The pathogenesis of essential thrombocythemia.

Purpose Of Review: The identification of new mutations continues to further our understanding of the molecular pathogenesis of essential thrombocythemia and related disorders, and offers opportunities for improvements in diagnosis, risk stratification and disease classification.

Recent Findings: Molecular lesions in essential thrombocythemia affect two distinct pathways: cytokine signaling and transcriptional regulation. Signaling pathway mutations show a high degree of phenotypic specificity, in contrast to alterations in transcriptional pathways in which the same mutations are seen in diverse myeloid malignancies.

Reversible luminescence switching of a redox-active ferrocene-europium dyad.

The copper-catalyzed cycloaddition reaction between a propargyl-appended europium complex and azidomethylferrocene yields a d-f dyad whose photophysical properties can be reversibly switched by varying the oxidation state of the ferrocene chromophore.

A redox-active [3]rotaxane capable of binding and electrochemically sensing chloride and sulfate anions.

A ferrocene functionalised redox-active [3]rotaxane which contains two interlocked anion recognition sites has been prepared by chloride anion templation. With chloride two equivalents of anion are bound, one in each of the interlocked cavities, while sulfate forms a 1:1 stoichimetric sandwich type complex; the rotaxane can also electrochemically sense the two anions in acetonitrile.

The frequency of detection of unexpected diabetes mellitus during haemoglobinopathy investigations.

Aims: To establish the frequency of detection of previously undiagnosed diabetes mellitus as a result of detection of an increased glycated fraction of haemoglobin during high performance liquid chromatography (HPLC) for haemoglobinopathy diagnosis.

Methods: A prospective study was carried out over a 3-month period. During that period a total of 2094 patient samples were received for haemoglobinopathy investigation and were included in the study.

Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients.

Core@shell bimetallic nanoparticle synthesis via anion coordination.

Core@shell structured bimetallic nanoparticles are currently of immense interest due to their unique electronic, optical and catalytic properties. However, their synthesis is non-trivial. We report a new supramolecular route for the synthesis of core@shell nanoparticles, based on an anion coordination protocol--the first to function by binding the shell metal to the surface of the pre-formed primary metal core before reduction.

Sodium and barium cation-templated synthesis and cation-induced molecular pirouetting of a pyridine N-oxide containing [2]rotaxane.

Sodium and barium metal cation templation has been used to construct a novel pyridine N-oxide containing [2]rotaxane. Upon addition and removal of metal cations, the macrocyclic component is observed to undergo a pirouetting motion around the pyridine N-oxide axle.

Chloride anion triggered motion in a bis-imidazolium rotaxane.

We report the first bis-imidazolium-containing rotaxane, synthesised via anion templated self-assembly. Its co-conformation is controlled by a chloride anion recognition mechanism, thus demonstrating the viability of this protocol as a stimulus for shuttling molecular motion.

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.

The hypoxia-inducible factors (HIFs; isoforms HIF-1α, HIF-2α, HIF-3α) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF.

Kinetic studies exploring the role of anion templation in the slippage formation of rotaxane-like structures.

The first examples of the slippage formation of rotaxane-like structures in the presence of an anion template are reported between a macrocycle, synthesised by exploiting Eglinton coupling, and stoppered pyridinium axle components. The role of the anion template in the slippage process has been explored by kinetic studies. (1)H NMR spectroscopic investigations reveal the slippage species formed are not rotaxanes but pseudorotaxanes with some rotaxane character.

Anion recognition and cation-induced molecular motion in a heteroditopic [2]rotaxane.

A heteroditopic [2]rotaxane consisting of a calix[4]diquinone-isophthalamide macrocycle and 3,5-bis-amide pyridinium axle components with the capability of switching between two positional isomers in response to barium cation recognition is synthesised. The anion binding properties of the rotaxane's interlocked cavity together with Na(+) , K(+) , NH(4) (+) and Ba(2+) cation recognition capabilities are elucidated by (1) H NMR and UV-visible spectroscopic titration experiments. Upon binding of Ba(2+) , molecular displacement of the axle's positively charged pyridinium group from the rotaxane's macrocyclic cavity occurs, whereas the monovalent cations Na(+) , K(+) and NH(4) (+) are bound without causing significant co-conformational change.

A new synthetic route to chloride selective [2]catenanes.

A novel anion templation route has been developed to synthesise two new catenanes, which are observed to selectively complex chloride in protic solvent media.

How I treat essential thrombocythemia.

In the past 5 years we have witnessed significant advances in both the diagnostic process and optimal therapy for patients with essential thrombocythemia (ET). Insights into the underlying molecular mechanisms have been accompanied by the development of new diagnostic tests and by an improved understanding of the relationship between ET and other related myeloproliferative neoplasms, such as polycythemia vera and primary myelofibrosis. In the first part of this review, we describe how recent molecular and histologic studies can be integrated into a streamlined diagnostic process that is applicable to everyday clinical practice.

Genetic variations in androgen metabolism genes and associations with prostate cancer in South African men.

Background. In South Africa white men have the highest incidence of prostate cancer (PCa), coloured (mixed ancestry) men have an intermediate incidence, and low incidences are reported for black and Asian men. It has been suggested that ethnic differences in incidence and mortality of PCa are related to genetic variations in genes that regulate androgen metabolism.

Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling.

The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype.

A ferrocene functionalized rotaxane host system capable of the electrochemical recognition of chloride.

A ferrocene appended rotaxane is prepared by chloride anion templation and ring closing metathesis. Upon removal of the chloride template, the rotaxane is demonstrated to be selective for chloride over more basic oxoanions by (1)H NMR spectroscopy and electrochemistry, in marked contrast to an acyclic analogue--the first example of a solution based redox-active interlocked host system capable of the electrochemical recognition of anions.

Rotaxanes capable of recognising chloride in aqueous media.

A new, versatile chloride-anion-templating synthetic pathway is exploited for the preparation of a series of eight new [2]rotaxane host molecules, including the first sulfonamide interlocked system. (1)H NMR spectroscopic titration investigations demonstrate the rotaxanes' capability to selectively recognise the chloride anion in competitive aqueous solvent media. The interlocked host's halide binding affinity can be further enhanced and tuned through the attachment of electron-withdrawing substituents and by increasing its positive charge.

Molecular dynamics study of a heteroditopic-calix[4]diquinone-assisted transfer of KCl and dopamine through a water-chloroform liquid-liquid interface.

The ability of two heteroditopic calix[4]diquinone receptors to transport a KCl ion-pair and a dopamine zwitterion through a water-chloroform interface was investigated via molecular dynamics (MD) simulations. Gas-phase conformational analysis has been carried on KCl and dopamine receptor binding associations and the lowest energy structures found in both cases show that the recognition of KCl and dopamine zwitterion occurs through multiple and cooperative N-H..