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To evaluate the effect of β-blockers according to heart rate in patients with acute myocardial infarction (AMI) without heart failure (HF) or left ventricular systolic dysfunction (LVSD).We enrolled patients with AMI without HF or LVSD between June 1, 2003, and February 28, 2015, from Seoul National University Hospital Acute Myocardial Infarction Registry. Patients were categorized according to discharge heart rate recorded on electrocardiographs and β-blocker use. Low heart rate was defined as less than 75 beats/min. The primary end point was 5-year all-cause mortality according to discharge heart rate and β-blocker use.Of 2271 patients, 1696 (74.7%) received β-blockers and 1427 (62.8%) had low heart rates. At 5 years after discharge, 205 patients died. Overall, patients with low heart rates (P.001) and those with β-blocker treatment had lower mortality (P.001). After adjustment for covariates, β-blocker use was associated with 48% reduced risk for 5-year mortality in patients with high heart rates (hazard ratio, 0.52; 95% CI, 0.35-0.76), but not in those with low heart rates (P=.97). In an inverse-probability treatment-weighted cohort, β-blocker use was also associated with improved mortality in those with a high heart rate. Findings were similar for 5-year cardiovascular mortality.Among survivors with AMI without HF or LVSD, β-blocker use was associated with reduced 5-year all-cause mortality in patients who have high heart rates, but not in those with low heart rates.

This study aimed to investigate clinical and coronary computed tomographic angiography (CTA) characteristics of lesions that progressed to chronic total occlusion (CTO).CTO is one of the most common reasons for referral to coronary artery bypass surgery. Prediction and adequate early management for future CTO lesions may be beneficial.The study evaluated patients with at least 1 vessel with a diameter stenosis of ≥70% on invasive coronary angiography (ICA) who underwent previous coronary CTA12 months before ICA, from 2006 to 2015. The study compared the baseline clinical and coronary CTA characteristics of the patients with future CTO lesions with those of the patients with future non-CTO lesions (patient-level analysis) and compared coronary CTA findings between the future CTO lesion with the most stenotic non-CTO lesion in each CTO patient (lesion-level analysis).Among the 216 patients, 32 (14.8%) had a CTO lesion on ICA. In patient-level analysis, no significant differences in clinical characteristics were found, whereas the coronary CTA culprit lesions of the CTO group had a smaller minimal lumen diameter (MLD) with more adverse plaque characteristics. In lesion-level analysis, future CTO lesions had a smaller MLD, a smaller reference segment diameter (RD), and longer lesion length. These lesions were more likely to be noncalcified plaques with a noneccentric cross-sectional distribution, and had a higher remodeling index, lower mean plaque attenuation (MPA), and more napkin-ring signs. In multivariate analysis and receiver-operating characteristic curve analysis, MLD of 2.0 mm, RD of 3.2 mm, and MPA of 50 Hounsfield units were independent predictors of future CTO lesions. The risk of CTO development in lesions with triple risk factors was 14-fold higher than that of the lesions with no risk factors.Lesions that progressed to CTO had more severe baseline coronary CTA features than non-CTO lesions. A small MLD, small RD, and low MPA were independent predictors of progression to CTO.

To test the hypothesis that the impact of diabetes mellitus on clinical outcomes after acute myocardial infarction (AMI) can vary by age.A total of 12,600 AMI patients from the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) between November 2011 and December 2015 was classified into young (n = 3,590 [29%]) and old (n = 9,010 [72%]). Those less than 55 years of age were considered young. We performed comparisons of baseline characteristics, in-hospital treatments, and 3-year clinical outcomes between patients with and without diabetes after stratification according to age group.The prevalence of diabetes mellitus was 27% in the young AMI group. In the multivariable adjusted model of the entire cohort, diabetes mellitus was associated strongly with 3-year all-cause mortality (13% vs. 6.8%; adjusted hazard ratio [HR], 1.318; 95% confidence interval [CI], 1.138-1.526; P0.001). When the entire cohort was subdivided into two age groups, young diabetic patients showed a 107% higher mortality rate than those without diabetes (adjusted HR, 2.07 [1.15-3.72];P = 0.015). Meanwhile, old diabetic patients had a 25% higher risk of mortality than non-diabetic patients (adjusted HR, 1.25 [1.08-1.46];P = 0.004). The interaction of diabetes with age was significant (adjusted P for interaction = 0.008).Diabetes mellitus is not uncommon in younger AMI patients, and the relative risk of 3-year mortality is significantly higher in young patients than in older counterparts. More aggressive treatments are needed to prevent future cardiovascular events in younger patients after AMI.

Background and Objective: Intra-operative X-ray angiography, the current standard method for visualizing and diagnosing cardiovascular disease, is limited in its ability to provide essential 3D information. These limitations are disadvantages in treating patients. For example, it is a cause of lowering the success rate of interventional procedures. Here, we propose a novel 2D-3D non-rigid registration method to understand vascular geometry during percutaneous coronary intervention. Methods: The proposed method uses the local bijection pair distance as a cost function to minimize the effect of inconsistencies from center-line extraction. Moreover, novel cage-based 3D deformation and multi-threaded particle swarm optimization are utilized to implement real-time registration. We evaluated the proposed method for 154 examinations from 10 anonymous patients by coverage percentage, comparing the average distance of the 2D extracted center-line with that of the registered 3D center-line. Results: The proposed 2D-3D non-rigid registration method achieved an average distance of 1.98 mm with a 0.54 s computation time. Additionally, in aiming to reduce the uncertainty of XA images, we used the proposed method to retrospectively visualize the connections between 2D vascular segments and the distal part of occlusions. Conclusions: Ultimately, the proposed 2D/3D non-rigid registration method can successfully register the 3D center-line of coronary arteries with corresponding 2D XA images, and is computationally sufficient for online usage. Therefore, this method can improve the success rate of such procedures as a percutaneous coronary intervention and provide the information necessary to diagnose cardiovascular diseases better.

The authors performed this analysis to examine whether the enhanced clopidogrel responsiveness in current smokers is maintained after adjusting the influence of hemoglobin on VerifyNow P2Y12 reaction unit (PRU).PRU is consistently reported to be lower in current smokers. However, PRU has a significant inverse relationship with hemoglobin level, and smokers have higher hemoglobin levels. Because the association between PRU and hemoglobin is likely to be an in vitro phenomenon, we hypothesized that the observed difference in PRU between nonsmokers and current smokers is the result of confounding effect of hemoglobin rather than true difference in platelet reactivity.Three cohorts were combined for the analysis (SNUBH [Seoul National University Bundang Hospital], n = 459; CILON-T [influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation], n = 715; HOST-ASSURE [Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfetyeffectiveneSS of drug-elUting stentsantiplatelet REgimen], n = 1,357). The final combined cohort consisted of 1,314 patients who underwent percutaneous coronary intervention and had VerifyNow P2Y12 assay results. General linear model (analysis of covariance) was used to control the effect of hemoglobin on PRU.A significant inverse correlation was observed between PRU and hemoglobin (r = -0.389; p 0.001). Current smokers showed a significantly higher hemoglobin level (13.5 ± 1.6 vs. 14.4 ± 1.5; p 0.001) but lower PRU level (230.1 ± 90.7 vs. 212.2 ± 83.6; p 0.001). After adjusting the influence of hemoglobin on PRU, there was no difference in PRU between nonsmokers and current smokers (224.1 [95% confidence interval: 218.7 to 229.5] vs. 225.3 [95% confidence interval: 217.2 to 233.3]; p = 0.813).The observed difference in PRU between nonsmokers and current smokers is largely attributable to the difference in hemoglobin level. Enhanced clopidogrel responsiveness in cigarette smokers is not confirmed in this study and the concept of the smokers' paradox needs further validation.

Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 in niche-mediated LT-HSC maintenance. We found that CD82/KAI1 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82(-/-) mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-β1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC(+) BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche.

Recent evidence suggests that the gut microbiome plays a role in the development of coronary artery diseases. In this study, we investigated whether microbial signature is detected in the coronary thrombus and how its composition is related with the oral and gut microbiome of the patients with ST

For the treatment of chronic total occlusion (CTO), the efficacy and safety of the everolimus-eluting stent (EES) remain less well defined. Also, there are limited data for the predictors of outcome after CTO intervention. The purpose of this study was to compare clinical outcomes of the EES with the first-generation drug-eluting stent (DES) in CTO intervention and to investigate the predictors of clinical outcome. The Korean National Registry of CTO Intervention is a retrospective cohort of 26 centers from the past 5 years. The primary end point was major adverse cardiovascular events (MACE) defined as a composite of cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Of the 1,754 all-comer patients, 1,509 patients (EES 311, sirolimus-eluting stent [SES] 642, paclitaxel-eluting stent 556) were finally analyzed after excluding 245 patients (mixed DESs in 46 and follow-up loss in 199). In the inverse probability weighting-adjusted population, the 1-year MACE rate of the EES was comparable with that of the SES (5.8% vs 3.4%, p = 0.796) and the paclitaxel-eluting stent (5.8% vs 6.9%, p = 0.740). Each component of MACE was also comparable among the 3 stents. Importantly, the independent predictors of MACE were diabetes mellitus, previous congestive heart failure, and left circumflex CTO. In conclusion, for the first time in the largest CTO cohort, the EES showed good 1-year clinical outcomes that were comparable with the SES. Independent predictors of MACE after CTO intervention were clinical factors (diabetes and congestive heart failure) and lesion location.

Background The rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation. Methods/design The SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment. Discussion The SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM. Trial registration National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643).

Purpose To examine the addition of genetic or pharmacologic inhibition of hypoxia-inducible factor 1α (HIF-1α) to radiation therapy (RT) and vascular endothelial growth factor A (VEGF-A) inhibition (ie trimodality therapy) for soft-tissue sarcoma. Methods and Materials Hypoxia-inducible factor 1α was inhibited using short hairpin RNA or low metronomic doses of doxorubicin, which blocks HIF-1α binding to DNA. Trimodality therapy was examined in a mouse xenograft model and a genetically engineered mouse model of sarcoma, as well as in vitro in tumor endothelial cells (ECs) and 4 sarcoma cell lines. Results In both mouse models, any monotherapy or bimodality therapy resulted in tumor growth beyond 250 mm 3 within the 12-day treatment period, but trimodality therapy with RT, VEGF-A inhibition, and HIF-1α inhibition kept tumors at 3 for up to 30 days. Trimodality therapy on tumors reduced HIF-1α activity as measured by expression of nuclear HIF-1α by 87% to 95% compared with RT alone, and cytoplasmic carbonic anhydrase 9 by 79% to 82%. Trimodality therapy also increased EC-specific apoptosis 2- to 4-fold more than RT alone and reduced microvessel density by 75% to 82%. When tumor ECs were treated in vitro with trimodality therapy under hypoxia, there were significant decreases in proliferation and colony formation and increases in DNA damage (as measured by Comet assay and γH2AX expression) and apoptosis (as measured by cleaved caspase 3 expression). Trimodality therapy had much less pronounced effects when 4 sarcoma cell lines were examined in these same assays. Conclusions Inhibition of HIF-1α is highly effective when combined with RT and VEGF-A inhibition in blocking sarcoma growth by maximizing DNA damage and apoptosis in tumor ECs, leading to loss of tumor vasculature.

This study was aimed at investigating the long-term safety and efficacy of the Absorb Bioresorbable Vascular ScaffoldTM (BVS), drug-eluting stents (DES), and bare metal stents (BMS). Randomized controlled trials that compared 2 or more coronary stents or scaffolds and reported long-term clinical

Background Protection of distal embolization by balloon occlusion and thrombus aspiration has not improved microvascular circulation nor decreased myocardial injury during primary percutaneous intervention (PCI) for ST-elevation myocardial infarction (STEMI) in randomized trials. In a prospective randomized trial, we investigated the mechanism of the poor effect of distal protection and thrombus aspiration (DP–TA) in 126 patients with STEMI. Methods Patients with first-diagnosed STEMI were randomly assigned to DP–TA pretreatment or conventional PCI (c-PCI). Primary endpoint was reduced left ventricular end-diastolic volume (LVEDV) measured by MRI at post-PCI and 6months after PCI. Secondary end points were infarct ratio (infarct size to entire LV size) by delayed enhancement (DE), area at risk (AAR) ratio (AAR to entire LV size) by T2 high signal, microvascular occlusion index (MVO) ratio (MVO to entire LV size) by DE, and myocardial salvage index (MSI: (AAR−infarct size)∗100/AAR) using cardiac magnetic resonance imaging (MRI) within 3days after PCI. Results Baseline characteristics of the patients including cardiovascular risk factors and lesion characteristics were similar between the two groups. DT–PA failed to improve LV remodeling at 6months (LVEDV 140±39 vs 133±37 in c-PCI group, p=0.418). Infarct ratio, AAR ratio and MSI were not statistically different between DP–TA group and c-PCI group. However, MVO ratio was significantly larger in DP–TA group than in c-PCI group (2.4±2.7 vs 1.1±1.9, p=0.045). Conclusion DP–TA was potentially hazardous in primary PCI for STEMI by increasing MVO. DP–TA should not be used in STEMI.

Atherosclerosis is an inflammatory process, and inflammatory biomarkers have been identified as useful predictors of clinical outcomes. The prognostic value of leukocyte count in patients with ST-segment elevation myocardial infarctions who undergo primary percutaneous coronary intervention is not clearly defined. In 325 patients with STEMIs treated with primary percutaneous coronary intervention, total and differential leukocyte counts, once at admission and 24 hours thereafter, were measured. The neutrophil/lymphocyte ratio (NLR) was calculated as the ratio of neutrophil count to lymphocyte count. The primary end point was all-cause death. Twenty-five patients (7.7%) died during follow-up (median 1,092 days, interquartile range 632 to 1,464). The total leukocyte count decreased (from 11,853 ± 3,946/μl to 11,245 ± 3,979/μl, p = 0.004) from baseline to 24 hours after admission. Patients who died had higher neutrophil counts (9,887 ± 5,417/μl vs 8,399 ± 3,639/μl, p = 0.061), lower lymphocyte counts (1,566 ± 786/μl vs 1,899 ± 770/μl, p = 0.039), and higher NLRs (8.58 ± 7.41 vs 5.51 ± 4.20, p = 0.001) at 24 hours after admission. Baseline leukocyte profile was not associated with outcomes. The best cut-off value of 24-hour NLR to predict mortality was 5.44 (area under the curve 0.72, 95% confidence interval [CI] 0.52 to 0.82). In multivariate analysis, a 24-hour NLR ≥5.44 was an independent predictor of mortality (hazard ratio 3.12, 95% CI 1.14 to 8.55), along with chronic kidney disease (hazard ratio 4.23, 95% CI 1.62 to 11.1) and the left ventricular ejection fraction (hazard ratio 0.94 for a 3% increase, 95% CI 0.76 to 0.93). In conclusion, NLR at 24 hours after admission can be used for risk stratification in patients with STEMIs who undergo primary PCI. Patients with STEMIs with 24-hour NLRs ≥5.44 are at increased risk for mortality and should receive more intensive treatment.

Ex vivo expansion of human circulating angiogenic cells is a major challenge in autologous cell therapy for ischemic diseases. Here, we demonstrate that hematosphere-derived CXCR4(+)CD31(+) myeloid cells using peripheral blood possess robust proangiogenic capacity such as formation of vessel-like structures and tip cell-like morphology in Matrigel. We also found that CD31 positive myeloid cells are principal cellular component of hematospheres by magnetic cell sorting. Flow cytometry analysis showed that fresh peripheral blood contained 40.3 ± 15.2% of CXCR4(+)CD31(+) myeloid cells, but at day 5 of hematosphere culture, most of myeloid cells were CXCR4(+)CD31(+) by 86.9 ± 5.4%. Hematosphere culture significantly increased the production of angiogenic niche-supporting cytokines. Moreover, CD31-homophilic interaction and VEGF-VEGF receptor loop signaling were essential for sphere formation and acquisition of angiogenic capacity in hematospheres. Matrigel plug and ischemic hindlimb model provide in vivo evidence that hematosphere-derived myeloid cells have highly vasculogenic capacities, participate in new and mature vessel formation, and exert therapeutic effects on ischemic hindlimb. In conclusion, our strategy for ex vivo expansion of human CXCR4(+)CD31(+) angiogenic cells using hematospheres provides an autologous therapeutic cell source for ischemic diseases and a new model for investigating the microenvironment of angiogenesis.

We investigated whether additional platelet inhibition with a glycoprotein IIb/IIIa inhibitor would be beneficial in reducing the risk of periprocedural myocardial infarction (PMI) in diabetic patients with high residual platelet reactivity (HPR). Patients with diabetes mellitus were administered aspirin and clopidogrel at a 300-mg loading dose 1 day before the procedure, and the VerifyNow P2Y(12) assay was performed just before percutaneous coronary intervention. Patients with HPR, defined as a P2Y(12) reaction unit of ≥270 were randomly assigned to group A or control group C1. Patients without HPR were assigned to control group C2. Conventional anticoagulation with heparin was given to groups C1 and C2, and group A received additional abciximab treatment. Clinically relevant PMI was defined as any elevation in the biomarkers creatine kinase-MB isoenzyme and cardiac troponin I >3 times the upper normal limit measured 8, 16, or 24 hours after percutaneous coronary intervention. Of the patients, 47 and 51 were assigned to group A and C1; the clinical and procedural characteristics in the 2 groups were balanced. Of the 47 patients in group A and 51 patients in group C1, 9 (19%) and 9 (18%), respectively, experienced a PMI event according to the creatine kinase-MB cutoff (p = 1.00), and 27 in group A (57%) and 29 in group C1 (57%) experienced a PMI event according to the troponin I cutoff (p = 1.00). Five minor bleeding events, including small and localized hematomas, were observed immediately after the procedure (4 in group A and 1 in group C1). Only 1 major bleeding event, retroperitoneal hemorrhage, was observed in group A. The patients in group C2 had a PMI event rate (50% of 32 patients, p = 1.00) similar to that of group C1. In conclusion, additional platelet inhibition using a tailored approach and a point-of-care assay did not improve the periprocedural outcome in diabetic patients with HPR.

Objectives: This study sought to investigate the extent of and factors related to lumen and vessel area change in coronary arteries after total occlusion (TO) recanalization.Background: TO of a cor...

This study evaluated the risk factors of postprocedure cardiac troponin I (cTnI) increase and its effects on repeat revascularization and on overall clinical outcomes in patients with angina and normal preprocedural cTnI levels who underwent successful drug-eluting stent implantation. Postprocedure cTnI increase (≥0.5 ng/ml) was observed in 207 of 802 patients (25.8%). Patients with cTnI increase had more extensive coronary disease than patients without cTnI increase, which necessitated for the cTnI group more multilesion interventions and a longer total stent length. In multivariate analysis, total stent length (odds ratio 1.02, 1.01 to 1.03, p = 0.001) and use of glycoprotein IIb/IIIa inhibitors (3.07, 1.54 to 6.11, p0.001) were identified as independent predictors of cTnI increase. During a median follow-up of 42 months, however, there were no significant between-group differences in Kaplan-Meier estimates of any repeat revascularization (24.8% vs 18.4%, hazard ratio 1.085, 0.723 to 1.627, p = 0.694) and major adverse cardiovascular events (27.0% vs 22.4%, 1.022, 0.703 to 1.485, p = 0.911). In conclusion, patients with postprocedure cTnI increase had more severe baseline coronary disease and received more complex interventional procedures. However, cTnI increase after successful drug-eluting stent implantation was not associated with an increased risk of repeat revascularization or of other adverse events.

Patient initials or identifier number LCG ### Relevant clinical history and physical exam This 74 year-old male visited SNUBH with progressive claudication (both legs, left leg more severe) since 5 years ago. He was admitted for percutaneous transluminal angioplasty (PTA) for peripheral

This prospective, randomized, double-blind study was performed to compare the incidence of contrast-induced nephropathy (CIN) after the administration of the iso-osmolar contrast medium iodixanol to the low-osmolar contrast medium iopromide during coronary angiography in patients with impaired renal function. Patients with creatinine clearance (CrCl)60 ml/min who underwent coronary angiography and/or percutaneous coronary intervention were randomized to receive either iodixanol (n = 215) or iopromide (n = 205). The primary study end point was the incidence of CIN, which was defined as an absolute increase in serum creatinine (SCr) ≥0.5 mg/dl (44.2 mol/L) or a relative increase ≥25% compared to baseline SCr. The secondary end points were the proportion of patients with increases in SCr ≥0.5 mg/dl, the proportion with SCr increases ≥1.0 mg/dl (88.4 mol/L), and the peak increase in SCr. Age, the presence of diabetes mellitus, mean baseline SCr, CrCl, the use of N-acetylcysteine, contrast volume, and the predicted risk score for CIN were similar in the 2 groups. CIN developed in 39 patients (9.3%); there was no significant difference between the iodixanol and iopromide groups (10.7% and 7.8%, respectively; absolute difference 2.9%, 95% confidence interval -3.1% to 8.9%, p = 0.394). The proportions of patients with SCr increases ≥0.5 mg/dl (6.5% vs 6.3%) and ≥1.0 mg/dl (2.8% vs 2.9%) were similar in the 2 groups. There was a tendency for more patients with relative increases ≥25% (10.2% vs 6.8%) and greater peak increases in SCr (0.037 ± 0.375 vs 0.029 ± 0.351 mg/dl) to be in the iodixanol group, but these differences were not statistically significant. In conclusion, the incidences of CIN after coronary angiography did not significantly differ between the iodixanol and iopromide groups in patients with impaired renal function.

A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133(+) cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.

Aerobic lactate production of which the final step is executed by lactate dehydrogenase (LDH) is one of the typical phenotypes in invasive tumor development. However, detailed mechanism of how LDH links to cancer cell invasiveness remains unclear. This study shows that suppressed LDHB expression plays a critical role in hepatoma cell invasiveness by inducing claudin-1 (Cln-1), a tight junction protein, via mitochondrial respiratory defects. First, we found that all the SNU human hepatoma cells with increased glycolytic lactate production have the defective mitochondrial respiratory activity and the Cln-1-mediated high invasive activity. Similar results were also obtained with human hepatocellular carcinoma tissues. Unexpectedly, the increased lactate production was due to LDH isozyme shifts to LDH5 by LDHB down-expression rather than LDHA induction, implying the importance of LDHB modulation. Second, LDHB knockdown did not only trigger Cln-1 induction at the transcriptional level, but also induced respiratory impairment. Interestingly, most respiratory inhibitors except KCN induced Cln-1 expression although complex I inhibition by rotenone was most effective on Cln-1 induction. Respiratory defect-mediated Cln-1 induction was further confirmed by knockdown of NDUFA9, one of complex I subunits. Finally, ectopic expression of LDHB attenuated the invasiveness of both SNU 354 and 449 cells whereas LDHB knockdown significantly augmented the invasiveness of Chang cells with Cln-1induction. The increased invasive activity by LDHB modulation was clearly reversed by knocking-down Cln-1. Taken together, our results suggest that LDHB suppression plays an important role in triggering or maintaining the mitochondrial defects and then contributes to cancer cell invasiveness by inducing Cln-1 protein.

Claudins are identified as members of the tetraspanin family of proteins, which are integral to the structure and function of tight junction. Recent studies showed an increase in expression of claudins during tumorigenesis, which is associated with loss of cell-cell contact, dedifferentiation, and invasiveness. However, the molecular basis for the causal relationship between claudin expression and cancer progression is not fully understood yet. In this study, we show that claudin-1 plays a causal role in the acquisition of invasive capacity in human liver cells and that c-Abl-protein kinase Cdelta (PKCdelta) signaling is critical for the malignant progression induced by claudin-1. Overexpression of claudin-1 clearly induced expression of matrix metalloproteinase-2 (MMP-2) and cell invasion and migration in normal liver cells as well as in non-invasive human hepatocellular carcinoma (HCC) cells. Conversely, small interfering RNA targeting of claudin-1 in invasive HCC cells completely inhibited cell invasion. Both c-Abl and PKCdelta are found to be activated in normal liver cell line clones that stably overexpress claudin-1. Inhibition of either c-Abl or PKCdelta alone clearly attenuated MMP-2 activation and impeded cell invasion and migration in both human HCC and normal liver cells expressing claudin-1. These results indicate that claudin-1 is both necessary and sufficient to induce invasive behavior in human liver cells and that activation of c-Abl-PKCdelta signaling pathway is critically required for the claudin-1-induced acquisition of the malignant phenotype. The present observations raise the possibility of exploiting claudin-1 as a potential biomarker for the spread of liver cancer and might provide pivotal points for therapeutic intervention in HCC.

Background Statins are known to have pleiotropic effects. We examined the effect and mechanism of simvastatin therapy on EPC differentiation and pro-angiogenic cytokines in patients with hypercholesterolemia. Methods Twenty-two hypercholesterolemia patients without any other modifiable cardiovascular risk factors or history of previous lipid-lowering therapy were given simvastatin 20 mg/day for 4 weeks. Blood were drawn pre- and post-therapy. The in vitro effects of simvastatin were studied in a separate set of experiments. Results Simvastatin treatment significantly increased the number of DiI-acLDL, UEA-1 lectin double-positive EPCs and facilitated its appearance. By FACS analysis of freshly isolated PBMNCs, KDR (+) cells increased after simvastatin treatment while there were no differences in CD34, AC133, and VE-cadherin. Also, serum concentration of IL-8 was markedly increased, while VEGF was only slightly increased. In vitro, PBMNCs co-cultured with simvastatin showed increased cluster formation at day 7, and simvastatin facilitated the appearance and networking of EPCs compared with vehicle. Simvastatin-co-cultured PBMNCs showed significantly increased KDR (+) cells, in contrast to CD34, CD31, and VE-Cadherin (+) cells. In response to simvastatin, IL-8 was mainly increased in monocyte culture supernatants while VEGF increased in smooth muscle cell culture supernatants. These cytokines were associated with increased EPC migratory function. The increase in IL-8 secretion from monocytes by statin treatment was associated with phosphorylation and inactivation of GSK3β, which was reversed by constitutive activation of GSK-3β. Conclusion Simvastatin enhances endothelial differentiation of peripheral blood mononuclear cells in patients with hypercholesterolemia and increases pro-angiogenic cytokine IL-8 secretion from monocytes. Our results may explain the pro-angiogenic effects associated with statin therapy and offer further evidence of statin pleiotropism.

Background: Heart failure (HF) has been associated with an increased risk for ischemic stroke. However, there are limited data regarding stroke risk among patients with HF and sinus rhythm. This population-based study estimated the risk of stroke and thromboembolism for patients with HF in the

Hyponatremia is a well-known risk factor for worse outcomes in acute heart failure (HF) patients. The impact of hyponatremia on short-term clinical outcomes according to the EF and BNP is unknown. 4,183 patients hospitalized for acute heart failure syndrome (AHFS) in ten regionally-representative

Anomalous origin of right coronary artery (RCA) from left coronary cusp (LCC) has become increasingly recognized with wide use of imaging technologies. However, the clinical relevance and management of this anomaly are ill-defined. Here, we evaluated the long-term clinical outcome of this anomaly.

Over the past 20 years, overall mortality rates for heart failure patients have decreased by 63%, while cardiac mortality in heart failure trials has decreased by almost 70%. This data suggests that historical mortality rates for heart failure patients are not representative of current expectations and may explain the repeated failure of recent heart failure trials to further impact these, already low, mortality rates. Because our analysis was based on mortality rates found in the control arm of published clinical trials, where patients are likely to be receiving contemporary care, the data suggests that optimal use of our evidence based therapies has significantly reduced the risk of death in patients with moderate heart failure.