Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers

Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.     

Allergic Inflammation—Innately Homeostatic

Allergic inflammation is associated closely with parasite infection but also asthma and other common allergic diseases. Despite the engagement of similar immunologic pathways, parasitized individuals often show no outward manifestations of allergic disease. In this perspective, we present the thesis that allergic inflammatory responses play a primary role in regulating circadian and environmental inputs involved with tissue homeostasis and metabolic needs. Parasites feed into these pathways and thus engage allergic inflammation to sustain aspects of the parasitic life cycle. In response to parasite infection, an adaptive and regulated immune response is layered on the host effector response, but in the setting of allergy, the effector response remains unregulated, thus leading to the cardinal features of disease. Further understanding of the homeostatic pressures driving allergic inflammation holds promise to further our understanding of human health and the treatment of these common afflictions.Buoyed by the successes of prophylactic immunization against toxins at the turn of the 20th century, Portier and Richet began studies with hypnotoxin from the cnidarian, Physalia physalis, commonly known as the Portuguese man o’ war, and a related toxin from the sea anemones, Actinia equina and Anemonia sulcata. These investigations led to the paradoxical discovery of immediate hypersensitivity reactions and even death among some immunized animals by a process termed “anaphylaxis” (Richet 1913). Recognized by a Nobel Prize, these seminal findings underpinned the modern field of allergy and led to the eventual identification of the transferable nature of the activating agent in serum, first noted by Richet, as immunoglobulin E (IgE) (Ishizaka et al. 1966). The rapid advances in molecular biology, genetics, and genomics from 1970 to 2000 elucidated the central role for cytokines, particularly the duplicated genes for interleukin (IL)-4, IL-13, IL-5, and IL-9, in mediating the effector functions of allergic immunity. Although initial studies fueled by the discoveries of helper T-cell subsets focused on T cells, designated Th2 cells, as sources of these cytokines, recent findings have increasingly highlighted the role of innate cells in allergic immunity. These discoveries have raised hopes that insights regarding the initiation and/or maintenance of tissue pathology mediated by interactions between innate and adaptive cells might translate to new therapeutic modalities for diseases underpinned by type 2 immunity.     

Mouse Tafazzin Is Required for Male Germ Cell Meiosis and Spermatogenesis

Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome.     

Scale dependence of diversity measures in a leaf-litter ant assemblage

A reliable characterization of community diversity and composition, necessary to allow inter‐site comparisons and to monitor changes, is especially difficult to reach in speciose invertebrate communities. Spatial components of the sampling design (sampling interval, extent and grain) as well as temporal variations of species density affect the measures of diversity (species richness S, Buzas and Gibson's evenness E and Shannon's heterogeneity H). Our aim was to document the small‐scale spatial distribution of leaf litter ants in a subtropical dry forest of the Argentinian Chaco and analyze how the community characterization was best achieved with a minimal sampling effort. The work was based on the recent standardized protocol for collecting ants of the leaf litter (“A.L.L.”: 20 samples at intervals of 10 m). To evaluate the consistency of the sampling method in time and space, the selected site was first subject to a preliminary transect, then submitted after a 9‐month interval to an 8‐fold oversampling campaign (160 samples at interval of 1.25 m). Leaf litter ants were extracted from elementary 1 m² quadrats with Winkler apparatus. An increase in the number of samples collected increased S and decreased E but did not affect much H. The sampling interval and extent did not affect S and H beyond a distance of 10 m between samples. An increase of the sampling grain had a similar effect on S than a corresponding increase of the number of samples collected, but caused a proportionaly greater increase of H. The density of species m^?2 varied twofold after a 9‐month interval; the effect on S could only be partially corrected by rarefaction. The measure of species numerical dominance was little affected by the season. A single standardized A.L.L. transect with Winkler samples collected <45% of the species present in the assemblage. All frequent species were included but their relative frequency was not always representative. A log series distribution of species occurrences was oberved. Fisher's α and Shannon's H were the most appropriate diversity indexes. The former was useful to rarefy or abundify S and the latter was robust against sample size effects. Both parametric and Soberón and Llorente extrapolation methods outperformed non‐parametric methods and yielded a fair estimate of total species richness along the transect, a minimum value of S for the habitat sampled.     

Préserver la fertilité chez les adolescents traités pour un cancer. Le point de vue du psycho-oncologue

The question of fertility is a major concern for young adults successfully treated for cancer, which is why semen preservation should be proposed to all adolescent boys prior to treatment of a cancer. This proposal is part of the oncologist’s approach to prevent sequelae. To ensure that semen cryopreservation is conducted under good conditions and is accepted by the adolescent, it is important to have a good understanding of the psychopathology and behaviour of adolescents with cancer: their preoccupation with their body, their appearance, their sexuality, their relationships to their peers and to their parents, their value and narcissism, their identity. This helps the clinician to understand and overcome the various reasons for their difficulty (and to lessen the painful feeling of failure) or their reticence to perform semen cryopreservation: paralysed by the diagnosis of cancer, sexual inhibition, lack of understanding and ignorance, pessimism concerning outcome, incapacity to project into the future, poor relationship with parents, discredit of parenthood, fear of transmitting the cancer, etc. A good understanding of these elements can avoid an excessively rapid acceptance of a superficial opposition to this procedure that the patient could subsequently regret. Closer collaboration should be developed between oncology-haematology departments and CECOS units to provide suitable information material to adolescents, to improve the understanding of the specific psychology of adolescents, and to understand the parents’ positions.     

Phenological influences on the utilization of woody plants by eland in semi-arid shrubland

Our study monitored the acceptability, shoot phenology and chemical content of karoid woody species over the seasonal cycle. Species favoured by eland as long as they retained leaves, were classified as palatable, while those neglected for part of the seasonal cycle, even though they retained leaves, were classified as unpalatable. Changes in the acceptability of unpalatable species over the seasonal cycle appeared to be related to changes in the proportion of young shoots on plants, as influenced by rainfall and temperature. These species were typically only favoured when they offered relatively high proportions of young shoots. Our study identified total fibre as the most important chemical factor influencing the acceptability of woody species to eland. The shoots of palatable species contained low fibre concentrations, while the shoots of unpalatable species were more variable in fibre content. When favoured, the shoots of unpalatable species typically had similar levels of fibre to palatable species, but when neglected, the shoots of unpalatable species generally had increased fibre levels. Eland have thrived since being introduced into our study area, which is dominated by microphyllous and leptophyllous woody species. We suggest that this is because eland are able to select a diet sufficiently low in fibre content.     

Lack of synergy for inhibitors targeting a multi-drug-resistant HIV-1 protease

The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements seen in the second tightest inhibitor complex. This occurs as adaptations in the S1 pocket of one monomer propagate through the dimer and affect the conformation of the S1 loop near P81 of the other monomer. Therefore, structural rearrangements that occur within the protease when it binds to an inhibitor with a single modification must be accounted for in the design of inhibitors with multiple modifications. This consideration is necessary to develop inhibitors that bind sufficiently tightly to drug-resistant variants of HIV-1 protease to potentially become the next generation of therapeutic agents.     

Importance of astrocytic inactivation of synaptically released glutamate for cell survival in the central nervous system--are astrocytes vulnerable to low intracellular glutamate concentrations?

Multiple levels of neuron-astrocyte interactions do exist at glutamatergic synapses, glial glutamate transporters being involved in most of them. Inactivation of synaptically released glutamate is not only important for the phasic aspect of glutamatergic transmission but also for astrocyte metabolism, which supply neurons with different metabolic precursors, and for cell survival in the central nervous system. Alteration of glutamate transport, which leads to abnormally high extracellular glutamate levels, has been involved in numerous neurodegenerative diseases. There are different ways by which elevated extracellular levels of glutamate can be toxic. Excitotoxic mechanisms, involving overstimulation of glutamate receptors, have been shown to induce the death of neurons and oligodendrocytes, but not of astrocytes. Oxidative glutamate toxicity, which can affect every cell type of the central nervous system, is currently viewed as the consequence of altered cystine transport, leading in turn to reduced glutathione synthesis and oxidative stress. This review summarizes the functional implications of astroglial glutamate transport and the consequences of its alteration. Emphasis is laid on our recent finding that alteration of glutamate transport, by depleting intracellular stores of glutamate, can induce oxidative toxicity in astrocytes. The consequences for the other cell types of the central nervous system are discussed in terms of neuron dependency on astrocytes for glutathione synthesis and therefore oxidative stress protection.     

A Genomewide Linkage Screen for Relative Hand Skill in Sibling Pairs

Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between minus sign0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.