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.     

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.     

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.     

Assessment of cytotoxicity and immune compatibility of phytochemicals‐mediated biosynthesised silver nanoparticles using Cynara scolymus

The study was focused on the phytochemicals‐mediated biosynthesis of silver nanoparticles using leaf extracts and infusions from Cynara scolymus. To identify the antioxidant activity and total phenolic content, the 1,1‐diphenyl‐1‐picrylhydrazyl and Folin–Ciocalteau methods were applied, respectively. The formation and stability of the reduced silver ions were monitored by UV–vis spectrophotometer. The particle sizes of the silver nanoparticles were characterised using the dynamic light scattering technique and scanning electron microscope. The phase composition of the obtained silver nanoparticles was characterised by X‐ray diffraction. The silver nanoparticles suspension, artichoke infusion, and silver ions were separately tested towards potential cytotoxicity and pro‐inflammatory effect using mouse fibroblasts and human monocytes cell line, respectively. The total phenolic content and antioxidant activity of ethanol extract and infusion were found significantly higher as compared to aqueous extract and infusion. The UV–visible spectrophotometric analysis revealed the presence of the characteristic absorption band of the Ag nanoparticles. Moreover, it was found that with the increasing volume of plant extract, the average size of particles was increased. Biocompatibility results evidently showed that silver nanoparticles do not induce monocyte activation, however in order to avoid their cytotoxicity suspension at a concentration <2 ppm should be applied.Inspec keywords: pharmaceuticals, health and safety, renewable materials, toxicology, organic compounds, antibacterial activity, X‐ray diffraction, nanomedicine, nanoparticles, nanofabrication, suspensions, ultraviolet spectra, visible spectra, scanning electron microscopy, silver, particle sizeOther keywords: phytochemicals‐mediated biosynthesis, antioxidant activity, total phenolic content, dynamic light scattering technique, silver nanoparticles suspension, scanning electron microscopy, Cynara scolymus, 1,1 diphenyl‐1‐picrylhydrazyl method, cytotoxicity, immune compatibility, leaf extracts, UV‐vis spectrophotometry, particle size, Folin‐Ciocalteau methods, phase composition, X‐ray diffraction, artichoke infusion, pro‐inflammatory effect, mouse fibroblasts, human monocytes cell line, Ag     

A Mixed Ligand Approach for the Asymmetric Hydrogenation of 2‐Substituted Pyridinium Salts

Herein we describe a new methodology for the asymmetric hydrogenation (AH) of 2‐substituted pyridinium salts. An iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine was shown to hydrogenate N‐benzyl‐2‐arylpyiridinium bromides to the corresponding N‐benzyl‐2‐arylpiperidines with full conversion and good enantioselectivity. The mechanism of the reaction under optimized conditions was investigated via kinetic measurements and isotopic labeling experiments. Our study suggests that the hydrogenation starts with a 1,4‐hydride addition and that the enantiodiscriminating step involves the reduction of an iminium intermediate.

     

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.