Prognostic impact of RAS mutations in patients with myelodysplastic syndrome

RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10–15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild‐type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome. Am. J. Hematol. 88:365–369, 2013. © 2013 Wiley Periodicals, Inc.     

The remarkable performance of a single iridium atom supported on hematite for methane activation: a density functional theory study

Methane is the major component of natural gas, and it significantly contributes to global warming. In this study, we investigated methane activation on the α-Fe₂O₃(110) surface and M/α-Fe₂O₃(110) surfaces (M = Ag, Ir, Cu, or Co) using the density-functional theory (DFT) + U method. Our study shows that the Ir/α-Fe₂O₃(110) surface is a more effective catalyst for C–H bond activation than other catalyst surfaces. We have applied electron density difference (EDD), density of states (DOS), and Bader charge calculations to confirm the cooperative CH⋯O and agostic interactions between CH₄ and the Ir/α-Fe₂O₃(110) surface. To further modify the reactivity of the Ir/α-Fe₂O₃(110) surface towards methane activation, we conducted a study of the effect of oxygen vacancy (O_V) on C–H activation and CH₄ dehydrogenation. In the comparison of pristine α-Fe₂O₃(110), Ir/α-Fe₂O₃(110), and Ir/α-Fe₂O₃(110)–O_V surfaces, the Ir/α-Fe₂O₃(110)–O_V surface is the best in terms of CH₄ adsorption energy and C–H bond elongation, whereas the Ir/α-Fe₂O₃(110) surface catalyst has the lowest C–H bond activation barrier for the CH₄ molecule. The calculations indicate that the Ir/α-Fe₂O₃(110)–O_V surface could be a candidate catalyst for CH₄ dehydrogenation reactions.

The Fe₂O₃(110)–O_V surface is the best in terms of CH₄ adsorption energy and C–H bond elongation. Therfore, the Ir/α-Fe₂O₃(110)–O_V surface could be a candidate catalyst for CH₄ dehydrogenation reaction.     

The effects of anagrelide on human megakaryocytopoiesis

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic-committed progenitor cells (CFU-M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU-M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU-M in vitro . In-vivo and in-vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.     

Seasonal fluctuations of nematode populations in breeding ewes and lambs

The seasonal changes in nematode populations of a flock of sheep in the Montreal area were determined using serial fecal egg counts, fecal culture of larvae and necropsy worm counts. It was found that Ostertagia spp.,Nematodirus spp., Trichostrongylus agei, Trichostrongylus spp. and Chabertia ovina over-wintered on pasture and could initiate patent infections the following spring. The development of populations of H. contortus was typical of that seen with most of the other species and was characterized by the following series of events. In early winter when the study was started with stabled pregnant ewes, most of the populations were immature and the egg counts were low and remained so throughout the entire winter. However, in the spring, following lambing, large numbers of adult worms were seen with a consequent decrease in immatures and a sudden increase in egg counts. When the ewes and lambs were pastured together, the egg counts in ewes dropped consequent to "self-cure", the "spring-rise" providing the major source of overwhelming infections for lambs with deaths by the end of July. As the season progressed larvae taken in by both ewes and lambs did not mature, and by early fall, most of the worm population consisted of immature forms. It appeared that H. contortus could not have more than two generations in ewes or lambs in a single grazing season.     

Seasonal fluctuation and inhibited development of populations of Dictyocaulus filaria in ewes and lambs

The fluctuation of populations of Dictyocaulus filaria in sheep was studied under field conditions in which animals are housed during the winter and grazed from late spring to autumn. A comparison was made between residual pasture contamination with overwintered larvae, the fecal larval deposition by ewes from June and both of these factors combined as sources of infection for spring born lambs. Ewes and lambs were killed serially over a year and worms were recovered from the lungs and counted. It was found that during the stabling period most of the ewes were carrying moderate numbers of D. filaria. However, while the vast majority of lungworm populations in the winter was inhibited in development at the early fifth larval stage, virtually all worms in the spring were adults. Any one source of infection studied contributed to the acquisition of important burdens of D. filaria by lambs as well as ewes. Worm counts reached peak in all lambs by November and this pointed to only one important Dictyocaulus generation per grazing season. It would also appear that larvae picked up by ewes and lambs as the grazing season advanced had become inhibited in development with the inhibition rate being most marked in autumn.     

Conventional and new treatment options for myelofibrosis with myeloid metaplasia

The pathogenetic mechanisms underlying the clonal myeloproliferation and reactive marrow fibrosis that characterize myelofibrosis with myeloid metaplasia (MMM) are poorly understood. Recent advances into the pathophysiology of the disease have not yet translated into effective therapeutic options for patients. There is no standard treatment, and no therapies identified yet, besides allogeneic stem cell transplantation, that will significantly change the natural history of MMM. Treatment is therefore palliative and is geared towards alleviating symptoms of the disease and improving blood counts. Conventional therapies for anemia include androgens and corticosteroids. Cytoreductive agents such as hydroxyurea are indicated for symptomatic organomegaly and the control of leucocytosis or thrombocytosis. Several novel agents have been investigated in the recent past, and include antiangiogenic agents and signal transduction inhibitors that target the angiogenic and fibrogenic cytokines that have been implicated in the pathogenesis of the detrimental bone marrow stromal reaction. Ultimately, an improved understanding of the biological factors that cause the clonal myeloproliferation in MMM will lead to the development of effective therapeutic interventions.     

Mapping of nuclear import signal and importin α3 binding regions of 52K protein of bovine adenovirus-3

Ideal vaccines against influenza viruses should elicit not only a humoral response, but also a cellular response. Mycobacterium tuberculosis HSP70 (mHSP70) have been found to promote immunogenic APCs function, elicit a strong cytotoxic T lymphocyte (CTL) response, and prevent the induction of tolerance. Moreover, it showed linkage of antigens to the C-terminus of mHSP70 (mHSP70c) can represent them as vaccines resulted in more potent, protective antigen specific responses in the absence of adjuvants or complex formulations. Hence, recombinant fusion protein comprising C-terminus of mHSP70 genetically fused to four tandem repeats of the ectodomain of the conserved influenza matrix protein M2 (M2e) was expressed in Escherichia coli, purified under denaturing condition, refolding, and then confirmed by SDS-PAGE, respectively. The recombinant fusion protein, 4xM2e.HSP70c, retained its immunogenicity and displayed the protective epitope of M2e by ELISA and FITC assays. A prime-boost administration of 4xM2e.HSP70c formulated in F105 buffer by intramuscular route in mice (Balb/C) provided full protection against lethal dose of mouse-adapted H1N1, H3N2, or H9N2 influenza A isolates from Iran compared to 0-33.34% survival rate of challenged unimmunized and immunized mice with the currently in use conventional vaccines designated as control groups. However, protection induced by immunization with 4xM2e.HSP70c failed to prevent weight loss in challenged mice; they experienced significantly lower weight loss, clinical symptoms and higher lung viral clearance in comparison with protective effects of conventional influenza vaccines in challenged mice. These data demonstrate that C-terminal domain of mHSP70 can be a superior candidate to deliver the adjuvant function in M2e-based influenza A vaccine in order to provide significant protection against multiple influenza A virus strains.     

A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway

JAK-STAT signaling is involved in the regulation of cell survival, proliferation, and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, whereas they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In the present study, we report that the kinase CK2 is a novel interaction partner of JAKs and is essential for JAK-STAT activation. We demonstrate that cytokine-induced activation of JAKs and STATs and the expression of suppressor of cytokine signaling 3 (SOCS-3), a downstream target, are inhibited by CK2 small interfering RNAs or pharmacologic inhibitors. Endogenous CK2 is associated with JAK2 and JAK1 and phosphorylates JAK2 in vitro. To extend these findings, we demonstrate that CK2 interacts with JAK2V617F and that CK2 inhibitors suppress JAK2V617F autophosphorylation and downstream signaling in HEL92.1.7 cells (HEL) and primary cells from polycythemia vera (PV) patients. Furthermore, CK2 inhibitors potently induce apoptosis of HEL cells and PV cells. Our data provide evidence for novel cross-talk between CK2 and JAK-STAT signaling, with implications for therapeutic intervention in JAK2V617F-positive MPDs.