IntroductionAcute myeloid leukemia (AML) is an aggressive form of a malignant disorder of the hematopoietic system that shows increasing incidence with age and is characterized by highly proliferative blast cells. [1][2][3] Aberrant activity of tyrosine kinases has been shown to be present in various malignant diseases and AML is no exception. The FMS-like tyrosine kinase 3 (FLT3) gene in chromosome band 13q12 encodes a receptor tyrosine kinase that belongs to the same family as FMS, KIT, and the 2 genes encoding PDGFR␣ and ␤. [4][5][6][7] It is normally expressed by hematopoietic stem/progenitor cells (HSPCs) and as hematopoietic cells differentiate FLT3 expression is lost. [8][9][10][11] A large body of work has shown that FLT3 plays roles in survival, proliferation, and differentiation. Aside from its role in regulating normal hematopoiesis, FLT3 is also highly expressed in several hematologic malignancies. 7 Mutations in the receptor, in the form of internal tandem duplication (ITD) of the juxtamembrane domain and point mutations of the kinase domain, both result in constitutive activation. 7 These mutations occur in one third of AML patients making it one of the most commonly mutated genes in AML. 12,13 Patients with FLT3/ITD mutations have been demonstrated to have very poor prognosis. 5,14,15 However, the molecular basis by which FLT3/ITD mutations lead to aggressive disease and poor prognosis in AML is not yet clearly understood.The process of activation, internalization, and degradation of FLT3 occurs in a similar fashion to other members of the class III receptor-type tyrosine kinases (RTKs) family. 16 Binding of FLT3 ligand (FL) causes homodimerization, tyrosine kinase activation, receptor autophosphorylation, and initiation of downstream signaling cascades. 7 The FLT3 receptor kinase shares structural homology with other type III receptor kinases, such as KIT and FMS, with all 3 playing an important role in survival, proliferation, and differentiation of hematopoietic cells. 17 We and other investigators have shown that STAT5 is one of the principal pathways involved in mediating gene expression in response to constitutive receptor activation through mutation. FLT3 signaling results in activation of pathways through phosphorylation of STAT5, MAPK, AKT, VAV, CBL, and BAD. [18][19][20] Phosphorylation and activation of STAT5 by FLT3/ITD mutants are particularly strong compared with its phosphorylation in the wild-type FLT3 allele. 21 STAT5 tyrosine phosphorylation mediates STAT5 protein dimerization through a mechanism involving SH2 domains and N-terminal regions and results in translocation to the nucleus where it activates transcription of a number of genes. 22 However, recent data suggest that STAT5 may have other interacting partners. 23,24 For example, signal-transducing adapter proteins (STAPs) have been shown to constitutively interact with inactive STAT5 in the cytoplasm but dissociate when STAT5 is phosphorylated. 24 STAT5 is also phosphorylated on serine residues, possibly by the ERK1/2 prote...

Ionizing radiation-induced oxidative stress is attributed to generation of reactive oxygen species (ROS) due to radiolysis of water molecules and is short lived. Persistent oxidative stress has also been observed after radiation exposure and is implicated in the late effects of radiation. The goal of this study was to determine if long-term oxidative stress in freshly isolated mouse intestinal epithelial cells (IEC) is dependent on radiation quality at a dose relevant to fractionated radiotherapy. Mice (C57BL/6J; 6 to 8 weeks; female) were irradiated with 2 Gy of γ-rays, a low-linear energy transfer (LET) radiation, and intestinal tissues and IEC were collected 1 year after radiation exposure. Intracellular ROS, mitochondrial function, and antioxidant activity in IEC were studied by flow cytometry and biochemical assays. Oxidative DNA damage, cell death, and mitogenic activity in IEC were assessed by immunohistochemistry. Effects of γ radiation were compared to 56Fe radiation (iso-toxic dose: 1.6 Gy; energy: 1000 MeV/nucleon; LET: 148 keV/µm), we used as representative of high-LET radiation, since it's one of the important sources of high Z and high energy (HZE) radiation in cosmic rays. Radiation quality affected the level of persistent oxidative stress with higher elevation of intracellular ROS and mitochondrial superoxide in high-LET 56Fe radiation compared to unirradiated controls and γ radiation. NADPH oxidase activity, mitochondrial membrane damage, and loss of mitochondrial membrane potential were greater in 56Fe-irradiated mice. Compared to γ radiation oxidative DNA damage was higher, cell death ratio was unchanged, and mitotic activity was increased after 56Fe radiation. Taken together our results indicate that long-term functional dysregulation of mitochondria and increased NADPH oxidase activity are major contributing factors towards heavy ion radiation-induced persistent oxidative stress in IEC with potential for neoplastic transformation.

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Risk of colorectal cancer (CRC) after exposure to low linear energy transfer (low-LET) radiation such as γ-ray is highlighted by the studies in atom bomb survivors. On the contrary, CRC risk prediction after exposure to high-LET cosmic heavy ion radiation exposure is hindered due to scarcity of in vivo data. Therefore, intestinal tumor frequency, size, cluster, and grade were studied in APCMin/+ mice (n = 20 per group; 6 to 8 wks old; female) 100 to 110 days after exposure to 1.6 or 4 Gy of heavy ion 56Fe radiation (energy: 1000 MeV/nucleon) and results were compared to γ radiation doses of 2 or 5 Gy, which are equitoxic to 1.6 and 4 Gy 56Fe respectively. Due to relevance of lower doses to radiotherapy treatment fractions and space exploration, we followed 2 Gy γ and equitoxic 1.6 Gy 56Fe for comparative analysis of intestinal epithelial cell (IEC) proliferation, differentiation, and β-catenin signaling pathway alterations between the two radiation types using immunoblot, and immunohistochemistry. Relative to controls and γ-ray, intestinal tumor frequency and grade was significantly higher after 56Fe radiation. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after 56Fe radiation relative to γ radiation. Staining for phospho-histone H3, indicative of IEC proliferation, was more and alcian blue staining, indicative of IEC differentiation, was less in 56Fe than γ irradiated samples. Activation of β-catenin was more in 56Fe-irradiated tumor-free and tumor-bearing areas of the intestinal tissues. When considered along with higher levels of cyclin D1, we infer that relative to γ radiation exposure to 56Fe radiation induced markedly reduced differentiation, and increased proliferative index in IEC resulting in increased intestinal tumors of larger size and grade due to preferentially greater activation of β-catenin and its downstream effectors.

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We have calculated the ground-state eigenvalues of the kx4 anharmonic oscillator nonperturbatirely, using the Hill determinant. Our results a r e in remarkable agreement with those obtained from the or el-pad6 approximants of the perturbation series.From an exhaustive numerical analysis of the integral exists for that z . To facilitate numerical perturbation series for the ground-state energy computation, Graffi et al. used Pad6 approximants level of the one-dimensional anharmonic oscillator for +(tz). for which the Hamiltonian i s given byIn this note, we wish to point out that exact values of the energy levels of the anharmonic oscillator d2can also be obtained without recourse to the stan-dard perturbation series and associated summability techniques. Our approach, essentially based Bender and Wu' have shown that the power series in h is divergent for all h though each term of the series is finite. Further, they show that the energy levels of the system orginally defined for real h > 0 can be analytically continued into the complex h plane and that the continuation has an infinite number of branch points with a limit point at h = 0. Such series a r e quite common in relativistic quantum mechanics and the usual belief i s that they a r e asymptotic in nature.' It i s well known in the mathematical literature3 that such series can often be summed4 uniquely through the use of such summability techniques a s the Stieltjes-Pad6 o r the Borel methods. Simon5 has recently investigated the anharmonic oscillator with the general anharmonic term AX'" ( m an integer > 0) and has shown that the pth energy level E:(h) i s analytic in a certain r egion of the X plane and that the perturbation series i s asymptotic to the value EF(h). In particular, he has calculated E;(A) by converting the perturbation series into a series of pad6 approximants for various values of A. In a recent communication, Graffi et uLs6 have shown how improved values of the ground-state energy level for arbitrary h can be obtained by using Pad6 approximants of the Borel transform of the asymptotic perturbation series. In essence, their method consists in r eplacing the s e r i e s C:=, anzn by the Borel sumWithin their regions of convergence both series a r e identical, but for values of z for which the series C ; = , u,zn diverges, the integral representation gives the value of the series provided the upon solving the Hill determinants in finding eigenvalues, has long been known in the literature of mathematical physics .7 From our analysis we find the following: (i) For small h (A <

The ground state as well as excited energy levels of the generalized anharmonic oscillator defined by the Hamiltonian Hm = − d2/dx2+x2+ λx2m, m = 2,3, …, have been calculated nonperturbatively using the Hill determinants. For the λx4 oscillator, the ground state eigenvalues, for various values of λ, have been compared with the Borel-Padé sum of the asymptotic perturbation series for the problem. The agreement is excellent. In addition, we present results for some excited states for m = 2 as well as the ground and the first even excited states for m = 3 and 4. The behaviour of all the energy levels with respect to the coupling parameter shows a qualitative similarity to the ground state of the λx4 oscillator. Thus the results are model independent, as is to be expected from the WKB approximation. Our results also satisfy the scaling property that εn(m)(λ)/λ1/(m+1) tend to a finite limit for large λ, and always lie within the variational bounds, where available.