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Ginsenosides, the active component of ginseng, exerts antidiabetic and anticancer effects. This study investigated the molecular basis of ginsenoside Rg3, a red ginseng rich constituent, focusing on its ability to inhibit adipocyte differentiation in 3T3-L1 cells. The data show that ginsenoside Rg3 was effective in the inhibition of adipocyte differentiation. This inhibitory effect of ginsenoside Rg3 on adipocyte differentiation was accompanied by PPAR-gamma inhibition in rosiglitazone-treated cells. The study also tested whether AMP-activated protein kinase (AMPK) activation was involved in the inhibitory effects of ginsenoside Rg3. AMPK plays a role in maintaining health in the context of diseases such as type 2 diabetes, obesity and cancer. AMPK was reported to control nutritional and hormonal signal modulating. Rg3 significantly and time-dependently activated AMPK. Taken together, these results suggest that the antiobesity effect of red ginseng rich constituent, ginsenoside Rg3, involves the AMPK signaling pathway and PPAR-gamma inhibition. [ABSTRACT FROM AUTHOR]

Electrolyte-gated organic synaptic transistors (EGOSTs) can have versatile synaptic plasticity in a single device, so they are promising as components of neuromorphic implants that are intended for use in neuroprosthetic electronic nerves that are energy-efficient and have simple system structure. With the advancement in transistor properties of EGOSTs, the commercialization of neuromorphic implants for practical long-term use requires consistent operation, so they must be stable in vivo. This requirement demands strategies that maintain electronic and ionic transport in the devices while implanted in the human body, and that are mechanically, environmentally, and operationally stable. Here, we cover the structure, working mechanisms, and electrical responses of EGOSTs. We then focus on strategies to ensure their stability to maintain these characteristics and prevent adverse effects on biological tissues. We also highlight state-of-the-art neuromorphic implants that incorporate these strategies. We conclude by presenting a perspective on improvements that are needed in EGOSTs to develop practical, neuromorphic implants that are long-term useable., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tae-Woo Lee reports financial support was provided by National Research Foundation of Korea. Seung-Woo Lee reports financial support was provided by National Research Foundation of Korea. Somin Kim reports financial support was provided by National Research Foundation of Korea. Kwan-Nyeong Kim reports financial support was provided by National Research Foundation of Korea. Min-Jun Sung reports financial support was provided by National Research Foundation of Korea. If there are other authors, they 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 © 2024 Elsevier B.V. All rights reserved.)

Introduction: Ginseng berry (GB) has previously been demonstrated to improve systemic insulin resistance and regulate hepatic glucose metabolism and steatosis in mice with diet-induced obesity (DIO)., Objectives: In this study, the role of GB in metabolism was assessed using metabolomics analysis on the total liver metabolites of DIO mice., Methods: Metabolomic profiling was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF/MS) of liver tissue from mice on a 12-wk normal chow diet (NC), high-fat diet (HFD), and HFD supplemented with 0.1% GB (HFD + GB). The detected metabolites, its pathways, and functions were analyzed through partial least square discriminant analysis (PLS-DA), the small molecular pathway database (SMPDB), and MetaboAnalyst 5.0., Results: The liver metabolite profiles of NC, HFD, and GB-fed mice (HFD + GB) were highly compartmentalized. Metabolites involved in major liver functions, such as mitochondrial function, gluconeogenesis/glycolysis, fatty acid metabolism, and primary bile acid biosynthesis, showed differences after GB intake. The metabolites that showed significant correlations with fasting blood glucose (FBG), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) were highly associated with mitochondrial membrane function, energy homeostasis, and glucose metabolism. Ginseng berry intake increased the levels of metabolites involved in mitochondrial membrane function, decreased the levels of metabolites related to glucose metabolism, and was highly correlated with metabolic phenotypes., Conclusion: This study demonstrated that long-term intake of GB changed the metabolite of hepatosteatotic livers in DIO mice, normalizing global liver metabolites involved in mitochondrial function and glucose metabolism and indicating the potential mechanism of GB in ameliorating hyperglycemia in DIO mice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endoscopic biliary stent insertion has been widely used for the treatment of benign biliary stricture (BBS). Thus, the development of stent materials in the perspectives of structure, mechanical properties, and biocompatibility has been also studied. However, conventional metal and plastic stents have several disadvantages, such as repeated procedures to remove or exchange them, dislodgment, restenosis, biocompatibility, and poor mechanical properties. Sustainable effectiveness, attenuation and prevention of fibrosis, and biocompatibility are key factors for the clinical application of stents to BBS treatment. In addition, loading drugs could show synergistic effects with stents' own performance. We developed a dexamethasone-eluting biodegradable stent (DBS) consisting of a sheath/core structure with outstanding mechanical properties and sustained release of dexamethasone, which maintained its functions in a BBS duct over 12 weeks in a swine model. The insertion of our DBS not only expanded BBS areas but also healed secondary ulcers as a result of the attenuation of fibrosis. After 16 weeks from the insertion, BBS areas were totally improved, and the DBS was degraded and thoroughly disappeared without re-intervention for stent removal. Our DBS would be an effective clinical tool for non-vascular diseases. STATEMENT OF SIGNIFICANCE: This study describes the insertion of a drug-eluting biodegradable stent (DBS) into the bile duct. The sheath/core structure of DBS confers substantial durability and a sustained drug release profile. Drug released from the DBS exhibited anti-fibrotic effects without inflammatory responses in both in vitro and in vivo experiments. The DBS maintained its function over 12 weeks after insertion into the common bile duct, expanding benign biliary stricture (BBS) and reducing inflammation to heal secondary ulcers in a swine BBS model. After 16 weeks from the DBS insertion, the DBS thoroughly disappeared without re-intervention for stent removal, resulting in totally improved BBS areas. Our findings not only spotlight the understanding of the sheath/core structure of the biodegradable stent, but also pave the way for the further application for non-vascular diseases., Competing Interests: Declaration of competing interest No other authors have potential conflicts of interest to declare., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Cannulation of the major papilla is the most challenging part of endoscopic retrograde cholangiopancreatography (ERCP) for which physician-controlled wire-guided cannulation (PCWGC) and assistant-controlled wire-guided cannulation (ACWGC) are used as the cannulation techniques. PCWGC can reportedly save up to about 30% of the labor cost by reducing the number of assistants. This study aims to compare the safety and efficacy of PCWGC and ACWGC., Materials and Methods: Of the 2151 patients aged >20 years (4193 cases) who underwent ERCP at Yonsei University Medical Center between January 2015 and December 2016, 989 were included in this study., Results: Among efficacy outcomes, cannulation success rate, rate of precut sphincterotomy (PCWGC vs. ACWGC: 21.3% vs. 25.9%), bile duct cannulation time (PCWGC vs. ACWGC: median 3.0 minutes vs. 3.6 minutes), and total procedure time (PCWGC vs. ACWGC: median 13.6 minutes vs. 13.1 minutes) were not significantly different. Among safety outcomes, lower rates of post-ERCP pancreatitis were observed with PCWGC than with ACWGC (PCWGC vs. ACWGC: 5.8% vs. 8.8%, p =0.128). Among other post-ERCP adverse events (bleeding, perforation, and cholangitis), the difference was not significant between the groups. Radiation exposure (total dose area product, PCWGC vs. ACWGC: median 1979.9 µGym² vs. 2062.0 µGym², p =0.194) and ERCP cost excluding labor cost (PCWGC vs. ACWGC: $1576 vs. $1547, p =0.606) were not significantly different., Conclusion: Requiring less assistants, PCWGC showed comparable efficacy and safety to ACWGC. PCWGC can be considered as an alternative option, especially in facilities lacking manpower and resources., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Triple‑negative breast cancer (TNBC) is associated with a poor prognosis; however, treatments for TNBC are limited, with poor outcomes. MicroRNAs (miRNAs/miRs) are small non‑coding RNA molecules that are able to regulate gene expression. The present study aimed to identify differentially expressed miRNAs in patients with breast cancer, and to investigate the functional role of the identified miRNA targets and their effects in vitro and in vivo . Transfection with miR‑606 suppressed TNBC cell proliferation, migration, invasion and tumor sphere‑forming ability, as determined using trypan blue, Transwell and sphere formation assays. Moreover, miR‑606 induced the apoptosis of TNBC cells, as determined by flow cytometric analysis. Furthermore, intratumoral injections of miR‑606 mimics suppressed tumor growth in MDA‑MB‑231 xenografts. In addition, MDA‑MB‑231 cells transfected with miR‑606 mimics exhibited decreased lung metastatic nodules in a mouse tail vein injection model. Notably, miR‑606 and STC1 expression had opposing effects on the overall survival of patients with TNBC. The results of the present study suggested a novel tumor suppressor function for miR‑606 in TNBC, thus indicating its potential application in the development of anticancer miRNA therapeutics.

Introduction: The incidence of postendoscopic retrograde cholangiopancreatography (ERCP) infections is reported to be up to 18% in patients with biliary obstruction. Antibiotic prophylaxis may reduce the risk of infectious complications after ERCP; however, the clinical value of prophylactic antibiotics in ERCP remains controversial., Methods: We conducted a double-blind, placebo-controlled, randomized trial to investigate whether the use of prophylactic antibiotics would reduce infectious complications after ERCP in patients with biliary obstruction. We randomly assigned patients in a 1:1 ratio to receive either a single dose of 1 g intravenous cefoxitin or normal saline as a placebo 30 minutes before undergoing ERCP. The primary outcome was the incidence of infectious complications after ERCP., Results: We enrolled 378 patients, and 189 patients were assigned to each group. The risk of infectious complications after ERCP was 2.8% (5 of 176 patients) in the antibiotic prophylaxis group and 9.8% (17 of 173 patients) in the placebo group (risk ratio, 0.29; 95% confidence interval [CI], 0.11-0.74, P = 0.0073). The incidence rates of bacteremia were 2.3% (4 of 176 patients) and 6.4% (11 of 173 patients), respectively (risk ratio, 0.36; 95% CI, 0.12-1.04; P = 0.0599). The incidence rate of cholangitis was 1.7% (3 of 176 patients) in the antibiotic prophylaxis group and 6.4% (11 of 173 patients) in the placebo group (risk ratio, 0.27; 95% CI, 0.08-0.87; P = 0.0267)., Discussion: Antibiotic prophylaxis before ERCP in patients with biliary obstruction resulted in a significantly lower risk of infectious complications, especially cholangitis, than placebo ( ClinicalTrials.gov trial number NCT02958059)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Hyperhomocysteinemia is a main risk factor for phenotypic modulation of vascular smooth muscle cells (VSMCs) and atherosclerosis. Phenotypic switching and proliferation of VSMCs are related to the progression of vascular inflammation. Chrysanthemum coronarium L. is a leafy vegetable with various biological functions, such as antioxidative, anti-inflammatory, and antiproliferative effects. In this study, we aimed to identify the mechanisms underlying the therapeutic and preventive effects of C. coronarium L. extract (CC) in regulating homocysteine (Hcy)-induced vascular inflammation in human aortic VSMCs. CC did not exhibit cytotoxicity and inhibited Hcy-stimulated VSMC proliferation and migration. In addition, CC promoted Hcy-induced expression of VSMC contractile phenotype proteins, including alpha-smooth muscle actin, calponin, and smooth muscle 22 α . CC also decreased Hcy-induced accumulation of reactive oxygen species and expression of inflammatory markers nicotinamide adenine dinucleotide phosphate oxidase-4 and soluble epoxide hydrolase. These results showed that CC attenuates Hcy-induced inflammatory responses, highlighting its potential as a therapeutic or preventive target for Hcy-induced vascular inflammation.

Mitochondrial dysfunction plays a pivotal role in diabetic kidney disease initiation and progression. PTEN-induced serine/threonine kinase 1 (PINK1) is a core organizer of mitochondrial quality control; however, its function in diabetic kidney disease remains controversial. Here, we aimed to investigate the pathophysiological roles of PINK1 in diabetic tubulopathy, focusing on its effects on mitochondrial homeostasis and tubular cell necroptosis, which is a specialized form of regulated cell death. PINK1-knockout mice showed more severe diabetes-induced tubular injury, interstitial fibrosis, and albuminuria. The expression of profibrotic cytokines significantly increased in the kidneys of diabetic Pink1 -/- mice, which eventually culminated in aggravated interstitial fibrosis. Additionally, the knockdown of PINK1 in HKC-8 cells upregulated the fibrosis-associated proteins, and these effects were rescued by PINK1 overexpression. PINK1 deficiency was also associated with exaggerated hyperglycemia-induced mitochondrial dysfunction and defective mitophagic activity, whereas PINK1 overexpression ameliorated these negative effects and restored mitochondrial homeostasis. Mitochondrial reactive oxygen species triggered tubular cell necroptosis under hyperglycemic conditions, which was aggravated by PINK1 deficiency and improved by its overexpression. In conclusion, PINK1 plays a pivotal role in suppressing mitochondrial dysfunction and tubular cell necroptosis under high glucose conditions and exerts protective effects in diabetic kidney disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Inflammatory bowel disease (IBD) can severely affect humans and animals and is difficult to treat. Black soldier fly ( Hermetia illucens ; Hi) larvae (BSFL) are a sustainable source of protein. However, no studies exist on the antioxidant and anti-inflammatory functions of BSFL or fermented BSFL with respect to IBD. In this study, riboflavin-producing Lactobacillus plantarum KCCM12757P was isolated from a fish farm tank, and in conjunction with hot water-extracted Hi (HeHi) (termed HeHi_Lp), was used to determine optimal fermentation conditions to increase vitamin B 2 concentration. This in vivo study investigated the therapeutic effects and mechanistic role of HeHi_Lp in chronic colitis-induced murine models. Histological changes, inflammatory cytokine levels, and intestinal barrier function were explored. Gut microbial communities and gene expression in the nuclear factor (NF)-κB signaling pathway were also studied. HeHi_Lp remarkably reduced the disease activity index, inflammatory cytokine (inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, interleukin (IL-6 and IL-1β) levels, and increased body weight and colon length. HeHi_Lp administration significantly raised zonula occludens 1, occludin and claudin 1 and improved the composition of the gut microbiota and beneficial intestinal bacteria. These results suggest that HeHi_Lp can be used as a dietary supplement in pet food to alleviate colitis.

Background/aims: The use of a self-expandable metal stent (SEMS) is recommended for unresectable malignant biliary obstruction (MBO). Stent-related adverse events might differ according to the position of the stent through the ampulla of Vater (AOV). We retrospectively evaluated SEMS patency and adverse events according to the position of the SEMS., Methods: In total, 280 patients who underwent endoscopic SEMS placement due to malignant distal biliary obstruction were analyzed retrospectively. Suprapapillary and transpapillary SEMS insertions were performed on 51 patients and 229 patients, respectively., Results: Between the suprapapillary group (SPG) and transpapillary group (TPG), the stent patency period was not significantly different (median [95% confidence interval]: 107 days [82.3 to 131.7] vs 120 days [99.3 to 140.7], p=0.559). There was also no significant difference in the rate of adverse events. In subgroup analysis, the stent patency for an MBO located within 2 cm from the AOV was found to be significantly shorter than that for an MBO located more than 2 cm from the AOV in the SPG (64 days [0 to 160.4] vs 127 days [82.0 to 171.9], p<0.001) and TPG (87 days [52.5 to 121.5] vs 130 [97.0 to 162.9], p<0.001). Patients with an MBO located within 2 cm from the AOV in both groups had a higher percentage of duodenal invasion (SPG: 40.0% vs 4.9%, p=0.002; TPG: 28.6% vs 2.9%, p<0.001) than patients with an MBO located more than 2 cm from the AOV., Conclusions: The SPG and TPG showed similar results in terms of stent patency and rate of adverse events. However, patients with an MBO located within 2 cm from the AOV had a higher percentage of duodenal invasion with shorter stent patency than those with an MBO located more than 2 cm from the AOV, regardless of stent position.

Chronic kidney disease (CKD) gradually leads to loss of renal function and is associated with inflammation and fibrosis. Chrysanthemum coronarium L., a leafy vegetable, possesses various beneficial properties, including anti-oxidative, anti-inflammatory, and antiproliferative effects. In this study, we investigated the renoprotective effect of Chrysanthemum coronarium L. extract (CC) on adenine (AD)-induced CKD in mice. CKD was induced by feeding mice with an AD diet (0.25% w / w ) for 4 weeks. Changes in renal function, histopathology, inflammation, and renal interstitial fibrosis were analyzed. The adenine-fed mice were characterized by increased blood urea nitrogen, serum creatinine, and histological changes, including inflammation and fibrosis; however, these changes were significantly restored by treatment with CC. Additionally, CC inhibited the expression of the inflammatory markers, monocyte chemoattractant protein-1, interleukins-6 and -1β, intercellular adhesion molecule-1, and cyclooxygenase 2. Moreover, CC suppressed the expression of the fibrotic markers, type IV collagen, and fibronectin. Furthermore, CC attenuated the expression of profibrotic genes (tumor growth factor-β and α-smooth muscle actin) in AD-induced renal injury mice. Thus, our results suggest that CC has the potential to attenuate AD-induced renal injury and might offer a new option as a renoprotective agent or functional food supplement to manage CKD.

Mitochondrial dysfunction is considered to be an important mediator of the pro-aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN-induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS-STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1 -/- ) C57BL/6 mice and senescence-induced renal tubular epithelial cells (HKC-8) treated with H 2 O 2 were used as the renal aging models. Extensive analyses at transcriptomic-metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS-STING pathway, we explored their expression levels in PINK1 knockout mice and senescence-induced HKC-8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence-associated secretory phenotype (SASP). These phenomena were most apparent in the 24-month-old Pink1 -/- mice and HKC-8 cells treated with PINK1 siRNA and H 2 O 2 . Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS-STING was prominent in the 24-month-old Pink1 -/- mice. The expression of SASPs was most noticeable in senescence-induced HKC-8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS-STING pathway, eventually leading to senescence-related inflammatory responses., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Context: Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis., Objective: The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset diabetes mellitus (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group., Methods: The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data were used. Regarding 88 396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multivariate time-dependent Cox regression analysis., Results: The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs 0.16%; P < .001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81; 95% CI, 2.97-4.88; P < .001; LSDM HR: 1.53; 95% CI, 1.11-2.11; P < .001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than in the LSDM group (HR: 1.55; P = .020). In subgroup analysis, NODM group showed that men (HR = 4.42; 95% CI, 3.15-6.19; P < .001) and patients who were in their 50 seconds (HR = 7.54; 95% CI, 3.24-17.56; P < .001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively., Conclusion: The risk of pancreatic cancer was greater in people with DM than in a non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than LSDM., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Various guidewires are used for biliary cannulation, and each one has its own characteristics affecting its effectiveness. This study aimed to measure the basic properties and evaluate the effectiveness of a newly developed 0.025-inch guidewire for selective biliary cannulation., Methods: A total of 190 patients at five referral hospitals were randomly allocated to undergo selective biliary cannulation using the newly developed guidewire (NGW group, n = 95) or a conventional guidewire (CGW group, n = 95). The primary outcome was the selective biliary cannulation rate in naïve papillae. The secondary outcome was to measure the NGW basic properties, compare them with those of the CGW, and analyze the importance of basic property differences., Results: There were no significant differences between the groups in the baseline characteristics. The primary outcome (75.8% vs. 84.2%, p = 0.102) and adverse event rate (6.3% vs. 4.2%, p = 0.374) were similar in both groups. However, compared with the CGW group, the NGW group showed a higher number of ampulla contacts (2.58 vs. 2.02, p = 0.011) and longer cannulation time (216.5 vs. 135.1 s, p = 0.016). Furthermore, the NGW group had higher maximum friction (34.6 ± 1.34 vs. 30.2 ± 4.09), lower stiffness, and better elastic resiliency. In the multivariate analysis, a curved-tip GW (OR = 0.26, 95% CI 0.11-0.62, p = 0.002) and normal papillary shape (OR = 0.39, 95% CI 0.17-0.86, p = 0.021) were contributing factors for successful selective biliary cannulation., Conclusions: The NGW group had high friction and low stiffness, characteristics affecting biliary cannulation. Clinically, the NGW group had similar success and adverse event rates as the CGW, but they showed a higher number of ampulla contacts and longer cannulation time.

Poly-L-lactic acid (PLLA) fillers correct cutaneous volume loss by stimulating fibroblasts to synthesize collagen and by augmenting the volume. PLLA triggers the macrophage-induced activation of fibroblasts that secrete transforming growth factor-β (TGF-β). However, whether M2 macrophage polarization is involved in PLLA-induced collagen synthesis via fibroblast activation in aged skin is not known. Therefore, we evaluated the effect of PLLA on dermal collagen synthesis via M2 polarization in an H 2 O 2 -induced cellular senescence model and aged animal skin. H 2 O 2 -treated macrophages had increased expression levels of the M1 marker CD80 and decreased expression levels of the M2 marker CD163, which were reversed by PLLA. The expression levels of interleukin (IL)-4 and IL-13, which mediate M2 polarization, were decreased in H 2 O 2 -treated macrophages and increased upon the PLLA treatment. CD163, IL-4, and IL-13 expression levels were decreased in aged skin, but increased after the PLLA treatment. The expression levels of TGF-β, pSMAD2/SMAD2, connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), collagen type 1A1 (COL1A1), and COL3A1 were also decreased in aged skin, but increased after the PLLA treatment. Moreover, PLLA upregulated phosphatidylinositol 3-kinase p85α (PI3-kinase p85α)/protein kinase B (AKT) signaling, leading to fibroblast proliferation. PLLA decreased the expression of matrix metalloproteinase (MMP) 2 and MMP3, which destroy collagen and elastin fibers in aged skin. The amount of collagen and elastin fibers in aged skin increased following the PLLA treatment. In conclusion, PLLA causes M2 polarization by increasing IL-4 and IL-13 levels and upregulating TGF-β expression and collagen synthesis in aged skin.

The prevalence of chronic kidney disease (CKD) is steadily increasing, and it is a global health burden. Exercise has been suggested to improve physical activity and the quality of life in patients with CKD, eventually reducing mortality. This study investigated the change in physical performance after exercise in dialysis-dependent patients with CKD and analyzed differentially expressed proteins before and after the exercise. Plasma samples were collected at enrollment and after 3 months of exercise. Liquid chromatography with tandem mass spectrometry analysis and data-independent acquisition results were analyzed to determine the significantly regulated proteins. A total of 37 patients on dialysis were recruited, and 16 were randomized to exercise for 3 months. The hand grip strength and the walking speed significantly improved in the exercise group. Proteome analysis revealed 60 significantly expressed proteins after 3 months of exercise. In the protein functional analysis, the significantly expressed proteins were involved in the immune response. Also, some of the key significantly expressed proteins [(M Matrix metallopeptidase 9 (MMP-9), Activin A Receptor Type 1B (ACVR1B), Fetuin B (FETUB)] were validated via an enzyme-linked immunosorbent assay. Our results showed that exercise in dialysis-dependent patients with CKD could improve their physical performance. These results indicated that this beneficial effect of exercise in these populations could be associated with immune response., (© 2023. The Author(s).)

Osteoporosis is a progressive metabolic disease characterized by decreased bone mineral density and increased fracture risk. Previous studies have shown that higher intake of vitamin K (VK) correlates with a reduced risk of osteoporosis. However, the effect of menaquinone-4 (MK-4), a specific form of VK, still remains obscure. Therefore, in this study, we investigated the effects of MK-4 on osteoclast differentiation by differentiating RAW 264.7 cells into osteoclasts with the help of receptor activator of nuclear factor-kappa B ligand (RANKL), assessed the mRNA expression of osteoclast-specific genes, and studied the effects of MK-4 in vivo in ovariectomized mice, a postmenopausal osteoporosis murine model. MK-4 inhibited osteoclast differentiation, decreased the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), osteoclast-associated receptor (OSCAR), and cathepsin K (CTSK), and inhibited bone loss in ovariectomized mice. The findings strongly suggest that MK-4 is a therapeutic alternative for postmenopausal osteoporosis.

Background: Children's motor development is a crucial tool for assessing developmental levels, identifying developmental disorders early, and taking appropriate action. Although the Korean Developmental Screening Test for Infants and Children (K-DST) can accurately assess childhood development, its dependence on parental surveys rather than reliable, professional observation limits it. This study constructed a dataset based on a skeleton of recordings of K-DST behaviors in children aged between 20 and 71 months, with and without developmental disorders. The dataset was validated using a child behavior artificial intelligence (AI) learning model to highlight its possibilities., Results: The 339 participating children were divided into 3 groups by age. We collected videos of 4 behaviors by age group from 3 different angles and extracted skeletons from them. The raw data were used to annotate labels for each image, denoting whether each child performed the behavior properly. Behaviors were selected from the K-DST's gross motor section. The number of images collected differed by age group. The original dataset underwent additional processing to improve its quality. Finally, we confirmed that our dataset can be used in the AI model with 93.94%, 87.50%, and 96.31% test accuracy for the 3 age groups in an action recognition model. Additionally, the models trained with data including multiple views showed the best performance., Conclusion: Ours is the first publicly available dataset that constitutes skeleton-based action recognition in young children according to the standardized criteria (K-DST). This dataset will enable the development of various models for developmental tests and screenings., (© The Author(s) 2023. Published by Oxford University Press GigaScience.)

The senescence of vascular endothelial cells (EC) leads to vascular dysfunction. However, the molecular mechanisms of EC senescence and its associated pathophysiological changes have not yet been clearly studied. This study sought to inspect the Chrysanthemum coronarium L. (CC) extract's mechanism in preventing premature senescence of EC. A senescent endothelial cell model was created in human umbilical vein endothelial cells (HUVECs) with 100 µmol/L H 2 O 2 treatment for 24 h. The effect of CC on senescent HUVECs was elucidated by measuring the activity of β-galactosidase (SA-β-gal), which exhibits an aging-related phenotype. SA-β-gal activity increased to 13.2 ± 2.85% in H 2 O 2 -treated HUVECs, whereas this activity was attenuated in the CC group. Immunoblot analyses revealed that p21, p53, and PAI-1 levels increased in the senescent HUVECs; however, the levels decreased in the HUVECs treated with various concentrations of CC (10, 20, and 50 μg/mL). The CC extract reduced the production of reactive oxygen species and reversed the decrease in NO production. Additionally, pretreatment with an Nω-nitro-l-arginine methyl ester (eNOS inhibitor) and nicotinamide (sirtuin 1 inhibitor) inhibited the anti-senescent effect of CC extract in HUVECs. Taken together, this study validated the novel endothelial protective effect of CC extract and its prevention of senescence in HUVECs through the mechanism regulated by eNOS and SIRT1 expression.

The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic cancer (PC) has been validated for pathological staging; however, its significance for clinical staging remains uncertain. We validated the prognostic performance and suitability of the current staging system for the clinical staging of PC. We identified 1043 patients from our PC registry who were staged by imaging according to the 8th edition staging system and conducted analysis, including overall survival (OS) comparison. Gradual prognostic stratification according to stage hierarchy yielded significant OS differences between stage groups, except between stage I and II (p = 0.193). A substage comparison revealed no survival differences between IB (T2N0) and IIA (T3N0), which were divided by the T3 criterion only (p = 0.278). A higher N stage had significantly shorter OS than a lower N stage (all pairwise p < 0.05). However, among the 150 patients who received upfront surgery, the pathological stage was more advanced than the clinical stage in 86 (57.3%), mostly due to a false-negative cN0 (70.9%). Our results suggest that the new definition of T3 and the number-based N criteria in the 8th edition AJCC staging system may be not adequate for clinical staging. Establishing separate criteria more suitable for clinical staging should be considered.

Some BTC types respond to pembrolizumab, but there are no known prognostic factors to predict its treatment benefits. In this study, we attempted to identify the prognostic factors associated with pembrolizumab as a second-line treatment for gemcitabine-refractory BTC. This retrospective and single tertiary-center study involved all the consecutive patients (n = 80) with refractory advanced BTC, who were diagnosed as programmed cell death ligand 1-positive and treated with pembrolizumab between August 2017 and February 2021. The overall survival (OS) was analyzed using Cox regression analysis. The median OS was 6.0 months [95% confidence interval (CI): 3.87−8.20]; median progression-free survival was 1.9 months (95% CI: 1.82−1.98); and the response rate was 15.9%. In the multivariate Cox regression analysis, the TB [adjusted hazard ratio (HR) = 2.286; 95% CI: 1.177−4.440; p = 0.015), albumin levels (adjusted HR = 0.392; 95% CI: 0.211−0.725; p = 0.003), ALP levels (adjusted HR = 1.938; 95% CI: 1.105−3.400; p = 0.021), and LMR (adjusted HR = 0.325; 95% CI: 0.173−0.609; p < 0.001) were identified as significant variables associated with the OS. High albumin levels and LMR and low ALP levels and TB were significantly associated with better OS in patients treated with pembrolizumab.

Atherosclerosis manifests as a chronic inflammation resulting from multiple interactions between circulating factors and various cell types in blood vessel walls. Growing evidence shows that phenotypic switching and proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the progression of atherosclerosis. Soluble epoxide hydrolase (sEH)/epoxyeicosatrienoic acids are mediated by vascular inflammation. N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]-urea (TPPU) is an sEH inhibitor. This study investigated the therapeutic effect of TPPU on atherosclerosis in vivo and homocysteine-induced vascular inflammation in vitro and explored their molecular mechanisms. We found that TPPU decreased WD-induced atherosclerotic plaque lesions, inflammation, expression of sEH, and nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox4), and increased the expression of contractile phenotype marker of aortas in ApoE (-/-) mice. TPPU also inhibited homocysteine-stimulated VSMC proliferation, migration, and phenotypic switching, and reduced Nox4 in human-aorta-VSMC regulation. We conclude that TPPU has anti-atherosclerotic effects, potentially because of the suppression of VSMC phenotype switching. Thus, TPPU could be a potential therapeutic target for phenotypic switching attenuation in atherosclerosis., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The use of endobiliary radiofrequency ablation (RFA) to generate a benign biliary stricture (BBS) model has a significant reproducibility problem. The aims of this animal study were to create an optimal BBS model using endobiliary RFA and determine the best way to develop it. The first step was performed on the common bile duct (CBD) of 10 miniature pigs using endoscopic RFA with a target temperature-controlled mode (80 ℃, 7 W for 90 s). The second step was performed on the CBD of five miniature pigs to understand more about the time-dependent changes in BBS development and the causes of adverse events. Using the conditions and techniques identified in the previous steps, the third step was conducted to create an optimal BBS model in 12 miniature pigs. In the first trial, four out of 10 animals died (40%) after the procedure due to cholangitis-induced sepsis. Based on this, biliary obstruction was prevented in further steps by placing a biliary plastic stent after RFA application. Histologic examinations over time showed that a severe abscess developed at the RFA application site on the fifth day, followed by fibrosis on the tenth day, and completion on the twentieth day. In the third trial, 11 animals survived (91.7%), the average BBS fibrotic wall thickness was 1107.9 µm (763.1-1864.6 µm), and the degree of upstream biliary dilation was 14.4 mm (11.05-20.7 mm). In conclusion, endobiliary RFA combined with a biliary plastic stent resulted in a safe and reproducible BBS animal model., (© 2022. The Author(s).)

Primary cervical spine infections progress quickly and cause neurological impairment at an early stage. Despite their clinical significance, few studies have investigated primary cervical spine infections, owing to the rarity of the condition. This study analyzed the characteristics of 59 patients treated for primary cervical spine infections between 1992 and 2018 at our hospital. Clinical and radiological analyses were conducted. Moreover, a comparative analysis was performed, incorporating each patient's underlying disease, mortality and complications, and treatment results. Comparison between groups based on the chronological period (1992-2000, 2001-2009, and 2010-2018) revealed that the mean age of onset has increased significantly in recent years. The rate of neurological impairment, duration of antibiotic use, and frequency of underlying disease increased significantly with time. No significant differences among groups were observed in the hematological and microbiological analyses. The incidence rate of epidural abscess and multisegmental infection increased significantly in recent years. There was no statistically significant difference in the complication and mortality rates, according to the time period. We think that prompt diagnosis and appropriate treatment are necessary, considering the current trends in primary cervical spine infection.

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a precancerous lesion of cholangiocarcinoma, for which surgical resection is the most effective treatment. We evaluated the predictors of malignancy in IPNB according to anatomical location and the prognosis without surgery. Methods: A total of 196 IPNB patients who underwent pathologic confirmation by surgical resection or endoscopic retrograde cholangiography or percutaneous transhepatic cholangioscopic biopsy were included. Clinicopathological findings of IPNB with invasive carcinoma or mucosal dysplasia were analyzed according to anatomical location. Results: Of the 116 patients with intrahepatic IPNB (I-IPNB) and 80 patients with extrahepatic IPNB (E-IPNB), 62 (53.4%) and 61 (76.3%) were diagnosed with invasive carcinoma, respectively. Multivariate analysis revealed that mural nodule > 12 mm (p = 0.043) in I-IPNB and enhancement of mural nodule (p = 0.044) in E-IPNB were predictive factors for malignancy. For pathologic discrepancy before and after surgery, IPNB has a 71.2% sensitivity and 82.3% specificity. In the non-surgical IPNB group, composed of nine I-IPNB and seven E-IPNB patients, 43.7% progressed to IPNB with invasive carcinoma within 876 days. Conclusions: E-IPNB has a higher rate of malignancy than I-IPNB. The predictive factor for malignancy is mural nodule > 12 mm in I-IPNB and mural nodule enhancement in E-IPNB.

Purpose: The current drain tubes for preventing surgically biliary anastomotic stricture are not naturally and easily removed. If a drain tube using biodegradable material is easily available and the degradation time of the tube is well controlled, surgical anastomotic stricture and fibrosis could be prevented. The aim of this animal study was to evaluate the preventive effect of novel biodegradable stents (BS) on biliary stricture and fibrosis after duct-to-duct (DD) biliary anastomosis., Methods: Ten mini-pigs were allocated to the control group (n = 5) and or the stent group (n = 5). The common bile duct was exposed through surgical laparotomy and then resected transversely. In the stent group, a 4-mm or 6-mm polydioxanone/magnesium sheath-core BS was inserted according to the width of the bile duct, followed by DD biliary anastomosis. In the control group, DD biliary anastomosis was performed without BS insertion., Results: In the stent group, stents were observed without deformity for up to 4 weeks in all animals. Eight weeks later, histopathologic examination revealed that the common bile duct of the anastomosis site was relatively narrower in circumference in the control group compared to the stent group. The degree of fibrosis in the control group was more marked than in the stent group (3.84 mm vs. 0.68 mm, respectively; P < 0.05)., Conclusion: Our study showed that novel BS maintained their original shape and radial force for an adequate time and then disappeared without adverse events. The BS could prevent postoperative complications and strictures after DD biliary anastomosis., Competing Interests: Conflict of Interest: Kyu Seok Kim, Jong Pil Moon, Sehwan Park, and Jinkyung Jeon are researchers at the Interventional Research Center of M.I.Tech Co., Ltd. which provided the prototype biodegradable stents used in our experiment. The other authors have no conflicts of interest to disclose., (Copyright © 2022, the Korean Surgical Society.)

Background/aims: : Controversy regarding the effectiveness of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC) still exists. Here, we aimed to identify the potential benefits of neoadjuvant therapy followed by surgery for resectable PDAC., Methods: We reviewed radiologically resectable PDAC patients who received resection with curative intent at a tertiary hospital in South Korea between January 2012 and August 2019. A total of 202 patients underwent curative resection for resectable PDAC: 167 underwent surgical resection first during this period, and 35 received neoadjuvant chemotherapy/chemoradiation therapy followed by surgery. Resectable PDAC patients were subdivided, and 1:3 propensity score matching (PSM) was performed to reduce selection bias., Results: Compared with the group that received surgery first, the group that received neoadjuvant treatment followed by surgery had significantly smaller tumors (22.0 mm vs 27.0 mm, p=0.004), a smaller proportion of patients with postoperative pathologic T stage (p=0.026), a smaller proportion of patients with lymphovascular invasion (20.0% vs 40.7%, p=0.022), and a larger proportion of patients with negative resection margins (74.3% vs 51.5%, p=0.049). After PSM, the group that received neoadjuvant therapy had a significantly longer progression-free survival than those in the group that underwent surgery first (29.6 months vs 15.1 months, p=0.002). Overall survival was not significantly different between the two groups after PSM analysis., Conclusions: We observed significantly better surgical outcomes and progression-free survival with the addition of neoadjuvant therapy to the management of resectable PDAC. However, despite PSM, there was still selection bias due to the use of different regimens between the groups receiving surgery first and neoadjuvant therapy. Large homogeneous samples are needed in the future prospective studies.

Sarcopenia is associated with obesity and might also be responsible for other disorders. Here, we investigated the prevalence of sarcopenia and its predictors in obese subjects. Subjects who underwent a medical health checkup and living-related liver donors were recruited. Obesity was defined as body mass index (BMI) ≥25 kg/m 2 . Muscle mass was assessed using computed tomography at the 3 rd lumbar vertebra. The lowest quartile of the lumbar skeletal muscle index (LSMI) was considered sarcopenia. Among 466 obese subjects, 53 (11.4%) had sarcopenia. Subjects with sarcopenia were significantly older (mean 66.6 vs. 53.3 years) and had a significantly higher prevalence of hypertension (62.3 vs. 46.0%) and diabetes (45.3 vs. 31.0%), higher fibrosis-4 (FIB-4) index (mean 1.57 vs. 1.16), and higher atherosclerotic cardiovascular disease (ASCVD) risk score (mean 22.86% vs. 11.15%), whereas they had a significantly lower prevalence of female gender (13.2% vs. 27.8%), lower BMI (mean 26.4 vs. 27.4 kg/m 2 ), and lower LSMI (mean 43 vs. 56 cm 2 /m 2 ) than subjects without sarcopenia (all P  < 0.05). On multivariate analysis, higher BMI (odd ratio [OR] = 0.599, P  = 0.001) was independently associated with a reduced risk of sarcopenia, whereas higher ASCVD risk scores (OR = 1.045, P  < 0.001) were independently associated with an increased risk of sarcopenia. Sarcopenia is significantly associated with lower BMI and higher cardiovascular risk in an obese Asian population.

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are emerging tissue-agnostic drug targets in malignancies including colorectal carcinomas (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. In this study, pan-tropomyosin receptor kinase (TRK) protein expression was assessed by immunohistochemistry (IHC) in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs [133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)] and 595 premalignant colorectal lesions (330 serrated lesions and 265 conventional adenomas). TRK-positive cases were then subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. TRK IHC positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) MLH1-methylated MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) sessile serrated lesions (SSLs). The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, BRAF/KRAS wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and BRAF/KRAS wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK expression was selectively observed in distorted serrated crypts within SSLs and was occasionally localized at the base of serrated crypts. NTRK fusions were detected only in SSLs of patients aged ≥50 years, whereas BRAF mutation was found in younger age-onset SSLs. In conclusion, NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI-high/CIMP-high. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited., Methods: We adopted an ovariectomy model in female wildtype and Pink1 -/- mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson's trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients., Results: A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1 -/- mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease., Conclusions: In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts., (© 2021. The Author(s).)

Background: Endoscopic biliary stenting (EBS) with a fully covered, self-expandable metallic stent (FC-SEMS) and plastic stent (PS) is safe and efficient for biliary anastomotic strictures (ASs) after a deceased donor liver transplantation. Limited studies have investigated the use of FC-SEMSs for biliary strictures post-living donor liver transplantation (LDLT). We compared the resolution rate of biliary ASs post-LDLT and the 12-month recurrence rates post-stent removal between EBS with an FC-SEMS, PS, and percutaneous transhepatic biliary drainage (PTBD)., Methods: Patients with biliary ASs after an LDLT (mean age: 57.3 years, 76.1% men) hospitalized between 2014 and 2017 were enrolled. Endoscopic retrograde cholangiopancreatography (ERCP) was repeated every 3-4 months. Patients were followed-up for at least 1-year post-stent removal., Results: Of the 75 patients enrolled, 16, 20, and 39 underwent EBS with an FC-SEMS, PS, and PTBD, respectively. Median follow-up period was 39.2 months. Fewer ERCP procedures were needed in the FC-SEMS group than in the PS group (median, 2 vs. 3; P = 0.20). Median stent indwelling periods were 4.7, 9.3, and 5.4 months in the FC-SEMS, PS, and PTBD groups, respectively (P = 0.006). The functional resolution rate was lower in the PS group (16/20) than in the FC-SEMS (16/16) or PTBD (39/39) group (P = 0.005). The radiologic resolution rate was higher in the FC-SEMS group (16/16) than in the PS group (14/20) (P = 0.07). The 12-month recurrence rates showed no significant differences (FC-SEMS, 4/16; PS, 3/16; PTBD, 6/39; P = 0.66). The rates of complications during treatment differed significantly between the groups (P = 0.04). Stent migration occurred in 1 (6.3%) and 5 (25.0%) patients in the FC-SEMS and PS groups, respectively (P = 0.59)., Conclusions: EBS with an FC-SEMS is comparable with EBS with a PS or PTBD in terms of biliary stricture resolution and 12-month recurrence rates. The use of FC-SEMSs is potentially effective and safe for biliary AS resolution after LDLT., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Approximately 80% of pancreatic ductal adenocarcinoma (PDAC) patients suffer from anorexia, weight loss, and asthenia. Most PDAC patients receive chemotherapy, which often worsens their nutritional status owing to the adverse effects of chemotherapy. Malnutrition of PDAC patients is known to be associated with poor prognosis; therefore, nutritional management during chemotherapy is a key factor influencing the outcome of the treatment. Mobile apps have the potential to provide readily accessible nutritional support for patients with PDAC., Objective: We aimed to evaluate the efficacy of a mobile app-based program, Noom, in patients receiving chemotherapy for PDAC., Methods: We prospectively enrolled 40 patients who were newly diagnosed with unresectable PDAC from a single university-affiliated hospital in South Korea, and randomly assigned them into a Noom user group (n=20) and a non-Noom user group (n=20). The 12-week in-app interventions included meal and physical activity logging as well as nutritional education feedback from dietitians. The non-Noom user group did not receive any nutrition intervention. The primary outcomes were the changes in the nutritional status and quality of life (QoL) from the baseline to 12 weeks. The secondary outcomes included the changes in the skeletal muscle index (SMI) from the baseline to 12 weeks. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Patient-Generated Subjective Global Assessment (PG-SGA) were used as paper questionnaires to assess the QoL and nutritional status of the patients. Intention-to-treat and per-protocol analyses were conducted. Regarding the study data collection time points, we assessed the nutritional status and QoL at the baseline (T0), and at 4 (T1), 8 (T2), and 12 (T3) weeks. Abdominal computed tomography (CT) imaging was conducted at the baseline and after 8 weeks for tumor response and SMI evaluation. The skeletal muscle area (cm 2 ) was calculated using routine CT images. The cross-sectional areas (cm 2 ) of the L3 skeletal muscles were analyzed., Results: Between February 2017 and January 2018, 48 patients were assessed for eligibility. Totally 40 patients with pancreatic cancer were included by random allocation. Only 17 participants in the Noom user group and 16 in the non-Noom user group completed all follow-ups. All the study participants showed a significant improvement in the nutritional status according to the PG-SGA score regardless of Noom app usage. Noom users showed statistically significant improvements on the global health status (GHS) and QoL scales compared to non-Noom users, based on the EORTC QLQ (P=.004). The SMI decreased in both groups during chemotherapy (Noom users, 49.08±12.27 cm 2 /m 2 to 46.08±10.55 cm 2 /m 2 ; non-Noom users, 50.60±9.05 cm 2 /m 2 to 42.97±8.12 cm 2 /m 2 ). The decrement was higher in the non-Noom user group than in the Noom user group, but it was not statistically significant (-13.96% vs. -3.27%; P=.11)., Conclusions: This pilot study demonstrates that a mobile app-based approach is beneficial for nutritional and psychological support for PDAC patients receiving chemotherapy., Trial Registration: ClinicalTrials.gov NCT04109495; https://clinicaltrials.gov/ct2/show/NCT04109495., (©Jiyoung Keum, Moon Jae Chung, Youngin Kim, Hyunyoung Ko, Min Je Sung, Jung Hyun Jo, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Si Young Song, Hee Seung Lee. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 31.08.2021.)

Background: The best treatment for degenerative medial meniscus posterior root tear (MMPRT) remains controversial. This study aimed to compare the clinical and radiological outcomes of arthroscopic meniscectomy and conservative treatment for degenerative MMPRT., Methods: From January 2007 to December 2014, 146 patients (Meniscectomy group, 90; Conservative group, 56) were evaluated. Clinical outcomes were assessed using the Visual Analog Scale, International Knee Documentation Committee subjective scoring scale, Tegner activity scale, and Lysholm knee scoring scale at the final follow-up. Radiologic outcomes evaluated the progression of osteoarthritis (OA) according to the Kellgren-Lawrence (K-L) classification. We compared the hip-knee-ankle angle (HKAA), medial proximal tibial angle, tibial posterior slope angle, and width of medial joint space. After an average follow-up of 6.3 years, the survivorship was analyzed using the Kaplan-Meier method., Results: All clinical outcomes were significantly improved in both groups after treatment, with no significant differences between the two groups at the final follow-up. The progression of OA according to the K-L classification, HKAA and width of medial joint space was significantly advanced in the meniscectomy group (p = 0.03, 0.04, 0.03, respectively). The 10-year survival rates in the meniscectomy and conservative groups were 87 and 88%, respectively., Conclusions: This study demonstrated that both conservative treatment and meniscectomy provided symptomatic relief. However, it was confirmed that OA progression was more severe in the meniscectomy. We conclude that arthroscopic meniscectomy had no advantage over conservative treatment in terms of clinical outcomes and OA progression in middle-aged patients with MMPRT., Level of Evidence: Level III; retrospective comparative study., (© 2021. The Author(s).)

Non-fullerene acceptors (NFAs) for organic solar cells (OSCs) have significantly developed over the past five years with continuous improvements in efficiency now over 18%. However, a key challenge still remains in order to fully realize their commercialization potential: the need to extend device lifetime and to control degradation mechanisms. Herein, we investigate the effect of two different molecular engineering routes on the widely utilized ITIC NFA, to tune its optoelectronic properties and interactions with the donor polymer in photoactive blends. Heavier selenium (Se) atoms substitute sulfur (S) atoms in the NFA core in either outer or inner positions, and methyl chains are attached to the end groups. By investigating the effects of these structural modifications on the long-term operational stability of bulk-heterojunction OSC devices, we identify outer selenation as a powerful strategy to significantly increase device lifetime compared to ITIC. Combining outer selenation and methylation results in an impressive 95% of the initial OSC efficiency being retained after 450 h under operating conditions, with an exceptionally long projected half-lifetime of 5600 h compared to 400 h for ITIC. We find that the heavier and larger Se atoms at outer-core positions rigidify the molecular structure to form highly crystalline films with low conformational energetic disorder. It further enhances charge delocalization over the molecule, promoting strong intermolecular interactions among acceptor molecules. Upon methylation, this strong intermolecular interaction stabilizes acceptor domains in blends to be resilient to light-induced morphological changes, thereby leading to superior device stability. Our results highlight the crucial role of NFA molecular structure for OSC operational stability and provide important NFA design rules via heteroatom position and end-group control.

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 ( SMN1 ) gene. Branaplam ( 1 ) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26 , which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.

The purpose of this study was to evaluate the outcomes of patients with Legg-Calvé-Perthes disease (LCPD) with disease onset before 6 years of age who were treated with conservative methods and to identify prognostic factors. Moreover, we evaluated the duration of the Waldenström stage and its correlation with the disease outcome. Disease severity was assessed using the lateral pillar classification, and the final outcome was evaluated using the Stulberg classification. We divided patients with LCPD into two groups according to the age at onset: group 1 (<4 years) and group 2 (4-6 years). The final outcomes of the two groups were compared. We also assessed the duration of each Waldenström stage. LCPD was noted in 49 hips of 49 patients. The lateral pillar class was A in one patient, B in 29 patients, and B/C or C in 19 patients. The Stulberg class was I or II (good) in 30 patients, III (fair) in 13 patients, and IV or V (poor) in six patients. The lateral pillar class significantly correlated with the final outcome. Groups 1 and 2 comprised 25 and 24 patients, respectively. The prevalence of good outcomes did not significantly differ between the groups ( p = 0.162). The duration of the initial stage was 4.1 months in the good outcome group and 6.2 months in the fair or poor outcome group. The duration of the fragmentation stage of the femoral head was 5.9 months in the good outcome group and 11.9 months in the fair or poor outcome group. The durations of initial and fragmentation stages significantly differed between good outcome group and fair or poor outcome group ( p = 0.009 and p < 0.001, respectively). The prognosis of patients with disease onset before the age of 6 years was favorable. The disease severity and duration of each Waldenström stage can be predictors of the outcome. Patients with prolonged initial and fragmentation stages showed worse outcomes and often required more active treatment to shorten the durations of the initial and fragmentation stages.

Osteoporosis is characterized by decreased bone mass and bone microarchitectural failure, leading to an enhanced risk of bone fractures. Chrysanthemum coronarium L . (CC) is a natural plant with powerful antioxidant activity. This study investigated the antiosteoporotic effects of CC extracts in in vitro cell cultures and in vivo bone loss animal models. CC stimulated osteoblast differentiation and mineralized bone formation by osteoblasts by increasing the expression of bone formation markers (alkaline phosphatase, osteoprotegerin, and osteoprotegerin/receptor activator nuclear factor- κ B ligand ratio) in the murine preosteoblastic cell line MC3T3-E1. Additionally, CC was found to inhibit osteoclast differentiation by downregulating bone resorption markers (tartrate-resistant acid phosphatase, cathepsin K, dendritic cell-specific transmembrane protein, and calcitonin receptor) in the murine macrophage-like cell line RAW264.7. CC prevented ovariectomy-induced bone loss, preserved trabecular microarchitecture, and improved serum bone turnover markers in an osteoporotic mouse model. These findings suggest that CC extract may be considered as a natural therapeutic or preventive agent for osteoporotic bone loss., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 So Ah Kim et al.)

Inflammatory bowel disease (IBD) is characterized by inflammation, angiogenesis, and lymphangiogenesis. Artemisinin (Art), a chemical compound isolated from Artemisia annua L. (sweet wormwood), has several biochemical properties including antibacterial, anticancer, anti-inflammation, and anti-angiogenesis effects. We investigated the effects of Art on inflammation-induced lymphangiogenesis in a dextran sulfate sodium (DSS)-induced mouse acute colitis model. The mice were orally administered Art for 7 days before being evaluated using the disease activity index (DAI) and documenting colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), proinflammatory cytokine levels, and vascular endothelial growth factor (VEGF)-C and VEGF-D/VEGF receptor (VEGFR)-3 mRNA expression levels in colon tissue. Art reduced DSS-induced lymphatic vessel endothelial hyaluronan receptor-1-positive LVD. Art also reduced the symptoms of colitis, improved tissue histology, and relieved inflammatory edema in mice affected by colitis. In addition, Art decreased the infiltration of immunomodulatory cells and inflammatory cytokines, which involved reduction of VEGF-C, -D, and VEGFR-3 expression. Taken together, our findings suggest that Art ameliorates inflammation-driven lymphangiogenesis in an experimental colitis mouse model via the VEGF-C/VEGFR-3 signaling pathway, implicating this pathway as a potential target for the treatment of IBD.

Nonalcoholic fatty liver disease (NAFLD) is associated with progressive metabolic diseases. Estrogen deficiency increases the NAFLD risk among postmenopausal women. Thus, effective agents to prevent and treat NAFLD in postmenopausal women are required. Quercitrin (Quer) is a natural glycosylated flavonoid with antimicrobial, anti-inflammatory, and hypolipidemic effects. This study investigated whether Quer improves dysregulated lipid metabolism and suppresses hepatic steatosis in ovariectomized (OVX) mice as an experimental model mimicking postmenopausal women. Mice were assigned to the following four groups: SHAM, OVX, OVX + β-estradiol (0.4 mg/kg diet), and OVX + Quer (500 mg/kg diet). Mice were administered a diet with or without Quer for three months. OVX mice displayed significantly higher body mass, epidermal fat, and liver weights than those of SHAM mice. However, these levels were reduced in Quer-treated mice. Quer treatment reduced the levels of serum lipid metabolites, including triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Furthermore, Quer reduced liver lipid steatosis and inhibited the expression of proinflammatory cytokines, such as tumor necrosis factor-α, IL-6, and IL-1β. The results of the present study indicate that Quer improves dysregulated lipid metabolism and reduces hepatic steatosis and inflammation by compensating for estrogen deficiency, suggesting that Quer may potentially exert protective effects during hepatic steatosis in postmenopausal women.

Background/aims: Sarcopenia is associated with liver fibrosis in patients with nonalcoholic fatty liver disease and chronic hepatitis B. We investigated the association between sarcopenia and hepatic fibrotic burden in patients with type 2 diabetes mellitus (T2DM)., Methods: Patients with T2DM who had received a comprehensive medical health checkup were recruited. Muscle mass was assessed using computed tomography. Fibrotic burden was assessed using the fibrosis-4 index (FIB-4). The study population was divided by quartile stratification of the lumbar skeletal muscle index (LSMI)., Results: Among 309 patients with T2DM, 75 (24.3%) had sarcopenia. These patients were significantly older and had higher FIB-4, whereas they had significantly lower body mass index (BMI) and LSMI than patients without sarcopenia (all p<0.05). The LSMI showed a significant negative correlation with the FIB-4 when analyzed in terms of quartile stratification (p=0.003). Multivariate analysis showed that female sex and higher BMI were independently associated with a reduced risk of sarcopenia (odds ratio [OR], 0.388; 95% confidence interval [CI], 0.199 to 0.755 and OR, 0.704; 95% CI, 0.618 to 0.801; all p<0.05), whereas a higher FIB- 4 was independently associated with an increased risk of sarcopenia (OR, 1.817; 95% CI, 1.180 to 2.797; p=0.007). Among patients with a BMI <25 kg/m 2 (n=165), those with sarcopenia (n=54, 32.7%) had a significantly higher FIB-4 than those without (n=111, 67.3%; 1.66 vs 1.38, p=0.004)., Conclusions: Sarcopenia is independently associated with fibrotic burden in patients with T2DM. Further studies should investigate whether the improvement of sarcopenia can ameliorate liver fibrosis in patients with T2DM.

Background: Venous invasion is not included in the pancreatic ductal adenocarcinoma (PDAC) staging, and its correlation with prognosis remains unclear. We evaluated the prognostic impact of radiographic portal/superior mesenteric vein (PV/SMV) invasion, and its possibility of complementing T staging., Methods: We identified patients with non-metastatic PDAC using our institutional cohort, and divided them according to PV/SMV invasion at imaging, defined as >180-degree tumor-vessel interface or contour deformity. We conducted Cox proportional hazard regression, and compared survival in the original and 1:1 propensity score matched datasets., Results: We identified 454 patients [PV/SMV(+): 172; PV/SMV(-): 282]. In the multivariate analysis, PV/SMV invasion, age (≥70 years), performance status, tumor size (2-4, >4 cm), lymph nodes >4, and arterial invasion was correlated with prognosis. The PV/SMV(+) group had a shorter overall survival (OS) than the PV/SMV(-) group in the original (14.4 vs. 20.9 months; P < 0.001) and matched datasets (14.3 vs. 17.2 months; P = 0.009). Among patients without arterial invasion (cT1-cT3), the PV/SMV(+) group had a shorter OS (15.9 vs. 21.2 months; P = 0.002). Moreover, their OS did not differ from that of patients with arterial invasion (cT4) (15.9 vs. 14.4 months; P = 0.907). Patients with vessel (artery/vein) invasion had a shorter OS than those without vessel invasion (14.5 vs. 21.2 months; P < 0.001)., Conclusions: Radiographic PV/SMV invasion in non-metastatic PDAC was correlated with a poor prognosis. It could identify a group with shorter OS among patients without arterial invasion (cT1-cT3). It is suggested that inclusion of PV/SMV invasion in clinical T4 criteria should be considered., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier B.V.)

The use of three-dimensional (3D) printing is becoming more common, including in the field of orthopaedic surgery. There are currently four primary clinical applications for 3D-printing in hip and pelvic surgeries: (i) 3D-printed anatomical models for planning and surgery simulation, (ii) patient-specific instruments (PSI), (iii) generation of prostheses with 3D-additive manufacturing, and (iv) custom 3D-printed prostheses. Simulation surgery using a 3D-printed bone model allows surgeons to develop better surgical approaches, test the feasibility of procedures and determine optimal location and size for a prosthesis. PSI will help inform accurate bone cuts and prosthesis placement during surgery. Using 3D-additive manufacturing, especially with a trabecular pattern, is possible to produce a prosthesis mechanically stable and biocompatible prosthesis capable of promoting osseointergration. Custom implants are useful in patients with massive acetabular bone loss or periacetabular malignant bone tumors as they may improve the fit between implants and patient-specific anatomy. 3D-printing technology can improve surgical efficiency, shorten operation times and reduce exposure to radiation. This technology also offers new potential for treating complex hip joint diseases. Orthopaedic surgeons should develop guidelines to outline the most effective uses of 3D-printing technology to maximize patient benefits., Competing Interests: CONFLICT OF INTEREST: The authors declare that there is no potential conflict of interest relevant to this article., (Copyright © 2020 by Korean Hip Society.)

Bone homeostasis is dynamically balanced between bone forming osteoblasts and bone resorbing osteoclasts. Osteoclasts play an important role in bone destruction and osteoporosis, and they are derived from monocyte/macrophages in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κ B (NF- κ B) ligand (RANKL). Amaranthus mangostanus L. (AM) is a plant with powerful antioxidant and other biological activities including anti-inflammatory, antidiabetic, and antihyperlipidemic effects. However, its effects on bone health are unknown. In this study, we explored whether AM could affect RANK-mediated osteoclastogenesis. AM significantly suppressed RANKL-induced osteoclast differentiation and expression of osteoclast-specific genes, TRAP, cathepsin K, NF-activated T-cells (NFATc1), and Dc-stamp in RAW 264.7 cells. Moreover, AM significantly inhibited extracellular signal-regulated kinase (ERK), Akt, and NF- κ B signaling pathways in RAW 264.7 cells. In addition, AM preserved ovariectomy-induced bone loss in mice. Taken together, our results suggest that AM might be a potential candidate for the treatment of postmenopausal osteoporosis., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Yeon-Hui Jeong et al.)

Small cell lung cancer (SCLC) is a fast-growing and malignant cancer that responds well to chemotherapy; however, the survival rate is less than 15% after 2 years of diagnosis. Therefore, novel therapeutic agents for treating SCLC patients need to be evaluated. This study aims to identify the therapeutic targets based on the comprehensive genomic profiling of SCLC patients. Among the molecular-profiled SCLC samples obtained using targeted sequencing, the array-based comparative genomic hybridization (array CGH) identified focal insulin receptor substrate 2 ( IRS2 ) amplification in the SCLC patients. IRS2 amplification was confirmed in 5% of 73 SCLC patients. To determine whether IRS2 amplification could act as a therapeutic target, we generated a patient-derived xenograft (PDX) model and subsequently screened 43 targeted agents using the PDX-derived cells (PDCs). Ceritinib significantly inhibited the cell growth and impaired the tumor sphere formation in IRS2-expressing PDCs. Its effects were confirmed in various in vitro assays and were further validated in the mouse xenograft models. In this study, we present that IRS2 amplification and/or expression serve as preclinical implications for a novel therapeutic target in SCLC progression. Furthermore, we suggest that insulin-like growth factor-1 (IGF-1) receptor inhibitor-based therapy could be used for treating SCLC with IRS2 amplification., (© 2020 The Authors.)

A series of acene-modified small molecules have been designed and synthesized, and their photovoltaic characteristics were studied by using the small molecules in organic photovoltaics (OPVs). Different cores were introduced to modulate the conjugation lengths of the small molecules and the bulk heterojunction (BHJ) morphologies. Three small-molecule donors were prepared, namely Ph-TTR, Na-TTR, and An-TTR, which have phenyl, naphthalene, and anthracene moieties, respectively, as conjugated cores. These donors were synthesized in a few steps and exhibited favorable BHJ morphologies, thereby giving promising power conversion efficiencies (PCEs). The donors showed excellent miscibility with the acceptor PC 71 BM, and the use of the additive 1,8-diiodooctane (DIO) led to a remarkable increase in crystallinity, thereby increasing the PCEs of their OPVs. Of the three donors, Na-TTR showed the most efficient charge carrier generation and favorable molecular packing structures; hence, of the three types of devices tested, the Na-TTR:PC 71 BM devices exhibited the highest PCE, specifically 6.27 %, without pre- or post-treatments. The promising PCEs achieved from these easily synthesized acene-modified small molecules suggested that acene-modified small molecules can be useful materials in OPVs., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hepatic steatosis is the most common chronic liver disease in Western countries. Both genetic and environmental factors are known as causes of the disease although their underlying mechanisms have not been fully understood. This study investigated the association of DNA methylation with oleic acid-induced hepatic steatosis. It also examined effects of food components on DNA methylation in hepatic steatosis. Genome-wide DNA methylation of oleic acid (OA)-induced lipid accumulation in vitro cell model was investigated using reduced representation bisulfite sequencing. Changes of DNA methylation were also analyzed after treatment with food components decreasing OA-induced lipid accumulation in the model. We identified total 81 regions that were hypermethylated by OA but hypomethylated by food components or vice versa. We determined the expression of seven genes proximally located at the selected differentially methylated regions. Expression levels of WDR27, GNAS, DOK7, MCF2L, PRKG1, and CMYA5 were significantly different between control vs OA and OA vs treatment with food components. We demonstrated that DNA methylation was associated with expression of genes in the model of hepatic steatosis. We also found that food components reversely changed DNA methylation induced by OA and alleviated lipid accumulation. These results suggest that DNA methylation is one of the mechanisms causing the hepatic steatosis and its regulation by food components provides insights that may prevent or alleviate lipid accumulation., Competing Interests: The authors declare that they have no conflict of interest.