Elevated tumor-associated antigen expression suppresses variant peptide vaccine responses

Variant peptide vaccines are used clinically to expand T cells that cross-react with tumor-associated Ags (TAA). To investigate the effects of elevated endogenous TAA expression on variant peptide-induced responses, we used the GP70 TAA model. Although young BALB/c mice display T cell tolerance to the TAA GP70(423-431) (AH1), expression of GP70 and suppression of AH1-specific responses increases with age. We hypothesized that as TAA expression increases, the AH1 cross-reactivity of variant peptide-elicited T cell responses diminishes. Controlling for immunosenescence, we showed that elevated GP70 expression suppressed AH1 cross-reactive responses elicited by two AH1 peptide variants. A variant that elicited almost exclusively AH1 cross-reactive T cells in young mice elicited few or no T cells in aging mice with Ab-detectable GP70 expression. In contrast, a variant that elicited a less AH1 cross-reactive T cell response in young mice successfully expanded AH1 cross-reactive T cells in all aging mice tested. However, these T cells bound the AH1/MHC complex with a relatively short half-life and responded poorly to ex vivo stimulation with the AH1 peptide. Variant peptide vaccine responses were also suppressed when AH1 peptide is administered tolerogenically to young mice before vaccination. Analyses of variant-specific precursor T cells from naive mice with Ab-detectable GP70 expression determined that these T cells expressed PD-1 and had downregulated IL-7Rα expression, suggesting they were anergic or undergoing deletion. Although variant peptide vaccines were less effective as TAA expression increases, data presented in this article also suggest that complementary immunotherapies may induce the expansion of T cells with functional TAA recognition.     

Catecholamine-induced insulin resistance of glucose transport in isolated rat adipocytes.

The effects of pre-incubation with isoprenaline and noradrenaline on insulin binding and insulin stimulation of D-glucose transport in isolated rat adipocytes are reported. (1) Pre-incubation of the cells with isoprenaline (0.1-10 microM) in Krebs-Ringer-Hepes [4-(2-hydroxyethyl)-1-piperazine-ethanesulphonic acid] buffer (30 min, 37 degrees C) at D-glucose concentrations of 16 mM, in which normal ATP levels were maintained, caused a rightward-shift in sensitivity of D-glucose transport to insulin stimulation by 50% and a decrease in maximal responsiveness by 30% (2) [A14-125I]insulin binding was reduced significantly by 35% at insulin concentrations less than 100 mu-units/ml and Scatchard analysis showed that this consisted mainly of a decrease in high-affinity binding. (3) Pre-incubation with catecholamines under the same conditions but at low glucose concentrations (0-5 mM) caused a fall in intracellular ATP levels of 65 and 45% respectively. (4) The fall in ATP additionally lowered insulin binding by 50% at all insulin concentrations and a parallel shift of the binding curves in the Scatchard plot showed that this was due to a decrease in the number of receptors. (5) At low and high ATP concentrations the insulin stimulation of D-glucose transport was inhibited to a similar extent. (6) Pre-incubation with catecholamines thus inhibited insulin stimulation of D-glucose transport in rat adipocytes mainly by a decrease in high-affinity binding of insulin, which was not mediated by low ATP levels. This mechanism may play a role in the pathogenesis of catecholamine-induced insulin resistance in vivo.     

Plasma Copper and Bone Mineral Density in Osteopenia: An Indicator of Bone Mineral Density in Osteopenic Females

Copper concentrations in blood plasma have been determined in 25 osteopenic females using inductively coupled plasma–mass spectrometry. A high degree of correlations has been demonstrated between the copper concentrations in plasma and the bone mineral density of the lumbar spine as measured using dual energy X-ray absorptiometry and quantitative computerized tomography. Results clearly indicate the involvement of copper in bone health and osteopenia. It is further suggested that plasma copper might be useful as a cheap and simple method indicative of bone mineral density in osteopenic postmenopausal females.     

Anaerobic degradation of protocatechuate (3,4-dihydroxybenzoate) by Thauera aromatica strain AR-1

The denitrifying bacterium Thauera aromatica strain AR-1 grows anaerobically with protocatechuate (3,4-dihydroxybenzoate (DHB)) as sole energy and carbon source. This bacterium harbors two distinct pathways for degradation of aromatic compounds, the benzoyl-coenzyme A (CoA) pathway for benzoate degradation and the hydroxyhydroquinone (HHQ) pathway for degradation of 3,5-DHB. In order to elucidate whether protocatechuate is degraded via the benzoyl-CoA or the HHQ pathway, induction experiments were carried out. Dense suspensions of cells grown on protocatechuate or benzoate readily degraded benzoate and protocatechuate but not 3,5-DHB. Dense suspensions of 3,5-DHB-grown cells degraded 3,4- and 3,5-DHB at similar rates, but benzoate was not degraded. 3,5-DHB hydroxylating activity was found only in cells grown with this substrate. HHQ dehydrogenase activity was found in extracts of cells grown with 3,5-DHB and at a low rate also in protocatechuate-grown cells, but not in extracts of cells grown with benzoate. Activities of protocatechuyl-CoA synthetase and protocatechuyl-CoA reductase leading to 3-hydroxybenzoyl-CoA were found in extracts of cells grown with protocatechuate. There was no repression of the HHQ pathway by the presence of protocatechuate, unlike by degradation of benzoate. We conclude that protocatechuate is not degraded via the HHQ pathway because there was no evidence of a hydroxylation reaction involved in this process. Instead, our results strongly suggest that protocatechuate is degraded via a pathway which connects to the benzoyl-CoA route of degradation.     

Long-term four-year exercise has a positive effect on menopausal risk factors: the Erlangen Fitness Osteoporosis Prevention Study

The purpose of the study was to determine the effect of long-term exercise on coronary heart disease, osteoporotic risk factors, and physical fitness parameters in postmenopausal women. Forty early postmenopausal women (age 55.1 +/- 3.3 years) with no medication or illness affecting bone metabolism exercised (high impact aerobic, multilateral jumps, multi-set resistance exercise) for 50 months (EG), while 28 women (age 55.5 +/- 3.0 years) served as a nontraining control (CG). Both groups were supplemented with calcium and cholecalciferol. Bone mineral density (BMD) was measured at the lumbar spine, hip, and forearm by dual energy x-ray absorptiometry. Blood lipids were determined using serum samples, and body composition was determined using the bioimpedance technique. Further, maximum isometric strength was determined (Schnell M3, Schnell Trainer). The BMD at the lumbar spine (+1.0%, p = 0.037) and the total hip (-0.3%, p = 0.194) were maintained in the EG, while significant (p < 0.001) decreases were observed in the CG (lumbar spine -3.2; total hip -2.3%). Differences between both groups were significant (p < 0.001). Significant differences between EG and CG were also observed, respectively, for total cholesterol (-6.1 vs. +3.5%, p = 0.008), HDL-cholesterol (+14.1 vs. -7.1%, p = 0.007), triglycerides (-10.2 vs. +27.5%, p = 0.002), body fat (-3.3 vs. +1.3%, p = 0.041), and waist-hip-ratio (-3.5 vs. +0.2%, p > 0.001). Maximum isometric strength significantly (p < 0.001) increased in the EG, while strength parameters decreased in the CG (-0.5 to -6.4%). Thus, the study demonstrated that multipurpose high-intensity exercise programs significantly affect relevant menopausal risk factors and, therefore, may be individually considered as an alternative to hormone replacement therapy.     

Effect of whole-body electromyostimulation on energy expenditure during exercise

The application of whole-body electromyostimulation (WB-EMS) in the area of fat reduction and body shaping has become more popular recently. Indeed, some studies prove positive outcomes concerning parameters related to body composition. However, there are conflicting data as to whether EMS relevantly impacts energy expenditure (EE) during or after application. Thus, the main purpose of the study was to determine the acute effect of WB-EMS on EE. Nineteen moderately trained men (26.4 ± 4.3 years) were randomly assigned to a typically used low-intensity resistance exercise protocol (16 minutes) with (85 Hz) and without WB-EMS. Using a crossover design, the same subjects performed both tests after completely recovering within 7 days. Energy expenditure as the primary endpoint of this study was determined by indirect calorimetry. The EE during low-intensity resistance exercise with adjuvant WB-EMS was significantly higher (p = 0.008) than that during the control condition (412 ± 60 vs. 352 ± 70 kcal; effect size; d = 0.92). This study clearly demonstrates the additive effect of WB-EMS on EE in moderately trained subjects during low-intensity resistance exercise training. Although this effect was statistically significant, the fast and significant reductions of body fat observed in recent studies suggest that the effect of WB-EMS on EE may still be underestimated by indirect calorimetry because of the inability of indirect calorimetry to accurately assess EE during "above-steady state conditions." Although from a statistically point of view WB-EMS clearly impacts EE, the relatively small effect did not suggest a broad application of this device in this area. However, taking other positive outcomes of this technology into account, WB-EMS may be a time-saving option at least for subjects unwilling or unable to exercise conventionally.