Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Extraordinary behaviour of the Y1?xPrxBa2Cu3O7?δ system

Investigations of Y_1–x M _x Ba₂Cu₃O_7– (M=Ce, Th)c-axis oriented thin film specimens show that the rate of depression ofT _c withx is larger for M=Th, than for M=Ce and Pr, and suggest that Ce, like Th, is tetravalent in this compound. Hall effect measurements on Y_1–x Pr _x Ba₂Cu₃O_7– single crystals reveal aT ² dependence of the cotangent of the Hall angle in the normal state and a negative Hall anomaly belowT _c in the superconducting state, in agreement with recent reports. Our research shows that the depth, , of the negative Hall signal scales withT/T _c and that the maximum value of decreases linearly withx and vanishes atx0.24. Magnetoresistance measurements on Y_1–x Pr _x Ba₂Cu₃O_7– single crystals indicate that the irreversibility lineH(T ^*) obeys a universal scaling relation characterized by anm=3/2 power law nearT _c, with a crossover to a more rapid temperature dependence of belowT/T _c 0.6, similar to that observed for polycrystalline specimens.     

Non fermi liquid ground states in strongly correlated f-electron materials

Experimental efforts to characterize and develop an understanding of non Fermi liquid (NFL) behavior at low temperature in f-electron materials are reviewed for three f-electron systems: M_1–xU_xPd₃ (M = Sc, Y), U_1–xTh_xPd₂Al₃, and UCu_5–xPd_x. The emerging systematics of NFL behavior in f-electron systems, based on the present sample of nearly ten f-electron systems, is updated. Many of the f-electron systems exhibit the following temperature dependences of the electrical resistivity p, specific heat C, and magnetic susceptibility for T T₀, where T_o is a characteristic temperature: P(T) 1 –aT/T ₀, where a < 0 or > 0, C(T)/T (-1/T _o) In (T/bT ₀), and (T) 1 –c(T/T_o)^1/2. In several of the f-electron systems, the characteristic temperature T_o can be identified with the Kondo temperature T_k.     

Uncertain variables and their applications for a class of uncertain systems

This paper presents definitions and basic properties of uncertain variables and shows how they may be applied to the analysis and decision making in static systems with unknown parameters in their mathematical models. The unknown parameters are assumed to be uncertain variables described by certainty distributions given by an expert. Two versions of the uncertain variables are described. The uncertain variable in the first version may be considered as a special case of the fuzzy number with a specific interpretation. Two forms of systems are considered in the paper: a system described by a function (functional system) and a system described by a relation (relational system). In both cases the statements and general solutions of the analysis and decision problems are presented. Simple examples illustrating the application of the uncertain variables are included.     

Fluorine-Containing Drug Administration in Rats Results in Fluorination of Selected Proteins in Liver and Brain Tissue

In many pharmaceuticals, a hydrogen atom or hydroxyl group is replaced by a fluorine to increase bioavailability and biostability. The fate of fluorine released from fluorine-containing drugs is not well investigated. The aim of this study was to examine possible fluorination of proteins in rat liver and brain after administration of the fluorinated drug cinacalcet. We assigned 18 Wistar rats to a control group (n = 6) and a group treated with cinacalcet (2 mg kg⁻¹/body weight, 5 days/week), divided into 7 day (n = 6) and 21 day (n = 6) treatment subgroups. Fluorinated proteins were identified using a free proteomics approach; chromatographic separation and analysis by high-resolution mass spectrometry; peptide/protein identification using the Mascot search algorithm; manual verification of an experimentally generated MS/MS spectrum with the theoretical MS/MS spectrum of identified fluorinated peptides. Three fluorinated proteins (spectrin beta chain; carbamoyl-phosphate synthase [ammonia], mitochondrial; 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 1) were identified in the liver and four (spectrin beta chain, dihydropyrimidinase-related protein 4, prominin-2, dihydropyrimidinase-related protein 4) in the brain tissue after 21 days of cinacalcet treatment, but not in the control group. Introduction of fluorine into an organism by administration of fluorinated drugs results in tissue-specific fluorination of proteins.     

Synthesis of Azafluorenones

Syntheses of azafluorenones from monoazaphenanthrenes and phenanthrolines has ben investigated. 1- and 4-monoazaphenanthrenes have been oxidized by J₂O₅ in acetic acid to give quinones which were converted to 4- and 1-azafluoren-9-ones in alkaline media. Phenanthrolines can be oxidized directly by means of permanganate in alkaline medium to 1,5-, 1,6-, 1,8-, 2,5- and 3,5-diazafluoren-9-ones. From 1-, 4-azaphenanthrene- and 1,8-phenanthrolinequinones new benzopyrido- and dipyridophenazines have been synthesized.     

Utilisation of neural networks to identify the status of the cutting tool point

The paper presents the results of a research work using artificial neural networks to classify the signals of machining forces typical for particular worn cutting tools. Prospectively, a proper classification of these signals may allow the identification of cutter tips condition in multi-tools heads status’ monitoring systems, and facilitate the construction of systems for controlling rocks excavating process.