Persistence of tumor-infiltrating CD8 T cells is tumor-dependent but antigen-independent

How tumor-infiltrating lymphocytes (TILs) that are tumor-specific but functionally tolerant persist in the antigen-expressing tumor tissue is largely unknown. We have previously developed a modified TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model where prostate cancer cells express the T-cell epitope SIYRYYGL (SIY) recognized by CD8 T cells expressing the 2C T-cell receptor (TCR) (referred to as TRP-SIY mice). In TRP-SIY mice, activated 2C T cells rapidly become tolerant following infiltration into the prostate tumor. In this study, we show that tolerant 2C T cells persist in the prostate tumor of TRP-SIY mice by proliferating slowly in a tumor-dependent, but antigen-, interleukin (IL)-7- and IL-15-independent manner. We also show that disappearance of 2C T cells from the lymphoid organs of TRP-SIY mice are due to antigen-induced T-cell contraction rather than altered trafficking or generalized T-cell depletion in the mice. Finally, we show that clonal T cells unreactive to SIY are equally capable of persisting in the prostate tumor. These findings suggest that while functional tolerance of TILs is induced by antigen, persistence of tolerant TILs in the tumor tissue is mediated by a novel mechanism: slow proliferation independent of antigen and homeostatic cytokines. These results also allow CD8 T-cell survival in the tumor environment to be compared with T-cell survival in chronic infection

Fluoride level in public water supplies of cities from the northwest region of São Paulo State, Brazil Concentração de flúor nas águas de abastecimento público de municípios da região noroeste do estado de São Paulo, Brasil

It may be difficult for small and medium cities to obtain information about the fluoride content of public water, because of the lack of equipments and technicians. This study aimed to analyze the fluoride levels of the water supplied by the public treatment stations of 40 cities situated in the northwest region of São Paulo State, during a period of 6 months, to verify if fluoridation occurs in a continuous manner and if the fluoride levels are within the recommended. Maps of the water distribution system were obtained from the water treatment companies and utilized to randomize the addresses of the collection sites, so that they included all regions with treated water sources. One water sample by month was collected and analyzed in duplicate using an ion-specific-electrode. Samples with 0.6 to 0.8 mgF/L were considered acceptable. In the 38 cities that regularly provided the samples in the 6 months of the study, water from 144 collection sites was collected and a total of 864 samples were analyzed, of which 61.81 percent were classified as unacceptable. It was observed that 33 cities performed fluoridation but in 78.79 percent of these cities there were variations in the fluoride level among the sites and in the same site during the period of study. One can conclude that most of these cities do not control the fluoride levels in the public water, since fluoridation occurs in a discontinuous manner and in most of the situations not within the recommended concentrations.<br>Municípios de pequeno e médio porte podem ter dificuldades em realizar o controle da adição de flúor nas águas de abastecimento público em função da falta de infra-estrutura laboratorial e técnica. Este estudo realizou análises do teor de flúor das águas de abastecimento de 40 municípios situados na região noroeste do estado de São Paulo, durante 6 meses, para verificar se a adição ocorre de forma contínua e se os teores adicionados encontram-se dentro dos parâmetros recomendados. Mapas com a rede de distribuição de água dos municípios foram solicitados e utilizados para definir as regiões de coleta e sortear os endereços dos pontos, de forma que abrangessem todas as fontes de água tratada. Uma amostra de água de cada ponto foi coletada por mês e analisada em duplicata pelo método íon-eletrodo específico. Amostras com 0,6 a 0,8 mg F/L foram consideradas aceitáveis. Nos 38 municípios que enviaram as amostras regularmente nos 6 meses de estudo, a água de 144 pontos foi coletada, perfazendo um total de 864 amostras analisadas, das quais 61,81% foram classificadas como inaceitáveis. Constatou-se que 33 destes municípios realizavam a fluoretação, sendo que em 78,79% deles as concentrações de flúor variavam entre os pontos e no mesmo ponto ao longo do período. Pode-se concluir que a maioria destes municípios não mantém controle adequado sobre os níveis de flúor em sua água, pois a adição de flúor ocorre de forma descontínua e na maioria das vezes em teores fora dos parâmetros recomendados

Avian mycoplasmosis update

Avian mycoplasmas occur in a variety of bird species. The most important mycoplasmas for chickens and turkeys are Mycoplasma gallisepticum (MG), M. synoviae (MS), and M. meleagridis. Besides, M. iowe (MI) is an emerging pathogen in turkeys, but of little concern for chickens. Mycoplasmas are bacteria that lack cell wall and belong to the class Mollicutes. Although they have been considered extracellular agents, scientists admit nowadays that some of them are obligatory intracellular microorganisms, whereas all other mycoplasmas are considered facultative intracellular organisms. Their pathogenic mechanism for disease include adherence to host target cells, mediation of apoptosis, innocent bystander damage to host cell due to intimate membrane contact, molecular (antigen) mimicry that may lead to tolerance, and mitotic effect for B and/or T lymphocytes, which could lead to suppressed T-cell function and/or production of cytotoxic T cell, besides mycoplasma by-products, such as hydrogen peroxide and superoxide radicals. Moreover, mycoplasma ability to stimulate macrophages, monocytes, T-helper cells and NK cells, results in the production of substances, such as tumor necrosing factor (TNF-alpha), interleukin (IL-1, 2, 6) and interferon (<FONT FACE=Symbol>a, b, g</FONT>). The major clinical signs seen in avian mycoplasmosis are coughing, sneezing, snicks, respiratory rales, ocular and nasal discharge, decreased feed intake and egg production, increased mortality, poor hatchability, and, primarily in turkeys, swelling of the infraorbital sinus(es). Nevertheless, chronic and unapparent infections are most common and more threatening. Mycoplasmas are transmitted horizontally, from bird to bird, and vertically, from dam to offspring through the eggs. Losses attributed to mycoplasmosis, mainly MG and MS infections, result from decreased egg production and egg quality, poor hatchability (high rate of embryonic mortality and culling of day-old birds), poor feed efficiency, increase in mortality and carcass condemnations, besides medication costs. Mycoplasmas are diagnosed by serologic tests, culture and PCR and are sensitive to antimicrobials whose action sites are other than the bacterial cell wall, such as tetracyclines, macrolides, quinolones and tiamulin. However, mycoplasma control is more efficiently achieved by acquisition of birds free of MG, MS, MM and/or MI, vaccination of layers, and monitoring of breeder flocks, followed by elimination of the infected flocks that are detected

The neural EGF family member CALEB/NGC mediates dendritic tree and spine complexity

The development of dendritic arborizations and spines is essential for neuronal information processing, and abnormal dendritic structures and/or alterations in spine morphology are consistent features of neurons in patients with mental retardation. We identify the neural EGF family member CALEB/NGC as a critical mediator of dendritic tree complexity and spine formation. Overexpression of CALEB/NGC enhances dendritic branching and increases the complexity of dendritic spines and filopodia. Genetic and functional inactivation of CALEB/NGC impairs dendritic arborization and spine formation. Genetic manipulations of individual neurons in an otherwise unaffected microenvironment in the intact mouse cortex by in utero electroporation confirm these results. The EGF-like domain of CALEB/NGC drives both dendritic branching and spine morphogenesis. The phosphatidylinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway and protein kinase C (PKC) are important for CALEB/NGC-induced stimulation of dendritic branching. In contrast, CALEB/NGC-induced spine morphogenesis is independent of PI3K but depends on PKC. Thus, our findings reveal a novel switch of specificity in signaling leading to neuronal process differentiation in consecutive developmental events