RF and ACPA titers showed significantly positive correlation with both citrullinated collagen and filaggrin OD values in sera of RA patients. 12G1 challenging aggravated the severity of murine arthritis. In summary, mAb 12G1 can directly detect citrullinated proteins in RA target tissue and in sera of RA patients and 12G1 showed direct arthritogenic potential in vivo . This, 12G1 might be useful for diagnosis of RA including seronegative RA and may help to elucidate the pathophysiological role of citrullination in RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Won, Kim, Jung, Rim, Sohn, Robinson, Moon and Ju.)

Objective : To investigate the relationship between the monocyte-to-high-density lipoprotein cholesterol ratio (MHR) and clinical manifestations in patients with systemic sclerosis (SSc). Method: This was a cross-sectional analysis of a cohort study comprising 111 female SSc patients recruited from a tertiary care rheumatology centre. We also assessed 222 age-matched female healthy controls. Serum MHR was measured in all study participants. Digital ulcer (DU) was defined as an active or healed ulceration, and the magnitude of skin fibrosis was determined according to the modified Rodnan skin score (mRSS). Results: The mean age and median disease duration in patients with SSc were 56.3 years and 98 months, respectively. The MHR in SSc patients was significantly higher than that in controls. DU was found in 35 patients (31.5%) with SSc (active in 12 and healed in 23), and the median mRSS was 8. SSc patients with DU had a significantly higher median MHR than those without (11.43 vs 7.62, p < 0.001), and MHR significantly positively correlated with mRSS (ρ = 0.289, p = 0.002). Multivariable logistic regression revealed that an elevated MHR was independently associated with increased risk of DU (odds ratio = 1.21; 95% confidence interval = 1.07-1.35; p = 0.002). In the multivariable linear regression analysis, higher MHR showed a significant association with increased log-transformed mRSS (unstandardized β = 0.052, p = 0.003). Conclusion: Our findings suggest that the MHR could be serve as a potential biomarker of the risk of DU and advanced skin fibrosis in patients with SSc.

We investigated whether the bone-synthetic activities of vertebral bodies or vertebral corners quantified using 18 F-fluoride positron emission tomography (PET) was associated with bone mineral density (BMD) at the corresponding lumbar vertebrae in ankylosing spondylitis (AS) at each vertebra level. We analyzed 48 lumbar vertebrae in 12 AS patients who underwent 18 F-fluoride PET and dual energy X-ray absorptiometry (DXA). The mean standardized uptake values (SUVmean) of the vertebral body and corners from L1 to L4 were measured using the spatially separated region of interest (ROI). The L1-L4 BMDs were calculated based on the DXA ("conventional BMD"). The BMD of the internal vertebral bodies was measured by manually drawing ROIs to represent the trabecular BMD ("alternative BMD"). After adjusting the within-patient correlation, the 18 F-fluoride SUVmean of the vertebral corners but not that of vertebral bodies was significantly related with the conventional BMD of the vertebra. Otherwise, the 18 F-fluoride uptake of both the vertebral and vertebral bodies was significantly related with the alternative BMD. The bone-synthetic activities of the vertebral corners may be more closely related with BMD than those of the vertebral bodies, suggesting that the effects of regional bone metabolism at the vertebral corners and bodies on BMD differ in AS.

We estimate precipitable water vapor (PWV) from data collected by the low-cost Global Navigation Satellite System (GNSS) receiver at a vessel. The dual-frequency GNSS receiver that the vessel ISABU is equipped with that is operated by the Korea Institute of Ocean Science and Technology. The ISABU served in the Pacific Ocean for scientific research during a period from August 30 to September 21, 2018. It also performs radiosonde observations to obtain a vertical profile of troposphere on the vessel's path. The GNSS-derived PWV is compared to radiosonde observations and the Atmospheric Infrared Sounder (AIRS) on NASA's Aqua satellite output. A bias and root-mean-square (RMS) error between shipborne GNSS-PWV and radiosonde-PWV were -1.48 and 5.22 mm, respectively. When compared to the ground GNSS-PWV, shipborne GNSS-PWV has a relatively large RMS error in comparison with radiosonde-PWV. However, the GNSS observations on the vessel are still in good agreement with radiosonde observations. On the other hand, the GNSS-PWV is not well linearly correlated with AIRS-PWV. The RMS error between the two observations was approximately 8.97 mm. In addition, we showed that the vessel on the sea surface has significantly larger carrier phase multipath error compared to the ground-based GNSS observations. This also can result in reducing the accuracy of shipborne GNSS-PWV. However, we suggest that the shipborne GNSS has sufficient potential to derive PWV with the kinematic precise point positioning (PPP) solution on the vessel.

Mammalian oocyte maturation is wholly dependent on the translation of accumulated maternal transcripts. Therefore, measuring the translation of specific genes, especially Ccnb1 and Ccnb2, which are key regulators of the oocyte cell cycle in mice, is essential to monitor oocyte cell cycle progression. For this purpose, almost all previous research has used a reporter construct containing the 3'-untranslated region (UTR) of Ccnb. It is based on the concept that the 3'-UTR is the main modulator of translation. Here, we investigated the expression pattern of Renilla luciferase (RL) reporters combining the 5'-UTR and/or open reading frame (ORF) as well as the 3'-UTR (RL-3', 5'-RL-3', RL-ORF-3', and 5'-RL-ORF-3') of Ccnb1 and Ccnb2 in somatic cells and mouse oocytes. The addition of the 5'-UTR and/or ORF of Ccnb altered the expression of the RL-3' reporter in HEK293T cells and mouse oocytes. The ORF tended to suppress RL expression, whereas the 5'-UTR enhanced the expression in most cases. The increased rate in expression was the highest when only the 3'-UTR of Ccnb1 (RL-3') was used, whereas the 5'-RL-ORF-3' reporter showed a relatively lower increase during oocyte maturation. For Ccnb2, the RL-ORF-3' reporter showed the largest increase, and other reporters exhibited a similar increase in expression during oocyte maturation. Results show that the expression of these genes is modulated not only by the 3'-UTR but also by the 5'-UTR and ORF. Therefore, special caution should be taken when using only the 3'-UTR to monitor the expression of specific genes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this study, we aimed to investigate the association of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with clinical manifestations in patients with systemic sclerosis (SSc). We conducted a cross-sectional analysis of data collected from a cohort study of 114 female patients with SSc and of 304 age-matched, healthy, female controls recruited from a tertiary rheumatology center. Patients with digital ulcers (DU) included those with either active or healed ulcers. Interstitial lung disease (ILD) was diagnosed on detection of diffuse ground-glass opacity or pulmonary fibrosis on chest X-ray or on high-resolution computed tomography. Patients with SSc had significantly higher PLR and NLR than ealthy controls. Of 114 patients with SSc, 35 (30.7%) and 54 (47.4%) patients had DU (active: 12, healed: 23) and ILD, respectively. PLR and NLR in SSc patients with concurrent DU or ILD were significantly higher than that in those without these respective complications. The PLR (OR = 1.008, 95% CI 1.002-1.015), but not the NLR, was independently associated with the presence of DU in SSc patients, based on multivariable logistic regression models. Additionally, both PLR (OR = 1.008, 95% CI 1.001-1.014) and NLR (OR = 1.515, 95% CI 1.066-2.155) correlated independently with the presence of ILD. However, both the PLR and NLR showed no significant association with the modified Rodnan skin score, pulmonary arterial hypertension, and gastrointestinal involvement. Our results suggest that PLR and NLR could be considered as potential biomarkers of DU and ILD, in patients with SSc.

Although the positive correlation between serum uric acid (UA) levels and bone mineral density (BMD) has been reported in the general population, there are little data regarding the effect of serum UA levels on bone loss in patients with rheumatoid arthritis (RA).We investigated whether increased serum UA levels were associated with a reduced risk of osteoporosis in postmenopausal women with RA.In this retrospective cross-sectional study, 447 postmenopausal female patients with RA and 200 age-matched, postmenopausal healthy controls underwent BMD examination by dual energy x-ray absorptiometry and serum UA levels measurement. Osteoporosis was diagnosed when the T-score was <-2.5.The median UA level in postmenopausal RA patients was found to be significantly lower than that in the healthy women (4 vs 4.1 mg/dL, P = .012) and the frequency of osteoporosis incidence in the lumbar spine, hip, and either site in RA patients was 25.5%, 15.9%, and 32.5%, respectively; the values were significantly higher than those of the controls. After adjusting for confounding factors, a significantly lower risk for osteoporosis of the hip in RA patients was observed within the highest quartile (odds ratio [OR] = 0.37, 95% confidence interval [CI] = 0.16-0.72, P = .021) and the second highest quartile (OR = 0.44, 95% CI = 0.2-0.95, P = .038) of serum UA levels as compared with the lowest quartile, but this association was not found to be consistent with respect to the lumbar spine. Serum UA levels also showed an independently positive correlation with femoral neck BMD (β = 0.0104, P = .01) and total hip BMD (β = 0.0102, P = .017), but not with lumbar BMD.Our data suggest that UA may exert a protective effect on bone loss in RA, especially in the hip.

Rheumatoid arthritis (RA) is a highly inflammatory autoimmune disease. Although proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-6, play a key role in the pathogenesis of RA, the causes of chronic inflammation are not fully understood. Here, we report that protein phosphatase magnesium-dependent 1A (PPM1A) levels were increased in RA synovial fluid compared with osteoarthritis (OA) synovial fluid and positively correlated with TNF levels. In addition, PPM1A expression was increased in synovial tissue from RA patients and joint tissue from a mouse model of arthritis. Finally, extracellular PPM1A induced inflammation by stimulating macrophages to produce TNF through toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) signaling pathway. Our findings suggest that extracellular PPM1A may contribute to the pathogenesis of RA by functioning as a damage-associated molecular pattern (DAMP) to induce inflammation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Tissue repair responses include transforming growth factor beta (TGFβ)-induced myofibroblast production of extracellular matrix. Fibronectins are an essential part of the extracellular matrix, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Fibronectin containing the ED-A domain is currently being used as drug delivery target in the development of anti-inflammatory drugs (e.g. Dekavil)., Methods: In this study, samples of synovial membrane were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A fibronectin and the myofibroblast marker alpha smooth muscle actin (αSMA) was performed on fibroblast-like synovial cells (FLS) and synovial membranes. RAW 264.7 macrophages were incubated with recombinant ED-A fibronectin., Results: The staining of ED-A fibronectin in OA FLS was increased by TGFβ but not by TNFα, lipopolysaccharide, or IL-6 ( n  = 3). ED-A fibronectin co-stained with the myofibroblast marker αSMA in both the OA FLS ( n  = 3) and in the OA synovial membranes ( n  = 8). ED-A fibronectin staining was associated with both number of lining layer cells (rho = 0.85 and p  = 0.011) and sublining cells (rho = 0.88 and p  = 0.007) in the OA synovium ( n  = 8), and co-distributed with TNFα ( n  = 5). Recombinant ED-A fibronectin increased the production of TNFα by RAW 264.7 macrophages ( n  = 3)., Conclusions: The disease process in OA shares features with the chronic wound healing response. Our findings support utilizing ED-A fibronectin for drug delivery or therapeutic targeting to reduce pro-inflammatory responses in OA., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Novel biomarkers of ccRCC may provide crucial information on tumor features and prognosis. The present study aimed to determine whether the expression of γ-aminobutyric acid (GABA) A receptor subunit θ ( GABRQ ) could serve as a novel prognostic marker of ccRCC. GABA is the main inhibitory neurotransmitter in the brain that activates the receptor GABA A , which is comprised of three subunit isoforms: GABRA3, GABRB3 and GABRQ. A recent study reported that GABRQ is involved in the initiation and progression of hepatocellular carcinoma; however, the role of GABRQ in ccRCC remains unknown. In the present study, clinical and transcriptomic data were obtained from cohorts of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Differential GABRQ expression levels among early (TI and II), late (TIII and IV), nonmetastatic (M0) and metastatic (M1, primary tumor) stages of ccRCC samples were then identified. Furthermore, the use of GABRQ as a prognostic gene was analyzed using Uno's C-index based on the time-dependent area under the curve (AUC), the AUC of the receiver operating characteristic curve at 5 years, the Kaplan-Meier survival curve and multivariate analysis. The survival curve analysis revealed that low GABRQ mRNA expression was significantly associated with a poor prognosis of ccRCC (P<0.001 and P=0.0012 for TCGA and ICGC data, respectively). In addition, analyses of the C-index and AUC values further supported this discriminatory power. Furthermore, the prognostic value of GABRQ mRNA expression was confirmed by multivariate Cox regression analysis. Taken together, these results suggested that GABRQ mRNA expression may be considered as a novel prognostic biomarker of ccRCC., (Copyright: © Lee et al.)

Three-dimensional (3D) printing has been recently employed in the design and formulation of various dosage forms with the aim of on-demand manufacturing and personalized medicine. In this study, we formulated a floating sustained release system using fused deposition modeling (FDM). Filaments were prepared using hypromellose acetate succinate (HPMCAS), polyethylene glycol (PEG 400) and pregabalin as the active ingredient. Cylindrical tablets with infill percentages of 25%, 50% and 75% were designed and printed with the FDM printer. An optimized formulation (F6) was designed with a closed bottom layer and a partially opened top layer. Filaments and tablets were characterized by means of fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and thermogravimetric analysis (TGA). The results show that the processing condition did not have a significant effect on the stability of the drug and the crystallinity of the drug remained even after printing. A dissolution study revealed that drug release is faster in an open system with low infill percentage compared to closed systems and open systems with a high infill ratio. The optimized formulation (F6) with partially opened top layer showed zero-order drug release. The results show that FDM printing is suitable for the formulation of floating dosage form with the desired drug release profile., Competing Interests: The authors declare no conflict of interest.

Objective: Renal cell carcinoma (RCC) is the most typical type of kidney cancer in adults. Hypercalcemia is a well known paraneoplastic syndrome associated with RCC and recent studies have reported that hypercalcemia is closely related to the poor prognosis of RCC patients. Clear cell RCC (ccRCC) is the most common and aggressive subtype of RCC. Although the histological classification of RCC is important for determination of appropriate treatment strategies, effective biomarkers for predicting prognosis of ccRCC have not yet been identified. Since calcium levels affect the prognosis of RCC patients, we evaluated whether the calcium-sensing genes on the plasma membrane, including those encoding calcium channels, CaSR, GPRC6a, and DYSF, could be used as biomarkers to predict the prognosis of ccRCC patients., Methods: Information from 537 patients from The Cancer Genome Atlas (TCGA; n = 446) and International Cancer Genome Consortium (ICGC; n = 91) was used in this study. Among these genes, DYSF was the only gene whose expression correlated with overall survival of both TGCA and ICGC patients., Results: Although DYSF gene expression was higher in ccRCC tissue than in normal kidney tissue, Kaplan-Meier curves showed that the survival rate of ccRCC patients with high DYSF expression was significantly higher than that of patients with low DYSF expression (TCGA, P < 0.0001; ICGC, P = 0.0011). We also validated the potential of DYSF as a prognostic biomarker for ccRCC by conducting a time-dependent area under the curve (AUC) analysis and 5-years receiver operating characteristic curve analysis. Finally, multivariate regression analysis revealed that the expression of DYSF is independent of other prognostic parameters (TCGA, P = 0.017; ICGC, P = 0.006)., Conclusions: These results suggested that DYSF may play a suppressive role in the progression of ccRCC and could act as a promising prognostic biomarker for predicting the survival of ccRCC patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is the leading cause of joint failure, yet the underlying mechanisms remain elusive, and no approved therapies that slow progression exist. Dysregulated integrin function was previously implicated in OA pathogenesis. However, the roles of integrin αVβ3 and the integrin-associated receptor CD47 in OA remain largely unknown. Here, transcriptomic and proteomic analyses of human and murine osteoarthritic tissues revealed dysregulated expression of αVβ3, CD47, and their ligands. Using genetically deficient mice and pharmacologic inhibitors, we showed that αVβ3, CD47, and the downstream signaling molecules Fyn and FAK are crucial to OA pathogenesis. MicroPET/CT imaging of a mouse model showed elevated ligand-binding capacities of integrin αVβ3 and CD47 in osteoarthritic joints. Further, our in vitro studies demonstrated that chondrocyte breakdown products, derived from articular cartilage of individuals with OA, induced αVβ3/CD47-dependent expression of inflammatory and degradative mediators, and revealed the downstream signaling network. Our findings identify a central role for dysregulated αVβ3 and CD47 signaling in OA pathogenesis and suggest that activation of αVβ3 and CD47 signaling in many articular cell types contributes to inflammation and joint destruction in OA. Thus, the data presented here provide a rationale for targeting αVβ3, CD47, and their signaling pathways as a disease-modifying therapy.

Sirtuin 1 (SIRT1) is a histone deacetylase implicated in stem cell homeostasis. Conditional Sirt1 deletion in the hematopoietic stem and progenitor system promotes hematopoietic stem and progenitor cell (HSPC) expansion under stress conditions. In addition, SIRT1 activators modulate the capacity and HSPC numbers in the bone marrow (BM). To investigate the role of SIRT1 in the BM niche, a conditional Sirt1 deletion in the BM niche was generated in a mouse model for the present study. Multicolor flow cytometric analyses were performed to determine HSC cell populations. Using 5-fluorouracil-induced proliferative stress, a survival curve was produced. In the present study, Sirt1 deletion in the BM niche demonstrated that the production of mature blood cells, lineage distribution within hematopoietic organs and frequencies of HSPC populations were comparable to those of controls. Additionally, Sirt1 deletion in the BM niche did not perturb HSC maturation under stress induced by transplantation. Therefore, these observations suggest that SIRT1 serves a dispensable role in HSC maturation in the BM niche.

3D printing is a method of rapid prototyping and manufacturing in which materials are deposited onto one another in layers to produce a three-dimensional object. Although 3D printing was developed in the 1980s and the technology has found widespread industrial applications for production from automotive parts to machine tools, its application in pharmaceutical area is still limited. However, the potential of 3D printing in the pharmaceutical industry is now being recognized. The ability of 3D printing to produce medications to exact specifications tailored to the needs of individual patients has indicated the possibility of developing personalized medicines. The technology allows dosage forms to be precisely printed in various shapes, sizes and textures that are difficult to produce using traditional techniques. However, there are various challenges associated with the proper application of 3D printing in the pharmaceutical sector which should be overcome to exploit the scope of this technology. In this review, an overview is provided on the various 3D printing technologies used in fabrication of complex dosage forms along with their feasibility and limitations., (© 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Data are scarce regarding the association of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with treatment response and persistence of anti-TNF-α agents in patients with rheumatoid arthritis (RA). Thus, we investigated whether baseline NLR and PLR could predict 12-week treatment response and long-term persistence of anti-TNF-α agents in RA patients. This is a retrospective chart review analysis of 82 women with RA who started anti-TNF-α agents as the first-line biologic therapy and 328 healthy age-matched women. RA patients were divided into high and low baseline NLR or PLR subgroups using the median split. European League against Rheumatism (EULAR) treatment response was evaluated at 12 weeks. RA patients had significantly higher NLR and PLR than controls. High baseline NLR and PLR groups showed higher 12-week EULAR non-response rate than low NLR (30% vs 7.1%, p = 0.01) and PLR groups (27.5% vs 9.5%, p = 0.047), respectively. After adjusting for confounding factors, high baseline NLR (OR 5.57, p = 0.014) and PLR (OR 4.24, p = 0.04) were significantly associated with a higher risk of EULAR non-response at 12 weeks. During the study period, 47 (57.3%) RA patients (lack of efficacy: n = 31; adverse events: n = 16) discontinued anti-TNF-α agents. High baseline NLR was associated with an increased risk of anti-TNF-α agent withdrawal due to lack of efficacy (HR 2.12, p = 0.045). Our data suggest that baseline NLR and PLR are useful markers for predicting the treatment outcome of anti-TNF-α agents in RA patients.

IL-32 exists as seven mRNA transcripts that can translate into distinct individual IL-32 variants with specific protein domains. These translated protein domains of IL-32 variants code for specific functions that allow for interaction with different molecules intracellularly or extracellularly. The longest variant is IL-32γ possessing 234 amino acid residues with all 11 protein domains, while the shortest variant is IL-32α possessing 131 amino acid residues with three of the protein domains. The first domain exists in 6 variants except IL-32δ variant, which has a distinct translation initiation codon due to mRNA splicing. The last eleventh domain is common domain for all seven IL-32 variants. Numerous studies in different fields, such as inflammation, autoimmunity, pathogen infection, and cancer biology, have claimed the specific biological activity of individual IL-32 variant despite the absence of sufficient data. There are 4 additional IL-32 variants without proper transcripts. In this review, the structural characteristics of seven IL-32 transcripts are described based on the specific protein domains., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest.

Although pathological observations provide approximate prognoses, it is difficult to achieve prognosis in patients with existing prognostic factors. Therefore, it is very important to find appropriate biomarkers to achieve accurate cancer prognosis. Renal cell carcinoma (RCC) has several subtypes, the discrimination of which is crucial for proper treatment. Here, we present a novel biomarker, VNN3, which is used to prognose clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer. Patient information analyzed in our study was extracted from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. VNN3 expression was considerably higher in stages III and IV than in stages I and II. Moreover, Kaplan-Meier curves associated high VNN3 expression with poor prognoses (TCGA, p  < .0001; ICGC, p  = .00076), confirming that ccRCC prognosis can be predicted via VNN3 expression patterns. Consistent with all patient results, the prognosis of patients with higher VNN3 expression was worse in both low stage (I and II) and high stage (III and IV) (TCGA, p < 0.0001 in stage I and II; ICGC, p = 0.028 in stage I and II; TCGA, p = 0.005 in stage III and IV). Area under the curve and receiver operating characteristic curves supported our results that highlighted VNN3 expression as a suitable ccRCC biomarker. Multivariate analysis also verified the prognostic performance of VNN3 expression (TCGA, p  < .001; ICGC, p  = .017). Altogether, we suggest that VNN3 is applicable as a new biomarker to establish prognosis in patients with ccRCC.

Introduction: Opioids are widely used after orthopaedic procedures. Nonmedical opioid use is a growing public health issue., Methods: An anonymous online survey was distributed by e-mail to the orthopaedic societies of all 50 states and several large private practices to assess practicing orthopaedic surgeons' opioid prescribing practices., Results: A total of 555 orthopaedic surgeons practicing in 37 states responded. The most commonly prescribed opioid for both teenagers and adults was hydrocodone/acetaminophen. Of note, 42.3% reported that a patient they have prescribed opioids for developed an opioid dependency, whereas 35.3% do not believe that opioid use is a problem in their practice. Of note, 30.3% reported prescribing refills, and factors significantly associated with increased prescribing of refills included a greater number of years in practice (P < 0.001) and practicing in a suburban rather than an urban or rural environment (P = 0.03)., Conclusion: Orthopaedic surgeons rarely prescribe any refills, tend to prescribe less opioids to teenagers than adults, and prescribe fairly uniformly for patients who are treated nonsurgically or undergo minor or arthroscopic surgery. They exhibit considerable variation in prescribing for fractures and major procedures.

IL-17 produced by Th17 cells has been implicated in the pathogenesis of rheumatoid arthritis (RA). It is important to prevent the differentiation of Th17 cells in RA. Homodimeric soluble γc (sγc) impairs IL-2 signaling and enhances Th17 differentiation. Thus, we aimed to block the functions of sγc by inhibiting the formation of homodimeric sγc. The homodimeric form of sγc was strikingly disturbed by sγc-binding DNA aptamer. Moreover, the aptamer effectively inhibited Th17 cell differentiation and restored IL-2 and IL-15 signaling impaired by sγc with evidences of increased survival of T cells. sγc was highly expressed in SF of RA patients and increased in established CIA mice. The therapeutic effect of PEG-aptamer was tested in CIA model and its treatment alleviated arthritis pathogenesis with impaired differentiation of pathogenic Th17, NKT1, and NKT17 cells in inflamed joint. Homodimeric sγc has pathogenic roles to exacerbate RA progression with differentiation of local Th17, NKT1, and NKT17 cells. Therefore, sγc is suggested as target of a therapeutic strategy for RA.

Protein kinase casein kinase 2 (CK2) is important in the regulation of cell proliferation and death, even under pathological conditions. Previously, we reported that CK2 regulates the expression of heme oxygenase‑1 (HO‑1) in stress‑induced chondrocytes. In the present study, it was shown that CK2 is involved in the dedifferentiation and cellular senescence of chondrocytes. Treatment of primary articular chondrocytes with CK2 inhibitors, 4,5,6,7‑terabromo‑2‑azabenzimidazole (TBB) or 5,6‑dichlorobenzimidazole 1‑β‑D‑ribofuranoside (DRB), induced an increase in senescence‑associated β‑galactosidase (SA‑β‑gal) staining. In addition, TBB reduced the expression of type II collagen and stimulated the accumulation of β‑catenin, phenotypic markers of chondrocyte differentiation and dedifferentiation, respectively. It was also observed that the abrogation of CK2 activity by CK2 small interfering RNA induced phenotypes of chondrocyte senescence. The association between HO‑1 and cellular senescence was also examined in CK2 inhibitor‑treated chondrocytes. Pretreatment with 3‑morpholinosydnonimine hydrochloride, an inducer of the HO‑1 expression, or overexpression of the HO‑1 gene significantly delayed chondrocyte senescence. These results show that CK2 is associated with chondrocyte differentiation and cellular senescence and that this is due to regulation of the expression of HO‑1. Furthermore, the findings suggest that CK2 is crucial as an anti‑aging factor during chondrocyte senescence.

Endothelial injury/dysfunction is thought to be one of the earliest events in the development of vascular diseases in systemic sclerosis (SSc). Although hyperuricemia is also known to induce endothelial dysfunction and vascular inflammation, the effect of uric acid on the microvascular involvement in SSc has not been well established. We investigated whether increased serum uric acid (SUA) levels are associated with digital ulcers (DUs) in SSc. In this cross-sectional study, we consecutively recruited 71 women with SSc and 349 age- and sex-matched healthy subjects, and SUA levels were measured in all study subjects. SSc patients had significantly higher mean SUA levels than healthy subjects (4.5 ± 1 mg/dL vs 4.2 ± 0.9 mg/dL, p = 0.017), although a significantly lower body mass index (BMI) was observed in SSc patients than in controls. Among 71 SSc patients, 22 (31%) had DUs ever (active DUs, 8; healed DUs, 14). SSc patients presenting with DUs ever showed significantly higher SUA levels than those without this feature (median, 5.2 mg/dL vs 4.1 mg/dL, p = 0.009). In multivariable logistic regression models adjusted for confounders such as BMI and estimated glomerular filtration rate, increased SUA levels were associated with a significantly higher risk for the presence of DUs ever (OR 2.3, 95% CI 1.16-4.57, p = 0.018). Our data revealed that elevated SUA levels are independently associated with the presence of DUs in SSc patients, thereby suggesting the potential role of hyperuricemia in the pathogenesis of SSc vasculopathy.

Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract caused by high levels of pro-inflammatory cytokines and epithelial barrier dysfunction. Alnus japonica Steud. (Betulaceae) has been used in traditional Asian medicine. However, the potential of A. japonica for the treatment of intestinal inflammation has not been investigated. This study investigated the effects of ethanol extract from A. japonica bark (AJE) on colonic mucosa injury in mice with dextran sodium sulfate (DSS)-induced colitis. Treatment with AJE ameliorated pathological damage and the histopathologic features of DSS-induced colitis. The administration of AJE also inhibits DSS-induced pro-inflammatory cytokines expression, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2. Notably, AJE administration attenuated the reduction of tight junction proteins, zonula occludens (ZO)-1 and occludin, in DSS-induced colitis. In addition, AJE increased heme oxygenase (HO)-1 expression and prevented DSS-induced apoptosis in colonic epithelial cells. Furthermore, in vitro studies demonstrated that AJE inhibits TNF-α-induced IL-8, IL-1β, and COX-2 expression in human intestinal epithelial HT-29 cells and tert-butyl hydroperoxide-induced reduction of ZO-1 and occludin expression in human intestinal epithelial Caco-2 cells. AJE-induced HO-1 protein expression was also found in both HT-29 and Caco-2 cells. Taken together, our findings demonstrated that AJE inhibits intestinal inflammation and protects against intestinal barrier disruption in mice with DSS-induced colitis in vivo and human intestinal epithelial cells in vitro. These results suggest that AJE might have beneficial effects for the treatment of IBD., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

In oriental medicine, centipede Scolopendra subspinipes mutilans has long been used as a remedy for rheumatoid arthritis (RA), a well-known chronic autoimmune disorder. However, the molecular identities of its bioactive components have not yet been extensively investigated. We sought to identify bioactive molecules that control RA with a centipede. A novel antimicrobial peptide (AMP) (scolopendrasin IX) was identified from Scolopendra subspinipes mutilans. Scolopendrasin IX markedly activated mouse neutrophils, by enhancing cytosolic calcium increase, chemotactic cellular migration, and generation of superoxide anion in neutrophils. As a target receptor for scolopendrasin IX, formyl peptide receptor (FPR)2 mediates neutrophil activation induced by the AMP. Furthermore, scolopendrasin IX administration strongly blocked the clinical phenotype of RA in an autoantibody-injected model. Mechanistically, the novel AMP inhibited inflammatory cytokine synthesis from the joints and neutrophil recruitment into the joint area. Collectively, we suggest that scolopendrasin IX is a novel potential therapeutic agent for the control of RA via FPR2.