Inpatient initiation of sodium-glucose cotransporter-2 inhibitors: the prescribing learning curve.

We aimed to describe the safety and tolerability of initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) during hospitalisation with heart failure, and the frequency of, and reasons for, subsequent discontinuation. In total, 934 patients who were not already prescribed a SGLT2i were hospitalised with heart failure, 77 (8%) were initiated on a SGLT2i a median of five (3-8.5) days after admission and two (0.

Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension.

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development.

Concise review: genetic dissection of hypoxia signaling pathways in normal and leukemic stem cells.

Adult hematopoiesis depends on rare multipotent hematopoietic stem cells (HSCs) that self-renew and give rise to progenitor cells, which differentiate to all blood lineages. The strict regulation of the fine balance between self-renewal and differentiation is essential for normal hematopoiesis and suppression of leukemia development. HSCs and progenitor cells are commonly assumed to reside within the hypoxic BM microenvironment, however, there is no direct evidence supporting this notion.

Array-based DNA methylation profiling in acute myeloid leukaemia.

Methylation in the promoter region of many genes is involved in regulating gene expression patterns. Using the Illumina GoldenGate© methylation assay, we examined the methylation status of 1505 CpG-sites from 807 genes in 32 samples from patients with acute myeloid leukaemia (AML) at diagnosis, nine at relapse and 15 normal controls and performed additional pyrosequencing and semiquantitative methylation specific polymerase chain reaction (MSP) of the GNMT promoter in 113 diagnostic AML samples. We found a gain of overall methylation in AML samples with a further increase at relapse.

Sequence of administration and methylation of SOCS3 may govern response to gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with refractory or relapsed acute myelogenous leukemia (AML).

In older patients suffering from acute myelogenous leukemia (AML), aggressive chemotherapy is accompanied with high treatment-related morbidity and mortality. Gemtuzumab ozogamicin (GO), a humanized monoclonal anti-CD33 antibody, represents a well tolerated treatment option, but optimal treatment schedules are still unknown. Additionally, Suppressor of cytokine signaling 3 (SOCS3) inhibits the CD33-induced block on cytokine-induced proliferation.

Impact of angiotensin I converting enzyme inhibitors and angiotensin II type 1 receptor blockers on survival in patients with advanced non-small-cell lung cancer undergoing first-line platinum-based chemotherapy.

Purpose: The renin-angiotensin system plays a crucial role in maintaining vascular homeostasis. Stimulation of angiotensin II type 1 receptors (AT1R) acts proangiogenically by increasing levels of vascular endothelial growth factor (VEGF). Consequently, cell culture experiments and animal studies have shown antiproliferative effects of AT1R blockers (ARB) and angiotensin I converting enzyme inhibitors (ACEI) in several malignancies.

CpG island methylation patterns in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. In CLL, a large number of genes affecting cancer-related pathways may be dysregulated by epigenetic silencing. We analysed by methylation-specific polymerase chain reaction the CpG island methylation status of 15 well-characterised cancer-related genes in 32 patients with CLL.

Epigenetic dysregulation of secreted Frizzled-related proteins in multiple myeloma.

We analysed the clinical impact of epigenetic dysregulation of the Wnt pathway in malignant plasma cell disorders. In multiple myeloma (MM) cell lines, aberrant promoter hypermethylation of the secreted Frizzled-related protein (SFRP) genes was a common event, and hypermethylation of SFRP1,-2 and -5 was associated with transcriptional silencing. Among 76 primary patient samples, the frequency of aberrant methylation was 35.

Rituximab-associated changes in platelet count in patients with non-Hodgkin lymphoma.

Rituximab is a monoclonal antibody specific for the CD20 antigen. Clinical factors associated with thrombocytopenia after administration of rituximab have only been reported as case reports. We have analysed retrospectively the change of platelet counts following the administration of rituximab in 253 patients with non-Hodgkin lymphoma (NHL).

Aberrant DNA methylation of the transcription factor C/EBPalpha in acute myelogenous leukemia.

We investigated the methylation status of the CCAAT/enhancer binding protein alpha (C/EBPalpha) promoter region near the transcription start site in acute myelogenous leukemia (AML). In hematopoietic tumor cell lines, CpG island hypermethylation of the proximal C/EBPalpha promoter region was associated with transcriptional silencing, and treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in C/EBPalpha reexpression and promoter demethylation. Aberrant methylation of the C/EBPalpha promoter region occurred in 10/80 diagnostic AML samples, and there was an inverse correlation between aberrant methylation of C/EBPalpha and the negative cell cycle regulator p15.

Epigenetic inactivation of secreted Frizzled-related proteins in acute myeloid leukaemia.

The Wnt signalling pathway has a key function in stem cell maintenance and differentiation of haematopoietic progenitors. Secreted Frizzled-related protein genes (SFRPs), functioning as Wnt signalling antagonists, have been found to be downregulated by promoter hypermethylation in many tumours. To analyse epigenetic dysregulation of SFRPs in acute myeloid leukaemia (AML), we examined the promoter methylation status of SFRP1, -2, -4 and -5 in AML cell lines by methylation-specific polymerase chain reaction (MSP).

Xenon or propofol anaesthesia for patients at cardiovascular risk in non-cardiac surgery.

Background: The results of two European multi-centre trials on xenon anaesthesia led to the hypothesis that a xenon-based anaesthetic would keep left ventricular (LV) and circulatory function more stable than a propofol-based anaesthetic, in patients with coronary artery disease (CAD).

Methods: In a prospective, randomized design, 40 patients of ASA classes III and IV with known CAD were anaesthetized for elective non-cardiac surgery with either xenon (n=20) or propofol (n=20), each combined with remifentanil. Target criteria were intraoperative LV function as evaluated by transoesophageal echocardiography (TOE: Tei index, circumferential fibre shortening), arterial pressure, and heart rate (HR).

EHA scientific workshop report: the role of epigenetics in hematological malignancies.

The clinical application of targeting the epigenome in cancer cells through demethylation and histone acetylation is an exiting novel pharmacologic concept in the treatment of malignant diseases. The manipulation of gene expression through epigenetic modifications represents a new strategy in targeted anti-cancer therapy. A workshop was held in Cannes, France in February 2007 to discuss the latest findings in basic and clinical research regarding the role of epigenetics in haematological malignancies.

Intraperitoneal application of rituximab in refractory mantle cell lymphoma with massive ascites resulting in local and systemic response.

In the past decade, rituximab in combination with polychemotherapy has become the standard approach in most patients with advanced CD20-positive B-cell lymphoma. In mantle cell lymphoma (MCL), follicular lymphoma and diffuse large B-cell lymphoma, rituximab has been used as monotherapy and in combination with various chemotherapy regimens in different treatment situations. Routinely, rituximab is given intravenously, but other routes of administration have also been described.

Autonomic cardiac control with xenon anaesthesia in patients at cardiovascular risk.

Background: The cardiovascular stability found with xenon anaesthesia may be caused by absence of circulatory depression. Xenon may also act directly on autonomic cardiovascular control.

Methods: In a prospective, randomized design, 26 patients (ASA class III and IV) with increased cardiac risk were anaesthetized for elective non-cardiac surgery with either xenon (n = 13) or propofol (n = 13), each combined with remifentanil.

Epigenetic alterations complement mutation of JAK2 tyrosine kinase in patients with BCR/ABL-negative myeloproliferative disorders.

An acquired autoactivating mutation with a V617F amino-acid substitution in the JAK2 tyrosine kinase is frequently found in BCR/ABL-negative myeloproliferative disorders (MPD). Hypermethylation of CpG islands within gene promoter regions is associated with transcriptional inactivation and represents an important mechanism of gene silencing in the pathogenesis of hematopoietic malignancies. In this study, we determined the DNA methylation status of 13 cancer-related genes in the context of JAK2 mutations in 39 patients with MPD.

The fundamental role of epigenetics in hematopoietic malignancies.

The term epigenetics defines a heritable alteration in gene expression without an accompanying change in primary DNA sequence. Two major mechanisms that foster epigenetic changes are DNA methylation at cytosine bases within a CpG dinucleotide and post-translational histone modifications. Disruption of the balanced epigenetic network may have significant impact on chromatin structure and transcriptional activity.

Heart and muscle involvement by extra-medullary myeloid leukemia: a case report and review of the literature.

Extra-medullary myeloid tumours (EMT) have been described after curative treatment for acute myeloid leukaemia (AML) in increasing numbers after allogeneic stem cell transplantation. The sites of manifestations are ubiquitous and the discovery is most frequently guided by symptoms reported by the patient or by findings on clinical examination. This study reports a case of EMT in muscles and the heart 1.

Methylation-specific polymerase chain reaction.

Methylation-specific polymerase chain reaction (MSP) is a method that can rapidly assess the methylation status of virtually any group of CpG sites within a CpG island, independent of the use of methylation-sensitive restriction enzymes. This assay entails the initial modification of DNA by sodium bisulfite, converting all unmethylated cytosines to uracils but leaving the methylated cytosines unchanged, followed by subsequent amplification with primers specific for methylated vs unmethylated DNA. The great sensitivity of this technique allows qualitative methylation analysis from DNA obtained not only from fresh frozen tissues, peripheral blood, bone marrow, or body fluids but also from paraffin-embedded samples.

Xenon anaesthesia may preserve cardiovascular function in patients with heart failure.

Background: The hypothesis that xenon anaesthesia provided haemodynamic stability was tested in patients with heart failure in a prospective, randomized, single-blind design.

Methods: Twenty-six patients scheduled for implantation of a cardioverter-defibrillator (ICD) received xenon 60-65% in oxygen (xenon group, n = 12) or propofol 3 mg/kg/h (propofol group, n = 14), both combined with remifentanil 0.2 microg/kg/min.

Effects of xenon anaesthesia on the circulatory response to hypoventilation.

Background: Circulatory response to hypoventilation is aimed at eliminating carbon dioxide and maintaining oxygen delivery (DO(2)) by increasing cardiac output (CO). The hypothesis that this increase is more pronounced with xenon than with isoflurane anaesthesia was tested in pigs.

Methods: Twenty pigs received anaesthesia with xenon 0.