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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.

Objective Hyponatraemia predicts poor prognosis in patients hospitalised for acute heart failure (AHF). Yet, the association of hyponatraemia improvement with better postdischarge outcome has not been elucidated. Here, we determined the clinical impact of hyponatraemia improvement during hospitalisation on postdischarge outcome in patients admitted for AHF. Design Prospective cohort study. Setting Nation-wide twenty-four academic hospitals in Korea (mean follow-up of 1.7 years after discharge). Patients 2888 patients hospitalised for AHF. Main outcome measures Primary endpoints were composite of death or rehospitalisation due to heart failure. Results Hyponatraemia was present in 575 of total 2888 patients hospitalised for AHF at admission. Hyponatraemia was normalised in 274 patients (47.7%) at discharge. During mean follow-up of 1.7 years total 735 rehospitalisations and 397 deaths were documented. Persistent hyponatraemia during hospitalisation was significantly associated with increased incidence of composite endpoint of death or rehospitalisation in multivariate analysis compared with normonatraemia at admission (HR 1.345, 95% CI 1.075 to 1.683, p=0.010). However, improvement of hyponatraemia during hospitalisation was not significantly associated with lower incidence of composite endpoint of death or rehospitalisation in multivariate analysis (HR 1.084, 95% CI 0.709 to 1.659, p=0.709). Improved hyponatraemia was not associated with better prognosis in analysis with propensity score matching, either (HR 1.111, 95% CI 0.588 to 2.100, p=0.746). Conclusions In patients hospitalised for AHF, hyponatraemia on admission is associated with a worse prognosis compared with normonatraemia, irrespective of whether hyponatraemia improves during hospitalisation.

Background Gestational hypertensive diseases (GHD) and gestational diabetes mellitus (GDM) increase the risk of cardiovascular disease (CVD) later in life. However, the association between gestational medical diseases and familial history of CVD has not been investigated to date. In the present study, we examined the association between familial history of CVD and GHD or GDM via reliable questionnaires in a large cohort of registered nurses. Methods The Korean Nurses’ Survey was conducted through a web-based computer-assisted self-interview, which was developed through consultation with cardiologists, gynecologists, and statisticians. We enrolled a total of 9,989 female registered nurses who reliably answered the questionnaires including family history of premature CVD (FHpCVD), hypertension (FHH), and diabetes mellitus (FHDM) based on their medical knowledge. Either multivariable logistic regression analysis or generalized estimation equation was used to clarify the effect of positive family histories on GHD and GDM in subjects or at each repeated pregnancy in an individual. Results In this survey, 3,695 subjects had at least 1 pregnancy and 8,783 cumulative pregnancies. Among them, 247 interviewees (6.3%) experienced GHD and 120 (3.1%) experienced GDM. In a multivariable analysis adjusted for age, obstetric, and gynecologic variables, age at the first pregnancy over 35 years (adjusted OR 1.61, 95% CI 1.02–2.43) and FHpCVD (adjusted OR 1.60, 95% CI 1.16–2.22) were risk factors for GHD in individuals, whereas FHH was not. FHDM and history of infertility therapy were risk factors for GDM in individuals (adjusted OR 2.68, 95% CI 1.86–3.86; 1.84, 95% CI 1.05–3.23, respectively). In any repeated pregnancies in an individual, age at the current pregnancy and at the first pregnancy, and FHpCVD were risk factors for GHD, while age at the current pregnancy, history of infertility therapy, and FHDM were risk factors for GDM. Conclusions The FHpCVD and FHDM are significantly associated with GHD and GDM, respectively. Meticulous family histories should be obtained, and women with family histories of these conditions should be carefully monitored during pregnancy.

The value of late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) for the prediction of functional recovery after surgical revascularization has been previously established. However, the impact of LGE-MRI on the long-term prognosis after coronary artery bypass grafting (CABG) remains incompletely understood. Therefore, we aimed to evaluate the long-term prognostic value of LGE-MRI, based on the presence or absence of left ventricular (LV) dysfunction, in patients with coronary artery disease undergoing CABG. One hundred forty-six consecutive patients underwent cine- and LGE-MRI before CABG. Adverse cardiac events included cardiac death, nonfatal myocardial infarction, heart failure, and unstable angina. A 3-year landmark analysis of the primary end point was also performed for patients surviving beyond 3 years after CABG. During a median follow-up of 9.4 years, 44 patients (30%) experienced adverse cardiac events. Although a LV ejection fraction50% was associated only with adverse cardiac events at 3 years after CABG, LGE was associated with a worse outcome both at and beyond 3 years after CABG. In the overall study population, LGE presence (adjusted hazard ratio [HR] 2.58; p = 0.027), score (adjusted HR 1.06; p0.001), and extent (adjusted HR 1.08; p0.001) were independent predictors of adverse cardiac events. Moreover, in both the LV ejection fraction50% and ≥50% groups, the LGE extent was an independent predictor of adverse cardiac events. In conclusion, our qualitative and quantitative analyses of LGE-MRI provide long-term prognostic information after surgical revascularization. The LGE extent was a strong predictor of adverse cardiac events, independent of the LV function.

// Changhwan Yoon 1 , Kevin K. Chang 1 , Jun Ho Lee 1 , William D. Tap 2 , Charles P. Hart 3 , M. Celeste Simon 4 and Sam S. Yoon 1 1 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Threshold Pharmaceuticals, South San Francisco, CA, USA 4 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Correspondence to: Sam S. Yoon, email: // Keywords : sarcomas, vascular endothelial growth factor A, hypoxia inducible factor 1α, hypoxia, chemotherapy Received : April 28, 2016 Accepted : June 07, 2016 Published : June 21, 2016 Abstract Vascular endothelial growth factor A (VEGF-A) inhibition with pazopanib is an approved therapy for sarcomas, but likely results in compensatory pathways such as upregulation of hypoxia inducible factor 1α (HIF-1α). In addition, cancer stem-like cells can preferentially reside in hypoxic regions of tumors and be resistant to standard chemotherapies. In this study, we hypothesized that the combination of VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy with evofosfamide would be an effective multimodal strategy. Multimodal therapy was examined in one genetically engineered and two xenograft mouse models of sarcoma. In all three models, multimodal therapy showed greater efficacy than any single agent therapy or bimodality therapy in blocking tumor growth. Even after cessation of therapy, tumors treated with multimodal therapy remained relatively dormant for up to 2 months. Compared to the next best bimodality therapy, multimodal therapy caused 2.8-3.3 fold more DNA damage, 1.5-2.7 fold more overall apoptosis, and 2.3-3.6 fold more endothelial cell-specific apoptosis. Multimodal therapy also decreased microvessel density and HIF-1α activity by 85-90% and 79-89%, respectively, compared to controls. Sarcomas treated with multimodal therapy had 95-96% depletion of CD133(+) cancer stem-like ells compared to control tumors. Sarcoma cells grown as spheroids to enrich for CD133(+) cancer stem-like cells were more sensitive than monolayer cells to multimodal therapy in terms of DNA damage and apoptosis, especially under hypoxic conditions. Thus multimodal therapy of sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy effectively blocks sarcoma growth through inhibition of tumor vasculature and cancer stem-like cells.

Patients with ST-segment elevation myocardial infarction (STEMI) initially presenting to non–percutaneous coronary intervention (PCI)-capable hospitals are frequently transferred to PCI-capable hospitals, and consequently, they have longer total ischemic time and worse outcomes. Potential targets

Coronary artery fistula is a rare congenital anomaly. Most patients with this anomaly are asymptomatic, but some may develop heart failure, myocardial ischemia or arrhythmias. We report a case of a patient who presented with myocardial ischemia secondary to persistent Thebesian veins. Coronary angiography demonstrated a marked capillary blush draining into the left ventricular cavity through multiple microfistulae from the left anterior descending artery, left circumflex artery and right coronary artery. The patient was discharged without chest pain and was medically maintained with a beta-blocker and angiotensin converting enzyme inhibitor.

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...

Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs are able to repopulate the tumor. Compounds that target GSCs might be helpful in overcoming resistance to anticancer treatments in human brain tumors. In this study, we showed that 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, suppressed the maintenance of the GSC population in both a glioma cell line and patient-derived glioma cells. Treatment of GSCs with BHP effectively inhibited sphere formation and suppressed the CD133(+) cell population. Treatment with BHP also suppressed expression of the stemness-regulating transcription factors Sox2, Notch2, and β-catenin in sphere-cultured glioma cells. Treatment of GSCs with BHP significantly suppressed two fundamental characteristics of cancer stem cells: self-renewal and tumorigenicity. BHP treatment dramatically inhibited clone-forming ability at the single-cell level and suppressed in vivo tumor formation. BHP markedly inhibited both phosphoinositide 3-kinase/Akt and Ras/Raf-1/extracellular signal-regulated kinase signaling, which suggests that one or both of these pathways are involved in BHP-induced suppression of GSCs. In addition, treatment with BHP effectively sensitized GSCs to chemotherapy and radiotherapy. Taken together, these results indicate that BHP targets GSCs and enhances their sensitivity to anticancer treatments and suggest that BHP treatment may be useful for treating brain tumors by eliminating GSCs.

Ki-Chun Yoo1, Chang-Hwan Yoon1, Dongwook Kwon2, Kyung-Hwan Hyun1, Soo Jung Woo1, Rae-Kwon Kim1, Eun-Jung Lim1, Yongjoon Suh1, Min-Jung Kim1, Tae Hyun Yoon2, Su-Jae Lee11Laboratory of Molecular Biochemistry, 2Laboratory of Nanoscale Characterization and Environmental Chemistry, Department of Chemistry, Hanyang University, Seoul, Republic of KoreaBackground: Titanium dioxide (TiO2) has been widely used in many areas, including biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some TiO2 particles have a considerable cytotoxic effect in normal human cells. However, the molecular basis for the cytotoxicity of TiO2 has yet to be defined.Methods and results: In this study, we demonstrated that combined treatment with TiO2 nanoparticles sized less than 100 nm and ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-dependent upregulation of Fas and conformational activation of Bax in normal human cells. Treatment with P25 TiO2 nanoparticles with a hydrodynamic size distribution centered around 70 nm (TiO2P25–70) together with ultraviolet A irradiation-induced caspase-dependent apoptotic cell death, accompanied by transcriptional upregulation of the death receptor, Fas, and conformational activation of Bax. In line with these results, knockdown of either Fas or Bax with specific siRNA significantly inhibited TiO2-induced apoptotic cell death. Moreover, inhibition of reactive oxygen species with an antioxidant, N-acetyl-L-cysteine, clearly suppressed upregulation of Fas, conformational activation of Bax, and subsequent apoptotic cell death in response to combination treatment using TiO2P25–70 and ultraviolet A irradiation.Conclusion: These results indicate that sub-100 nm sized TiO2 treatment under ultraviolet A irradiation induces apoptotic cell death through reactive oxygen species-mediated upregulation of the death receptor, Fas, and activation of the preapoptotic protein, Bax. Elucidating the molecular mechanisms by which nanosized particles induce activation of cell death signaling pathways would be critical for the development of prevention strategies to minimize the cytotoxicity of nanomaterials.Keywords: TiO2, reactive oxygen species, apoptotic cell death, Fas upregulation, Bax activation, mitochondrial membrane potential loss, caspase activation

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.

SummaryFixed-dose combination (FDC) drugs can simplify the medication regimen and potentially improve adherence. However, evidence is lacking about the efficacy and safety of FDC drugs of clopidogrel plus aspirin. Individual data from the three independent MR-CAPCIS trials were pooled and analysed. In those trials, subjects who had been treated with either dual antiplatelet therapy (DAPT) or aspirin alone after drug-eluting stent (DES) implantation were randomly assigned to one-pill or to two-pill DAPT group. Platelet reactivity was measured with VerifyNow-P2Y12 and aspirin point-of-care assays at baseline and eight weeks after treatment. In the present study, primary efficacy endpoint was changes in platelet reactivity unit (PRU) between baseline and eight weeks. A total of 965 subjects were analysed. In prior clopidogrel and aspirin users, PRU was well maintained regardless of switching to either one-pill or two-pill DAPT (ΔPRU=0.4 vs 0.0, p=0.939). In prior aspirin users, PRU was decreased by 73.7 in one-pill DAPT and 77.5 in two-pill DAPT group, with no differences between them (p=0.499). The incidence of high on-treatment platelet reactivity at eight weeks, defined as PRU≥235 in Western people, was 34.8 % in one-pill DAPT group and 37.6 % in two-pill DAPT group (p=0.380), and that defined as PRU ≥275 in Oriental people was 17.7 vs 21.7 % (p=0.129). Independent predictors of high platelet reactivity on clopidogrel were female gender, increasing age, and diabetes. Study drugs were well tolerated. In conclusion, FDC one-pill DAPT showed similar efficacy to two-pill DAPT in terms of platelet reactivity in patients receiving DES in Korea.

Objectives: We investigated the risk factors for contrast-induced acute kidney injury (CIAKI) after coronary angiography (CAG) in patients with acute heart failure (AHF), especially with regard to the volume status. Background: Heart failure is a well-known risk factor for CIAKI after CAG. In HF patients, renal perfusion decreases with systemic congestion. Thus, the standard prevention strategy with isotonic solution infusion may be inappropriate while decongestion may be beneficiary in AHF patients undergoing CAG. Deviation from dry body weight suggests imbalanced volume status. Methods: A total of 199 AHF patients who underwent CAG were eligible for the analysis. Absolute deviation of body weight (

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

Comparisons of protocatechuic acid (PA) and caffeic acid (CA) adsorption isotherm on C18 column and competitive adsorption of the two compounds were investigated. By linear and nonlinear regression analysis, the experimental parameters in the equilibrium isotherms were estimated. Adsorption equilibrium data of the two compounds were investigated using six different models including linear, Langmuir, Freundlich, Langmuir-Freundlich, competitive Langmuir and Quadratic. In the moderate range of concentrations, the competitive Langmuir isotherm proved to be the best model for these experimental data. The regression coefficients of the competitive Langmuir adsorption isotherms were 0.9860 for PA and 0.9898 for CA, respectively. The coefficients obtained for the six isotherm models confirmed the superiority of the competitive Langmuir isotherm for analyzing the competitive adsorption data of solutes.

Brain tumors frequently recur or progress as focal masses after treatment with ionizing radiation. However, the mechanisms underlying the repopulation of tumor cells after radiation have remained unclear. In this study, we show that cellular signaling from Abelson murine leukemia viral oncogene homolog (Abl) to protein kinase Cδ (PKCδ) is crucial for fractionated-radiation-induced expansion of glioma-initiating cell populations and acquisition of resistance to anticancer treatments. Treatment of human glioma cells with fractionated radiation increased Abl and PKCδ activity, expanded the CD133-positive (CD133+) cell population that possesses tumor-initiating potential and induced expression of glioma stem cell markers and self-renewal-related proteins. Moreover, cells treated with fractionated radiation were resistant to anticancer treatments. Small interfering RNA (siRNA)-mediated knockdown of PKCδ expression blocked fractionated-radiation-induced CD133+ cell expansion and suppressed expression of glioma stem cell markers and self-renewal-related proteins. It also suppressed resistance of glioma cells to anticancer treatments. Similarly, knockdown of Abl led to a decrease in CD133+ cell populations and restored chemotherapeutic sensitivity. It also attenuated fractionated-radiation-induced PKCδ activation, suggesting that Abl acts upstream of PKCδ. Collectively, these data indicate that fractionated radiation induces an increase in the glioma-initiating cell population, decreases cellular sensitivity to cancer treatment and implicates activation of Abl–PKCδ signaling in both events. These findings provide insights that might prove pivotal in the context of ionising-radiation-based therapeutic interventions for brain tumors.

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.

Background— Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow–derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle. Methods and Results— To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22α)-, and cardiomyocyte (α-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow–derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22α-expressing cells, but not cardiac-committed cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase–expressing cells 2 weeks after injection reduced capillary and arteriole density. Conclusions— This study demonstrates that elimination of bone marrow mononuclear cells reexpressing endothelial nitric oxide synthase particularly induced a deterioration of cardiac function, which indicates a functional contribution of the vascular cell fate decision of human bone marrow–derived mononuclear cells in vivo.

Background: Newly released guideline standardizing a negative margin after breast-conservative surgery (BCS) as “no ink on tumor” by SSO-ASTRO stressed the importance of estimation tumor extent with comprehensive breast imaging studies. To evaluate clinical value of breast magnetic resonance imaging (MRI) in patients with BCS, we compared the degree of correlation between MRI-pathology and ultrasonography (US)-pathology according to subtypes. In addition, we investigated the margin-positive rates and secondary operation rates for margin clearance. Methods: We identified patients with invasive breast cancer who had preoperative breast MRI and ultrasound between 2011 and 2016. We excluded patients having large tumor more than 5cm or multiple tumors or undergoing mastectomy. Patients were classified into 4 subtypes based on the immunohistochemistry; luminal A, luminal B/HER2, HER2, triple-negative breast cancer (TNBC). Lin's concordance correlation coefficient was used to measure the agreement between the MRI or US and tumor extent. Tumor extent was defined as pathologic tumor size including in situ carcinoma. Margin-positivity was assessed based on intraoperative frozen examination. Results: A total 516 patients with single tumor undergoing BCS were included. Means of tumor size were 1.99 ± 0.91 cm by pathologic examination, 1.91 ± 1.01 cm by MRI, and 1.76 ± 0.92 cm by US, respectively. The correlation coefficient of MRI-pathology was significantly higher than that of US-pathology (r=0.6975 vs. 0.6211, P=0.001). A superiority of MRI than US in measuring pathologic extent was only observed in TNBC (r=0.8089 vs. 0.6014, P0.999). Margin positive and re-excision rates according to the subtypes Luminal A (n=302)Luminal B (n=80)HER2 (n=27)TNBC (n=107)P valuePositive margin35 (11.6)14 (17.5)8 (29.6)19 (17.8)0.0382Re-excision14 (4.6)4 (5.0)1 (3.7)5 (4.7)>0.9999 Conclusions: Given a superiority of MRI to US in preoperative assessment, MRI-guided BCS did not reduce the margin-positive rate in TNBC. In the HER2, size correlation of MRI-pathology was very low, and the margin-positive rate was high. Collectively, our findings suggest that accuracy of MRI has limited value to reduce the margin-positive rate. Citation Format: Bae SJ, Ahn SG, Yoon C, Cha YJ, Jeong J. Accuracy of breast magnetic resonance imaging has limited value to reduce the margin-positive rate: A study in relation to the molecular subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-11.

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.

Naturally occurring triterpenoid compounds have long been used as anti-inflammatory, antimalarial, and insecticidal agents. It has become evident that some of the natural or synthetic triterpenoids have promising clinical potential as both a therapeutic and chemopreventive agent for cancer. However, the molecular basis for the antitumor activity of triterpenoid has yet to be defined. In this study, we show that pristimerin, a natural triterpenoid, induces mitochondrial cell death in human cervical cancer cells and that reactive oxygen species (ROS)-dependent activation of both Bax and poly(ADP-ribose) polymerase-1 (PARP-1) is critically required for the mitochondrial dysfunction. We also showed that c-Jun N-terminal kinase (JNK) is involved in ROS-dependent Bax activation. Treatment of pristimerin induced an increase in intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. The PARP-1 was also found to be activated by pristimerin treatment. An antioxidant, N-acetyl-l-cysteine (NAC), inhibited pristimerin-induced JNK activation, Bax relocalization, and PARP-1 activation, as well as mitochondrial cell death. Moreover, inhibition of JNK clearly suppressed conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death but did not affect PARP-1 activation. Inhibition of PARP-1 with 1,5-dihydroxyisoquinoline (DIQ) or with small interfering RNA of PARP-1 significantly attenuated pristimerin-induced mitochondrial membrane potential loss and cell death but did not affect JNK activation and Bax relocalization. These results indicate that the natural triterpenoid pristimerin induces mitochondrial cell death through ROS-dependent activation of both Bax and PARP-1 in human cervical cancer cells and that JNK is involved in ROS-dependent Bax activation.

OBJECTIVE—Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib. RESEARCH DESIGN AND METHODS—Glucose tolerance and insulin tolerance tests were done after daily intraperitoneal injection of 25 mg/kg imatinib into db/db and C57BL/6 mice for 4 weeks. Insulin signaling and endoplasmic reticulum stress responses were studied by Western blotting. β-Cell mass and apoptotic β-cell number were determined by combined terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining and insulin immunohistochemistry. The in vitro effect of imatinib was studied using HepG2 cells. RESULTS—Imatinib induced remission of diabetes in db/db mice and amelioration of insulin resistance. Expression of endoplasmic reticulum stress markers in the liver and adipose tissues of db/db mice, such as phospho-PERK, phospho-eIF2α, TRB3, CHOP, and phospho–c-Jun NH2-terminal kinase, was reduced by imatinib. Insulin receptor substrate-1 tyrosine phosphorylation and Akt phosphorylation after insulin administration were improved by imatinib. Serum aminotransferase levels and hepatic triglyceride contents were decreased by imatinib. Pancreatic β-cell mass was increased by imatinib, accompanied by decreased TUNEL+ β-cell and increased BrdU+ β-cell numbers. Imatinib attenuated endoplasmic reticulum stress in hepatoma cells in vitro. CONCLUSIONS—Imatinib ameliorated endoplasmic reticulum stress and induced remission of diabetes in db/db mice. Imatinib or related compounds could be used as therapeutic agents against type 2 diabetes and metabolic syndrome.

Circulating blood–derived vasculogenic cells improve neovascularization of ischemic tissue by a broad repertoire of potential therapeutic actions. Whereas initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. The question remains to what extent a physical incorporation is contributing to the beneficial effects of cell therapy. By using the inducible suicide gene thymidine kinase to deplete transplanted cells, we determined the contribution of physical incorporation in 3 animal models. After acute myocardial infarction, depletion of cells 14 days after infusion resulted in a reduction of capillary density and a substantial deterioration of heart function. Likewise, neovascularization of Matrigel plugs and ischemic limbs was significantly suppressed when infused cells were depleted 7 days after infusion. Induction of cell death in the previously transplanted cells reduced perfusion and led to vascular leakage as evidenced by Evans blue extravasation. These results indicate that physical incorporation and persistence of cells contribute to cell-mediated improvement of neovascularization and cardiac function. Long-term paracrine activities and/or cell intrinsic mechanisms may have contributed to the maintenance of functional improvement.

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.

E-selectin plays critical roles in tethering leukocytes to endothelial cells (ECs). We studied the role of E-selectin in endothelial progenitor cell (EPC) homing and vasculogenesis. After ischemia, the expression of E-selectin on ECs peaked 6 to 12 hours and returned to baseline at 24 hours, whereas the level of soluble E-selectin (sE-selectin) in serum increased over 24 hours and remained high at day 7. Mouse bone marrow–derived EPCs expressed not only E-selectin but also its ligand. Homing of circulating EPCs to ischemic limb was significantly impaired in E-selectin knock-out mice, as well as wild-type mice pretreated with blocking antibody against E-selectin, which was rescued by local sE-selectin injection. Mechanism for this is that sE-selectin stimulated not only ECs to express ICAM-1, but also EPCs to secrete interleukin-8 (IL-8), leading to enhanced migration and incorporation to ECs capillary formation. In therapeutic aspect, local treatment with sE-selectin enhanced efficacy of EPC transplantation for vasculogenesis and salvage of ischemic limb. Conversely, when E-selectin was knocked down by E-selectin small interfering RNA, blood flow recovery after EPC transplantation was significantly impaired. But this impaired vasculogenesis was rescued by sE-selectin. In conclusion, these data demonstrate E-selectin is a pivotal molecule for EPCs' homing to ischemic limb and vasculogenesis.

Trafficking of transplanted endothelial progenitor cells (EPCs) to ischemic tissue is enhanced by stromal-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF). However, it has not been studied how these cytokines modulate the local milieu to entrap EPCs. This study was performed to elucidate a molecular pathway of trafficking EPCs through Akt and to test its application as an adjuvant modality to increase EPC homing. In a mouse hind limb ischemia model, systemically administered 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-labeled mouse EPCs showed three stages of homing to ischemic limb: adhesion to endothelial cells (ECs), incorporation to capillary, and transendothelial migration into extravascular space. As an underlying mechanism to control adhesion of EPCs to ECs, we found that Akt was activated in ECs of ischemic muscle by ischemia-induced VEGF and SDF-1. In vitro and in vivo experiments using adenoviral vector for constitutively active or dominant-negative Akt genes showed that activated Akt enhanced intercellular adhesion molecule 1 (ICAM-1) expression on ECs. Akt activation in ECs also enhanced EPC incorporation to ECs and transendothelial migration in vitro experiments. Activated Akt was sufficient for induction of EPC homing even in normal hind limb, where VEGF or SDF-1 was not increased. Finally, local Akt gene transfer to ischemic limb significantly enhanced homing of systemically administered EPCs, new vessel formation, blood flow recovery, and tissue healing. Akt plays a key role in EPC homing to ischemic limb by controlling ICAM-1 and transendothelial migration. Modulation of Akt in the target tissue may be an adjunctive measure to enhance homing of systemically administered stem cells, suggesting a possibility of cell-and-gene hybrid therapy. Disclosure of potential conflicts of interest is found at the end of this article.

Platelets play a critical role in hemostasis and also have ability to promote angiogenesis and tissue repair by secreting of numerous cytokine and making angiogenic condition. We investigated whether autologous ‘activated platelet supernatant (APS)’ has effect on enhancing pro-angiogenic potential of peripheral blood stem cells (PBSC) for stem cell-based therapy for ischemic diseases. Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (mobPBSC) were isolated from healthy volunteers, while APS was collected from platelet rich plasma by thrombin activation. mobPBSCs were primed with APS (APS primed mobPBSCs) for 6 hours, and APS primed mobPBSCs characterized their angiogenic ability. For the safety analysis, we estimated the thrombogenicity of platelets in whole blood mixed with APS primed mobPBSCs by expression of glycoprotein IIb and IIIa on platelets. APS had a higher level of various cytokines, such as IL8, IL17, PDGF and VEGF than naïve platelet supernatants. And APS primed mobPBSCs had more expression of angiogenic factors, surface markers (i.e. CD34, CD31, and CXCR4) and integrins (integrin α5, β1 and β2) than Veh primed and Pre primed mobPBSC. Also APS primed mobPBSCs were polarized toward CD14++/CD16+ pro-angiogenic monocytes. And result in adhesion to endothelial cells and fibronectin which represents cell to cell and cell to extracellular matrix adhesion, respectively. The culture supernatant of APS-primed mobPBSCs contained high levels of IL8, IL10, IL17 and TNFα, and augmented proliferation and capillary network formation of HUVEC. In-vivo transplantation of APS-primed mobPBSC into athymic mice ischemic hindlimbs and Matrigel plugs elicited vessel differentiation and tissue repair. In thrombogenicity test, platelet activity increased after mixing whole blood with mobPBSC regardless of the priming agent. However, this was reduced by pretreatment of aspirin, which is an antiplatelet agent prescribed to patients with ischemic diseases. Our data demonstrate that mobPBSCs primed with APS improve angiogenic potential, and that can be adjunctive strategy to enhance the efficiency of stem cell therapy for ischemic diseases.

Lymphatic vessels are involved in the development of various inflammatory disorders, and lymphatic vessel regeneration has been increasingly investigated to develop therapies for lymphatic diseases. Here we report that Podoplanin+/VEGFR-3+/LYVE-1+ is a valid marker for human lymphatic endothelial precursors and the triple-positive cells can be used in lymphatic regeneration. During 5-day culture on an ultra-low attachment surface dish, human peripheral blood mononuclear cells (PBMCs) underwent exponential growth, aggregating into a sphere-like structure and expressing several lymphatic endothelial cell (LEC) markers and lymphangiogenic transcription factors. When dissociated from the aggregate and cultured on a gelatin-coated dish, the cells were attached to the surface. The attached cells were triple positive for LEC markers e.g. Podoplanin, LYVE-1, VEGFR-3. Furthermore, seeded in Matrigel with LECs, the 5-day aggregate-derived cells were incorporated into lymphatic endothelial network. The 5-day aggregates were largely positive for CD14+, a monocyte marker. The CD14+ population was sorted into Podoplanin-positive and negative group for further characterization. Notably, CD14+/Podoplanin+ cells showed increased expression of lymphangiogenic molecules (e.g. VEGFR-3, LYVE-1) both at the genetic and protein levels. Also, CD14+/Podoplanin+ cells secreted higher levels of lymphangiogenic cytokines (VEGF, HGF, PDGF-BB). ELISA results showed that CD14+/Podoplanin+ cells produced more lymphangiogenic cytokines than CD14+/Podoplanin- cells. Local injection of monocyte aggregates significantly increased lymphatic neovascularization and facilitated healing of the skin wound model of nude mice, with CD14+/Podoplanin+ group showing the most dramatic result. Our data suggests that Podoplanin-positive monocytes can be transdifferentiated into lymphatic endothelial precursor cells, and cells with triple positivity for Podoplanin, VEGFR-3, and LYVE-1 can be a promising cell source for therapy against human lymphatic vessel diseases.

Despite the benefits of successful percutaneous coronary interventions (PCIs) for chronic total occlusion (CTO) lesions, PCIs of CTO lesions still carry a high rate of adverse events, including in-stent restenosis (ISR). Because previous reports have not specifically investigated the intravascular ultrasound (IVUS) predictors of ISR in CTO lesions, we focused on these predictors. We included 126 patients who underwent successful PCIs, using drug-eluting stents, and post-PCI IVUS of CTO lesions. Patient and lesion characteristics were analyzed to elucidate the ISR predictors. In each lesion, an average of 1.7 ± 0.7 (mean length, 46.4 ± 20.3 mm) stents were used. At 9 months follow-up, 14 (11%) patients demonstrated ISR, and 8 (6.3%) underwent target lesion revascularization. Multivariate logistic regression analysis showed that the independent predictors of ISR were the post-PCI minimal luminal diameter (MLD) and the stent expansion ratio (SER; minimal stent cross-sectional area (CSA) over the nominal CSA of the implanted stent), measured using quantitative coronary angiography (QCA) and IVUS, respectively. A receiver operating characteristic analysis indicated that the best post-PCI MLD and SER cut-off values for predicting ISR were 2.4 mm (area under the curve [AUC], 0.762; 95% confidence interval (CI), 0.639–0.885) and 70% (AUC, 0.714; 95% CI, 0.577–0.852), respectively. Lesions with post-PCI MLD and SER values less than these threshold values were at a higher risk of ISR, with an odds ratio of 23.3 (95% CI, 2.74–198.08), compared with lesions having larger MLD and SER values. Thus, the potential predictors of ISR, after PCI of CTO lesions, are the post-PCI MLD and SER values. The ISR rate was highest in lesions with a post-PCI MLD ≤2.4 mm and an SER ≤70%.

Clinical trials of agents targeting the vascular endothelial growth factor A (VEGF-A) pathway in gastric adenocarcinoma (GA) suggest that these therapies may have varying efficacy in different races. VEGF-A in serum and/or VEGF receptor 2 (VEGFR-2) in CD31-positive tumor vessels (VEGFR-2/CD31) were measured in 118 Caucasians and 263 Asians who underwent gastric resection at two institutions and correlated with overall survival (OS). Blood was drawn before any treatment. Patients receiving neoadjuvant treatment were excluded from VEGFR-2 analysis. Compared with Asians, Caucasians were older (mean age 66–73 vs 59–62 years), had more proximal tumors, and had more advanced TNM stage. In the VEGF-A cohort, Caucasians had a median VEGF-A level that was 95 % higher than that of Asians and a much higher standard deviation (88 ± 6.206 vs 45 ± 76 pg/ml, p

Plasma level of N-terminal-pro-brain natriuretic peptide (NT-proBNP) is a reliable prognostic factor in patients with heart failure (HF). However, it is unclear how differently the biomarker predicts adverse outcomes in HF with preserved EF (HFpEF) versus HF with reduced EF (HFrEF).From the Korean Heart Failure registry, a prospective multicentre cohort for consecutive patients who were hospitalised for acute HF syndrome, those with available NT-proBNP and LVEF measurements were extracted. Patients with LVEF ≥50% were categorised as the HFpEF group (N=528) and those with ≤40% as the HFrEF group (N=1142).Patients with HFpEF had significantly lower NT-proBNP level than those with HFrEF (median 2723 vs 5644 ng/L, p0.001). Event-free survival did not differ between the two groups either in terms of death from any cause (88.4% vs 86.9%; p=0.471) or the composite of death or HF readmission at 1 year (73.8% vs 70.6%; p=0.225). High levels of NT-proBNP were significantly associated with poor outcomes. However, the relationship was not different among the HFpEF and HFrEF groups (interaction p=0.956 for all-cause death; p=0.351 for the composite of all-cause death or HF hospitalisation).Plasma level of NT-proBNP is the most powerful prognostic factor in both HFpEF and HFrEF. Although patients with HFpEF have lower NT-proBNP levels, the prognosis of a patient with HFpEF expected from a given NT-proBNP level is similar with his/her counterpart with HFrEF.

Background It has not been well evaluated whether late gadolinium enhanced (LGE)-MRI can provide prognostic information in patients who underwent coronary artery bypass graft (CABG) surgery, especially in patients with preserved left ventricular ejection fraction (LVEF). Further, long-term follow-up data after MRI and CABG surgery are not available. The purpose of this study was to evaluate the impact of myocardial viability assessment by LGE-MRI on prognosis in patients who underwent CABG surgery.

Proangiogenic cells (PACs) display surface markers and secrete angiogenic factors similar to those used by myelomonocytic cells, but, unlike myelomonocytic cells, PACs enhance neovascularization activity in experimental ischemic diseases. This study was performed to reveal the differential neovascularization activities of PACs compared with those of myelomonocytic cells. We cultured PACs and CD14(+)-derived macrophages (Macs) for 7 days. Most of the surface markers and cytokines in the two cell types were alike; the exceptions were KDR, β8 integrin, interleukin-8 and monocyte chemotactic protein-1. Unlike Macs, PACs significantly enhanced mesenchymal stem cell (MSC) transmigration. PACs and Macs increased neovascularization activity in an in vitro co-culture of human umbilical vein endothelial cells and MSCs and in an in vivo cotransplantation in Matrigel. However, the use of Macs resulted in inappropriately dilated and leaky vessels, whereas the use of PACs did not. We induced critical hindlimb ischemia in nude mice, and then transplanted PACs, Macs or vehicle into the mice. We obtained laser Doppler perfusion images weekly. At 2 weeks, mice treated with PACs showed significantly enhanced perfusion recovery in contrast to those treated with Macs. After day 7, when cells were depleted using a suicidal gene, viral thymidine kinase, to induce apoptosis of the cells in vivo by ganciclovir administration, we found that the improved perfusion was significantly abrogated in the PAC-treated group, whereas perfusion was not changed in the Mac-treated group. PACs caused an increase in healthy new vessels in in vitro and in vivo models of angiogenesis and enhanced long-term functional neovascularization activity in the hindlimb ischemia model, whereas Macs did not. Nevertheless, the angiogenic potential and long-term functional results for a specific cell type should be validated to confirm effectiveness and safety of the cell type for use in therapeutic angiogenesis procedures.

Purpose To investigate the incidence and risk factors of the no-reflow phenomenon in central retinal artery occlusion (CRAO) patients and to determine its effects on visual and anatomic outcomes. Methods In 102 eyes with CRAO in which arterial recanalization was obtained within 1 week from baseline, fluorescein angiography images obtained at baseline and 1 week were retrospectively reviewed. The no-reflow phenomenon in the retina was defined as macular capillary nonperfusion following arterial recanalization on fluorescein angiographs. We investigated the incidence and risk factors for the no-reflow phenomenon and compared the anatomical and visual outcomes between eyes with and without the phenomenon. Results Among the 102 CRAO eyes with arterial recanalization, 39 exhibited the no-reflow phenomenon, resulting in an incidence of 38.2%. The incidence among the eyes with treatment-induced and spontaneous recanalization was 43.4% and 15.8%, respectively, and it increased with the CRAO stage. CRAO stage and increased central macular thickness were risk factors for the phenomenon, with an odds ratio of 4.47 [95% confidence interval (CI), 1.19-16.8; P = 0.027] and 1.69 (95% CI, 1.12-2.55; P = 0.012) per 100-μm increase, respectively. The visual outcome was significantly poorer and retinal atrophy and photoreceptor disruption was greater in eyes with the no-reflow phenomenon than in those without. Conclusions The no-reflow phenomenon may occur after arterial recanalization in approximately one-third of CRAO patients and can affect anatomical and visual outcomes. This phenomenon may provide an additional explanation regarding the permanent retinal damage and vision loss in eyes with CRAO.

We sought to evaluate the effect of cigarette smoking on long-term outcomes after successful percutaneous coronary intervention for chronic total occlusion (CTO) lesions.Cigarette smoking promotes the progression of atherosclerosis but enhances the antiplatelet effect of clopidogrel.The Korea National Registry of CTO Intervention included 2,167 patients with CTO lesions from 26 centers who were successfully revascularized with drug-eluting stents from 2007 to 2009. Thrombotic events were defined as the composite of cardiac death, nonfatal myocardial infarction, and stent thrombosis.Current-smokers had more favorable baseline characteristics such as a younger age and lower prevalence of hypertension and diabetes mellitus. At 1 year, current-smokers had a significantly lower thrombotic event rate (1.1% vs. 2.7%, P = 0.034), but a significantly higher target vessel revascularization (TVR) rate (7.2% vs. 4.2%, P = 0.017) compared with never-smokers. After adjustment, current-smoking was independently associated with a 72% decreased risk for thrombotic events, and 73% increased risk for TVR.In patients with a revascularized CTO lesion, cigarette smoking is associated with fewer thrombotic events but with a higher incidence of TVR. Patients with CTO may benefit from smoking cessation to reduce TVR in conjunction with the use of new more potent antiplatelet agents whose effect is independent of cigarette smoking to improve thrombotic events. © 2015 Wiley Periodicals, Inc.

Background: Gestational hypertensive disorders and diabetes are well-known to increase the risk of cardiovascular disease (CVD) and diabetes later in life. However, there were few researches to evaluate the association between family history of cardiovascular disease and the occurrence of pregnancy-related medical disorders. We aimed to investigate whether family history of CVD could predict gestational hypertensive disorders and diabetes. Methods: The Korean Nurses’ Survey was conducted through web-based computer-assisted self-administered questionnaires, which were compiled by consultation to cardiologists, gynecologists, and statisticians, from October to December 2011. We enrolled a total of 9,989 female registered nurses who could answer reliably the questionnaires based on their medical knowledge. Multivariate logistic regression analysis was used to clarify the effect of family history of CVD on pregnancy-related medical disorders. Result: In this survey, 3900 subjects had more than 1 pregnancy. Among them, 247 interviewees (6.3%) had experienced hypertensive disorders during pregnancy, which included preeclampsia (n = 160, 4.1%) and transient hypertension (n = 144, 3.7%), and 120 (3.1%) had experienced gestational diabetes. And, 2872 subjects (73.6%) answered that they had at least 1 family history of CVD. Having family history of CVD increased the risk of gestational hypertensive disorders (adjusted RR 1.51, 95% CI 1.08-2.11, p = 0.015) and diabetes (adjusted RR 2.40, 95% CI 1.38-4.17, p = 0.002). In particular, family history of hypertension was significantly associated with gestational hypertensive disorders (adjusted RR 2.00, 95% CI 1.47-2.50, p p Conclusion: Family history of CVD was a significant predictor of pregnancy-related medical disorders in this survey. Meticulous history taking for family history of CVD can provide the risk of gestational hypertensive disease and diabetes. Thus, special attention should be paid to women with family history of CVD during pregnancy.

Objective Previous studies have reported a considerable association between the VerifyNow (Accumetrics, San Diego, CA, USA) P2Y12 assay results and hematocrit. No reports, however, have described an association between the multiple electrode platelet aggregometry (MEA; Dynabyte, Munich, Germany) adenosine diphosphate (ADP) assay results and hematocrit. This study was conducted to evaluate the influence of hematocrit on the results of 2 different point-of-care platelet function tests. Methods A total of 462 consecutive patients who were undergoing percutaneous coronary intervention were enrolled. Platelet function was evaluated with both the VerifyNow P2Y12 and MEA ADP assays. Results Anemic patients (n = 152, 32.9%) demonstrated a significantly higher rate of cardiac death, myocardial infarction, and stroke (5.3% vs. 2.3%, p = 0.046) during the follow-up (median: 18.8 months). Although the VerifyNow P2Y12 assay results demonstrated a significant inverse correlation with hematocrit (r = −0.409, p

Rationale:Primary effusion lymphoma (PEL) is a rare disease of lymphomatous effusion in the body cavities in the absence of detectable mass and lymphadenopathy. PEL is predominantly related to the immunosuppressed patients infected with human herpes virus 8 (HHV-8). PEL-like lymphoma is nega

INTRODUCTION: The Cancer Genome Atlas found that the receptor tyrosine kinase (RTK)-Ras signaling pathway is altered in half of gastric adenocarcinomas (GAs). We added oncogenic Kras to the Atp4b-Cre;Cdh1fl/fl;Trp53fl/fl mouse model of GA and found accelerated tumorigenesis and metastasis. We also found Kras activity to be higher in gastric cancer stem-like cells (CSCs). Thus we hypothesized that Kras activty is critical for maintenance of gastric CSCs and promotes CSC phenotypes. METHODS: Human and murine GA cell lines were examined. The effect of Kras pathway inhibition was examined in GA spheroid cells and monolayer cells in various in vitro assays. Kras activity and Kras pathway inhibition was examined in CSCs, primary tumors and metastases in our GA mouse model. The combination of chemotherapy and Kras pathway inhibition was tested in human GA xenografts. RESULTS: Kras inhibition with shRNA or MEK inhibitor PD0325901 decreased the ability of GA cells to form spheroids and deceased expression of the stem cell transcription factor, Sox2. CD44(+) gastric CSCs had 65.8-75.4% higher migration, 64.2-79.5% higher invasion, and 63.1-70.2% more anchorage-independent growth compared to unselected cells. These properties could all blocked by 71.1-82.7% with Kras shRNA or PD0325901. In our GA mouse model, PD0325901 starting at 6 weeks of life increased median survival from 76 days to 95 days. Primary tumors and metastases from these mice with and without treatment with MEK inhibition are being analyzed for level of CD44 CSCs, Kras activity, and extent of metastases. Gastric CSCs were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed in human GA xenografts transducing cells with Kras shRNA. CONCLUSION: Kras is more active in gastric CSCs than non-CSCs and promotes malignant phenotypes including metastasis and chemotherapy resistance. Kras pathway inhibition can block these CSC phenotypes, and thus may prove useful in various combination therapies. Note: This abstract was not presented at the meeting. Citation Format: Changhwan Yoon, Kevin K. Chang, Jacob Till, Sandra W. Ryeom, Sam S. Yoon. Oncogenic Kras activation in gastric adenocarcinoma promotes cancer stem cell phenotypes including metastasis & chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2897. doi:10.1158/1538-7445.AM2017-2897

Introduction: Sarcomas often thrive in hypoxic conditions to proliferate and metastasize. To survive in such an environment, sarcomas upregulate hypoxia inducible factor-1α (HIF-1α), which enhances the transcription of over 150 genes mediating tumor metabolism, angiogenesis, and metastasis. HIF-1α may be important for the maintenance of a subset of tumor cells referred to as “sarcoma stem-like cells” or SSCs. Platelet-derived growth factor receptor (PDGFR) is important in mesenchymal biology and may be a potential target of HIF-1α. Methods: Three human sarcoma cell lines were examined: HT1080 (fibrosarcoma), SK-LMS-1 (leiomyosarcoma), and DDLS8817 (dedifferentiated liposarcoma). Cell lines were grown as spheroids on ultra-low attachment dishes to enrich for SSCs. The roles of HIF-1α and PDGFR-α/β in promoting SSC phenotypes, such as migratory/invasive capacity, were assessed via several in vitro assays under hypoxic conditions. Results: Sarcoma cell lines grown as spheroids had increased levels of HIF-1α and increased phosphorylation of PDGFR-α/β as compared to when grown as monolayers; these effects were even more pronounced when sarcoma spheroids were grown under hypoxic conditions. Hypoxic conditions also increased migratory and invasive capacity in spheroid cells by 65-73% as compared to normoxic conditions. HIF-1α knockdown using shRNA in the three cell lines decreased expression of self-renewal proteins and decreased spheroid formation by 67-80%. HIF-1α knockdown decreased expression of epithelial-mesenchymal transition (EMT) transcription factors and reduced migratory and invasive capacity by 80-87% under normoxic conditions and 85-87% under hypoxic conditions. Phosphorylation of PDGFR-α/β was decreased in sarcoma cell lines following HIF-1α knockdown under normoxic and hypoxic conditions. PDGFR-α/β inhibition with imatinib reversed chemotherapy resistance in normally resistant SSCs, and treatment of HT1080 xenografts with doxorubicin chemotherapy and imatinib reduced tumor formation by 85% as compared to control and by 77% as compared to chemotherapy alone. Conclusions: The HIF-1α/PDGFR axis supports the maintenance of SSCs, especially under hypoxic conditions, and promotes SSC phenotypes such as migratory/invasive capacity and chemotherapy resistance. Combining chemotherapy with PDGFR-α/β inhibition may be a promising strategy to reverse chemotherapy resistance and prevent metastasis in sarcomas. Note: This abstract was not presented at the meeting. Citation Format: Kevin K. Chang, Changhwan Yoon, Sam S. Yoon. Hypoxia-inducible factor 1-α maintains sarcoma stem-like cells in hypoxic regions of tumors and promotes migration and invasion via upregulation of platelet-derived growth factor receptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2899. doi:10.1158/1538-7445.AM2017-2899

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

Background and objectives The Korean Vascular Intervention Society Endovascular Therapy in Lower Limb Artery Diseases (K-VIS ELLA) Registry is a multicenter observational study with retrospective and prospective cohorts of patients with lower extremity peripheral artery disease (PAD) undergoing endovascular treatment. In this study, we report the baseline characteristics of this retrospective cohort. Subjects and methods In the present study we analyzed datasets of 3073 patients with 3972 target limbs from a retrospective cohort treated with endovascular therapy in 31 Korean hospitals. Data regarding patient baseline clinical and lesion characteristics and postintervention medications were collected from electronic medical records. Results The mean patient age was 68.3±9.4 years. The majority were male (82.1%) with comorbidities such as diabetes mellitus (58.0%), hypertension (73.4%), and coronary artery disease (CAD; 55.3%). Patients more commonly presented with intermittent claudication (66.3%) than with critical limb ischemia (CLI; 33.7%). Femoropopliteal artery (41.2%) was the most common target vessel for endovascular treatment, followed by the aortoiliac (35.6%) and infrapopliteal arteries (23.2%). TransAtlantic Inter-Society Consensus for the Management of Peripheral Artery Disease (TASC II) type C/D aortoiliac (48.0%) or femoropopliteal lesions (60.2%) were frequent targets of endovascular treatment. At hospital discharge, only 73.1% of patients received dual antiplatelet therapy and 69.2% received a statin. Conclusion The majority of Korean patients with PAD exhibited conventional risk factors, such as male sex, older age, diabetes, and hypertension with coexisting CAD. Complex lesions were frequently treated with endovascular therapy. However, the rate of adherence to guidelines regarding post-procedural medical treatment requires improvement.