AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells.

Unlabelled: The survival rates for relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we performed genome-wide RNA-seq and ChIP-seq in CCRF-CEM (T-ALL) cells expressing HA-AMPKα2 (CN2) under normal and energy/metabolic stress conditions.

Protein Kinase D-Dependent Downregulation of Immediate Early Genes through Class IIA Histone Deacetylases in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in children and adolescents, and cure rates for relapsed/refractory ALL remain dismal, highlighting the need for novel targeted therapies. To identify genome-wide metabolic-stress regulated genes, we used RNA-sequencing in ALL cells treated with AICAR, an AMPK activator. RNA-sequencing identified the immediate early genes (IEGs) as a subset of genes downregulated by AICAR.

Analysis of the COMPARE-AMI trial: First report of long-term safety of CD133+ cells.

Background: Data related to long-term safety of intracoronary (IC) injection of CD133+ bone marrow stem cells (BMSC) following an acute myocardial infarction (MI) are still lacking.

Methods: COMPARE-AMI is a double-blind, placebo-controlled phase II clinical trial evaluating the safety and efficacy of IC injection of CD133+ enriched hematopoietic BMSC in patients with ST-elevation myocardial infarction (STEMI) and persistent left ventricular (LV) dysfunction following successful primary percutaneous coronary intervention (PCI). Herein, we report outcomes up to ten years of follow-up.

Preclinical evaluation of a thin-strut bioresorbable scaffold (ArterioSorb): acute-phase invasive imaging assessment and hemodynamic implication.

Aims: The aim of this study was to assess the acute performance of the 95 µm ArterioSorb oriented poly L-lactic acid (PLLA) scaffold in comparison with the XIENCE metallic drug-eluting stent (DES) in porcine coronary arteries.

Methods And Results: In 15 non-atherosclerotic Yucatan mini pigs, the ArterioSorb (3.0/14 mm) and XIENCE (3.

An Animal Model of Human Peripheral Arterial Bending and Deformation.

Background: Designing peripheral arterial stents has proved challenging, as implanted devices will repetitively and unpredictably deform and fatigue during movement. Preclinical testing is often inadequate, given the lack of relevant animal models. The purpose of this study was to test the hypothesis that deformation of the human peripheral vasculature could be qualitatively and quantitatively modeled using an experimental animal.

Preclinical evaluation of degradation kinetics and elemental mapping of first- and second-generation bioresorbable magnesium scaffolds.

Aims: Because vascular restoration therapy using bioresorbable vascular scaffolds (BRS) remains an appealing concept to restore vasoreactivity, an understanding of biodegradation remains paramount during preclinical testing. We therefore aimed to investigate the qualitative and temporal course of degradation of magnesium alloy-based bioresorbable vascular scaffolds in juvenile swine.

Methods And Results: Qualitative characterisation of biodegradation was performed in 41 DREAMS 1G up to three years, while degradation kinetics were acquired in 54 DREAMS 2G implanted into porcine coronary arteries for 28, 90 and 180 days, one and two years.

Second-generation magnesium scaffold Magmaris: device design and preclinical evaluation in a porcine coronary artery model.

Aims: The second-generation drug-eluting absorbable magnesium scaffold Magmaris, recently introduced for the treatment of obstructive coronary atherosclerotic lesions, suggests a good safety profile, but preclinical assessment is important for predicting clinical performance. The aim of the present study was to assess subacute and long-term safety as well as pharmacokinetic properties of the Magmaris compared with a current-generation metallic DES and an approved BRS in porcine and rabbit animal models.

Methods And Results: Ninety Magmaris scaffolds were implanted into non-diseased porcine and rabbit models.

The NEDD8-activating enzyme inhibitor pevonedistat activates the eIF2α and mTOR pathways inducing UPR-mediated cell death in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms.

Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress.

Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types.

Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress.

BCR-ABL positive (+) acute lymphoblastic leukemia (ALL) accounts for ∼30% of cases of ALL. We recently demonstrated that 2-deoxy-d-glucose (2-DG), a dual energy (glycolysis inhibition) and ER-stress (N-linked-glycosylation inhibition) inducer, leads to cell death in ALL via ER-stress/UPR-mediated apoptosis. Among ALL subtypes, BCR-ABL+ ALL cells exhibited the highest sensitivity to 2-DG suggesting BCR-ABL expression may be linked to this increased vulnerability.

Impact of intracoronary injection of CD133+ bone marrow stem cells on coronary atherosclerotic progression in patients with STEMI: a COMPARE-AMI IVUS substudy.

Objectives: Adverse effects of intracoronary injection of stem cells on in-stent restenosis and atherosclerotic progression remain unclear. We sought to evaluate the adverse effects of intracoronary injection of CD133 cells on in-stent restenosis and atherosclerotic progression in the infarct-related and contralateral arteries using serial intravascular ultrasound (IVUS) analysis.

Methods: Baseline and 4-month follow-up IVUS images were obtained from 17 patients treated with intracoronary stem cell injection and 20 placebo patients after primary percutaneous coronary intervention in the COMPARE-AMI trial.

Head-to-head comparison of a drug-free early programmed dismantling polylactic acid bioresorbable scaffold and a metallic stent in the porcine coronary artery: six-month angiography and optical coherence tomographic follow-up study.

Background: We aimed to evaluate a new drug-free fully bioresorbable lactic acid-based scaffold designed to allow early dismantling synchronized with artery wall healing in comparison with a bare metal stent (BMS).

Methods And Results: Twenty-three BMS (3.0×12 mm) and 36 lactic acid-based bioresorbable scaffolds (BRS, 3.

Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts.

The outcome of patients with resistant phenotypes of acute lymphoblastic leukemia (ALL) or those who relapse remains poor. We investigated the mechanism of cell death induced by metformin in Bp- and T-ALL cell models and primary cells, and show that metformin effectively induces apoptosis in ALL cells. Metformin activated AMPK, down-regulated the unfolded protein response (UPR) demonstrated by significant decrease in the main UPR regulator GRP78, and led to UPR-mediated cell death via up-regulation of the ER stress/UPR cell death mediators IRE1α and CHOP.

Vascular response and mechanical integrity of the new biodegradable polymer coated sirolimus-eluting PROLIM stent implanted in porcine coronary arteries.

Background: Although durable polymer coated drug-eluting stents (DES) are standard care in percutaneous coronary interventions, new stent platforms employing biodegradable polymer based drug delivery are increasingly being used in clinical practice.

Aim: To evaluate the short- (28 days) and medium-term (90 days) vascular effects of the new biodegradable polymer coated sirolimus-eluting stent - the PROLIM stent.

Methods: The objectives of the study were evaluated using standard angiographic and histological methods.

Inhibition of Akt potentiates 2-DG-induced apoptosis via downregulation of UPR in acute lymphoblastic leukemia.

The ability to pair the regulation of metabolism and cellular energetics with oncogenes and tumor suppressor genes provides cancer cells with a growth and survival advantage over normal cells. We investigated the mechanism of cell death induced by 2-deoxy-D-glucose (2-DG), a sugar analog with dual activity of inhibiting glycolysis and N-linked glycosylation, in acute lymphoblastic leukemia (ALL). We found that, unlike most other cancer phenotypes in which 2-DG only inhibits cell proliferation under normoxic conditions, ALL lymphoblasts undergo apoptosis.

Preclinical evaluation of a novel drug-eluting balloon in an animal model of in-stent stenosis.

Despite advances in contemporary stent technology, in-stent restenosis (ISR) remains the major limitation following revascularization procedures. We developed a porcine model of ISR to specifically investigate the preclinical outcomes of a novel drug-eluting balloon (DEB) in this particular setting. Fifteen pigs received bare metal stents in each of the major coronary arteries for 28 days to induce neointimal growth.

One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133 Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction.

Bone marrow stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium. Despite initial excitement, recent clinical trials using non-homogenous stem cells preparations showed variable and mixed results. Selected CD133(+) hematopoietic stem cells are candidate cells with high potential.

AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia.

AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types.

AMPK-induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia.

Background: Children with Acute Lymphoblastic Leukemia (ALL) diagnosed with resistant phenotypes and those who relapse have a dismal prognosis for cure. In search for novel treatment strategies, we identified the AMP activated protein kinase (AMPK) as a potential drug target based on its effects on cell growth and survival. We have shown previously that AICAR-induced AMPK activation also induced a compensatory survival mechanism via PI3K/Akt signaling.

COMPARE-AMI trial: comparison of intracoronary injection of CD133+ bone marrow stem cells to placebo in patients after acute myocardial infarction and left ventricular dysfunction: study rationale and design.

Stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium, to treat or prevent cardiac failure, and to restore lost cardiac function. Despite initial excitement, recent clinical trials using nonhomogenous human stem cells preparations showed variable results, raising concerns about the best cell type to transplant. Selected CD133(+) hematopoietic stem cells are promising candidate cells with great potential.

Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia.

Acute Lymphoblastic Leukemia (ALL) non-random fusions influence clinical outcome and alter the accumulation of MTX-PGs in vivo. Analysis of primary ALL samples uncovered subtype-specific patterns of folate gene expression. Using an FPGS-luciferase reporter gene assay, we determined that E2A-PBX1 and TEL-AML1 expression decreased FPGS transcription.

Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy.

Background: Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy affecting children. Despite significant progress and success in the treatment of ALL, a significant number of children continue to relapse and for them, outcome remains poor. Therefore, the search for novel therapeutic approaches is warranted.

Analysis of folylpoly-gamma-glutamate synthetase gene expression in human B-precursor ALL and T-lineage ALL cells.

Background: Expression of folylpoly-gamma-glutamate synthetase (FPGS) gene is two- to three-fold higher in B-precursor ALL (Bp- ALL) than in T-lineage ALL (T-ALL) and correlates with intracellular accumulation of methotrexate (MTX) polyglutamates and lymphoblast sensitivity to MTX. In this report, we investigated the molecular regulatory mechanisms directing FPGS gene expression in Bp-ALL and T-ALL cells.

Methods: To determine FPGS transcription rate in Bp-ALL and T-ALL we used nuclear run-on assays.

32P-oligodeoxynucleotide-coated coils to prevent arterial recanalization after embolization.

Background And Purpose: Endovascular treatment of aneurysms with coils, a less invasive alternative to surgery, is too often associated with recurrences. In a canine model, recanalization after coil embolization can be inhibited by in situ beta radiation.

Methods: Radioactive platinum coils were produced by immersion in a (32)P-oligodeoxynucleotide solution.