Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects

Liquid ropes: a geometrical model for thin viscous jet instabilities.

Thin, viscous fluid threads falling onto a moving belt behave in a way reminiscent of a sewing machine, generating a rich variety of periodic stitchlike patterns including meanders, W patterns, alternating loops, and translated coiling. These patterns form to accommodate the difference between the belt speed and the terminal velocity at which the falling thread strikes the belt. Using direct numerical simulations, we show that inertia is not required to produce the aforementioned patterns. We introduce a quasistatic geometrical model which captures the patterns, consisting of three coupled ordinary differential equations for the radial deflection, the orientation, and the curvature of the path of the thread's contact point with the belt. The geometrical model reproduces well the observed patterns and the order in which they appear as a function of the belt speed.P.-T. B. was partially funded by the ERC Grant No. SIMCOMICS 280117.This is the author accepted manuscript. The final version is available from APS via http://dx.doi.org/10.1103/PhysRevLett.114.17450

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks

Plexin-B1 Activates NF-κB and IL-8 to Promote a Pro-Angiogenic Response in Endothelial Cells

The semaphorins and their receptors, the plexins, are proteins related to c-Met and the scatter factors that have been implicated in an expanding signal transduction network involving co-receptors, RhoA and Ras activation and deactivation, and phosphorylation events. Our previous work has demonstrated that Semaphorin 4D (Sema4D) acts through its receptor, Plexin-B1, on endothelial cells to promote angiogenesis in a RhoA and Akt-dependent manner. Since NF-\u3baB has been linked to promotion of angiogenesis and can be activated by Akt in some contexts, we wanted to examine NF-\u3baB in Sema4D treated cells to determine if there was biological significance for the pro-angiogenic phenotype observed in endothelium. METHODS/PRINCIPAL FINDINGS: Using RNA interference techniques, gel shifts and NF-\u3baB reporter assays, we demonstrated NF-\u3baB translocation to the nucleus in Sema4D treated endothelial cells occurring downstream of Plexin-B1. This response was necessary for endothelial cell migration and capillary tube formation and protected endothelial cells against apoptosis as well, but had no effect on cell proliferation. We dissected Plexin-B1 signaling with chimeric receptor constructs and discovered that the ability to activate NF-\u3baB was dependent upon Plexin-B1 acting through Rho and Akt, but did not involve its role as a Ras inhibitor. Indeed, inhibition of Rho by C3 toxin and Akt by LY294002 blocked Sema4D-mediated endothelial cell migration and tubulogenesis. We also observed that Sema4D treatment of endothelial cells induced production of the NF-\u3baB downstream target IL-8, a response necessary for angiogenesis. Finally, we could show through co-immunofluorescence for p65 and CD31 that Sema4D produced by tumor xenografts in nude mice activated NF-\u3baB in vessels of the tumor stroma. CONCLUSION/SIGNIFICANCE: These findings provide evidence that Sema4D/Plexin-B1-mediated NF-\u3baB activation and IL-8 production is critical in the generation a pro-angiogenic phenotype in endothelial cells and suggests a new therapeutic target for the anti-angiogenic treatment of some cancer

Liver Parasites and Body Condition in Relation to Environmental Contaminants in Caribou (Rangifer tarandus) from Labrador, Canada

Over the last several decades, elders and hunters of the Innu Nation in Labrador, Canada, have expressed concerns over perceived declines in environmental health and the integrity of country food, including caribou. The primary objective of this study was to determine links between specific health parameters and contaminants found in caribou from the George River herd. Twenty-seven caribou killed by local Innu hunters between February and December 2001 were evaluated for gross and microscopic pathology, body condition, liver parasitology, and contaminant levels in kidney and fat. Overall, the sampled caribou appeared to be in adequate body condition for the time of year, and no clinically significant lesions were found. Concentrations of selenium, metals (Hg, Cd, and Pb), 20 organochlorine pesticides (HCB, a-HCH, g-HCH, aldrin, dieldrin, methoxychlor, mirex, a- and b-endosulfan, heptachlor, heptachlor epoxide, g-CHL, cis-CHL, trans-nonachlor, and o,p'- and p,p'-DDD, DDE, DDT), and 24 PCB congeners were within the ranges reported for caribou in Canada. In general, contaminant levels were relatively low, with the exception of cadmium in kidneys (geometric mean: 6.5 μg/g wet weight; range: 1.5–44.0 μg/g). Two types of liver parasites were found: the liver fluke Fascioloides magna (prevalence: 78%; geometric mean abundance: 4.2 flukes/caribou) and a tapeworm larva consistent with Taenia hydatigena (prevalence: 50%; geometric mean abundance: 0.6 larvae/caribou). Using multiple variable regression analysis, we found renal concentrations of cadmium to be positively associated, and selenium to be negatively associated, with F. magna abundance.Ces dernières décennies, les aînés et les chasseurs de la nation montagnaise du Labrador, au Canada, ont exprimé des inquiétudes au sujet du déclin de la santé de l’environnement et de l’intégrité de la nourriture provenant de la campagne, telle que le caribou. L’objectif principal de cette étude consistait à déterminer les liens qui existent entre certains paramètres de santé précis et les contaminants se trouvant dans le caribou du troupeau de la rivière George. Vingt-sept caribous ayant été tués par les chasseurs montagnais de la région entre les mois de février et de décembre 2001 ont subi des examens pathologiques macroscopiques et microscopiques, en plus d’avoir été évalués pour en déterminer l’état du corps, la parasitologie du foie et les taux de contaminants dans le foie et le gras. Dans l’ensemble, l’état des corps de caribous échantillonnés semblait adéquat pour cette période de l’année et aucune lésion clinique importante n’a été signalée. Les concentrations de sélénium, de métaux (Hg, Cd et Pb), de 20 pesticides organochlorés (HCB, a-HCH, g-HCH, aldrine, dieldrine, méthoxychlore, mirex, a- et b-endosulfane, heptachlore, heptachlorépoxyde, g-CHL, cis-CHL, trans-nonachlore ainsi que o,p'- et p,p'-DDD, DDE, DDT) et de 24 congénères de PCB s’établissaient dans les étendues signalées pour le caribou au Canada. En général, les niveaux de contaminants étaient relativement faibles, à l’exception du cadmium se trouvant dans les reins (moyenne géometrique : 6,5 μg/g poids humide; étendue : 1,5–44,0 mg/g). Deux types de parasites du foie ont été trouvés : la douve Fascioloides magna (prévalence : 78 %; abondance moyenne géométrique : 4,2 douves/caribou) et un cestode du genre Taenia hydatigena (prévalence : 50 %; abondance moyenne géométrique : 0,6 larves/caribou). Nous avons également réalisé une analyse de régression à variables multiples qui nous a permis de constater que les concentrations de cadmium sont positivement associées et celles de sélénium sont négativement associées à l’abondance de F. magna

Low expression of MSH2 DNA repair protein is associated with poor prognosis in head and neck squamous cell carcinoma

OBJECTIVE: This study aimed to investigate the expression of the MSH2 DNA repair protein in head and neck squamous cell carcinoma (HNSCC) in order to analyze its association with clinicopathologic factors and overall survival of patients. MATERIAL AND METHODS: Clinical data and primary lesions of HNSSC were collected from 55 patients who underwent surgical resection with postoperative radiotherapy in Montes Claros, state of Minas Gerais, Brazil, between 2000 and 2008. Immunohistochemical reactions were performed to analyze MSH2 protein expression. RESULTS: Bivariate analysis showed no significant correlation or association between MSH2 expression and clinicopathologic parameters by Mann-Whitney and Kruskal-Wallis tests. Patients with locoregional metastatic disease (OR=4.949,

Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis

BACKGROUND: Crescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β(1 )is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β(1 )levels in patients with crescentic nephritis could be used as a marker of response to treatment. METHODS: Fifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β(1 )was estimated in biopsy sections by immunohistochemistry and urinary TGF-β(1 )levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β(1 )levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls. RESULTS: Improvement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β(1 )levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β(1 )was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β(1 )immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05). CONCLUSION: Increased TGF-β(1 )renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β(1 )levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis

Conservation physiology of marine fishes: state of the art and prospects for policy

The state of the art of research on the environmental physiology of marine fishes is reviewed from the perspective of how it can contribute to conservation of biodiversity and fishery resources. A major constraint to application of physiological knowledge for conservation of marine fishes is the limited knowledge base; international collaboration is needed to study the environmental physiology of a wider range of species. Multifactorial field and laboratory studies on biomarkers hold promise to relate ecophysiology directly to habitat quality and population status. The 'Fry paradigm' could have broad applications for conservation physiology research if it provides a universal mechanism to link physiological function with ecological performance and population dynamics of fishes, through effects of abiotic conditions on aerobic metabolic scope. The available data indicate, however, that the paradigm is not universal, so further research is required on a wide diversity of species. Fish physiologists should interact closely with researchers developing ecological models, in order to investigate how integrating physiological information improves confidence in projecting effects of global change; for example, with mechanistic models that define habitat suitability based upon potential for aerobic scope or outputs of a dynamic energy budget. One major challenge to upscaling from physiology of individuals to the level of species and communities is incorporating intraspecific variation, which could be a crucial component of species' resilience to global change. Understanding what fishes do in the wild is also a challenge, but techniques of biotelemetry and biologging are providing novel information towards effective conservation. Overall, fish physiologists must strive to render research outputs more applicable to management and decision-making. There are various potential avenues for information flow, in the shorter term directly through biomarker studies and in the longer term by collaborating with modellers and fishery biologists.EU COST Action FA1004 Conservation Physiology of Marine Fishesinfo:eu-repo/semantics/publishedVersio