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Abstract Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta. Although aortic aneurysms are generally asymptomatic, they can threaten human health by sudden death due to aortic rupture. Aortic aneurysms are estimated to lead to 150,000 ~ 200,000 deaths per year worldwide. Currently, there are no effective drugs to prevent the growth or rupture of aortic aneurysms; surgical repair or endovascular repair is the only option for treating this condition. The pathogenic mechanisms and therapeutic targets for aortic aneurysms have been examined over the past decade; however, there are unknown pathogenic mechanisms involved in cellular heterogeneity and plasticity, the complexity of the transforming growth factor-β signaling pathway, inflammation, cell death, intramural neovascularization, and intercellular communication. This review summarizes the latest research findings and current pathogenic mechanisms of aortic aneurysms, which may enhance our understanding of aortic aneurysms.

Abdominal aortic aneurysm: Potential enzyme biomarker identified An enzyme with antioxidant properties may provide a biomarker and therapeutic agent to help treat abdominal aortic aneurysm (AAA). AAA involves the structural deterioration of the aorta through chronic inflammation and oxidative stress, and can trigger life-threatening artery rupture. An antioxidant enzyme called peroxiredoxin 2 (PRDX2) is increased in patients with ruptures, but whether its role in AAA is beneficial or detrimental is unclear. Goo Taeg Oh at the Ewha Womans University in Seoul, Jong-Gil Park at the Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea, and co-workers examined the effect of PRDX2 on AAA progression. PRDX2 suppressed structural damage in mice, limiting artery dilation and protein degradation. Loss of PRDX2 accelerated AAA development. Measuring levels of PRDX2 may indicate AAA severity in patients, while boosting the enzyme could repair aortic damage.

Abstract Background Silica nanoparticles (SiNPs) are widely used for biosensing and diagnostics, and for the targeted delivery of therapeutic agents. Safety concerns about the biomedical and clinical applications of SiNPs have been raised, necessitating analysis of the effects of their intrinsic properties, such as sizes, shapes, and surface physicochemical characteristics, on human health to minimize risk in biomedical applications. In particular, SiNP size-associated toxicological effects, and the underlying molecular mechanisms in the vascular endothelium remain unclear. This study aimed to elucidate the detailed mechanisms underlying the cellular response to exposure to trace amounts of SiNPs and to determine applicable size criteria for biomedical application. Methods To clarify whether these SiNP-mediated cytotoxicity due to induction of apoptosis or necrosis, human ECs were treated with SiNPs of four different non-overlapping sizes under low serum-containing condition, stained with annexin V and propidium iodide (PI), and subjected to flow cytometric analysis (FACS). Two types of cell death mechanisms were assessed in terms of production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress induction, and autophagy activity. Results Spherical SiNPs had a diameter of 21.8 nm; this was further increased to 31.4, 42.9, and 56.7 nm. Hence, we investigated these effects in human endothelial cells (ECs) treated with these nanoparticles under overlap- or agglomerate-free conditions. The 20-nm SiNPs, but not SiNPs of other sizes, significantly induced apoptosis and necrosis. Surprisingly, the two types of cell death occurred independently and through different mechanisms. Apoptotic cell death resulted from ROS-mediated ER stress. Furthermore, autophagy-mediated necrotic cell death was induced through the PI3K/AKT/eNOS signaling axis. Together, the present results indicate that SiNPs within a diameter of

Summary: Pluripotent stem cells (PSCs) represent the most promising clinical source for regenerative medicine. However, given the cellular heterogeneity within cultivation and safety concerns, the development of specific and efficient tools to isolate a pure population and eliminate all residual undifferentiated PSCs from differentiated derivatives is a prerequisite for clinical applications. In this study, we raised a monoclonal antibody and identified its target antigen as desmoglein-2 (DSG2). DSG2 co-localized with human PSC (hPSC)-specific cell surface markers, and its expression was rapidly downregulated upon differentiation. The depletion of DSG2 markedly decreased hPSC proliferation and pluripotency marker expression. In addition, DSG2-negative population in hPSCs exhibited a notable suppression in embryonic body and teratoma formation. The actions of DSG2 in regulating the self-renewal and pluripotency of hPSCs were predominantly exerted through the regulation of β-catenin/Slug-mediated epithelial-to-mesenchymal transition. Our results demonstrate that DSG2 is a valuable PSC surface marker that is essential for the maintenance of PSC self-renewal. : DSG2 is a desmosomal cadherin molecule. In this article, Min and colleagues show that DSG2 is a valuable PSC surface marker that is essential for the maintenance of PSC self-renewal and pluripotency and the acquisition of pluripotency during somatic cell reprogramming through the regulation of β-catenin-mediated EMT signaling. keywords: desmoglein-2, cell surface marker, pluripotent stem cells, monoclonal antibody, EMT

Atrial fibrillation (AF) is a common arrhythmia requiring effective heart rate (HR) management. Conventional therapies may not always achieve the desired HR control during intraoperative conditions. We present two cases of AF patients in whom dexmedetomidine, an alpha-2 receptor agonist, was utilized during surgery when conventional treatments proved ineffective. In Case 1, a 65-year-old male with multiple comorbidities underwent surgery. Despite receiving intraoperative medications for AF, his HR remained uncontrolled. Dexmedetomidine successfully stabilized his HR without complications. In Case 2, a 75-year-old male with heart disease experienced a sudden HR surge during surgery, which remained uncontrolled despite conventional treatment. Dexmedetomidine effectively managed his HR, ensuring a safer surgical course. While the primary indication of dexmedetomidine is not arrhythmia management, this case report suggests its potential in challenging cases. Further research is needed to explore its therapeutic role in tachyarrhythmia management and establish appropriate dosing strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by the Dabie bandavirus, [or SFTS virus (SFTSV)] that has become increasingly widespread since it was first reported in 2009. The SFTSV comprises three essential single-stranded RNA gene segments, with the S segment encoding the nucleocapsid (N) protein. Since the N protein is the most abundant and stable viral protein, it is a useful diagnostic marker of infection. Various SFTSV N-protein-based detection methods have been developed. However, given the limited research on antibodies of an SFTSV N-protein, here we report the characterization of the antibodies against SFTSV N protein especially their mapping results which is essential for more efficient and optimized detection of SFTSV. Methods To generate SFTSV-N-protein-specific monoclonal antibodies, recombinant full-length SFTSV N protein was expressed in E. coli, and the purified N protein was immunized to mice. The binding epitope positions of the antibodies generated were identified through binding-domain mapping. An antibody pair test using a lateral flow immunoassay (LFIA) was performed to identify effective diagnostic combinations of paired antibodies. Results Nine monoclonal antibodies specific for the SFTSV N protein were generated. Antibodies #3(B4E2) and #5(B4D9) were specific for sequential epitopes, while the remainder were specific for conformational epitopes. Antibody #4(C2G1) showed the highest affinity for the SFTSV N protein. The binding domain mapping results indicated the binding regions of the antibodies were divided into three groups. The antibody pair test demonstrated that #3(B4E2)/#4(C2G1) and #4(C2G1)/#5(B4D9) were effective antibody pairs for SFTSV diagnosis. Conclusions Effective virus detection requires at least two strong antibodies recognizing separate epitope binding sites of the virus antigen. Here, we generated SFTSV-N-protein-specific monoclonal antibodies and subsequently performed epitope mapping and an antibody pair test to enhance the diagnostic efficiency and accuracy of SFTSV. Confirmation of epitope mappings and their combination immune response to the N protein provide valuable information for effective detection of SFTSV as well as can respond actively to detect a variant SFTSV.

In November 2020, an unusual increase in fungal endophthalmitis cases after cataract surgery was reported to the Korea Disease Control and Prevention Agency, South Korea. We initiated an outbreak investigation to identify the cause. We identified 156 cases nationwide, 62 confirmed and 94 probable. Most case-patients were exposed during surgery to ocular viscoelastic devices (OVDs) from the same manufacturer (company A). We isolated Fusarium spp. from 50 confirmed cases. Molecular identification of 39 fungal isolates from clinical samples and 13 isolates from OVDs confirmed F. oxysporum caused the infections. The risk ratio for fungal endophthalmitis from company A’s OVDs was 86.0 (95% CI 27.4–256.9), much higher than risk from other manufacturers’ products. We determined this fungal endophthalmitis outbreak was caused by a contaminated lot of OVDs and recommended discontinued use of this product. Early recognition of outbreaks and joint responses from related government agencies can reduce risk for fungal endophthalmitis.

ABSTRACT We newly detected two (sinking and floating) phenotypes of Candida parapsilosis among bloodstream infection (BSI) isolates from Korean hospitals and assessed their microbiological and clinical characteristics. During the performance of a Clinical and Laboratory Standards Institute (CLSI) broth microdilution antifungal susceptibility testing, the sinking phenotype had a characteristic smaller button-like appearance because all yeast cells sank to the bottoms of the CLSI U-shaped round-bottom wells, whereas the floating phenotype comprised dispersed cells. Phenotypic analysis, antifungal susceptibility testing, ERG11 sequencing, microsatellite genotyping, and clinical analysis were performed on C. parapsilosis isolates from 197 patients with BSI at a university hospital during 2006 to 2018. The sinking phenotype was detected in 86.7% (65/75) of the fluconazole-nonsusceptible (FNS) isolates, 92.9% (65/70) of the isolates harboring the Y132F ERG11 gene substitution, and 49.7% (98/197) of all isolates. Clonality was more frequently observed for the Y132F-sinking isolates (84.6% [55/65]) than for all other isolates (26.5% [35/132]; P

We analyzed the virulence traits and azole resistance mechanisms of 104 Candida auris isolates collected from 13 Korean hospitals from 1996 to 2022. Of these 104 isolates, 96 (5 blood and 91 ear isolates) belonged to clade II, and 8 (6 blood and 2 other isolates) belonged to clade I. Fluconazole resistance (minimum inhibitory concentration ≥32 mg/L) was observed in 68.8% of clade II and 25.0% of clade I isolates. All 104 isolates were susceptible to amphotericin B and three echinocandins. In 2022, six clade I isolates indicated the first nosocomial C. auris cluster in Korea. Clade II C. auris isolates exhibited reduced thermotolerance at 42 °C, with diminished in vitro competitive growth and lower virulence in the Galleria mellonella model compared to non-clade II isolates. Of the 66 fluconazole-resistant clade II isolates, several amino acid substitutions were identified: Erg11p in 14 (21.2%), Tac1Ap in 2 (3.0%), Tac1Bp in 62 (93.9%), and Tac1Bp F214S in 33 (50.0%). Although there were a limited number of non-clade II isolates studied, our results suggest that clade II C. auris isolates from Korean hospitals might display lower virulence traits than non-clade II isolates, and their primary fluconazole resistance mechanism is linked to Tac1Bp mutations.

We investigated the clinical outcomes and molecular mechanisms of fluconazole-resistant (FR) Candida glabrata bloodstream infections. Among 1,158 isolates collected during multicenter studies in South Korea during 2008–2018, 5.7% were FR. For 64 patients with FR bloodstream infection isolates, the 30-day mortality rate was 60.9% and the 90-day mortality rate 78.2%; these rates were significantly higher than in patients with fluconazole-susceptible dose-dependent isolates (30-day mortality rate 36.4%, 90-day mortality rate 43.8%; p

Background: Sarpogrelate is expected to reduce restenosis by protecting blood vessels from oxidative stress and vascular endothelial dysfunction as well as by acting as an antiplatelet agent after endovascular treatment (EVT). This trial was designed to compare aspirin plus sustained-release (SR) sarpogrelate with aspirin plus clopidogrel for the prevention of restenosis in patients with femoro-popliteal (FP) peripheral artery disease (PAD) who underwent EVT.Methods/design: This is an open label, multicenter, prospective randomized controlled clinical trial. Patients will be eligible for inclusion in this study if they require EVT for stenosis or occlusion of a de novo FP lesion. Patients in each group will receive aspirin 100 mg with clopidogrel 75 mg or aspirin 100 mg with SR sarpogrelate 300 mg (Anplone®) orally once a day for six months. The primary outcome of the study is the restenosis rate, defined as > 50% luminal reduction by computed tomography angiography or catheter angiography in the six-month follow-up period. Secondary outcomes include target lesion revascularization, major bleeding, ipsilateral major amputation, all-cause mortality, and all adverse events that take place in those six months.Discussion: This study is a multicenter randomized controlled trial designed to show non-inferiority in terms of the re-stenosis rate of SR sarpogrelate compared to clopidogrel for EVT for PAD in FP lesion patients.Trial Registration: ClinicalTrials.gov, NCT02959606 . Registered on 9 November 2016. [ABSTRACT FROM AUTHOR]

Purpose: To examine the therapeutic effect of Vactosertib, a small molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor (activin receptor-like kinase-5, ALK5), in an experimental model of Peyronie’s disease (PD) and determining anti-fibrotic mechanisms of Vactosertib in primary fibroblasts derived from human PD plaques. Materials and Methods: Male rats were randomly divided into three groups (n=6 per group); control rats without treatment; PD rats receiving vehicle; and PD rats receiving Vactosertib (10 mg/kg). PD-like plaques were induced by administering 100 μL of each of human fibrin and thrombin solutions into the tunica albuginea on days 0 and 5. Vactosertib was given orally five times a week for 2 weeks. On day 30, we performed electrical stimulation of the cavernous nerve to measure erectile function, and the penis was obtained for histological examination. Fibroblasts isolated from human PD plaques were used to determine the anti-fibrotic effects of Vactosertib in vitro. Results: Vactosertib induced significant regression of fibrotic plaques in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which recovered erectile function. Vactosertib also abrogated TGF- β1-induced enhancement of extracellular matrix protein production and hydroxyproline content in PD fibroblasts in vitro by hindering the TGF-β1-induced Smad2/3 phosphorylation and nuclear translocation, and fibroblast-to-myofibroblast transdifferentiation. Conclusions: In view of the critical role of TGF-β and the Smad pathway in the pathogenesis of PD, inhibition of this pathway with an ALK5 inhibitor may represent a novel, targeted therapy for PD.

Whole-genome sequencing (WGS) was used to determine the molecular mechanisms of multidrug resistance for 10 serial Candida glabrata bloodstream isolates obtained from a neutropenic patient during 82 days of amphotericin B (AMB) or echinocandin therapy. For WGS, a library was prepared and sequenced using a Nextera DNA Flex Kit (Illumina) and the MiseqDx (Illumina) instrument. All isolates harbored the same Msh2p substitution, V239L, associated with multilocus sequence type 7 and a Pdr1p substitution, L825P, that caused azole resistance. Of six isolates with increased AMB MICs (≥2 mg/L), three harboring the Erg6p A158fs mutation had AMB MICs ≥ 8 mg/L, and three harboring the Erg6p R314K, Erg3p G236D, or Erg3p F226fs mutation had AMB MICs of 2–3 mg/L. Four isolates harboring the Erg6p A158fs or R314K mutation had fluconazole MICs of 4–8 mg/L while the remaining six had fluconazole MICs ≥ 256 mg/L. Two isolates with micafungin MICs > 8 mg/L harbored Fks2p (I661_L662insF) and Fks1p (C499fs) mutations, while six isolates with micafungin MICs of 0.25–2 mg/L harbored an Fks2p K1357E substitution. Using WGS, we detected novel mechanisms of AMB and echinocandin resistance; we explored mechanisms that may explain the complex relationship between AMB and azole resistance.

Background: Candida auris was first isolated from the ears of Japanese and Korean patients. However, the prevalence of yeast isolates from ear cultures and their antifungal susceptibility profiles in these nations remain unclear. Methods: We assessed yeast isolates recovered from ear cultures from a university hospital in Korea over a 4-year period from January 2014 to December 2017. Species identification was performed by matrix- assisted laser desorption/ionization time-of-flight mass spectrometry and/or sequence analysis. Antifungal minimal inhibitory concentrations (MICs) were determined using the broth microdilution method of the Clinical and Laboratory Standards Institute. Results: Among 81 non-duplicate isolates from ear cultures, Cadida parapsilosis was the most frequently detected yeast species (34.6%), followed by C. auris (28.4%), Candida metapsilosis (9.9%), Candida orthopsilosis (8.6%), Candida albicans (7.4%), and others (11.1%). The MICs of the isolates were 0.125 to >64 μg/mL, ≤0.03 to 4 μg/mL, 0.25 to 1 μg/mL, 0.125 to 1 μg/mL, and ≤0.03 to 2 μg/mL for fluconazole, voriconazole, amphotericin B, caspofungin, and micafungin, respectively. Of the 81 isolates, 44.4% (36/81) showed decreased susceptibility to fluconazole (MIC ≥4 μg/mL). Of the 23 C. auris isolates, 19 (82.6%) had a fluconazole MIC of ≥32 μg/mL. None of the isolates showed resistance to amphotericin B or echinocandins. Most of these patients suffered from chronic otitis media (84%). Conclusion: Candida parapsilosis complex and C. auris were the yeast species identified most frequently from ear cultures and they exhibited a high rate of fluconazole non-susceptibility, particularly C. auris. (Ann Clin Microbiol 2019;22:81-89)

We incorporated nationwide Candida antifungal surveillance into the Korea Global Antimicrobial Resistance Surveillance System (Kor-GLASS) for bacterial pathogens. We prospectively collected and analyzed complete non-duplicate blood isolates and information from nine sentinel hospitals during 2020–2021, based on GLASS early implementation protocol for the inclusion of Candida species. Candida species ranked fourth among 10,758 target blood pathogens and second among 4050 hospital-origin blood pathogens. Among 766 Candida blood isolates, 87.6% were of hospital origin, and 41.3% occurred in intensive care unit patients. Adults > 60 years of age accounted for 75.7% of cases. Based on species-specific clinical breakpoints, non-susceptibility to fluconazole, voriconazole, caspofungin, micafungin, and anidulafungin was found in 21.1% (154/729), 4.0% (24/596), 0.1% (1/741), 0.0% (0/741), and 0.1% (1/741) of the isolates, respectively. Fluconazole resistance was determined in 0% (0/348), 2.2% (3/135, 1 Erg11 mutant), 5.3% (7/133, 6 Pdr1 mutants), and 5.6% (6/108, 4 Erg11 and 1 Cdr1 mutants) of C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis isolates, respectively. An echinocandin-resistant C. glabrata isolate harbored an F659Y mutation in Fks2p. The inclusion of Candida species in the Kor-GLASS system generated well-curated surveillance data and may encourage global Candida surveillance efforts using a harmonized GLASS system.

We recently observed the emergence of fluconazole-resistant Candida parapsilosis bloodstream isolates harboring a Y132F substitution in Erg11p in South Korea. These Y132F isolates had a higher propensity to cause clonal transmission than other fluconazole-resistant isolates and persisted within hospitals for several years, as revealed by microsatellite typing.

We investigated mortality and predictors of mortality due to intensive care unit-associated candidemia (ICUAC) versus non-ICUAC by Candida species. This study included all candidemia cases in 11 hospitals from 2017 to 2018 in South Korea. The all-cause mortality rates in all 370 patients with ICUAC were approximately twofold higher than those in all 437 patients with non-ICUAC at 7 days (2.3-fold, 31.1%/13.3%), 30 days (1.9-fold, 49.5%/25.4%), and 90 days (1.9-fold, 57.8%/30.9%). Significant species-specific associations with 7- and 30-day ICUAC-associated mortality were not observed. Multivariate analysis revealed that ICU admission was an independent predictor of Candida glabrata (OR, 2.07–2.48) and Candida parapsilosis-associated mortality (OR, 6.06–11.54). Fluconazole resistance was a predictor of C. glabrata-associated mortality (OR, 2.80–5.14). Lack (less than 3 days) of antifungal therapy was the strongest predictor of 7-day mortality due to ICUAC caused by Candida albicans (OR, 18.33), Candida tropicalis (OR, 10.52), and C. glabrata (OR, 21.30) compared with 30- and 90-day mortality (OR, 2.72–6.90). C. glabrata ICUAC had a stronger association with lack of antifungal therapy (55.2%) than ICUAC caused by other species (30.6–36.7%, all p < 0.05). Most predictors of mortality associated with ICUAC were distinct from those associated with non-ICUAC and were mediated by Candida species.

Candida glabrata bloodstream infection (BSI) isolates from a particular geographic area have been reported to comprise a relatively small number of the major sequence types (STs) by multilocus sequence typing (MLST) analysis. Yet little is known about the characteristics of major ST strains of C. glabrata. To address this question in Korea, we investigated antifungal resistance and non-synonymous mutations of the mismatch repair gene (msh2 mutations) in C. glabrata BSI isolates, as well as associated clinical characteristics, and compared the results according to MLST genotype. We assessed a total of 209 C. glabrata BSI isolates from seven hospitals in Korea for 2 years (2009 and 2014). Clinical features of candidemia and their outcomes were analyzed for 185 available cases. According to MLST, ST7 (47.8%) was the most common type, followed by ST3 (22.5%); the remainder represented 28 types of minor STs (29.7%). Fluconazole-resistance (FR) rates for ST7, ST3, and other strains were 9.0% (9/100), 8.5% (4/47), and 4.8% (3/62), respectively, and all were susceptible to amphotericin B and micafungin. All ST7 isolates harbored the V239L mutation in msh2, known to confer hypermutability, while 91.5% of ST3 isolates did not harbor the msh2 mutation. Overall, isolates of the same ST had identical msh2 mutations, with the exception of nine isolates. The msh2 mutations were identified in 68.8% (11/16) of the FR isolates and 67.4% (130/193) of the fluconazole susceptible-dose dependent isolates. There was no significant difference in all clinical characteristics between ST3 and ST7. However, the 30-day mortality of C. glabrata candidemia due to the two major ST (ST3 or ST7) strains was significantly higher than that of candidemia due to other minor ST strains (45.1 vs. 25.0%, p < 0.05). Multivariate logistic regression analysis also showed that two major STs (ST3 and ST7) were independent predictors of 30-day mortality. This study showed for the first time that two STs (ST7 and ST3) were predominant among BSI isolates in Korea, and that C. glabrata BSI isolates belonging to two major MLST genotypes are characterized by higher mortality. In addition, most msh2 mutations align with MLST genotype, irrespective of FR.

Transforming growth factor-β1 (TGF-β1) has been identified as one of the most important fibrogenic cytokines associated with Peyronie's disease (PD). The mothers against decapentaplegic homolog 7 (SMAD7) is an inhibitory Smad protein that blocks TGF-β signaling pathway. The aim of this study was to examine the anti-fibrotic effect of the SMAD7 gene in primary fibroblasts derived from human PD plaques. PD fibroblasts were pretreated with the SMAD7 gene and then stimulated with TGF-β1. Treated fibroblasts were used for Western blotting, fluorescent immunocytochemistry, hydroxyproline determination, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. Overexpression of the SMAD7 gene inhibited TGF-β1-induced phosphorylation and nuclear translocation of SMAD2 and SMAD3, transdifferentiation of fibroblasts into myofibroblasts, and quashed TGF-β1-induced production of extracellular matrix protein and hydroxyproline. Overexpression of the SMAD7 gene decreased the expression of cyclin D1 (a positive cell cycle regulator) and induced the expression of poly (ADP-ribose) polymerase 1, which is known to terminate Smad-mediated transcription, in PD fibroblasts. These findings suggest that the blocking of the TGF-β pathway by use of SMAD7 may be a promising therapeutic strategy for the treatment of PD.

We analyzed the antifungal susceptibility profiles, genotypes, and virulence of clinical Aspergillus terreus isolates from six university hospitals in South Korea. Thirty one isolates of A. terreus, comprising 15 respiratory and 16 ear isolates were assessed. Microsatellite genotyping was performed, and genetic similarity was assessed by calculating the Jaccard index. Virulence was evaluated by Galleria mellonella survival assay. All 31 isolates were susceptible to itraconazole, posaconazole, and voriconazole, while 23 (74.2%) and 6 (19.4%) showed amphotericin B (AMB) minimum inhibitory concentrations (MICs) of ≤ 1 mg/L and > 4 mg/L, respectively. Notably, respiratory isolates showed significantly higher geometric mean MICs than ear isolates to AMB (2.41 vs. 0.48 mg/L), itraconazole (0.40 vs. 0.19 mg/L), posaconazole (0.16 vs. 0.08 mg/L), and voriconazole (0.76 vs. 0.31 mg/L) (all, P

Using multilocus sequence typing (MLST), Candida albicans can be subdivided into 18 different clades. Farnesol, a quorum-sensing molecule secreted by C. albicans, is thought to play an important role in the development of C. albicans biofilms and is also a virulence factor. This study evaluated whether C. albicans bloodstream infection (BSI) strains belonging to different MLST clades secrete different levels of E,E-farnesol (FOH) and whether they have different clinical characteristics. In total, 149 C. albicans BSI isolates from ten Korean hospitals belonging to clades 18 (n = 28), 4 (n = 23), 1 (n = 22), 12 (n = 17), and other clades (n = 59) were assessed. For each isolate, the FOH level in 24-hour biofilms was determined in filtered (0.45 μm) culture supernatant using high-performance liquid chromatography. Marked differences in FOH secretion from biofilms (0.10-6.99 μM) were observed among the 149 BSI isolates. Clade 18 isolates secreted significantly more FOH than did non-clade 18 isolates (mean ± SEM; 2.66 ± 0.22 vs. 1.69 ± 0.10 μM; P < 0.001). Patients with isolates belonging to clade 18 had a lower mean severity of illness than other patients, as measured using the "acute physiology and chronic health evaluation" (APACHE) III score (14.4 ± 1.1 vs. 18.0 ± 0.7; P < 0.05). This study provides evidence that C. albicans BSI isolates belonging to the most prevalent MLST clade (clade 18) in Korea are characterized by increased levels of FOH secretion and less severe illness.

Background/Aims Compared to surgery, adjuvant TS-1 and XELOX regimen in gastric cancer (GC) has shown survival benefit after D2 gastrectomy. As the elderly population continues to grow, adjuvant chemotherapy (AC) has become important. Clinicians hesitate to offer chemotherapy to elderly patients because of comorbidities and intolerability. This study aims to investigate the efficacy, safety, and compliance of AC with TS-1 and XELOX regimen in patients aged >70 years. Methods We collected data on stage II/III GC patients who underwent D2 gastrectomy followed by AC (TS-1 or XELOX regimen) between January 2013 and December 2018 at Chungnam National University Hospital. They were classified into two groups by age which is over 70 years or not; we analyzed baseline characteristics, adverse events, overall survival (OS), relapse free survival (RFS), rates of regimen completion, and dose reduction. Results There was no significant difference in OS and RFS between both regimens. The TS-1 group had 232 patients (92 elderly). For grade >3 adverse events, elderly patients had more anemia (p=0.029) and lower completion rates (78.4% vs 91.5%, p<0.001) but not dose reduction rates; both OS and RFS were lower (p=0.034 and 0.026) (Fig. 1A and B). The XELOX group had 119 patients (27 elderly). For grade >3 adverse events, elderly patients had more thrombocytopenia (p=0.02); no differences in completion and dose reduction rates; and no differences in OS and RFS (Fig. 1C and D). Conclusions There was no difference in efficacy between the TS-1 and XELOX regimens; both were tolerable in elderly patients. The XELOX group showed no differences in OS and RFS, which were lower in the TS-1 group, possibly due to decreased completion rates. Clinicians should not hesitate to prescribe AC to elderly patients. Furthermore, completing chemotherapy schedule should be important. [ABSTRACT FROM AUTHOR]

Background/Aims Ischemic colitis (IC) is considered to be an intestinal injury as a result of insufficient blood flow and severities of IC can range from mild to life-threatening. The aim of this study was to identify predictive risk factors and propose a scoring model of severe IC. Methods In a retrospective study, we analyzed medical records of patients with IC admitted to Chungnam National University Hospital from January 2010 to December 2018. The patients were divided into two groups by Favier endoscopic classification: non-severe (stage 1) and severe (stage 2, 3). By using the logistic regression analysis, we obtained a new risk scoring model for early prediction of severe IC. Results A total of 274 patients with endoscopic evaluated IC were included. One hundred and eighty-one patients (66.1%) were classified as severe IC. In a multivariate analysis, five factors were independently and significantly associated with severe IC: tachycardia (odds ratio [OR], 3.83; 95% confidence interval [CI], 1.65 to 8.87; p=0.002), low-dose aspirin (OR, 4.45; 95% CI, 2.05 to 9.69; p<0.001), non-aspirin antiplatelet agents (OR, 4.67; 95% CI, 1.68 to 12.95; p=0.003), elevated C-reactive protein (OR, 4.80; 95% CI, 2.57 to 8.97; p<0.001) and thrombocytopenia (OR, 7.86; 95% CI, 2.01 to 30.7; p=0.003). AUROC (area under receiver operating characteristic curve) of our new risk scoring model was 0.796 (95% CI, 0.743 to 0.842; p<0.001) (Fig. 1). Conclusions A new risk scoring model based on presence of tachycardia, administration of low-dose aspirin and non-aspirin antiplatelet agents, elevated C-reactive protein and thrombocytopenia could be used to predict the severity of IC in early stage. [ABSTRACT FROM AUTHOR]

Background/Aims Elevated cytochrome p450 (CYP) 4A gene expression has been linked to the aggravation of various cancers and affects various regulated metabolites. In hepatocellular carcinoma (HCC), the clinicopathological value of CYP4A has not yet been explored, although CYP4A is expressed at high levels in the liver. The goal of this study was to evaluate the clinicopathological value of CYP4A11 expression in HCC. Methods We performed immunohistochemical analysis of CYP4A11 and correlated the results with clinicopathological features of HCC (n=155). Western blotting and reverse transcription-polymerase chain reaction against CYP4A11 and CYP4A22 were also performed for 15 and 20 pairs of fresh-frozen primary HCC and non-neoplastic liver tissue, respectively. Moreover, we analyzed the underlying mechanism by comparing the high and low CYP4A11 mRNA expression groups using gene set enrichment analysis. Results CYP4A11 expression level was higher in nonneoplastic hepatocytes than those in HCC cells (p<0.001), and CYP4A11 expression positively correlated with favorable prognostic factors, including tumor size, histological grade, and pathological tumor stage (p=0.007, p=0.005, and p=0.007). Multivariate analysis revealed that CYP4A11 expression was an independent prognostic factor of overall and disease-free survival (p=0.002 and p=0.033). Based on gene set enrichment analysis, high CYP4A11 mRNA expression negatively correlated with the expression of cell cycle-related genes. Conclusions These findings support the notion that CYP4A11 expression is a favorable prognostic factor of HCC and suggest potential predictive diagnostic and prognostic roles of CYP4A11 expression in HCC. [ABSTRACT FROM AUTHOR]

Background/Aims Cytochrome P450 family 4 (CYP4) enzymes are known as microsomal omega (ω)-hydroxylases that metabolize fatty acids, eicosanoids, vitamin D and carcinogens. Thus, CYP4 enzymes may influence tumor development and progression. The aim of this study was to evaluate the CYP4 expression profile in hepatocellular carcinoma (HCC) and its clinical relevance. Methods We obtained CYP4 mRNA expression data for 377 HCC cases from The Cancer Genome Atlas cohort and performed Kaplan-Meier survival, gene ontology functional enrichment, and gene set enrichment (GSEA) analyses. In addition, we evaluated the level of CYP4F2 protein expression in matched pairs of HCC and non-tumor tissue samples and correlated the results with the clinicopathological characteristics of HCC (n=113). Results HCC survival analyses indicated better overall survival in patients with high CYP4F2, CYP4F12 and CYP4V2 mRNA expression levels; the results for histologic grade and Tumor-Node-Metastasis stage supported these data. GSEA revealed high levels of CYP4F2, CYP4F12, and CYP4V2 mRNA expression to be negatively correlated with expression of cell cycle-related genes.CYP4F2 protein expression was higher in non-neoplastic liver tissue than in HCC tissue and positively correlated with favorable pathological tumor stage (I vs II-IV) (p=0.022) and was a good independent prognostic factor for overall survival (p=0.004). Conclusions These findings demonstrate that the expression levels of genes CYP4F2, CYP4F12 and CYPV2 are favorable prognostic factors in HCC and suggest the potential predictive diagnostic and prognostic roles of CYP4F2, CYP4F12 and CYPV2 gene expression in HCC. [ABSTRACT FROM AUTHOR]

Background/Aims Despite the highly complete tumor necrosis rate of radiofrequency ablation, tumor recurrence, either locoregional or newly developing lesion, was regarded as significant issue. Recurrence reduction through appropriate procedure selection as well as patients' selection could improve survival. Therefore, we analyzed the conditional factor for recurrence after intraoperative radiofrequency ablation (RFA) treatment on hepatocellular carcinoma (HCC). Methods We investigated 98 patients who were treated with intra-operative RFA as initial treatment for HCC. The mean follow-up period was 33±14.5 months. We evaluated the disease-free survival of recurred patients, including local tumor progression (LTP) and intrahepatic distant recurrence (IDR). For these patients, multiple factors were assessed to their significance for recurrence and survival. Results Almost baseline characteristics were not shown statistically significant difference, except for few factors between the groups. The incidence of overall recurrence was 47.9%. LTP was found in 20 of 47 patients (20.4%) and occurred 4 to 33 months (median period, 14 months) after RFA. IDR was found in 27 of 47 patients (27.5%) and occurred 6 to 88 months (median period, 22 months) after RFA. Interestingly, on multivariate analysis for whole recurred patients, serum α-fetoprotein was significantly associated factor with recurrence of the tumor (p=0.006; 95% CI, 1.001 to 1.007; hazard ratio [HR], 1.004). In addition, international normalized ratio and Child-Pugh scores, factors representing severity of underlying liver status, were significantly associated with survival of the patients (p=0.039, p=0.046). Especially, AFP was also significantly associated factor with patients' survival (p=0.016; 95% CI, 1.001 to 1.006;HR, 1.004]. After subgroup analysis for recurred patients, we found that patients with higher AFP levels had more recurrence patterns of LTP rather than IDR. Conclusions Patients with high AFP level received intraoperative RFA for HCC should be carefully followed-up and considered more active radical treatment modality because of higher risk of recurrence and mortality. [ABSTRACT FROM AUTHOR]

Background/Aims Oxidative stress occurs due to the excessive generation of cellular reactive oxygen species and antioxidant system dysfunction. The thioredoxin (TXN) system and TXN-domain-containing protein (TXNDC) family form networks maintaining the cellular reducing environment. Recently, the importance of these genes in the tumor environment has been emphasized. To investigate the clinical significance of TXNs and TXNDC family members in hepatocellular carcinoma (HCC). Methods Genomic data from 367 HCC patients whom underwent hepatic resections were analyzed to determine genetic alterations in mRNA and protein levels between patients and healthy controls. In addition, functional enrichment and survival analyses were performed. Results HCC patients were shown to have the enhanced expression of TXN, TXNRD1, TXNDC7/9/14 mRNA and protein compared with that of controls. In accordance to the survival analyses, strong associations were found that patients with TXN, TXNRD1, and TXNDC1/7/9 alterations were proven to have poor prognosis in overall survival. Moreover, gene set enrichment analyses and network analyses revealed that positive correlations were found in mRNA expression of TXN, TXNRD1, and TXNDC7/9 genes with upregulation of the genes to tumor promoting genes, specifically mTORC1, E2F targets, and Myc targets. On the other hand, elevated expressions of TXNIP and TXNDC11 genes were correlated with suppression of the above tumor promoting genes. Conclusions TXN system and TXNDC family gene panel obtained from the resected tissue of the HCC patients could be used to predict survival prognosis of HCC and these genes could be considered as potential therapeutic targets for improving HCC survival. [ABSTRACT FROM AUTHOR]

We applied the new clinical breakpoints (CBPs) of the Clinical and Laboratory Standards Institute (CLSI) to a multicenter study to determine the antifungal susceptibility of bloodstream infection (BSI) isolates of Candida species in Korea, and determined the relationship between the frequency of antifungal-resistant Candida BSI isolates and antifungal use at hospitals. Four hundred and fifty BSI isolates of Candida species were collected over a 1-year period in 2011 from nine hospitals. The susceptibilities of the isolates to four antifungal agents were determined using the CLSI M27 broth microdilution method. By applying the species-specific CBPs, non-susceptibility to fluconazole was found in 16.4% (70/428) of isolates, comprising 2.6% resistant and 13.8% susceptible-dose dependent isolates. However, non-susceptibility to voriconazole, caspofungin, or micafungin was found in 0% (0/370), 0% (0/437), or 0.5% (2/437) of the Candida BSI isolates, respectively. Of the 450 isolates, 72 (16.0%) showed decreased susceptibility to fluconazole [minimum inhibitory concentration (MIC) ≥4 μg/ml]. The total usage of systemic antifungals varied considerably among the hospitals, ranging from 190.0 to 7.7 defined daily dose per 1,000 patient days, and fluconazole was the most commonly prescribed agent (46.3%). By Spearman's correlation analysis, fluconazole usage did not show a significant correlation with the percentage of fluconazole resistant isolates at hospitals. However, fluconazole usage was significantly correlated with the percentage of fluconazole non-susceptible isolates (r = 0.733; P = 0.025) or the percentage of isolates with decreased susceptibility to fluconazole (MIC ≥4 μg/ml) (r = 0.700; P = 0.036) at hospitals. Our work represents the first South Korean multicenter study demonstrating an association between antifungal use and antifungal resistance among BSI isolates of Candida at hospitals using the new CBPs of the CLSI.

Although the functional roles of zinc finger-containing glycine-rich RNA-binding proteins (RZs) have been characterized in several plant species, including Arabidopsis thaliana and rice (Oryza sativa), the physiological functions of RZs in wheat (Triticum aestivum) remain largely unknown. Here, the functional roles of the three wheat RZ family members, named TaRZ1, TaRZ2, and TaRZ3, were investigated using transgenic Arabidopsis plants under various abiotic stress conditions. Expression of TaRZs was markedly regulated by salt, dehydration, or cold stress. The TaRZ1 and TaRZ3 proteins were localized to the nucleus, whereas the TaRZ2 protein was localized to the nucleus, endoplasmic reticulum, and cytoplasm. Germination of all three TaRZ-expressing transgenic Arabidopsis seeds was retarded compared with that of wild-type seeds under salt stress conditions, whereas germination of TaRZ2- or TaRZ3-expressing transgenic Arabidopsis seeds was retarded under dehydration stress conditions. Seedling growth of TaRZ1-expressing transgenic plants was severely inhibited under cold or salt stress conditions, and seedling growth of TaRZ2-expressing plants was inhibited under salt stress conditions. By contrast, expression of TaRZ3 did not affect seedling growth of transgenic plants under any of the stress conditions. In addition, expression of TaRZ2 conferred freeze tolerance in Arabidopsis. Taken together, these results suggest that different TaRZ family members play various roles in seed germination, seedling growth, and freeze tolerance in plants under abiotic stress.

Abstract Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1β without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner.

Background: Push-up are effective exercises for shoulder stability. Previous studies have documented the effects of support plane and hand position and width on muscle activities during a push-up.Objects: This study aimed to investigate the changes in muscle activities in the upper extrem-ity when performing the standard and the knee-flexed push-up with different hand shapes.Methods: A total of twenty-six healthy males participated in this study. Three different hand shapes (finger abduction, finger adduction, and fists) and two types of push-up posture (stan-dard and knee-flexed push-up) were set as the independent variables. Electrograms were used to measure the muscle activity of the upper trapezius (UT), triceps brachii (TB), pectoralis major (PM), and serratus anterior (SA). Each participant performed the randomly assigned push-up to the sound of the metronome. The mixed-effect linear regression model was used to detect the changes in muscle activities after changing the hand shape and push-up posture. Statisti-cal significance was set at α = 0.05.Results: The UT muscle activity was statistically significantly higher when performing push-up with fists than finger abduction (p = 0.035) or finger adduction (p = 0.044). During the stan-dard push-up, the muscle activity in all muscles was that the push-up with fists showed the highest muscle activity compared to the finger abduction (p < 0.01) and finger adduction (p < 0.01). Regardless of the shape of the hand, UT had the lowest muscle activity compared to other muscles (p < 0.001). In contrast, the SA muscle had the highest muscle activity among four muscles during the standard push-up.Conclusion: Based on the results of this study, we suggest hand shape is related to the difficulty level of push-up either in the standard or the knee-flexed push-up, especially in the push-up with fists. In addition, knee push-up can be recommended as shoulder muscle-strengthening exercises for individuals with low shoulder muscle strength.

Objectives:The use of risky and persistent organochlorine pesticides was prohibited, but is still detected in many agricultural lands. In this study, Phanerochaete chrysosporium Y-2 (KCCM-10725P) and Streptomyces sp. MJM14747 (KACC 81078BP), which were finally selected among various candidate microorganisms, were applied to field soil and estimated the endosulfan removal rate. Methods:The field testing sites were set to an area of 3 m × 3 m, respectively. A 35% endosulfan emulsion was sprayed on both sites so that the final concentration was about 20 µg/g. Thereafter, 12 kg of original sawdust and 12 kg of sawdust loaded with microbial consortia were mixed at each of the two sites. During the test period for a total of 100 days, samples were taken every 30 days. Soil samples were extracted according to the QuEChERS AOAC method and analyzed by gas chromatography. Results and Discussion:The concentrations immediately after endosulfan emulsion treatment at both sites were detected as 21.2 µg/g and 21.9 µg/g, respectively. The removal rate of endosulfan at the site without microbial consortia treatment (Control) was about 21.9% until the 30th day, and 54.4% on the 100th day. On the other hand, the endosulfan removal rate on the 100th day of the site treated with microbial consortia was 89.5%, which was 1.6 times higher than that of the control site. On the 30th day, the removal rate was 56.8%, and the rate of degradation of endosulfan increased thereafter. Among the major components of endosulfan, the removal rate of α-endosulfan was higher than that of β-endosulfan. After 100 days, the removal rates of α-endosulfan and β-endosulfan were 98.0% and 83.5%, respectively. Conclusions:Streptomyces sp. MJM14747 showed good degradation ability in the presence of endosulfan at a high concentration of around 100 µg/g. Moreover, Phanerochaete chrysosporium Y-2 has a good performance in the removal of β-endosulfan, which is slow degrading components of endosulfan. Microbial consortia are expected to be applied not only to domestic and foreign agricultural land but also to overall bioremediation projects.

Abstract T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed “bystander activation”, has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4+ T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4+ T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer.

A 62-year-old man with progressive swelling on his left thigh and leg was referred to the Division of Vascular Surgery. Anticoagulation therapy did not prevent or improve the symptoms of chronic deep vein thrombosis (DVT) from his left external iliac vein to posterior tibial vein. He had no trauma history nor any accidents. He underwent femoral endovenectomy, thrombectomy and stent insertion in left iliac vein. The patient had additional balloon angioplasty for stenosis in left common femoral vein. He had an uneventful postoperative recovery without complication. Leg swelling has been improving and follow-up continues under anticoagulation. We report a case of femoral endovenectomy with iliac stenting, which may be an efficacious treatment for chronic DVT.

A 71-year-old woman presented with an enlarging mass in the right buttock, with pain and tingling sensation in sitting position. Five years ago, she was diagnosed with acute limb ischemia due to acute thrombosis of right persistent sciatic artery (PSA), and she underwent successful thromboembolectomy and femoro-tibioperoneal trunk bypass. Computed tomography angiography revealed a huge PSA aneurysm (PSAA). During the previous bypass, the distal popliteal artery was ligated just above the distal anastomosis to exclude the PSAA, whose proximal end was already thrombosed. However, PSAA has grown to cause compression symptoms, and the mechanism of aneurysm growth can be ascribed to type 1a or type 2 endoleak. In order to relieve the compression symptoms, aneurysm excision was performed without any injury to the sciatic nerve. A postoperative tingling sensation due to sciatic-nerve stimulation in the supine position resolved spontaneously one month after surgery.