0165: Outcome after drug-eluting stents for cardiac allograft vasculopathy

PurposeCardiac allograft vasculopathy (CAV) constitues a primary cause of death after heart transplantation. Bare metal stents (BMS) have been used for revascularization, but they are associated with a high-risk of restenosis.Abstract 0474 – Figure: Kaplan-Meier estimates of one-year mortalityLimited data have shown favourable results with percutaneous coronary interventions (PCI) using drug-eluting stents (DES) in this specific population. Our study focuses on intra-stent restenosis (ISR) for DES in CAV, on new revascularisation and mortality.Methods97 consecutive heart transplant recipients with successful PCI were treated with DES (n=106) and BMS (n=25). They were prospectively followed-up at one year after PCI. An angiographic lesion-based analysis at 12-month follow-up and a patient-based survival analysis were performed.ResultsThe lesion-based analysis within 12 months after PCI showed an ISR rate with BMS of 12% and an ISR rate with DES of 3.8%. The target lesion revascularization (TLR) was 8% for BMS and 2.8% for DES. However, the target vessel revascularization was higher (16.5%) and the remote lesion revascularization was 8.7%, indicating the rapid occurrence of new significant lesions. Cardiac mortality at one year was 9.7% and extra- cardiac mortality was 2.9%.ConclusionsDES are associated with a low rate of TLR and can safely be used in heart transplant recipients with coronary artery disease. However, new significant lesions occurred at one year indicating a progression of CAV

European Society of Cardiology: Cardiovascular Disease Statistics 2019

Aims The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets. Methods and results In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% [interquartile range (IQR) 22.5–23.1%] vs. 15.7% (IQR 14.5–21.1%)}, diabetes [7.7% (IQR 7.1–10.1%) vs. 5.6% (IQR 4.8–7.0%)], and among males smoking [43.8% (IQR 37.4–48.0%) vs. 26.0% (IQR 20.9–31.7%)] although among females smoking was less common in middle-income countries [8.7% (IQR 3.0–10.8) vs. 16.7% (IQR 13.9–19.7%)]. There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income [7160 (IQR 5655–8115)] compared with high-income [2235 (IQR 1896–3602)] countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures. Conclusion A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest

THE ROLE OF GLUTAMINE AND MEVALONATE PATHWAY IN AFFECTING THE STEMNESS AND VIABILITY OF GLIOBLASTOMA STEM CELLS

Glioblastoma (GBM) remains the deadliest form of brain tumors. The poor prognosis of glioblastoma patients is associated with a high rate of relapse after therapy. It has been suggested that the presence of cancer stem cells, which are relatively resistant to radiation and chemotherapy, may play a significant role in the recurrence of brain tumor. Understanding the biological property of glioblastoma stem cells is important to develop effective therapeutic strategies for glioblastoma. In vitro, glioblastoma stem cells cultured in serum-free medium form self-renewing neurospheres, express the neural stem marker CD133, and are highly tumorigenic. On the other hand, in the presence of fetal bovine serum (FBS), the glioblastoma stem cells undergo differentiation. In this study we used glioblastoma stem cells, GSC11 and GSC23, previously isolated from glioblastoma patients and expressed stem cell markers CD133, Olig2 and SOX2, to explore their bioenergetics by monitoring the oxygen consumption as an indication of mitochondrial respiration cultured in serum-free medium in comparison with that incubated in medium containing FBS. We found that GSC11 and GSC23 stem cells exhibited low mitochondrial respiration when cultured in stem cell medium. Upon exposure to FBS mitochondrial respiration increased significantly. Metabolic changes were also observed. Furthermore, we found that glutamine uptake was higher in GBM stem cells compared with FBS induced cells. Additionally, treatment of the cells with Compound 968, a glutaminase inhibitor, depleted the cells from the CD133 marker, slowed proliferation and limited growth on soft agar. Moreover, GBM stem cells showed an increase in the expression of genes related to the mevalonate pathway. We also found that simvastatin, an inhibitor of the mevalonate pathway, induced GBM stem cells death. This study showed mitochondria metabolic reprograming of GBM stem cells during differentiation. It also showed the importance of glutamine in maintaining CD133 expression and GBM stem cells growth. Lastly, the study showed that mevalonate pathway is a target to eliminate GBM stem cells

Tracking Tumor Regression in ENO1-Deleted Glioblastoma via IVIS Spectrum

Glioblastoma (GBM) is a fast-growing and aggressive form of brain cancer arising from astrocytes, which are the star-shaped cells that form the supportive tissue of the brain. In GBM, the glycolytic gene Enolase 1 (ENO1) in the 1p36 locus is deleted, but this loss is tolerated through the expression of Enolase 2 (ENO2). Previous work in research has shown that the selective inhibition of ENO2 (both genetically and pharmacologically) can lead to GBM tumor stasis, regression, and/or eradication. Altering the structural activity of the potent natural Enolase inhibitor SF2312 forms the active drug HEX, which becomes the prodrug POMHEX through the addition of Pivaloyloxymethyl (POM) groups that neutralize the negative charge of the phosphonates and make the drug more lipid-soluble, allowing it to cross cell membranes and become even more effective in terms of potency. To test the efficacy of various drugs (POMHEX, DMSO, HEX, and PBS) on mice with D423 GBM tumors, the IVIS Spectrum was used to analyze the bioluminescent signals from tumors. Based on the data, POMHEX selectively kills ENO1-deleted GBM cells through the inhibition of glycolysis, making it an effective anti-tumor therapeutic strategy. This project was completed with contributions from Sunada Khadka, Naima Hammoudi, Yu-His Lin, and Florian Muller from the MD Anderson Cancer Center.Psychological, Health, and Learning Sciences, Department ofHonors Colleg

ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase

<div><p>Inhibition of glycolysis is of great potential for the treatment of cancer. However, inhibitors of glycolytic enzymes with favorable pharmacological profiles have not been forthcoming. Due to the nature of their active sites, most high-affinity transition-state analogue inhibitors of glycolysis enzymes are highly polar with poor cell permeability. A recent publication reported a novel, non-active site inhibitor of the glycolytic enzyme Enolase, termed ENOblock (N-[2-[2-2-aminoethoxy)ethoxy]ethyl]4-4-cyclohexylmethyl)amino]6-4-fluorophenyl)methyl]amino]1,3,5-triazin-2-yl]amino]benzeneacetamide). This would present a major advance, as this is heterocyclic and fully cell permeable molecule. Here, we present evidence that ENOblock does not inhibit Enolase enzymatic activity <i>in vitro</i> as measured by three different assays, including a novel ³¹P NMR based method which avoids complications associated with optical interferences in the UV range. Indeed, we note that due to strong UV absorbance, ENOblock interferes with the direct spectrophotometric detection of the product of Enolase, phosphoenolpyruvate. Unlike established Enolase inhibitors, ENOblock does not show selective toxicity to <i>ENO1</i>-deleted glioma cells in culture. While our data do not dispute the biological effects previously attributed to ENOblock, they indicate that such effects must be caused by mechanisms other than direct inhibition of Enolase enzymatic activity.</p></div

Effective Killing of Leukemia Cells by the Natural Product OSW-1 Through Disruption of Cellular Calcium Homeostasis

3β,16β,17α-Trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-β-D-xylopyranosyl)-(1→3) -2-O-acetyl-α-L-arabinopyranoside (OSW-1) is a natural product with potent antitumor activity against various types of cancer cells, but the exact mechanisms of action remain to be defined. In this study, we showed that OSW-1 effectively killed leukemia cells at subnanomolar concentrations through a unique mechanism by causing a time-dependent elevation of cytosolic Ca 2+ prior to induction of apoptosis. A mechanistic study revealed that this compound inhibited the sodium-calcium exchanger 1 on the plasma membrane, leading to an increase in cytosolic Ca2+ and a decrease in cytosolic Na+. The elevated cytosolic Ca2+ caused mitochondrial calcium overload and resulted in a loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3. Furthermore, OSW-1 also caused a Ca2+-dependent cleavage of the survival factor GRP78. Inhibition of Ca2+ entry into the mitochondria by the uniporter inhibitor RU360 or by cyclosporin A significantly prevented the OSW-1-induced cell death, indicating the important role of mitochondria in mediating the cytotoxic activity. The extremely potent activity of OSW-1 against leukemia cells and its unique mechanism of action suggest that this compound may be potentially useful in the treatment of leukemia

Non-selective toxicity of ENOBlock to ENO1-deleted glioma cells.

<p>A representative plate of cancer cells treated with ENOblock is shown in panel <b>a</b>, with quantification shown in panel <b>b</b> A plate treated with SF2312 is shown in panel <b>c</b>, with quantification shown in panel <b>d</b>. Cell were treated for 7 days. <b>(b, d)</b> D423 <i>ENO1</i>-deleted (red diamonds), D423 <i>ENO1</i>-rescued (blue squares) and LN319 <i>ENO1</i> WT (grey circles) were treated with the indicated doses of ENOblock in panel <b>b</b> (N = 4 ± S.D) or SF2312 in panel <b>d</b> (N = 4 ± S.D). Cell density was quantified by crystal violet and expressed relative to vehicle control as a function of inhibitor concentration. At high concentrations, SF2312 selectively killed D423 <i>ENO1</i>-deleted cells as compared to D423 <i>ENO1</i>-rescued cells (p<0.05, Repeated Measures one-way ANOVA with Bonferroni correction). ENOblock failed to show such selectivity regardless of dose.</p