The combination of FLT3 and DNA methyltransferase inhibition is synergistically cytotoxic to FLT3/ITD acute myeloid leukemia cells

Effective treatment regimens for elderly acute myeloid leukemia (AML) patients harboring internal tandem duplication mutations in the FMS-like tyrosine kinase-3 (FLT3) gene (FLT3/ITD) are lacking and represent a significant unmet need. Recent data on the effects of FLT3 tyrosine kinase inhibitors on FLT3/ITD+ AML showed promising clinical activity, including in elderly patients. DNA methyltransferase (DNMT) inhibitors such as decitabine (5-aza-2-deoxycytidine, DEC) and 5-azacitidine (AZA) demonstrated clinical benefit in AML, are well tolerated and are associated with minimal increases in FLT3 ligand, which can represent a potential resistance mechanism to FLT3 inhibitors. In addition, both FLT3 and DNMT inhibition are associated with the induction of terminal differentiation of myeloid blasts. Consequently, there is a strong theoretical rationale for combining FLT3 and DNMT inhibition for FLT3/ITD+ AML. We therefore sought to study the anti-leukemic effects of DEC, AZA and FLT3 inhibitors, either as single agents or in combination, on AML cell lines and primary cells derived from newly diagnosed and relapsed AML patients. Our studies indicate that combined treatment using FLT3 inhibition and hypomethylation confers synergistic anti-leukemic effects, including apoptosis, growth inhibition and differentiation. The simultaneous administration of AZA and FLT3 inhibition appears to be the most efficacious combination in this regard. These drugs may provide a novel therapeutic approach for FLT3/ITD+ AML, in particular for older patients

PPAR Alpha Regulation of the Immune Response and Autoimmune Encephalomyelitis

PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in the regulation of lipid metabolism, energy balance, artherosclerosis and glucose control. Recent studies suggest that they play an important role in regulating inflammation. This review will focus on PPAR-α regulation of the immune response. We describe how PPAR-α regulates differentiation of T cells by transactivation and/or interaction with other transcription factors. Moreover, PPAR-α agonists have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE) in mice, suggesting that they could provide a therapy for human autoimmune diseases such as multiple sclerosis

How strange are compact star interiors ?

We discuss a Nambu--Jona-Lasinio (NJL) type quantum field theoretical approach to the quark matter equation of state with color superconductivity and construct hybrid star models on this basis. It has recently been demonstrated that with increasing baryon density, the different quark flavors may occur sequentially, starting with down-quarks only, before the second light quark flavor and at highest densities also the strange quark flavor appears. We find that color superconducting phases are favorable over non-superconducting ones which entails consequences for thermodynamic and transport properties of hybrid star matter. In particular, for NJL-type models no strange quark matter phases can occur in compact star interiors due to mechanical instability against gravitational collapse, unless a sufficiently strong flavor mixing as provided by the Kobayashi-Maskawa-'t Hooft determinant interaction is present in the model. We discuss observational data on mass-radius relationships of compact stars which can put constraints on the properties of dense matter equation of state.Comment: 7 pages, 2 figures, to appear in the Proceedings of the International Conference SQM2009, Buzios, Rio de Janeiro, Brazil, Sep.27-Oct.2, 200

Rooting Cuttings of Northern Red Oak (Quercus rubra L.)

Several techniques have been used experimentally to vegetatively propagate northern red oak (Quercus rubra L.), including: 1) rooting juvenile softwood cuttings in intermittent mist, 2) rooting shoots originating from mature buds grafted onto juvenile root stocks, and 3) in vitro shoot proliferation of juvenile or mature shoots followed by in vitro rooting. Of these techniques, rooting juvenile softwood cuttings has provided the most consistent results for northern red oak (NRO). Juvenility (or at least the associated ability to form adventitious roots) disappears rapidly among progressive flushes of growth in NRO seedlings. Decreased rooting has been reported for NRO shoots obtained from progressive flushes of growth produced within a growing season, as well as shoots representing flushes obtained from successive seasons of growth. However, as with many other tree species, the process of maturation in NRO can be slowed by pruning to encourage juvenile shoot production. Optimizing the number of juvenile cuttings produced from each stock plant is necessary for efficient rooted cutting production systems. In addition, rooting conditions must be determined for the shoots produced under these pruning regimes. Two NRO rooted cutting studies are currently being conducted at NCSU. The objective of the first study is to evaluate the effects of stock plant pruning location, diameter, and age on new shoot production. Treatments include pruning first-year seedlings, as well as one-, two-, and three-year-old seedlings to the base of the first, second, third, or fourth flush of growth produced during the first growing season. The objective of the second study is to evaluate the ability of the shoots produced in the first study to form adventitious roots. Treatments include three rooting hormone levels (0.5%, 1%, and 1.5% IBA) and a control (45% EtOH). Preliminary results from both studies will be presented.Papers and abstracts from the 27th Southern Forest Tree Improvement Conference held at Oklahoma State University in Stillwater, Oklahoma on June 24-27, 2003

Monomorphic post-transplant lymphoproliferative disorder of the tongue: case report and review of literature

<p>Abstract</p> <p>Background</p> <p>Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of hematological diseases arising in context of immunosuppression after organ transplantation. PTLD can involve any organ; however, it is extremely rare in oral cavity.</p> <p>Methods</p> <p>Using morphologic and immunophenotypic approaches we have studied a case of monomorphic PTLD of the tongue that developed in a patient following unilateral kidney and pancreas transplantation on immunosuppressive therapy. Additionally, cases of PTLD in the oral cavity were reviewed in the English literature.</p> <p>Results</p> <p>The neoplasm showed large cell morphology and B-cell phenotype. In situ hybridization for Epstein-Barr virus was positive. Complete remission was obtained after decreasing immunosuppressive therapy. The patient remained in remission at 790 days' follow up.</p> <p>Conclusion</p> <p>This rare case increased our awareness of PTLD in the oral cavity of patients following solid organ transplantation and immunosuppressive therapy.</p

Diquark condensation effects on hot quark star configurations

The equation of state for quark matter is derived for a nonlocal, chiral quark model within the mean field approximation.We investigate the effects of a variation of the formfactors of the interaction on the phase diagram of quark matter. Special emphasis is on the occurrence of a diquark condensate which signals a phase transition to color superconductivity and its effects on the equation of state under the condition of beta- equilibrium and charge neutrality. We calculate the quark star configurations by solving the Tolman- Oppenheimer- Volkoff equations and obtain for the transition from a hot, normal quark matter core of a protoneutron star to a cool diquark condensed one a release of binding energy of the order of Delta M c^2 ~ 10^{53} erg. We find that this energy could not serve as an engine for explosive phenomena since the phase transition is not first order. Contrary to naive expectations the mass defect increases when for a given temperature we neglect the possibility of diquark condensation.Comment: 24 pages, 2 tables, 8 figures, references added, figures and text improve

Modern compact star observations and the quark matter equation of state

We present a hybrid equation of state (EoS) for dense matter that satisfies phenomenological constraints from modern compact star (CS) observations which indicate high maximum masses (M = 2 M_sun) and large radii (R> 12 km). The corresponding isospin symmetric EoS is consistent with flow data analyses of heavy-ion collisions and a deconfinement transition at approx. 0.55 fm^{-3}. The quark matter phase is described by a 3-flavor Nambu--Jona-Lasinio model that accounts for scalar diquark condensation and vector meson interactions while the nuclear matter phase is obtained within the Dirac-Brueckner-Hartree-Fock (DBHF) approach using the Bonn-A potential. We demonstrate that both pure neutron stars and neutron stars with quark matter cores (QCSs) are consistent with modern CS observations. Hybrid star configurations with a CFL quark core are unstable.Comment: 16 pages, 4 figures; published version, important note added in proo

Association of acute myeloid leukemias most immature phenotype with risk groups and outcomes

The precise phenotype and biology of acute myeloid leukemia stem cells remain controversial, in part because the “gold standard” immunodeficient mouse engraftment assay fails in a significant fraction of patients and identifies multiple cell-types in others. We sought to analyze the clinical utility of a novel assay for putative leukemia stem cells in a large prospective cohort. The leukemic clone’s most primitive hematopoietic cellular phenotype was prospectively identified in 109 newly-diagnosed acute myeloid leukemia patients, and analyzed against clinical risk groups and outcomes. Most (80/109) patients harbored CD34+CD38− leukemia cells. The CD34+CD38− leukemia cells in 47 of the 80 patients displayed intermediate aldehyde dehydrogenase expression, while normal CD34+CD38− hematopoietic stem cells expressed high levels of aldehyde dehydrogenase. In the other 33/80 patients, the CD34+CD38− leukemia cells exhibited high aldehyde dehydrogenase activity, and most (28/33, 85%) harbored poor-risk cytogenetics or FMS-like tyrosine kinase 3 internal tandem translocations. No CD34+ leukemia cells could be detected in 28/109 patients, including 14/21 patients with nucleophosmin-1 mutations and 6/7 acute promyelocytic leukemia patients. The patients with CD34+CD38− leukemia cells with high aldehyde dehydrogenase activity manifested a significantly lower complete remission rate, as well as poorer event-free and overall survivals. The leukemic clone’s most immature phenotype was heterogeneous with respect to CD34, CD38, and ALDH expression, but correlated with acute myeloid leukemia risk groups and outcomes. The strong clinical correlations suggest that the most immature phenotype detectable in the leukemia might serve as a biomarker for “clinically-relevant” leukemia stem cells. ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01349972","term_id":"NCT01349972"}}NCT01349972