Induction of immunogenic apoptosis by blockade of epidermal growth factor receptor activation with a specific antibody

Despite promising results in the use of anti-epidermal growth factor receptor (EGFR) Abs for cancer therapy, several issues remain to be addressed. An increasing emphasis is being placed on immune effector mechanisms. It has become clear for other Abs directed to tumor targets that their effects involve the adaptive immunity, mainly by the contribution of Fc region-mediated mechanisms. Given the relevance of EGFR signaling for tumor biology, we wonder whether the oncogene inhibition could contribute to Ab-induced vaccine effect. In a mouse model in which 7A7 (an anti-murine EGFR Ab) and AG1478 (an EGFR-tyrosine kinase inhibitor) displayed potent antimetastatic activities, depletion experiments revealed that only in the case of the Ab, the effect was dependent on CD4(+) and CD8(+) T cells. Correspondingly, 7A7 administration elicited a remarkable tumor-specific CTL response in hosts. Importantly, experiments using 7A7 F(ab')(2) suggested that in vivo Ab-mediated EGFR blockade may play an important role in the linkage with adaptive immunity. Addressing the possible mechanism involved in this effect, we found quantitative and qualitative differences between 7A7 and AG1478-induced apoptosis. EGFR blocking by 7A7 not only prompted a higher proapoptotic effect on tumor metastases compared with AG1478, but also was able to induce apoptosis with immunogenic potential in an Fc-independent manner. As expected, 7A7 but not AG1478 stimulated exposure of danger signals on tumor cells. Subcutaneous injection of 7A7-treated tumor cells induced an antitumor immune response. This is the first report, to our knowledge, of a tumor-specific CTL response generated by Ab-mediated EGFR inhibition, suggesting an important contribution of immunogenic apoptosis to this effect.     

Hidden prenatal malnutrition in the rat: role of β₁-adrenoceptors on synaptic plasticity in the frontal cortex

Moderate reduction in the protein content of the mother's diet (hidden malnutrition) does not alter body and brain weights of rat pups at birth, but leads to dysfunction of neocortical noradrenaline systems together with impaired long-term potentiation and visuo-spatial memory performance. As β?-adrenoceptors and downstream protein kinase signaling are critically involved in synaptic long-term potentiation and memory formation, we evaluated the β?-adrenoceptor density and the expression of cyclic-AMP dependent protein kinase, calcium/calmodulin-dependent protein kinase and protein kinase Fyn, in the frontal cortex of prenatally malnourished adult rats. In addition, we also studied if β?-adrenoceptor activation with the selective β? agonist dobutamine could improve deficits of prefrontal cortex long-term potentiation presenting these animals. Prenatally malnourished rats exhibited half of β?-adrenoceptor binding, together with a 51% and 65% reduction of cyclic AMP-dependent protein kinase α and calcium/calmodulin-dependent protein kinase α expression, respectively, as compared with eutrophic animals. Administration of the selective β? agonist dobutamine prior to tetanization completely rescued the ability of the prefrontal cortex to develop and maintain long-term potentiation in the malnourished rats. Results suggest that under-expression of neocortical β?-adrenoceptors and protein kinase signaling in hidden malnourished rats functionally affects the synaptic networks subserving prefrontal cortex long-term potentiation. β?-adrenoceptor activation was sufficient to fully recover neocortical plasticity in the PKA- and calcium/calmodulin-dependent protein kinase II-deficient undernourished rats, possibly by producing extra amounts of cAMP and/or by recruiting alternative signaling cascades.     

Voltage-dependent anion channel as a resident protein of lipid rafts: post-transductional regulation by estrogens and involvement in neuronal preservation against Alzheimer's disease

The voltage-dependent anion channel, VDAC, is present at the neuronal membrane, where it appears to participate, among others, in the extrinsic apoptotic pathway and in the modulation of amyloid-beta induced injury, suggesting the involvement of this channel in Alzheimer's disease (AD) neurotoxicity. VDAC is also highly concentrated in neuronal lipid raft microdomains of different mouse and human cognitive areas, where it has been shown associated with estrogen receptor alpha (ERα), as a part of a `signalosome' that may activate some intracellular signal transduction. At the plasma membrane level, estrogens and antiestrogens (tamoxifen) have been demonstrated to exert rapid antagonist effects on the activation of VDAC, through their distinct effects on the channel post-transductional modulation. Therefore, part of the alternative mechanisms of estrogen related to neuroprotection against amyloid-beta may involve VDAC phosphorylation, in order to maintain the channel in an unactivated (closing) state. Interestingly, VDAC-ERα association has been shown to be disrupted in neuronal lipid rafts of AD brains, in correlation with the aberrant lipid composition observed in these microstructures, suggesting that disturbance of protein interactions may be related to variation in the physico-chemical properties of these microdomains.     

New species of Trichuris (Nematoda:Trichuridae) from Akodon montensis, Thomas, 1913, of the Paranaense Forest in Argentina

Species of Trichuris (Nematoda:Trichuridae) parasitize a broad range of mammalian hosts. To date, 21 Trichuris species infecting nine families of rodents have been found in North and South America. Trichuris navonae n. sp. is described on the basis of specimens recovered from a species of forest-dwelling mice, Akodon montensis (Cricetidae: Sigmodontinae), from nine localities of Misiones Province, Argentina. A comparison with all the species of Trichuris from North and South American rodents is given. The separation of the new species of Trichuris is based on morphologic and morphometrica features, such as the absence of a spicular tube, the presence of a cylindrical spicular sheath with sharp spines, a non-protrusive vulva, a long anterior-posterior portion of the body, a lengthy spicule, and a proximal and distal cloacal tube. This is the third record of this genus in rodents of the Sigmodontinae from Argentina and the fifth record from South American rodents. Despite the large number of potential host species, only about 1.9% of sigmodontine rodent species have been reported as hosts of Trichuris spp. It is suggested that this number represents but a small fraction of Trichuris spp. that occur in sigmodontine rodents, and that additional survey of this group should yield additional species.     

Simulating northern bobwhite population responses to nest predation,nesting habitat,and weather in south Texas

Nest predation is thought to be one of the major factors limiting northern bobwhite (Colinus virginianus) populations. We examined the relative impact of altering nest-predation rate, nesting habitat, and weather (i.e., temp and precipitation) on northern bobwhite population dynamics in a hypothetical 15,000-ha subtropical-rangeland ecosystem in south Texas using a simulation model. The systems model consisted of a 3-stage (i.e., eggs, juv, and ad) bobwhite population with dynamics influenced by variables affecting production, recruitment, nest predation, and mortality. We based model parameters on data collected from a 3-yr nest-predator study employing infrared-camera technology, from ongoing field research using a radio-marked population of wild bobwhites, and from the literature. The baseline simulated bobwhite population dynamics corresponded closely to empirical data, with no difference between medians of simulated (n = 30 yr) and observed bobwhite age ratios over a 28-yr period. Similarly, a time-series comparison of simulated and observed age ratios showed most (89%) observed values fell within the 5th and 95th percentiles of the simulated data over the 28-yr period. We created simulated population scenarios representing 1) baseline historical conditions, 2) predator control, 3) low precipitation, 4) low precipitation with predator control, 5) high temperature, 6) high temperature with predator control, 7) reduced nest-clump availability, and 8) reduced nest-clump availability with predator control that resulted in considerably different median bobwhite densities over 10 yr. For example, under simulated predator control, populations increased by about 55% from the baseline scenario, whereas under simulated reduced nest-clump availability, populations decreased by about 75% from the baseline scenario. Comparisons of time-series for each scenario showed that reduced nest-clump availability, low precipitation, and high temperature reduced bobwhite densities to a larger degree compared to a natural nest predation rate. Reduced nest-clump availability resulted in the most substantial decline of simulated bobwhite densities. Simulations suggested that management efforts should focus on maintaining adequate nest-clump availability and then possibly consider nest predator control as a secondary priority. © 2010 The Wildlife Society     

Presence of Ctenocephalides canis (Curtis) and Ctenocephalides felis (Bouché) infesting dogs in the city of Aguascalientes, México

Prevalence and seasonal distribution of Ctenocephalides canis (Curtis) and Ctenocephalides felis (Bouché) infestations in urban dogs of the city of Aguascalientes, Mexico, were studied. Between January and December 2007, 863 dogs in the Municipal Canine and Feline Control Center were examined. Overall prevalence of infestation was 12% (95% CI 10-14). Seasonal distribution revealed that prevalences in spring and summer were highest, while autumn and winter had lower prevalences. Two infestation peaks were observed, i.e., in April (17.7%) and July (18.9%). A positive correlation was detected between prevalence and temperature during the winter season (P < 0.05). Prevalence in relation to gender showed that males were more frequently infested, 14% (95% CI 11-17), than females, 9.4% (95% CI 7-13); hair length did not affect differences in prevalence. Six hundred twenty-nine fleas were examined; 62% were C. canis and 38% C. felis . Dogs infested with only C. canis were 48% (95% CI 38-58), while 18% were infested only with C. felis (95% CI 11-27); the remainder, 34% (95% CI 24-44), had mixed infestations.     

Quick methods for evaluating survival of age-characterizable long-lived territorial birds

Survival is a key life-history trait in animals. However, most methods of survival estimation require substantial human and economic investment in the long term, particularly in species occurring in low densities, the case of most endangered species. An alternative to traditional recapture (CR) methods is estimation of adult survival based indirectly on either age ratios (AGR) or turnover rates (TOR) in territorial species. These 2 methods are applicable to bird species in which recruited individuals enter into the breeding population whilst still exhibiting the external traits that distinguish those animals from experienced adults. The main advantages of these methods are that survival can be easily estimated for all monitored individuals after just 1 or 2 breeding seasons and that disturbance to the species is minimized. The main constraints of indirect methods are that the assumptions are more restrictive than in CR methods, and survival estimates, although comparable between sites and years, may be biased. We used data from a long-term monitoring survey of 2 populations of the endangered Bonelli's eagle (Aquila fasciata), one in Catalonia (NE Spain) and the other in Provence and Languedoc-Roussillon (SE France). We evaluated survival estimates using the AGR and TOR methods and compared them with CR methods and provide suitable corrections for refining survival estimates based on indirect methods. In Catalonia (2002–2008), survival was estimated at 0.84 by CR methods (SE = 0.047; n = 25 radio tagged eagles), at 0.86 by the corrected AGR method (SE = 0.011; n = 558 bird * year), and at 0.86 by the corrected TOR method (SE = 0.022; n = 547 bird * year). In France (1999–2008), survival was estimated at 0.88 by CR methods (SE = 0.040; n = 45 darvic banded eagles), at 0.87 by the corrected AGR method (SE = 0.015; n = 443 bird * year), and at 0.87 by the corrected TOR method (SE = 0.015; n = 438 bird * year). All analyses suggest that females survive better than males and that individuals from the French population survive better than individuals from the Catalan population. We conclude that indirect methods, which should not be regarded as a substitute of CR methods, will allow wildlife managers and researchers to estimate accurately adult survival in a territorial species over a short period of time and to monitor survival across populations over large geographic ranges and over time. © 2011 The Wildlife Society.     

Flavonoids and oxidative stress in Drosophila melanogaster

Flavonoids are a family of antioxidants that are widely represented in fruits, vegetables, dry legumes, and chocolate, as well as in popular beverages, such as red wine, coffee, and tea. The flavonoids chlorogenic acid, kaempferol, quercetin and quercetin 3β-d-glycoside were investigated for genotoxicity using the wing somatic mutation and recombination test (SMART). This test makes use of two recessive wing cell markers: multiple wing hairs (mwh) and flare (flr(3)), which are mutations located on the left arm of chromosome 3 of Drosophila melanogaster and are indicative of both mitotic recombination and various types of mutational events. In order to test the antioxidant capacities of the flavonoids, experiments were conducted with various combinations of oxidants and polyphenols. Oxidative stress was induced using hydrogen peroxide, the Fenton reaction and paraquat. Third-instar transheterozygous larvae were chronically treated for all experiments. The data obtained in this study showed that, at the concentrations tested, the flavonoids did not induce somatic mutations or recombination in D. melanogaster with the exception of quercetin, which proved to be genotoxic at only one concentration. The oxidants hydrogen peroxide and the Fenton reaction did not induce mutations in the wing somatic assay of D. melanogaster, while paraquat and combinations of flavonoids produced significant numbers of small single spots. Quercetin 3β-d-glycoside mixed with paraquat was shown to be desmutagenic. Combinations of the oxidants with the other flavonoids did not show any antioxidant activity.