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The role of matrix metalloproteinase-2 (MMP-2) in tumor cell migration has been widely studied, however, the characteristics and effects of MMP-2 in clinical sample of metastatic colorectal cancer (CRC) remain poorly understood. Here, in order to unveil the perturbed proteomic signal during MMP-2 induced cancer progression, we analyzed plasma proteome of CRC patients according to disease progression, HCT116 cancer secretome upon MMP-2 knockdown, and publicly available CRC tissue proteome data. Collectively, the integrative analysis of multi-layered proteomes revealed that a protein cluster containing EMT (Epithelial-to-Mesenchymal Transition)-associated proteins such as CD9-integrin as well as MMP-2. The proteins of the cluster were regulated by MMP-2 perturbation and exhibited significantly increased expressions in tissue and plasma as disease progressed from TNM (Tumor, Node, and Metastasis) stage I to II. Furthermore, we also identified a plausible association between MMP-2 up-regulation and activation of focal adhesion kinase signaling in the proteogenomic analysis of CRC patient tissues. Based on these comparative and integrative analyses, we suggest that the high invasiveness in the metastatic CRC resulted from increased secretion of MMP-2 and CD9-integrin complex mediated by FAK signaling activation.

TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.

The pharmacological inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to drastically affect low-density lipoprotein cholesterol levels and associated cardiovascular diseases. However, the potential effectiveness of PCSK9 serum levels as a biomarker for cardiovascular risk remains unclear. Serum PCSK9 levels in patients who underwent percutaneous coronary intervention (PCI) may predict long-term outcomes. PCSK9 levels were measured in 749 consecutive patients with coronary artery disease undergoing PCI. These patients were classified into 2 groups according to their serum levels of PCSK9. The primary end point was a composite of the major adverse cardiac events (MACE), including cardiac death, myocardial infarction, stroke, and any revascularization. The median PCSK9 level was 302.82 ng/ml. During a median follow-up of 28.4 months, a total of 38 (5.1%) MACE was recorded, and 50 (6.7%) patients died from any cause. Multivariate Cox regression analysis showed that compared with a lower serum PCSK9 level, a higher serum PCSK9 level was independently associated with a higher rate of MACE (adjusted hazard ratio 2.290, 95% confidence interval 1.040 to 5.045, p = 0.040) and all-cause death (adjusted hazard ratio 2.511, 95% confidence interval 1.220 to 5.167, p = 0.026). Results were consistent after propensity-score matching (MACE, adjusted HR 2.236, 95% CI 1.011-5.350, p = 0.047; all-cause death, adjusted HR 2.826, 95% CI 1.258-6.349, p = 0.012). Baseline serum PCSK9 levels were associated with long-term cardiovascular clinical outcomes and mortality during the long-term follow-up after PCI in patients with coronary artery disease.

This study examined the determinants of perceived accessibility of maternity leave and childcare leave in South Korea. Although maternity leave and childcare leave are mandated in Korea, many employees are hesitant to use the policies. The purpose of this study was to empirically examine why some women are more likely than others to perceive the policies as inaccessible and to identify what those women’s characteristics are. The results revealed that nonregular workers were significantly less likely than regular workers with secure contracts to perceive the policies as accessible even though they were eligible for them. In addition, workers who worked in the private sector, did not belong to a labor union, worked in small firms, or worked long hours were significantly less likely to perceive the policies as accessible than those who worked in the public sector, belonged to a labor union, worked in large firms, or worked short hours. Further, workers with low salaries were significantly less likely than workers with high salaries to perceive the policies as accessible. The study underscores that accessibility of leave policies in Korea is significantly correlated with women’s employment status and wage level in the labor market.

Purpose: Because of disease heterogeneity, limited studies on effective chemotherapies and therapeutic agents for advanced gastric cancer are available. Erythrocyte membrane protein band 4.1-like 5 (EPB41L5) has critical roles in renal and breast cancer metastasis. However, its role in metastatic gastric cancer remains unknown. Experimental Design: The specimens of 78 gastric cancer patients were analyzed by oligonucleotide microarray and survival analysis. In vitro experiments and metastatic mice models were used to assess the effects of EPB41L5 on gastric cancer metastasis. Results: Gastric cancer patients with high EPB41L5 levels had poor prognosis and low survival rate. Further, TGFβ1-induced EPB41L5 expression promoted gastric cancer cell migration and invasion by Smad-dependent TGFβ signaling. Phospho-Smad3 recruitment to the EPB41L5 promoter was significantly inhibited by a TGFβ inhibitor. EPB41L5 overexpression increased lung metastasis of gastric cancer cells in nude mice, which was completely reversed by anti-EPB41L5 monoclonal antibody treatment. Importantly, p120-catenin knockdown abolished EPB41L5-enhanced gastric cancer cell metastasis. Anti-EPB41L5 monoclonal antibody treatment blocked the association of EPB41L5 with p120-catenin. Conclusions: TGFβ/EPB41L5/p120-catenin axis regulates gastric cancer cell metastasis, and EPB41L5 is a promising therapeutic target for advanced gastric cancer.

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a nearly complete loss of β cells1. Restoration of insulin-producing β cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D2–4. Here we report that enhancing β-cell mass early in life, in two models of female non-obese diabetic (NOD) mice, results in immunomodulation of T cells, reduced islet infiltration and lower β-cell apoptosis, which together protect them from developing T1D. The animals displayed altered β-cell antigens; islet transplantation studies showed prolonged graft survival in the NOD-liver-specific insulin receptor knockout (LIRKO) model. Adoptive transfer of splenocytes from NOD-LIRKO mice prevented development of diabetes in prediabetic NOD mice. A substantial increase in the splenic CD4+CD25+Foxp3+ regulatory T cell (Treg) population was observed to underlie the protected phenotype since Treg-cell depletion rendered NOD-LIRKO mice diabetic. An increase in Treg cells coupled with activation of transforming growth factor-β/SMAD family member 3 signalling pathway in pathogenic T cells favoured reduced ability to kill β cells. These data support a previously unidentified observation that initiating β-cell proliferation, alone, before islet infiltration by immune cells alters the identity of β cells, decreases pathological self-reactivity of effector T cells and increases Treg cells to prevent the progression of T1D. Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic β cells. Here, the authors show that inducing β-cell replication before immune cell infiltration of the pancreas alters β-cell antigen expression and prevents T1D disease progression in female NOD mice in a regulatory-T-cell-dependent manner.

Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF., Idiopathic pulmonary fibrosis (IPF) is a fatal adult lung disease. Here the authors investigate the functional significance of PDCD5 in club cells as a mediator of lung fibrosis and potential therapeutic target for IPF.

Angiogenesis plays a crucial role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation and migration are critical steps in tumor angiogenesis. Here, we investigated the anti-angiogenic activity of xanthorrhizol, a sesquiterpenoid isolated from the Indonesian medicinal plant Curcuma xanthorrhiza. Xanthorrhizol at noncytotoxic concentrations inhibited the proliferation, migration, and formation of capillary-like tubes in VEGF-treated human umbilical vein endothelial cells (HUVECs). Xanthorrhizol inhibited the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and the expression of vascular cell adhesion molecule (VCAM)-1 and E-selectin in VEGF-treated HUVECs. The expression and transcriptional activity of NF-[Formula: see text]B were downregulated by xanthorrhizol in VEGF-treated HUVECs. Furthermore, xanthorrhizol significantly inhibited VEGF-induced angiogenesis in the chorioallantoic membrane of fertilized eggs and Matrigel plugs subcutaneously injected into mice. Xanthorrhizol inhibited tumor volume and tumor-derived angiogenesis in mice inoculated with breast cancer cells. The in vitro and in vivo anti-angiogenic activities of xanthorrhizol were as potent as those of curcumin, a well-known anticancer agent derived from C. longa. Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-[Formula: see text]B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.

Background: Scoping reviews of the literature on the development and application of mental health apps based on theoretical suggestions are lacking. This study systematically examines studies on the effects and results of mental health mobile apps for the general adult population. Methods: Following PICOs (population, intervention, comparison, outcome, study design), a general form of scoping review was adopted. From January 2010 to December 2019, we selected the effects of mental health-related apps and intervention programs provided by mobile to the general adult population over the age of 18. Additionally, evaluation of methodological quality was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) checklist. Results: Fourteen studies were analyzed of 1205 that were identified; duplicate and matching studies were excluded. One was a descriptive study and 13 were experimental, of which randomized control trials (RCTs) accounted for 71.4%. Four of the mobile apps were developed based on cognitive behavior theory, one based on stress theory, and one on ecological instant intervention theory. These apps included breathing training, meditation, and music therapy. Stress, depression, and anxiety decreased using these apps, and some were effective for well-being. Conclusion: With the rapid development of technology related to mental health, many mobile apps are developed, but apps based on theoretical knowledge and well-designed research are lacking. Further research and practices should be conducted to develop, test, and disseminate evidence-based mHealth for mental health promotion. RCT studies are needed to expand the application to mental health services to various populations.

Neighborhood characteristics are important when raising children. Traditional approaches to parental stress research have focused on the impacts of daily hassles and how individual factors, such as children’s temperament, family resources, and social support from friends and family reduce or exacerbate parental stress. There have been few studies on neighborhood characteristics and parental stress, and even fewer studies have examined the association longitudinally. The goal of the present study was to explore the association between mothers’ parental stress and neighborhood characteristics longitudinally across early childhood (ages 0–4). Using the 2008–2012 Panel Study on Korean Children, we followed 1536 mothers. The results showed that mothers’ parenting stress was highest when children were aged two to three, and neighborhood characteristics had significant associations with parenting stress. The study indicated that mothers who reported that their neighborhoods had sufficient childcare facilities, were convenient to access public recreational and cultural facilities, and those who reported that their neighborhoods were good places to raise children, exhibited significantly lower levels of parenting stress. Further, the effects of neighborhoods on mothers’ parenting stress were greatest when children were aged one and four. Hence, such findings should be incorporated when designing and developing communities.

The quantitative flow ratio (QFR) is a novel angiography-based computational method assessing functional ischemia caused by coronary stenosis. This study aimed to evaluate the diagnostic performance of quantitative flow ratio (QFR) in patients with angina and acute myocardial infarction (AMI) and to identify the conditions with low diagnostic performance. We assessed the QFR for 1077 vessels under fractional flow ratio (FFR) evaluation in 915 patients with angina and AMI. The diagnostic accuracies of the QFR for identifying an FFR ≤ 0.8 were 95.98% (95% confidence interval [CI] 94.52 to 97.14%) for the angina group and 92.42% (95% CI 86.51 to 96.31%) for the AMI group. The diagnostic accuracy of the QFR in the borderline FFR zones (> 0.75, ≤ 0.85) (91.23% [95% CI 88.25 to 93.66%]) was significantly lower than that in others (difference: 4.32; p = 0.001). The condition accompanying both AMI and the borderline FFR zone showed the lowest QFR diagnostic accuracy in our data (83.93% [95% CI 71.67 to 92.38]). The diagnostic accuracy was reduced for tandem lesions (p = 0.04, not correcting for multiple testing). Our study found that the QFR method yielded a high overall diagnostic performance in real-world patients. However, low diagnostic accuracy has been observed in borderline FFR zones with AMI, and the hybrid FFR approach needs to be considered.

Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a tumor suppressor that functions as an Mcl-1 E3 ligase to degrade Mcl-1 by ubiquitination. Here we discovered that treatment of various human lung cancer cells with DAC resulted in activation of FBW7 expression, decreased levels of Mcl-1 protein, and growth inhibition. DAC-activated FBW7 expression promoted Mcl-1 ubiquitination and degradation leading to a significant reduction in the half-life of Mcl-1 protein. Mechanistically, treatment of lung cancer cells or lung cancer xenografts with DAC induced the conversion of the FBW7 gene from a methylated form to an unmethylated form, which was associated with the increased expression of FBW7 and decreased expression of Mcl-1 in vitro and in vivo. DAC suppressed lung cancer growth in a dose-dependent manner in vivo. Combined treatment with DAC and a Bcl2 inhibitor, venetoclax, exhibited strong synergistic potency against lung cancer without normal tissue toxicity. These findings uncover a novel mechanism by which DAC suppresses tumor growth by targeting the FBW7/Mcl-1 signaling pathway. Combination of DAC with Bcl2 inhibitor venetoclax provides more effective epigenetic therapy for lung cancer.

Coronavirus disease 2019 (COVID-19) is a newly emerged human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In a global pandemic, development of a cheap, rapid, accurate, and easy-to-use diagnostic test is necessary if we are to mount an immediate response to this emerging threat. Here, we report the development of a specific lateral flow immunoassay (LFIA)-based biosensor for COVID-19. We used phage display technology to generate four SARS-CoV-2 nucleocapsid protein (NP)-specific single-chain variable fragment-crystallizable fragment (scFv-Fc) fusion antibodies. The scFv-Fc antibodies bind specifically and with high affinity to the SARS-CoV-2 NP antigen, but not to NPs of other coronaviruses. Using these scFv-Fc antibodies, we screened three diagnostic antibody pairs for use on a cellulose nanobead (CNB)-based LFIA platform. The detection limits of the best scFv-Fc antibody pair, 12H1 as the capture probe and 12H8 as the CNB-conjugated detection probe, were 2 ng antigen protein and 2.5 × 104 pfu cultured virus. This LFIA platform detected only SARS-CoV-2 NP, not NPs from MERS-CoV, SARS-CoV, or influenza H1N1. Thus, we have successfully developed a SARS-CoV-2 NP-specific rapid diagnostic test, which is expected to be a simple and rapid diagnostic test for COVID-19., Highlights • SARS-CoV-2 NP-specific scFv-Fc antibodies were generated. • Antibody pairs for the specific and sensitive detection of SARS-CoV-2 were found. • Lateral flow immunoassay-based rapid diagnostic tests sensitively detected NP antigen and SARS-CoV-2 virus. • The COVID-19 biosensor showed no cross-reactivity with other coronaviruses, SARS-CoV and MERS-CoV.

BackgroundNeprilysin has an essential role in regulating fluid balance and vascular resistance, and neprilysin inhibitors have shown beneficial effects in patients with heart failure. However, the potential predictive value of neprilysin levels as a biomarker for cardiovascular risk remains unclear. The aim of this study was to assess the prognostic value of soluble neprilysin (sNEP) levels in patients with ischemic heart disease.MethodsNeprilysin levels were measured in 694 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). These patients were classified into two groups according to their serum levels of neprilysin and categorized into the lower neprilysin group (n = 348) and the higher neprilysin group (n = 346). The primary clinical endpoint was all-cause mortality, and the secondary endpoint was a composite of major adverse cardiac events (MACE).ResultsThe median sNEP level was 76.0 pg/ml. The median sNEP levels were higher in patients with left ventricular ejection fraction (LVEF) ≥40% (77.6 pg/ml, interquartile range 46.6–141.3) than in those with LVEF P = 0.032). Among all patients, each clinical outcome and MACE did not differ significantly according to the groups divided into median, tertile, or quartile of sNEP levels during a median follow-up of 28.4 months. We did not find a significant relationship between sNEP levels and clinical outcomes in multivariate Cox regression analysis. Among patients with LVEF P = 0.039).ConclusionSerum sNEP levels are not associated with long-term mortality or cardiovascular outcomes after PCI in patients with CAD. In the LVEF

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&kappa, B) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 negatively regulates Toll-like receptor 4 (TLR4)-mediated signaling via TRAF6-ECSIT signaling axis, we herein investigated whether p62 is functionally implicated in the TRAF6-BECN1 signaling axis, thereby regulating cancer cell migration and invasion. p62 interacted with TRAF6 and BECN1, to interrupt the functional associations required for TRAF6-BECN1 complex formation, leading to inhibitions of BECN1 ubiquitination and autophagy activation. Importantly, p62-deficient cancer cells, such as p62-knockdown (p62KD) SK-HEP-1, p62KD MDA-MB-231, and p62-knockout (p62KO) A549 cells, showed increased activation of autophagy induced by TLR4 stimulation, suggesting that p62 negatively regulates autophagy activation. Moreover, these p62-deficient cancer cells exhibited marked increases in cell migration and invasion in response to TLR4 stimulation. Collectively, these results suggest that p62 is negatively implicated in the TRAF6-BECN1 signaling axis, thereby inhibiting cancer cell migration and invasion regulated by autophagy activation in response to TLR4 stimulation.

Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for containing the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clinical samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was determined using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concentrations of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clinical transport medium. In addition, the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 × 101 pfu/mL) and clinical samples (LOD: 2.42 × 102 copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunological diagnostic method for COVID-19 that requires no sample pretreatment or labeling.

Gastric cancer (GC) patients usually receive surgical treatment. Postoperative therapeutic options such as anticancer adjuvant therapies (AT) based on prognostic prediction models would provide patient-specific treatment to decrease postsurgical morbidity and mortality rates. Relevant prognostic factors in resected GC patient’s serum may improve therapeutic measures in a non-invasive manner. In order to develop a GC prognostic model, we designed a retrospective study. In this study, serum samples were collected from 227 patients at a 4-week recovery period after D2 lymph node dissection, and 103 cancer-related serum proteins were analyzed by multiple reaction monitoring mass spectrometry. Using the quantitative values of the serum proteins, we developed SEPROGADIC (SErum PROtein-based GAstric cancer preDICtor) prognostic model consisting of 6 to 14 serum proteins depending on detailed purposes of the model, prognosis prediction and proper AT selection. SEPROGADIC could clearly classify patients with good or bad prognosis at each TNM stage (1b, 2, 3 and 4) and identify a patient subgroup who would benefit from CCRT (combined chemoradiation therapy) rather than CTX (chemotherapy), or vice versa. Our study demonstrated that serum proteins could serve as prognostic factors along with clinical stage information in patients with resected gastric cancer, thus allowing patient-tailored postsurgical treatment.

Overcoming drug resistance is one of key issues in treating refractory acute myeloid leukemia (AML). The Toll-like receptor 4 (TLR4) signaling pathway is involved in many aspects of biological functions of AML cells, including the regulation of pro-inflammatory cytokine products, myeloid differentiation, and survival of AML cells. Thus, targeting TLR4 of AML patients for therapeutic purposes should be carefully addressed. In this regard, we investigated the possible role of TLR4 as a regulatory factor against fludarabine (FA) cytotoxicity activity. Here, we identified the differential expression of TLR4 and CD14 receptors in AML cell lines and examined their relationship to FA sensitivity. We found that the stimulation of TLR4 with lipopolysaccharide (LPS) in a TLR4-expressing cell line, THP-1, increased cell viability under FA treatment condition and showed that TLR4 stimulation overcame FA sensitivity through the activation of NF-κB, which subsequently upregulated several anti-apoptotic genes. The inhibition of TLR4/NF-κB signaling could partially or completely reverse LPS-induced cell survival under FA treatment conditions. Interestingly, we found that the expression of thioredoxin-interacting protein (TXNIP), a well-known tumor suppressor, was induced by FA treatment; however, it was suppressed by LPS treatment. Furthermore, the expression level of TXNIP was critical for FA-induced cytotoxicity or LPS-induced FA resistance of THP-1 cells. Our data suggest that TXNIP plays an important role in FA-induced cytotoxicity and TLR4/NF-κB-mediated FA resistance of AML cells. Therefore, TXNIP may be a potential therapeutic target for AML treatment.

The purpose of this study was to investigate bacterial communities and health-benefit-related parameters in doenjang prepared with various brine concentrations (8, 12, 16, and 20%). Phenolic, flavonoid, melanoidin and isoflavone contents, antioxidation, and antiproliferation of doenjang (AD8, AD12, AD16, and AD20) aged for 3 months were compared with those of initial doenjang (ID8, ID12, ID16, and ID20). The ID8 and AD8 doenjang, made with 8% brine, contained higher phenolics, melanoidins, and isoflavones than those with high salinity. As results of bacterial communities, Enterococcus was a dominant bacterium in most doenjang, while Lactobacillus was predominant in AD8. Trolox equivalent antioxidant capacity (32.5 µmol TE/g dwb) and DPPH radical-scavenging capacity (57 µmol TE/g dwb) values of AD8 were the highest among samples. The EC50 of HT-29 cell proliferation treated with AD8 was 0.47 mg/mL, while EC50 of AD20 was 1.07 mg/mL, indicating stronger antiproliferative activity in low-salinity doenjang.

Summary Background CT radiation is arguably carcinogenic. Results from single-centre studies, mostly retrospective, have advocated lowering the CT radiation dose for the diagnosis of appendicitis. However, adoption of low-dose CT has been slow. We aimed to assess the effectiveness of low-dose CT compared with standard-dose CT in the diagnosis of appendicitis in adolescents and young adults. Methods We did this pragmatic, multicentre, randomi s ed controlled non-inferiority trial at 20 South Korean teaching hospitals with little experience with low-dose CT. Patients aged 15–44 years with suspected appendicitis were randomly assigned (1:1), via computer-generated random assignments (permuted block sizes of two, four, six, and eight) concealed in sequentially numbered envelopes, to receive low-dose CT (2 mSv) or standard-dose CT (≤8 mSv). Randomisation was stratified by site. Group allocation was concealed from patients, outcome assessors, and adverse event adjudicators; care providers, site pathologists, and data collectors were aware of allocation. The primary endpoint was the negative (unnecessary) appendectomy rate among all appendectomies, with a non-interiority margin of 4·5% for low-dose versus standard-dose CT. Primary analy s is was by modified intention to treat, which included all patients who received an appendectomy in the group to which they were assigned. This trial is registered with ClinicalTrials.gov, number NCT01925014. Findings Between Dec 4, 2013, and Aug 18, 2016, we assigned 1535 patients to the low-dose CT group and 1539 patients to the standard-dose CT group. 22 (3·9%) of 559 patients had a negative appendectomy in the low-dose group versus 16 (2·7%) of 601 patients in the standard-dose group (difference 1·3%, 95% CI −0·8 to 3·3; p=0·0022 for the non-inferiority test). We recorded 43 adverse events in 43 (2·8%) of 1535 patients in the low-dose group and 41 adverse events in 40 (2·6%) of 1539 patients in the standard-dose group. One life-threatening adverse event of anaphylaxis caused by an iodinated contrast material occurred in the low-dose group. Interpretation Radiation dose of appendiceal CT for adolescents and young adults can be reduced to 2 mSv without impairing clinical outcomes. In view of the vast number of appendiceal CT examinations done worldwide, use of low-dose CT could prevent a sizeable number of radiation-associated cancers in the future. Funding Korea Health Industry Development Institute, Seoul National University Bundang Hospital, Dasol Life Science, and Bracco Imaging Korea.

OBJECTIVE We investigated the efficacy of coronary computed tomography angiography (CCTA) in predicting the long-term risks in asymptomatic patients with type 2 diabetes and compared it with traditional risk factors. RESEARCH DESIGN AND METHODS We analyzed 933 patients with asymptomatic type 2 diabetes who underwent CCTA. Stenosis was considered obstructive (≥50%) in each coronary artery segment using CCTA. The extent and severity scores for coronary artery disease (CAD) were evaluated. The primary end point was major adverse cardiovascular events (MACE), including all-cause mortality, nonfatal myocardial infarction, and late coronary revascularization during a mean follow-up period of 5.5 ± 2.1 years. RESULTS Ninety-four patients with MACE exhibited obstructive CAD with a greater extent and higher severity scores (P < 0.001 for all). After adjusting for confounding risk factors, obstructive CAD remained an independent predictor of MACE (hazard ratio 3.11 [95% CI 2.00–4.86]; P < 0.001]). The performance of a risk prediction model based on C-statistics was significantly improved (C-index 0.788 [95% CI 0.747–0.829]; P = 0.0349) upon the addition of a finding of obstructive CAD using CCTA to traditional risk factors, including age, male, hypertension, hyperlipidemia, smoking, estimated glomerular filtration rate, and HbA1c. Both integrated discrimination improvement (IDI) and net reclassification improvement (NRI) analyses further supported this finding (IDI 0.046 [95% CI 0.020–0.072], P < 0.001, and NRI 0.55 [95% CI 0.343–0.757], P < 0.001). In contrast, the risk prediction power of the coronary artery calcium score remained unimproved (C-index 0.740, P = 0.547). CONCLUSIONS Based on our data, the addition of CCTA-detected obstructive CAD to models that include traditional risk factors improves the predictions of MACE in asymptomatic patients with type 2 diabetes.

The nuclear factor kappa B (NF-κB) pathway is pivotal in controlling survival and apoptosis of cancer cells. Macrophage migration inhibitory factor (MIF), a cytokine that regulates the immune response and tumorigenesis under inflammatory conditions, is upregulated in various tumors. However, the intracellular functions of MIF are unclear. In this study, we found that MIF directly interacted with thioredoxin-interacting protein (TXNIP), a tumor suppressor and known inhibitor of NF-κB activity, and MIF significantly induced NF-κB activation. MIF competed with TXNIP for NF-κB activation, and the intracellular MIF induced NF-κB target genes, including c-IAP2, Bcl-xL, ICAM-1, MMP2 and uPA, by inhibiting the interactions between TXNIP and HDACs or p65. Furthermore, we identified the interaction motifs between MIF and TXNIP via site-directed mutagenesis of their cysteine (Cys) residues. Cys57 and Cys81 of MIF and Cys36 and Cys120 of TXNIP were responsible for the interaction. MIF reversed the TXNIP-induced suppression of cell proliferation and migration. Overall, we suggest that MIF induces NF-κB activity by counter acting the inhibitory effect of TXNIP on the NF-κB pathway via direct interaction with TXNIP. These findings reveal a novel intracellular function of MIF in the progression of cancer.

Two prospective, multi-centre, observational studies (GlaxoSmithKline [GSK] identifier No. 110938 and 112519) were performed over 2 influenza seasons (2007–2008 and 2008–2009) in the Republic of Korea (ROK) with the aim to evaluate the burden of laboratory-confirmed influenza (LCI) in patients ≥ 50 years of age seeking medical attention for acute respiratory illness (ARI). The median participant age was 58 years in the 2007–2008 season and 60 years in the 2008–2009 season. LCI was observed in 101/346 (29.2%) of ARI patients in the 2007–2008 season and in 166/443 (37.5%) of ARI patients in the 2008–2009 season. Compared to patients with non-influenza ARI, those with LCI had higher rates of decreased daily activities (60.4% vs. 32.9% in 2007–2008 and 46.4% vs. 25.8% in 2008–2009), work absenteeism (51.1% vs. 25.6% and 14.4% vs. 7.7%), and longer duration of illness. These results indicated that influenza is an important cause of ARI in adults aged 50 and older causing more severe illness than non-influenza related ARI., Graphical Abstract

Cereblon (CRBN) as a multifunctional protein has been extensively studied. Here, we show that CRBN is a negative regulator of bactericidal activity and autophagy activation. Mitochondrial localization of CRBN was significantly increased in response to Toll-like receptor 4 (TLR4) stimulation. CRBN interrupted the association of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT)-TNF-receptor associated factor 6 (TRAF6) complex, thereby inhibiting the ubiquitination of ECSIT, which plays a pivotal role for the production of mitochondrial reactive oxygen species (mROS). Subsequently, mROS levels were markedly elevated in CRBN-knockdown (CRBNKD) THP-1 cells, and that led to resistance against S. typhimurium infection, indicating CRBN is a negative regulator of bactericidal activity through the regulation of mROS. Additionally, CRBN inhibited TRAF6-induced ubiquitination of BECN1 (Beclin 1), and that induced autophagy activation in CRBNKD THP-1, CRBN-knockout (CRBNKO) H1299, and CRBNKO MCF7 cancer cells in response to TLR4 stimulation. Notably, we found that the ability of cancer migration and invasion was significantly enhanced in CRBNKO H1299 and CRBNKO MCF7 cancer cells, as compared with those of control cancer cells. Collectively, these results suggest that CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the TRAF6-induced ubiquitination of ECSIT and BECN1, respectively.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are used in various fields but raise concerns regarding human health and environmental consequences. Among PFASs, perfluorooctanoic acid (PFOA) and short-chain perfluoroalkyl carboxylic acids (SC PFCAs) are detectable in skin-contact consumer products and have dermal absorption potential. Here, we investigated the effects of dermal exposure to PFOA and SC PFCAs using in vitro and in vivo models. Human skin equivalents were topically treated with 0.25 mM and 2.5 mM PFOA and SC PFCAs (perfluoropentanoic acid, PFPeA; perfluorohexanoic acid, PFHxA; and perfluoroheptanoic acid, PFHpA) for 6 days, and cell viability, interleukin (IL)-1α, oxidative stress markers (malondialdehyde, MDA; and 8-hydroxydeoxyguanosine, 8-OHdG), and histopathology were examined. MDA levels were significantly higher in the PFASs groups than in controls. Compared with SC PFCAs, 2.5 mM PFOA caused more IL-1α (p

Alzheimer's disease accounts for the majority of dementia and shows hallmarks such as sequential cognitive dysfunction and abnormal behavior.

Upon bioprinting, cells are mixed with a biomaterial to fabricate a living tissue, thus emphasizing the importance of biomaterials. The biomaterial used in this study was a bio-ink prepared using skin decellularized extracellular matrix (dECM). Skin dECM was extracted by treating the dermis with chemicals and enzymes; the basic structural and functional proteins of the ECM, including collagen, glycosaminoglycans (GAGs), bioreactive materials and growth factors, were preserved, whereas the resident cells that might cause immune rejection or inflammatory responses were removed. The bio-ink based on dECM powder, together with human dermal fibroblasts (HDFs), was loaded into the nozzle of the 3D bioprinter to create the 3D construct. This construct underwent gelation with changing temperature while its shape was maintained for 7 days. The cells showed over 90% viability and proliferation. By analysing the gene expression pattern in the cells of the construct, the skin regenerative mechanism of the bio-ink was verified. Microarray results confirmed that the gene expression related to skin morphology and development had been enhanced because the bioreactive molecules and growth factors, in addition to residual ECM in dECM, provided an optimal condition for the HDFs.

2-Deoxy-2-[[[There was no difference in the pattern of [

To prospectively assess radiation dose, image quality, and diagnostic performance of computed tomography (CT) urography for detection of urothelial carcinomas by performing reduced-dose scanning with iterative reconstruction (IR) compared with standard-dose scanning with filtered back projection (FBP).The institutional review board approved the study with written informed patient consent. In total, 2163 patients at high risk for urothelial carcinomas randomly underwent standard-dose scanning with FBP (protocol A, 120 kVp for80 kg body weight; protocol B, 100 kVp for 50-80 kg body weight) or reduced-dose scanning with IR (protocol C, 100 kVp for80 kg body weight; protocol D, 80 kVp for 50-80 kg body weight). Objective image quality (signal-to-noise ratio and contrast-to-noise ratio) between the two groups with same weight range was measured for various regions of interest. Subjective image quality (visual image noise, artifact, ureter depiction, and overall image quality) and diagnostic accuracy (per lesion and per patient) were assessed with three- and five-point scores, respectively.Size-specific dose estimate (protocol A vs protocol C, 24.2 mGy vs 19.2 mGy, respectively; protocol B vs protocol D,13.9 mGy vs 8.8 mGy, respectively) was significantly lower in reduced-dose scanning (P.001 for both). There were significantly higher signal-to-noise and contrast-to-noise ratios in reduced-dose scanning, except for the abdominal aorta (P.05 for all). There was no significant difference in subjective image quality, except for artifacts in protocols B and D (range, 4-5 vs 3-4; P.05). Per-lesion diagnostic accuracy was 90.8% (89 of 98, protocol A), 91.3% (105 of 115, protocol B), 92.9% (79 of 85, protocol C), and 88.8% (111 of 125, protocol D).Reduced-dose scanning with IR showed dose reduction and no significant difference of image quality in detection of urothelial carcinomas, except for some artifacts in 80-kVp scanning.

The purpose of this study was to retrospectively assess whether measurement of quantitative enhancement during three-phase MDCT can help differentiate clear cell renal cell carcinoma (RCC) from papillary RCC, chromophobe RCC, and fat-poor angiomyolipoma.During preoperative three-phase MDCT (unenhanced, corticomedullary, and early excretory phases), 563 lesions were identified in 552 consecutively registered patients. The lesions were assessed for attenuation in each phase, and the attenuation values were compared by t test. Cutoff analysis of enhancement values (percentage enhancement ratio, enhancement change, and absolute washout ratio) was performed to determine optimal thresholds for the four types of lesions.The mean attenuation of clear cell RCC was significantly greater than that of papillary RCC and chromophobe RCC in the corticomedullary phase (clear cell, 139.7 HU; papillary, 56.8 HU [p = 0.003]; chromophobe, 85.4 HU [p = 0.005]) and early excretory phase (clear cell, 86.9 HU; papillary, 73.4 HU [p = 0.03]; chromophobe, 68.2 HU [p = 0.02]). It was also significantly greater than that of fat-poor angiomyolipoma in the corticomedullary phase (139.7 vs 99.6 HU, p = 0.02). Establishment of threshold enhancement values helped to differentiate clear cell RCC from papillary RCC, chromophobe RCC, and fat-poor angiomyolipoma with the following accuracies: percentage enhancement ratio, 84.7% (399/471) for papillary RCC, 71.1% (325/457) for chromophobe RCC, and 81.9% (377/460) for fat-poor angiomyolipoma; enhancement change, 80.9% (381/471) for papillary RCC, 70.2% (321/457) for chromophobe RCC, and 80.6% (371/460) for fat-poor angiomyolipoma; absolute washout ratio, 88.5% (417/471) for papillary RCC, 74.1% (339/457) for chromophobe RCC, and 85.0% (391/460) for fat-poor angiomyolipoma.Quantitative enhancement measurement may be useful for differentiating clear cell RCC from papillary RCC, chromophobe RCC, and fat-poor angiomyolipoma.

The purpose of this study was to investigate the effects of salinity on the antioxidant properties, sensory attributes, and metabolite profiles of doenjang prepared with different brine concentrations (8, 12, 16, and 20%). The oxygen radical absorbance capacity (0.49 mM/g dry weight basis, dwb) and the Trolox equivalent antioxidant capacity (0.46 mM/g dwb) were the highest for the doenjang samples with the lowest salinity. The consumer acceptability and intensity of sensory characteristics were evaluated by consumers (n = 147). The doenjang with the lowest salinity tended to have an increased bitterness and reduced umami taste, resulting in decreased consumer acceptance. Additionally, 39 and 24 metabolites were identified by gas chromatography–mass spectrometry and ultra-performance liquid chromatography–quadrupole/time-of-flight mass spectrometry. Overall, the correlation between sensory attributes and metabolite profiles of doenjang showed that bitter taste was closely related to tyrosine and phenylalanine, while umami was highly related to glutamic and aspartic acids.

Rheumatoid arthritis (RA) is a chronic disease with systemic inflammation resulting in destruction of multiple articular cartilages and bones. Activated macrophage plays a pivotal role during the disease course and has been one of main targets to inhibit inflammatory reaction of RA by using biological disease-modifying anti-rheumatic drugs (bDMARDs).

Although glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) are known as major proteins involved in the molecular mechanisms for accumulating 2-deoxy-2-[ANT2 expression was evaluated in various cancer cell lines and human cancer tissues (microarrays) using western blot and immunohistochemical (IHC) staining, respectively. The expression levels of ANT2 were compared to [[In various cancer cells and tissues, the expression levels of ANT2 explained [

TRAF6 (TNF receptor associated factor 6) plays a pivotal role in NFKB activation and macroautphagy/autophagy activation induced by TLR4 (toll like receptor 4) signaling. The objective of this study was to determine the functional role of PRDX1 (peroxiredoxin 1) in NFKB activation and autophagy activation. PRDX1 interacted with the ring finger domain of TRAF6 and inhibited its ubiquitin-ligase activity. The inhibition on TRAF6 ubiquitin-ligase activity by PRDX1 induced the suppression of ubiquitination of an evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) essential for NFKB activation and BECN1 (beclin 1) required for autophagy activation. An inhibitory effect of PRDX1 on TRAF6 was clearly evidenced in PRDX1-knockdown (PRDX1KD) THP-1, PRDX1KD MDA-MB-231, and PRDX1KD SK-HEP-1 cells. PRDX1KD THP-1 cells showed increases of NFKB activation, pro-inflammatory cytokine production, NFKB-dependent gene expression induced by TLR4 stimulation, and resistance against Salmonella typhimurium infection. Additionally, migration and invasion abilities of PRDX1KD MDA-MB-231 and PRDX1KD SK-HEP-1 cancer cells were significantly enhanced compared to those of control cancer cells. Taken together, these results suggest that PRDX1 negatively regulates TLR4 signaling for NFKB activation and autophagy functions such as bactericidal activity, cancer cell migration, and cancer cell invasion by inhibiting TRAF6 ubiquitin-ligase activity. Abbreviations: 3-MA: 3-methyladenine; BECN1: beclin 1; CHUK/IKKA: conserved helix-loop-helix ubiquitous kinase; ECSIT: ECSIT signalling integrator; ELISA: enzyme-linked immunosorbent assay; NFKB: nuclear factor kappa-light-chain-enhancer of activated B cells; IB: immunoblotting; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IL1B: interleukin 1 beta; IL6: interleukin 6; IP: immunoprecipitation; LPS: lipopolysaccharide; MAP1LC3/LC3: microtuble associated protein 1 light chain 3; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAPK14/p38: mitogen-activated protein kinase 14; mROS: mitochondrial reactive oxygen species; PRDX1: peroxiredoxin 1; PRDX6: peroxiredoxin 6; RELA/p65: RELA proto-oncogene, NF-kB subunit; TRAF6 TNF: receptor associated factor 6.

PURPOSE Recently, the diastolic strain rate (DSR) utilizing speckle-tracking echocardiography has been proposed as a novel parameter for left ventricular diastolic function. We aimed to present normal reference data for those in a large-sized, selected group of healthy individuals. METHODS The current study was a part of the Normal echOcardiogRaphic Measurements in KoreAn popuLation (NORMAL), a prospective nationwide survey from 23 centers in Korea. We analyzed 447 subjects (age 48 ± 15 years, 234 females) without any history of cardiovascular disease and presented the early and late DSRs (SRe and SRa , respectively) in a total and gender-/age-specified groups. RESULTS Among the total subjects, the mean SRe and SRa were 1.6 ± 0.4 S-1 and 0.8 ± 0.3 S-1 , respectively. With increasing age, there were significant trends of decreasing SRe and increasing SRa . Although both gender groups showed comparable age, the female group presented significantly higher SRe compared to male subjects with age of 20-59 years, which diminished after the age of 60 years. However, the SRa was comparable between genders in all age groups. On multiple linear regression, age showed independent associations with both SRe (β = -0.132, P = .010) and SRa (β = 0.440, P

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Amyloid-β (Aβ) peptide plays a major role in the pathogenesis of Alzheimer's disease (AD), and is generated by β- and γ-secretase-mediated proteolytic processing of amyloid-β protein precursor (AβPP). In the present study, we investigated the effect of 118 natural compounds on Aβ production in the medium of HEK293 cells stably expressing human AβPP695 (HEK293-AβPP) using Aβ42 sandwich ELISA to find natural compounds that can modulate Aβ production. We found that a coumarin derivative of citrus fruits, auraptene, increased Aβ production. Treatment of HEK293-AβPP cells and rat primary cortical neurons with auraptene significantly increased the secretion of Aβ40, Aβ42, and the Aβ42/40 ratio. However, auraptene did not change the protein levels of the AβPP processing enzymes, a disintegrin and metalloproteinases 10 (ADAM10, α-secretase), β-site AβPP cleaving enzyme-1 (BACE-1, β-secretase), and presenilin 1 (PS1, γ-secretase component). Auraptene increased the activity of γ-secretase but not that of α- and β-secretase. Furthermore, auraptene enhanced γ-secretase-mediated production of Aβ from AβPP or AβPP-C99, but not through α- and β-secretase. Auraptene also phosphorylated c-Jun N-terminal kinase (JNK), and pretreatment with the JNK inhibitor, SP600125, reduced auraptene-induced γ-secretase activity. Overall, our results suggest that auraptene-mediated activation of JNK may contribute to the production of Aβ by promoting γ-secretase activity.

Background Natural products play a significant role in human health in relation to the prevention and treatment of inflammatory conditions. One of the plants with great medicinal potentials is Diospyros kaki which is mainly cultivated in Asian countries including Korea, Japan, and China. Astringent D. kaki is a wild species with an astringent taste until they are Ripened. kaki calyx is a traditional Korean medicine (TKM) made from the stalks of astringent D. kaki and is used in treating bed-wetting, vomiting, and hiccupping. The present study was designed to investigate the potential anti-inflammatory activities of astringent D. kaki stalks based on cultivar types and stages of maturity. Methods The anti-inflammatory effects of the stalk extracts of local astringent D. kaki cultivar species were evaluated on RAW 264.7 cells. Cell viability was measured using a Cell Counting Kit-8 (CCK8) method. The anti-inflammatory effects were determined by measuring the nitric oxide (NO) concentration of the supernatant. Cellular signaling pathways were determined by quantitative polymerase chain reactions of inducible nitric oxide synthase (iNOS). Protein expression of iNOS and phospho-p65 was determined using western blot, and the nuclear localization of p65 was determined using confocal imaging in RAW 264.7 cells. Results We found that the stage 1 (8–9 month) samples all showed a high percentage of tannic acid content and Gojongsi (Hamyang) stalks had the highest content. The stage 1 samples also showed the highest inhibition of NO production. Decreases in the expression of iNOS and phosphorylated p65, and in the nuclear localization of p65, were dose-dependent. All the extracts were nontoxic under 100 μg/ml concentration. Conclusion This study provides insight into the changes in tannic acid content in astringent D. kaki and their anti-inflammatory effects, in relation to their stage of maturity. These results are expected to be useful in the verification of the efficacy of oriental medicine and the timing of proper harvest for medical use.

Background Uterine arteriovenous malformations (AVMs) are known to spontaneously regress. Purpose To assess the predictive value of ultrasonography for patients requiring conservative treatment for pregnancy related to AVMs. Material and Methods Our prospective study included 75 patients (conservative management:therapeutic management = 45:30) with vaginal bleeding from pregnancy-related AVM. Clinical and ultrasonography examinations were reviewed, and the following information was gathered: complete blood count, AVM maximal diameter, AVM echogenicity, retained product of conception, number of blood vessels, and spectral Doppler (pulsatility index [PI], resistance index [RI], peak systolic velocity [PSV], time-averaged maximum velocity [TAMXV]). The Doppler criteria by Timmerman (mean PSV >70 cm/s: therapeutic management, mean PSV Results Features strongly associated with conservative management and their accuracy were PSV 89.6%, hemoglobin 84.7%, RI 83.1%, TAMXV 79.3%, and PI 78.6%. The overall accuracy for correct outcome classification was 64 (85.3%) of 75 patients. Most patients with conservative management had quicker improvement of symptoms and spontaneous regression at follow-up. Conclusion Ultrasonography can accurately predict selection of conservative management.

The cytoplasmic C-terminal domain of amyloid-β protein precursor (AβPP) binds to several proteins that regulate the trafficking and processing of AβPP and affects amyloid-β (Aβ) production. We previously reported that levels of AT-motif binding factor 1 (ATBF1) are increased in the brains of 17-month-old Tg2576 mice compared with wild-type controls, and that Aβ42 increases ATBF1 expression, inducing death in primary rat cortical neurons. Here, we show that ATBF1 levels are increased in the cytoplasm of hippocampal neurons in Alzheimer's disease (AD) brains compared with non-AD brains. Furthermore, cotransfection of human embryonic kidney (HEK293T) and human neuroblastoma (SH-SY5Y) cells with ATBF1 and AβPP695 increased steady-state levels of AβPP via the binding of ATBF1 to the AβPP cytoplasmic domain (amino acids 666-690), resulting in increased Aβ production and cellular and soluble AβPP (sAβPP) levels without affecting the activity or levels of AβPP processing enzymes (α-, β-, or γ-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular AβPP, sAβPP, and Aβ in HEK293 cells overexpressing human AβPP695. Our findings provide insight into the dynamics of AβPP processing and Aβ production, and suggest that ATBF1 is a novel AβPP binding protein that may be a suitable therapeutic target for AD.

To retrospectively determine diagnostic performance with multiparametric magnetic resonance (MR) imaging for detection of cancer of different tumor volumes and Gleason grades in patients with clinically low-risk prostate cancer.The local ethical committee and institutional review board approved this study. Consecutive patients with clinically determined low-risk cancer (n = 100) were examined with multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast material enhanced) by using a 3.0-T imager before prostatectomy. Two radiologists independently assessed the likelihood of cancer per sextant. Cancers with a volume of 0.5 cm(3) or more identified at histopathologic examination were compared with multiparametric MR images. Cancer detection with multiparametric MR imaging was assessed for tumors of different volumes and Gleason grades by using a logistic generalized estimating equation model with 95% confidence intervals (CIs) with two optimal dichotomized cutoff scores.For cancers greater than or equal to 0.5 cm(3), with respect to cancer volume and Gleason grade, multiparametric MR imaging showed high diagnostic performance for the detection of cancer. Diagnostic accuracy with multiparametric MR imaging was significantly higher for cancers with a volume greater than 1 cm(3) than for those with a volume of 0.5-1 cm(3) (87.7%; 95% CI: 82.4%, 94.3% vs 82.6%; 95% CI: 79.0%, 88.7%; P = .02) and for cancers with Gleason grades of 7 or more than for those with grades of 6 or less (89.2%; 95% CI: 85.4%, 93.8% vs 80.6%; 95% CI: 71.2%, 89.8%; P = .01). Detection rates for cancers with a volume more than 1 cm(3) and a Gleason grade of 7 or more were significantly higher than for those with a volume of 0.5-1 cm(3) and a Gleason grade of 6 or less(87.8%; 95% CI: 85.3%, 93.7% vs 82.0%; 95% CI: 75.6%, 86.1%; P = .01).Detection of prostate cancer in patients with clinically low-risk cancer with multiparametric MR imaging is highly accurate, and larger cancer volume and higher Gleason grade are associated with higher detection accuracy.

Summary Introduction The CellaVision DM96 system (CellaVision AB, Lund, Sweden) was developed as one of the automated digital cell morphology analyzer for determining leukocyte differential counts in peripheral blood smears (PBS) and we evaluated this system. Methods A total of 308 PB samples with abnormalities were analyzed in this study. For each sample, manual differential counts were performed by two independent technologists, and the CellaVision DM96 system was applied in duplicate. Correlations between the two methods and ability of this system to identify six abnormalities were assessed. Results The correlation coefficients between two methods were consistently high, ranged from 0.864 to 0.992. The sensitivity, specificity, positive predictive value, negative predictive values of this system for the identification of abnormalities were consistently high, especially for blasts (98.2%, 99.2%, 96.6%, 99.6%). When the instrument was ordered to count 300 or 500 cells from the operator, better performance was demonstrated than 100 cells in the leukopenic samples by sacrificing only 40 s/slide in average. Conclusions The CellaVision DM96 system is useful in the clinical laboratory providing comparative accuracy compared with manual counts in samples with abnormalities. In leukopenic samples, report quality can be improved by ordering to count 300 or 500 cells from the operator without severe prolongation of turnaround time.

Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy that causes systolic heart failure (HF) in previously healthy young women. Despite latest remarkable achievement, unifying pathophysiologic mechanism is not well established. Considering close temporal relationship to pregnancy, the recent prolactin theory is promising. Abnormal short form of 16-kDa prolactin may be produced in the oxidative stress milieu, show anti-angiogenic effect and damage cardiovascular structure in late pregnancy. Future study is needed to determine whether abnormal prolactin system is useful as a biomarker for diagnosis and therapy of PPCM. Diagnosis is made based on the finding of left ventricular systolic dysfunction after excluding other causes of HF. A multidisciplinary team approach is essential for acute HF, antepartum, labor and postpartum care. Recovery from left ventricular dysfunction is critical for prognosis. As PPCM can recur and cause serious clinical events, subsequent pregnancy is not recommended. This review focuses on the practical management of PPCM.

A 64-year-old man presented with left hemiplegia. Brain magnetic resonance imaging showed multifocal acute infarctions involving the temporal and occipital lobes, thalami, and cerebellum. Blood pressure was 173/64 mmHg and body temperature was normal. There was no microbial yield. Transesophageal echocardiography showed broad-based fuzz-like vegetation attached to the left …

Our work aimed to investigate the protective effects of saponin-based nanoemulsions of vitamin A and E against oxidative stress-induced cellular damage in AML-12 cells. Saponin nanoemulsions of vitamin A (SAN) and vitamin E (SEN) were prepared by high-pressure homogenization and characterized in terms of size, zeta potential, and polydispersity index. SEN and SAN protect AML-12 cells against oxidative stress-induced cellular damage more efficiently via scavenging reactive oxygen species (ROS), and reducing DNA damage, protein carbonylation, and lipid peroxidation. These results provide valuable information for the development of nanoemulsion-based delivery systems that would improve the antioxidant properties of vitamin A and E.

Background Cytoreduction is important as a survival predictor in advanced ovarian cancer. Purpose To determine the prediction of suboptimal resection (SOR) in advanced ovarian cancer based on clinical and computed tomography (CT) parameters. Material and Methods Between 2007 and 2015, 327 consecutive patients with FIGO stage III–IV ovarian cancer and preoperative CT were included. During 2007–2012, patients were assigned to a derivation dataset ( n = 220) and the others were assigned to a validation dataset ( n = 107). Clinical parameters were reviewed and two radiologists assessed the presence or absence of tabulated parameters on CT images. Logistic regression analyses based on area under the receiver-operating characteristic curve (AUROC) were performed to identify variables predicting SOR, and generated simple score using Cox proportional hazards model. Results There was no statistical difference in patients’ characteristics in both datasets, except for residual disease ( P = 0.001). Optimal resection improved from 45.0% (99/220) in the derivation dataset to 64.4% (69/107) in the validation dataset. Logistic regression identified that Eastern Cooperative Oncology Group-performance status (ECOG-PS 2), involvements of peritoneum, diaphragm, bowel mesentery and suprarenal lymph nodes, and pleural effusion were independent variables of SOR. Overall AUROC for score predicting SOR was 0.761 with sensitivity, specificity, and positive and negative predictive values of 70.6%, 73.2%, 68.7%, and 91.9%, respectively. In the derivation dataset, AUROC was 0.792, with sensitivity of 71.4% and specificity of 74.3%, and AUROC of 0.758 with sensitivity of 69.2% and specificity of 72.8% in the validation dataset. Conclusion CT may be a useful preoperative predictor of SOR in advanced ovarian cancer.

The aspects of cellular metabolism controlled by phosphatidylinositol phosphates (PtdInsPs) have been broadly expanded, and these phospholipids have drawn tremendous attention as pleiotropic signaling molecules. PtdInsPs analysis using LC/MS/MS has remained challenging due to the strong hydrophilicity of these lipids. Multiple reaction monitoring (MRM) or a neutral loss scan has been performed to quantitatively measure PtdInsPs after chemical derivatization on the phosphate groups of inositol moieties. Only predefined PtdInsPs can be measured in MRM mode, and fatty acyl compositions of sn-1 and sn-2 positions of PtdInsPs cannot be obtained from a neutral loss scan. In our present study, we developed a simple LC/MS/MS method for structural identification of sn-1 and sn-2 fatty acids of PtdInsPs and their relative quantitation. Precursor ion scans of sn-1 monoacylglycerols (MAGs) of PtdInsPs provided structural information about the lipids, and ammonium adduction enhanced signal intensities of PtdInsPs. The relative amount of observed PtdInsPs in biological samples could be compared using chromatographic peak areas from the neutral loss scans. Using precursor ion scans of sn-1 MAG and neutral loss scans of headgroups, major PtdInsPs in cells and tissues were successfully identified with structural information of sn-1 and sn-2 fatty acids, and their relative amounts in different samples were compared.

Aims We aimed to evaluate whether prolapsing leaflet-specific exercise pulmonary hypertension (PHT) exists and to identify the related mechanisms. Methods and results Resting and bicycle exercise transthoracic echocardiography was performed in 35 consecutive patients (aged 56 ± 11, 69% men) with asymptomatic, moderate-to-severe, and degenerative mitral regurgitation (MR). The patients were classified into two groups according to the prolapsing leaflet: an anterior mitral leaflet (AML) group ( n = 17) and a posterior mitral leaflet (PML) group ( n = 18). At rest, the MR severity and systolic pulmonary artery pressure (SPAP) were similar between the two groups. During exercise, changes in the regurgitant volume (ΔRV) were markedly increased in the PML group compared with the AML group (23.9 ± 13.6 vs. 13.9 ± 10.5 mL, P = 0.022). Moreover, exercise-induced changes in SPAP (ΔSPAP) were more significant in the PML group (35.8 ± 10.7 vs. 26.7 ± 8.7 mmHg, P = 0.009). Further analysis of the resting left atrial (LA) characteristics revealed decreased LA reservoir function and a more ellipsoid left atrium in the PML group. Multiple linear regression analysis revealed that ΔRV was an independent determinant of ΔSPAP ( β = 0.34, P = 0.013) after adjustment for other confounding factors. Conclusion PML prolapse is associated with a greater increase in exercise-induced SPAP, and the prominent increase in MR severity in PML prolapse is thought to be the main mechanism responsible for this increase. The current study suggests the need for more frequent follow-up of patients with PML prolapse.