Tissue factor pathway inhibitor is a potential modifier of bleeding risk in factor XI deficiency.

Background: Factor (F) XI deficiency is associated with increased bleeding risk in some individuals. Neither FXI levels nor clinical clotting assays predict the bleeding risk. Compared with controls, FXI-deficient bleeders have reduced clot formation, decreased fibrin network density, and increased susceptibility to fibrinolysis.

The Use and Effectiveness of an Online Diagnostic Support System for Blood Film Interpretation: Comparative Observational Study.

Background: The recognition and interpretation of abnormal blood cell morphology is often the first step in diagnosing underlying serious systemic illness or leukemia. Supporting the staff who interpret blood film morphology is therefore essential for a safe laboratory service. This paper describes an open-access, web-based decision support tool, developed by the authors to support morphological diagnosis, arising from earlier studies identifying mechanisms of error in blood film reporting.

A diagnostic evaluation of single screen testing for malaria in the returning traveler: A large retrospective cohort study.

Background: Screening for malaria in the returning traveler has often required repeat testing; however, audit data suggest that patients have not been reattending. We sought to ascertain if this was safe by examining the diagnostic efficacy of a single screen consisting of a rapid diagnostic test (RDT) and a thin film.

Methods: We conducted a retrospective cohort study of patients with suspected malaria who attended in the past 5 years from two large teaching hospitals.

Switchable foldamer ion channels with antibacterial activity.

Synthetic ion channels may have applications in treating channelopathies and as new classes of antibiotics, particularly if ion flow through the channels can be controlled. Here we describe triazole-capped octameric α-aminoisobutyric acid (Aib) foldamers that "switch on" ion channel activity in phospholipid bilayers upon copper(ii) chloride addition; activity is "switched off" upon copper(ii) extraction. X-ray crystallography showed that CuCl complexation gave chloro-bridged foldamer dimers, with hydrogen bonds between dimers producing channels within the crystal structure.

Quantitative Assay of Mutated Nucleophosmin in Acute Myeloid Leukemia.

Background: In our previous work, we provided strong evidence that nucleophosmin (NPM) gene mutation has an important role in leukemogenesis of primary acute myeloid leukemia (AML). Furthermore, we speculated a new targeted therapy in patients with primary AML and bearing mutated NPM (mNPM). Based on these results together with findings of other researchers, it was essential to develop a method for accurate detection of mNPM.

Dual-action CXCR4-targeting liposomes in leukemia: function blocking and drug delivery.

CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes).

Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid.

A bis(cyclam)-capped cholesterol lipid designed to bind C-X-C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 μM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C-X-C motif chemokine ligand 12 (CXCL12) concentration gradient.

Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency.

Individuals with factor XI (FXI) deficiency have a variable bleeding risk that cannot be predicted from plasma FXI antigen or activity. This limitation can result in under- or overtreatment of patients and risk of bleeding or thrombosis. Previously, plasma clot fibrinolysis assays showed sensitivity to bleeding tendency in a small cohort of patients with severe FXI deficiency.

ASP2215 in the treatment of relapsed/refractory acute myeloid leukemia with FLT3 mutation: background and design of the ADMIRAL trial.

Acute myeloid leukemia (AML) is a heterogeneous disease with cure rates of only 30-40% in patients <60 years old. Cytogenetic and molecular markers have improved our understanding of the different prognostic entities in AML. FLT3 mutations are present in 30-40% of AML cases, conferring a poor prognosis with reduced survival.

Role of Nucleophosmin Gene Mutation in Leukemogenesis of Acute Myeloid Leukemia.

Background: Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder that carries very poor prognosis. Understanding molecular basis of AML leukemogenesis could lead to the emergence of effective targeted therapies for AML. AML bearing nucleophosmin (NPM) gene mutation has distinct features.

Web-Based Virtual Microscopy of Digitized Blood Slides for Malaria Diagnosis: An Effective Tool for Skills Assessment in Different Countries and Environments.

Background: Morphological examination of blood films remains the reference standard for malaria diagnosis. Supporting the skills required to make an accurate morphological diagnosis is therefore essential. However, providing support across different countries and environments is a substantial challenge.

Graphene in therapeutics delivery: Problems, solutions and future opportunities.

Graphene based nanomaterials are being used experimentally to deliver therapeutic agents to cells or tissues both in vitro and in vivo. However, substantial challenges remain before moving to safe and effective use in humans. In particular, it is recognised that graphene molecules undergo complex interactions with solutes, proteins or cellular systems within the body, and that these interactions impact significantly on the behaviour or toxicity of the molecule.

Do We Know Why We Make Errors in Morphological Diagnosis? An Analysis of Approach and Decision-Making in Haematological Morphology.

Background: The laboratory interpretation of blood film morphology is frequently a rapid, accurate, and cost-effective final-stage of blood count analysis. However, the interpretation of findings often rests with a single individual, and errors can carry significant impact. Cell identification and classification skills are well supported by existing resources, but the contribution and importance of other skills are less well understood.

Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency.

Individuals with Factor XI (FXI) deficiency have a variable bleeding tendency that does not correlate with FXI:C levels or genotype. Comparing a range of sample conditions, we tested whether the thrombin generation assay (TGA) could discriminate between control subjects (n = 50) and FXI-deficient individuals (n = 97), and between those with bleeding tendency (n = 50) and without (n = 24). The comparison used platelet-rich plasma (PRP) and platelet-poor plasma (PPP), either with or without corn trypsin inhibitor (CTI) to prevent contact activation, over a range of tissue factor (TF) concentrations.

Lymphocytes from chronic lymphocytic leukaemia undergo ABL1-linked amoeboid motility and homotypic interaction as an early adaptive change to ex vivo culture.

Background: Those stimuli that together promote the survival, differentiation and proliferation of the abnormal B-lymphocytes of chronic lymphocytic leukaemia (CLL) are encountered within tissues, where together they form the growth-supporting microenvironment. Different tissue-culture systems promote the survival of the neoplastic lymphocytes from CLL, partly replicating the in vivo tissue environment of the disorder. In the present study, we focussed on the initial adaptive changes to the tissue culture environment focussing particularly on migratory behaviour and cellular interactions.

Monocyte-derived dendritic cells from chronic myeloid leukaemia have abnormal maturation and cytoskeletal function that is associated with defective localisation and signalling by normal ABL1 protein.

Objectives: Mature dendritic cells (DCs) may be derived from the BCR/ABL1 expressing monocytes in chronic myeloid leukaemia. These cells have potential therapeutic applications, but are recognised to have defective function. In normal DCs, activation and maturation depend on ABL1 dependent signals.

Single-cell analysis of K562 cells: an imatinib-resistant subpopulation is adherent and has upregulated expression of BCR-ABL mRNA and protein.

In chronic myeloid leukemia (CML) cells from different stages of maturation may have differential expression of BCR-ABL at both messenger RNA (mRNA) and protein level. However, the significance of such differential expression to clinical disease behavior is unknown. Using the CML-derived, BCR-ABL expressing cell line, K562, distinct plastic-adherent (K562/Adh) and nonadherent (K562/NonAdh) subpopulations were established and then analyzed both as single cells and as bulk cell populations.

Ribosome-associated nucleophosmin 1: increased expression and shuttling activity distinguishes prognostic subtypes in chronic lymphocytic leukaemia.

Two distinct groups of chronic lymphocytic leukaemia (CLL) are distinguished by the presence or absence of somatic hypermutation of the immunoglobulin heavy-chain gene. CLL without somatic hypermutation has an adverse outcome, but the precise biological differences that underlie this more aggressive clinical-course are unclear. Using a proteomic approach, we found that the two prognostic forms of CLL were consistently distinguished according to their protein expression pattern.

Hydroxycarbamide associated platelet count oscillations in a patient with polycythaemia vera. A case report and review of the literature.

We describe an unusual case of oscillating platelet counts in a patient with polycythaemia vera. Following commencement of cytoreductive hydroxycarbamide therapy, episodes of thrombocytopenia were followed regularly by thrombocytosis. Platelet counts fluctuated periodically between approximately 200 and 800 x 109/l, with a 28 day cycle duration.

The use of isobaric tag peptide labeling (iTRAQ) and mass spectrometry to examine rare, primitive hematopoietic cells from patients with chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease, associated with a t(9, 22) chromosomal translocation leading to formation of the BCR/ABL chimeric protein, which has an intrinsic tyrosine kinase activity. Recently, the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (imatinib) has been successfully used clinically, although, disease relapse can still occur. The precise detail of the mechanism by which CML cells respond to imatinib is still unclear.