Glutamine prevents DMBA-induced squamous cell cancer

The etiology of oral squamous cell carcinoma has been linked to environmental carcinogens, such as activated aromatic heterocyclic radicals and epoxides. Our previous work on implantable and 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer showed that oral glutamine (GLN) inhibited tumor growth possibly through stimulation of host - and selective inhibition of tumor glutathione (GSH). This finding was associated with up-regulation of NK cell activity, decreased IGF-1 and TGF-beta in the circulation and downregulation of PI-3K/Akt antiapoptotic signaling in tumors. The present study was designed to investigate the effect of topically applied GLN on DMBA-induced hamster buccal pouch squamous cell carcinoma. Histopathological alterations in buccal pouches were studied by light microscopy. GLN and GSH levels in blood and buccal mucosa were determined using specific enzyme assays. The protein expression of bax, bcl-2 and PARP was determined by western blotting. H-ras and p53 genes were examined for presence of mutations using direct DNA sequencing. Fourteen weeks after DMBA application none of the GLN-supplemented animals developed tumors, while all of the control animals had well developed squamous cell carcinomas. The inhibition of DMBA-carcinogenesis by GLN application was associated with increased arterial GLN and GSH, elevated buccal mucosa GSH as well as induction of bax and PARP, and inhibition of bcl-2. H-ras and p53 were wild type. The results from this study in combination with our previous data suggest that the chemopreventive effects of GLN are exerted by enhancing the antioxidant status of the body and activation of apoptosis.     

Facilitated Synthesis of Mg2Ni Based Composites with Attractive Hydrogen Sorption Properties

Composites based on Mg₂Ni with 5% activated carbon from apricot stones (ACAP) have been prepared by ball milling and subsequent annealing in hydrogen atmosphere. The purpose of the primary metal (Mg, Ni, and V) milling was to reduce the particle size and achieve a good contact between them, without forming intermetallic compounds. During hydriding/dehydriding at 300 °C the amount of the Mg₂Ni phase progressively increased, and after 10 cycles about 50% Mg₂(Ni,V) was achieved. The hydrogenation produced mainly Mg₂NiH₄, but small amounts of MgH₂ and VH_x were also detected in the powder mixture. Relatively high hydrogen storage capacity and fast hydriding/dehydriding kinetics of the Mg_2.1Ni_0.7V_0.3—5 wt.% ACAP composite were determined both from hydrogen gas phase and electrochemically.     

Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation

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Serum lipids,uric acid and leptin/adiponectin ratio in clinically healthy normal weight and overweight young men,aged 17–20 years

BackgroundObesity is reaching epidemic proportions worldwide and is associated with an increased risk of cardiovascular morbidity and mortality. Some mechanisms linking obesity with cardiovascular disease (CVD) are metabolic and hormonal alterations such as dyslipidemia, hyperuricemia and hyperleptinemia. These mechanisms are well studied in the elderly population, but data concerning adolescents are still scarce. The aim of this study was to evaluate body-weight associated alterations of these risk factors in young men, aged 17–20 years.MethodsThe cross-sectional study included 80 men, divided into two groups according to their body mass index (BMI: cutoff = 25 kg/m²): group N (normal: n = 55; BMI <25; age 17.9 ± 1.5 years), and group OW/O (overweight/obese: n = 25; BMI>25; age 17.9 ± 1.6 years). Anthropometric indices included BMI, waist circumference, and waist/hip ratio. Total cholesterol (TC), triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), uric acid and leptin/adiponectin (L/A) ratio were determined in both groups. Data were analyzed using variation and correlation tests from SPSS 10.0. Values are expressed as mean ± standard deviation (SD).ResultsTC and TG were significantly higher in the OW/O group in comparison with the controls (4.59 ± 0.93 versus 4.05 ± 0.71, and 1.46 ± 0.78 versus 1.04 ± 0.46 mmol/l, respectively, p < 0.05 for both). In the OW/O group, blood pressure, L/A ratio, and uric acid were also significantly higher compared with group N (0.68 ± 0.81 versus 0.14 ± 0.14 for L/A ratio, p < 0.01, and 385.0 ± 74.6 versus 344.6 ± 65.3 μmol/L for uric acid, p < 0.05). The L/A ratio in the control group correlated significantly with body weight, waist circumference and TG levels, and with body weight, BMI, waist circumference and uric acid in the OW/O group. Uric acid correlated significantly with anthropometric parameters in both groups.ConclusionsOur data indicate that unfavorable metabolic and hormonal alterations occur early in overweight subjects, while they are still clinically healthy. In the OW/O group both L/A ratio and uric acid are more strongly associated with anthropometric indices, which suggests that they can be modified by lifestyle interventions.     

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.     

Some recent insights into the prothrombogenic mechanisms of antiphospholipid antibodies

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, detected in the sera of patients with both autoimmune and various non-autoimmune diseases. They are also detected in subjects with no overt underlying disease - the primary antiphosphilipid syndrome (PAPS). High titers of APL are associated with arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. There have been many suggestions explaining the potential mechanisms of the procoagulant effect of aPL. These include endothelial cell (EC) activation; increased adhesion molecule expression; inhibition of EC prostacyclin release, increased leucocyte adhesion to EC, downregulation of thrombomodulin expression. APL induce the procoagulant activity of monocytes via increased tissue factor expression and directly stimulate platelet hyperactivity with resultant production of enhanced amounts of the proaggregatory molecule of TXA(2). In vitro studies show that prepro-endothelin-1 mRNA is induced by human monoclonal anticardiolipin antibodies and this might contribute to vasospasm, and, ultimately, to arterial occlusion. The hypercoagulable state in APS patients is associated with alterations in the protein C/S pathway. It is suggested that aPL may impair the protein C anticoagulant system. Acquired protein C and protein S deficiency is described in patients with APS. Beta2- glycoprotein I, (Beta2-GPI) a natural anticoagulant, is involved in the regulation of protein S anticoagulant activity by preventing the binding of protein S to C4b-binding protein. APL were shown to inhibit this effect of Beta2- GP I. As the group of aPL is very heterogeneous, it is unlikely that a single mechanism is responsible for the thrombogenic activity of all aPLs associated with thrombosis.     

Synthesis and use of 4-peptidylhydrazido-N-hexyl-1,8-naphthalimides as fluorogenic histochemical substrates for dipeptidyl peptidase IV and tripeptidyl peptidase I

Gly-Pro-, Gly-Pro-Met- and Ala-Ala-Phe-N'-(2-hexyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)-hydrazides are synthesized by guanidinium/uronium type condensing reagent and used as fluorogenic substrates to localize dipeptidyl peptidase IV and tripeptidyl peptidase I activities in mammalian tissue sections. Enzyme hydrolysis releases 2-hexyl-6-hydrazino-1H-benzo[de]isoquinoline-1,3(2H)-dione, which couples with piperonal to form insoluble fluorescent hydrazone, precipitating on the enzyme locations and marking them. The fluorescent technique reveals precisely the enzymes locations at the lack of background noise in a single incubation step. It avoids most of the drawbacks of the previously proposed fluorescent histochemical techniques and can be valuable for the in situ studies of these enzymes in norm and pathology.