Inhibitory effect of combined treatment with the aromatase inhibitor exemestane and tamoxifen on DMBA-induced mammary tumors in rats

The antitumor effect of exemestane (FCE 24304), an irreversible aromatase inhibitor, given alone or in combination with tamoxifen, was investigated in rats with 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumors. The compounds were given once daily, 6 days a week for 4 weeks. Exemestane, given at the dose of 20 mg/kg/day s.c., induced 26% complete (CR) and 18% partial (PR) tumor regressions, compared to 0% CR and 6% PR observed in controls. Tamoxifen, given at 1 mg/kg/day p.o., induced 16% CR and 13% PR. The combined treatment caused 41% CR and 16% PR, thus resulting in a higher antitumor effect than either single treatment. The apperance of new tumors was reduced by each single treatment and almost totally prevented by the combined treatment. Serum prolactin (PRL) levels, assayed 4 h after the last dose, were unchanged in the group treated with the combination, whereas tamoxifen alone caused a slight increase of serum PRL. These results indicate that estrogen deprivation through aromatase inhibition and estrogen receptor antagonism causes a better inhibition of DMBA-induced mammary tumors than either treatment modality alone.     

Evaluation of a radioreceptor assay to assess exogenous estrogen activity in serum of patients with breast cancer.

A radioreceptor assay (RRA) for the determination of total estrogen activity, was set up and used to assess the possible presence of exogenous molecules with estrogen activity in serum; a comparison was made with the specific radioimmunoassay (RIA) for the endogenous estrogen 17-B estradiol (17-B-E2). The assay was first performed on sera from healthy people taking estrogens in the form of oral contraceptives or lotions for local application whose total estrogenic activity in the blood was assumed to be abnormal. The assay was then performed on serum from 98 patients with early breast cancer and 20 patients with metastasis, not undergoing hormone therapy. A higher estrogen activity was found in 2.5% of sera compared to the activity found using the RIA method which is specific for endogenous estrogen 17-B-E2, the RRA/17-B-E2 ratio being higher than 3. Increased estrogen activity was found in 10% serum samples from digoxin treated cardiopathic patients, with an RRA/17-B-E2 ratio ranging from 4.4 to 20. The RRA assay could prove useful for showing up exogenous estrogen activity from various sources (drugs, food) in sera of people in whom estrogen stimulation could be potentially dangerous (i.e. in patients with hormone-sensitive tumors). This exogenous activity could support a certain degree of neoplastic stimulation and, therefore, unfavourably condition the patients' therapeutic response.     

Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier

Bacteria communicate with each other by the use of signaling molecules, a process called ‘quorum sensing’. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (K_in = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (K_in = 2.68 μl/(g×min)) and very low (K_in = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis.     

Cytokine cross-talk between phagocytic cells and lymphocytes: Relevance for differentiation/activation of phagocytic cells and regulation of adaptive immunity

Cytokines represent one of the most important elements in the communication among different cell types. They play an increasingly better understood role in the communication among hematopoietic cells and in particular in the reciprocal regulation of effector cell types of innate or natural resistance (phagocytic cells and Natural Killer (NK) cells) and those of adaptive immunity (T and B lymphocytes). Lymphocytes produce several cytokines with either stimulatory (e.g., colony stimulatory factor) or suppressive (e.g., tumor necrosis factors and interferons) effects on proliferation of early hematopoietic cells. Many of these cytokines, alone or acting in synergistic combinations, also have a differentiation-inducing ability on immature myeloid cells and act as powerful potentiators of the cellular functions of terminally differentiated phagocytic cells. The communication between lymphocytes and phagocytic cells is not unidirectional, as phagocytic cells produce factors that regulate lymphocyte activation. In addition to their role as antigen presenting cells expressing costimulatory accessory molecules and secreting cytokines (e.g., IL-1, IL-6, TNF), phagocytic cells have been recently shown to produce Natural Killer cell Stimulatory Factor (NKSF/IL-12). IL-12 is a heterodimeric cytokine with important modulatory functions on cytotoxicity of NK and T cells, lymphocyte proliferation, lymphokine production, and development of T helper cell subsets. These communications between phagocytic cells and lymphocytes are further regulated by negative and positive feedback mechanisms that contribute to maintain the homeostasis of the system in physiologic conditions and to govern the changes in this equilibrium needed for the response to infectious or other foreign agents.     

A retrovirus carrying the polyomavirus middle T gene induces acute thrombocythemic myeloproliferative disease in mice.

Mice inoculated with an artificially constructed retrovirus carrying the middle T gene of polyomavirus develop acute myeloproliferative disease with severe thrombotic and hemorrhagic disorder and impaired platelet function. The megakaryocytic lineage appears to be a target for polyoma-murine leukemia virus infection and middle T gene expression. This newly described disease represents a unique model system for studying disorders of the megakaryocytic lineage.     

Distribution and microhabitats of native and non-native gammarids (Amphipoda, Crustacea) in Brittany, with particular reference to the endangered endemic sub-species Gammarus duebeni celticus

Aim  To assess temporal changes in gammarid distribution in Brittany and microhabitat-use overlap between the endangered endemic Gammarus duebeni celticus Stock & Pinkster, 1970 , the expanding natives G. pulex (Linnaeus, 1758) and Echinogammarus berilloni (Catta, 1878), and the introduced G. tigrinus Sexton, 1939.
Location  Brittany and adjacent regions in western France.
Methods  The spatial and temporal patterns in distribution of gammarids at the scale of Brittany were studied using 351 sites. Longitudinal distributions (from the source to the estuary of the river) and microhabitat-use (substratum type and water velocity) were also considered in selected rivers.
Results  At the regional scale, all species occurred together less often than expected statistically, with significant deviations from expected for G. pulex vs. both G. duebeni celticus and G. tigrinus , and for E. berilloni vs. both G. duebeni celticus and G. tigrinus . However, at the microhabitat scale, E. berilloni occurred significantly more often than expected with the endemic G. duebeni celticus , and this appears to be due to similar substratum and water velocity preferences, although at both the regional and microhabitat scales E. berilloni prefers wider streams than G. duebeni celticus . This study reveals a decline in the endangered G. duebeni celticus since 1970.
Main conclusions  The longitudinal and local distributions of G. duebeni celticus , and the higher-than-expected co-occurrence of the species with G. pulex , suggest that the decline of the endemic species may be due to changes in the environment and/or interference from native G. pulex , which is expanding its range in Brittany. The results are discussed as regards to the consequences for regional biodiversity.     

PHOTOACCLIMATION IN THE TROPICAL CORALLINE ALGA HYDROLITHON ONKODES (RHODOPHYTA, CORALLINACEAE) FROM A FRENCH POLYNESIAN REEF

Pigment concentration, in vivo absorption, and photosynthetic parameters of the coralline alga Hydrolithon onkodes (Heydrich) Penrose and Woelkerling were compared among samples from a lagoon and from a reef crest of Tahiti Island. Four groups of specimens were considered, differing in their natural exposure to PAR. For specimens collected from the lagoon, the tissues from low-light samples had significantly higher pigment concentration, particularly chl a and phycobilins, compared with the high-light exposed plants that contained more total carotenoids. The in vivo absorption spectra normalized to chl a (called a* values) also revealed differences. The low-light samples had a reduced absorption capacity and a well-marked phycobilin absorption signature, whereas sunlit samples showed a greater absorption at wavelengths absorbed mainly by chl a and carotenoids. The decrease of a* when pigment concentration increased is interpreted as a consequence of the pigment packaging. Significantly lower α (chlorophyll basis) and higher E_k values were found in the shaded plants. The values of P _max for the four groups of specimens were not significantly different. The samples showed various degrees of photoinhibition depending on the light exposure during growth, and this effect was more pronounced in the shaded plants. The specimens from the reef crest deviate from the general model presented for the lagoon samples and show a mix of sun- and shade-exposed characteristics. We have shown that the coralline alga H. onkodes responds to its light environment, probably by acclimation rather than ecotypic genetic variation, by adjusting its physiology, but some morphological differences are also involved. Photoacclimation can explain partly the wide distribution of this species over the reef ecosystem and its major contribution to the building of the reef.     

Behavioural expression of D-1 receptor supersensitivity depends on previous stimulation of D-2 receptors

SKF 38393 (2 mg/kg s.c.), a reportedly selective D-1 agonist, failed to induce contralateral turning behaviour in naive rats bearing 12 days old unilateral 6-hydroxydopamine lesions. On the other hand strong contraversive turning in response to SKF 38393 was obtained if rats had been tested 2 or 7 days before with apomorphine (0.1 mg/kg s.c.) or with LY 171555 (0.2 mg/kg s.c.), a selective D-2 receptor agonist. Contraversive turning in response to SKF 38393 was blocked by a low dose (0.05 mg/kg s.c.) of the specific D-1 antagonist SCH 23390. The results indicate that the behavioural expression of D-1 receptor supersensitivity following lesion of dopaminergic neurons depends on previous exposure to a stimulation of D-2 receptors.