Rapid progression of vascular and soft tissue calcification while being managed for severe and persistent hypocalcemia induced by denosumab treatment in a patient with multiple myeloma and chronic kidney disease.

We herein present the case of a patient with myeloma and chronic kidney disease (CKD) who developed rapidly progressive vascular and soft tissue calcification during the course of treatment for severe hypocalcemia induced by the administration of denosumab for myeloma and hypercalcemia. Because a large amount of supplementation with active vitamin D and calcium was required to correct the severe hypocalcemia, rapidly progressive vascular calcification developed. Seeing that patients with CKD are prone to developing severe and prolonged hypocalcemia after denosumab treatment, physicians should closely monitor the patients' serum calcium levels and manage their hypocalcemia appropriately so as to avoid the development of significant ectopic calcification.

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation.

The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.

Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis.

Perforin gene (PRF1) mutations cause the primary form of hemophagocytic lymphohistiocytosis (HLH). We report a genetic defect of PRF1 in a 62-year-old Japanese man with recurrent episodes of HLH. Sequencing of PRF1 from both peripheral blood mononuclear cells and nail clippings showed compound heterozygous mutation, including deletion of two base pairs at codons 1090 and 1091 (1090-1091delCT) and guanine-to-adenine conversion at nucleotide position 916 (916GAEA). Although primary HLH has been detected in infants and children, genetic mutation of PRF1 or other genes should be considered a differential diagnosis of HLH even in the elderly.

Distinctive expression of myelomonocytic markers and down-regulation of CD34 in acute myelogenous leukaemia with FLT3 tandem duplication and nucleophosmin mutation.

OBJECTIVE: Patients with acute myelogenous leukaemia (AML) show co-existing frequently internal tandem duplications of FLT3 (FLT3-ITD) and mutations of nucleophosmin (NPM1-Mt). We investigated the biological and clinical significance of FLT3-ITD and/or NPM1-Mt in this context. METHODS: We analysed 89 AML patients according to whether NPM1 and FLT3-ITD were single mutants, double mutants, or wild type for both. RESULTS: FLT3-ITD was detected in 19 of 89 patients (21.3%), while NPM1-Mt was detected in 19 of 89 patients (21.3%); eight of 89 patients (9.0%) carried both FLT3-ITD and NPM1-Mt. By multivariate analysis, white blood cell count and peripheral blood blast cell count at diagnosis were significantly higher in patients with FLT3-ITD but not in those with only NPM1-Mt. NPM1-Mt was significantly related to female gender, normal karyotype, and M4 or M5 disease according to French-American-British criteria. In addition, leukaemic blast cells with NPM1-Mt, FLT3-ITD, or both expressed CD34 less frequently than wild-type blasts (P < 0.0001 and P = 0.005 respectively), while myelomonocytic markers such as CD11b and CD14 were expressed more frequently in patients with NPM1-Mt. CONCLUSION: FLT3-ITD may increase potential for cell proliferation to produce a leukaemic population; NPM1-Mt may cause cells to develop along the myelomonocytic lineage. Extensive analyses and detailed experiments will be required to clarify how NPM1 and FLT3 mutations interact in leukaemogenesis.

Tyk2 mutation homologous to V617F Jak2 is not found in essential thrombocythaemia, although it induces constitutive signaling and growth factor independence.

A single somatic mutation, V617F, in the pseudokinase domain of the Jak2 is the primary cause of many chronic myeloproliferative diseases. As valine 617 of Jak2 is conserved as valine 678 of Tyk2, we examined the effect of a homologous mutation in Tyk2 (V678F Tyk2) on cell growth. V678F Tyk2 augmented the transcriptional activity of Stat3 and Stat5. The expression of V678F Tyk2 in Ba/F3 cells induced autonomous cell growth and showed hyper-responsiveness to IL-3. Although V678F Tyk2 might cause MPD, no cases of ET patients lacking the V617F Jak2 mutation harbored the Tyk2 mutation.

Syntheses, characterization, and catalytic ability in alkane oxygenation of chloro(dimethyl sulfoxide)ruthenium(II) complexes with tris(2-pyridylmethyl)amine and its derivatives.

New ruthenium(II) complexes having a tetradentate ligand such as tris(2-pyridylmethyl)amine (TPA), tris[2-(5-methoxycarbonyl)pyridylmethyl]amine [5-(MeOCO)3-TPA], tris(2-quinolylmethyl)amine (TQA), or bis(2-pyridylmethyl)glycinate (BPG) have been prepared. The reaction of the ligand with [RuCl2(Me2SO)4] resulted in a mixture of trans and cis isomers of the chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complexes containing a TPA or a BPG, whereas a trans(Cl,N(amino)) isomer was selectively obtained for 5-(MeOCO)3-TPA and TQA. The trans and cis isomers of the [RuCl(TPA)(Me2SO)]+ complex were easily separated by fractional recrystallization. The molecular structures of trans- and cis(Cl,N(amino))-[RuCl(TPA)(Me2SO)]+ complexes and the trans(Cl,N(amino))-[RuCl{5-(MeOCO)3-TPA}(Me2SO)]+ complex have been determined by X-ray structural analyses. The reaction of TPA with [RuCl2(PhCN)4] gave a single isomer of the chloro(benzonitrile)ruthenium(II) complex, whereas the bis(benzonitrile)ruthenium(II) complex was obtained with BPG. The cis(Cl,N(amino))-[RuCl(TPA)(Me2SO)]+ complex is thermodynamically much less stable than the trans isomer and isomerizes in dimethyl sulfoxide at 65-100 degrees C. Oxygenation of alkanes catalyzed by these ruthenium(II) complexes has been examined. The chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complexes with TPA and its derivatives using m-chloroperbenzoic acid as a cooxidant showed high catalytic ability. Adamantane was efficiently and selectively oxidized to give 1-adamantanol up to 88%. The chloro(dimethyl sulfoxide-kappaS)ruthenium(II) complex with 5-(MeOCO)3-TPA was found to be the most active catalyst among the complexes examined.

Photoassisted oxygenation of alkane catalyzed by ruthenium complexes using 2,6-dichloropyridine N-oxide under visible light irradiation.

The chloro(Me(2)SO)ruthenium(II) complexes with tris(2-pyridylmethyl)amine or its derivative catalyses the selective, stereospecific, and photoregulative alkane oxidation in the presence of 2,6-dichloropyridine N-oxide under visible light irradiation.