The chemopreventive polyphenol Curcumin prevents hematogenous breast cancer metastases in immunodeficient mice

Dissemination of metastatic cells probably occurs long before diagnosis of the primary tumor. Metastasis during early phases of carcinogenesis in high risk patients is therefore a potential prevention target. The plant polyphenol Curcumin has been proposed for dietary prevention of cancer. We therefore examined its effects on the human breast cancer cell line MDA-MB-231 in vitro and in a mouse metastasis model. Curcumin strongly induces apoptosis in MDA- MB- 231 cells in correlation with reduced activation of the survival pathway NF kappa B, as a consequence of diminished I kappa B and p65 phosphorylation. Curcumin also reduces the expression of major matrix metalloproteinases (MMPs) due to reduced NF kappa B activity and transcriptional downregulation of AP-1. NF kappa B/p65 silencing is sufficient to downregulate c-jun and MMP expression. Reduced NF kappa B/AP-1 activity and MMP expression lead to diminished invasion through a reconstituted basement membrane and to a significantly lower number of lung metastases in immunodeficient mice after intercardiac injection of 231 cells (p=0.0035). 68% of Curcumin treated but only 17% of untreated animals showed no or very few lung metastases, most likely as a consequence of down-regulation of NF kappa B/AP-1 dependent MMP expression and direct apoptotic effects on circulating tumor cells but not on established metastases. Dietary chemoprevention of metastases appears therefore feasible. Copyright (c) 2007 S. Karger AG, Basel

The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination

Lifelong persistence of Epstein-Barr virus (EBV) in infected hosts is mainly owed to the virus' pronounced abilities to evade immune responses of its human host. Active immune evasion mechanisms reduce the immunogenicity of infected cells and are known to be of major importance during lytic infection. The EBV genes BCRF1 and BNLF2a encode the viral homologue of IL-10 (vIL-10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both are known immunoevasins in EBV's lytic phase. Here we describe that BCRF1 and BNLF2a are functionally expressed instantly upon infection of primary B cells. Using EBV mutants deficient in BCRF1 and BNLF2a, we show that both factors contribute to evading EBV-specific immune responses during the earliest phase of infection. vIL-10 impairs NK cell mediated killing of infected B cells, interferes with CD4+ T-cell activity, and modulates cytokine responses, while BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8+ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, pre-latent phase of infection and may improve the establishment of a latent EBV infection in vivo

Evidence for early life in Earth’s oldest hydrothermal vent precipitates

Although it is not known when or where life on Earth began, some of the earliest habitable environments may have been submarine-hydrothermal vents. Here we describe putative fossilized microorganisms that are at least 3,770 million and possibly 4,280 million years old in ferruginous sedimentary rocks, interpreted as seafloor-hydrothermal vent-related precipitates, from the Nuvvuagittuq belt in Quebec, Canada. These structures occur as micrometre-scale haematite tubes and filaments with morphologies and mineral assemblages similar to those of filamentous microorganisms from modern hydrothermal vent precipitates and analogous microfossils in younger rocks. The Nuvvuagittuq rocks contain isotopically light carbon in carbonate and carbonaceous material, which occurs as graphitic inclusions in diagenetic carbonate rosettes, apatite blades intergrown among carbonate rosettes and magnetite–haematite granules, and is associated with carbonate in direct contact with the putative microfossils. Collectively, these observations are consistent with an oxidized biomass and provide evidence for biological activity in submarine-hydrothermal environments more than 3,770 million years ago

Systems of Differential Algebraic Equations in Computational Electromagnetics

Starting from space-discretisation of Maxwell's equations, various classical formulations are proposed for the simulation of electromagnetic fields. They differ in the phenomena considered as well as in the variables chosen for discretisation. This contribution presents a literature survey of the most common approximations and formulations with a focus on their structural properties. The differential-algebraic character is discussed and quantified by the differential index concept

Tumor Microenvironment Conditioning by Abortive Lytic Replication of Oncogenic γ-Herpesviruses

Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) constitute the human γ-herpesviruses and two of the seven human tumor viruses. In addition to their viral oncogenes that primarily belong to the latent infection programs of these viruses, they encode proteins that condition the microenvironment. Many of these are early lytic gene products and are only expressed in a subset of infected cells of the tumor mass. In this chapter I will describe their function and the evidence that targeting them in addition to the latent oncogenes could be beneficial for the treatment of EBV- and KSHV-associated malignancies

Antarctic glaciation caused ocean circulation changes at the Eocene–Oligocene transition

Two main hypotheses compete to explain global cooling and the abrupt growth of the Antarctic ice sheet across the Eocene–Oligocene transition about 34 million years ago: thermal isolation of Antarctica due to southern ocean gateway opening1,2,3,4, and declining atmospheric CO2 (refs 5, 6). Increases in ocean thermal stratification and circulation in proxies across the Eocene–Oligocene transition have been interpreted as a unique signature of gateway opening2,4, but at present both mechanisms remain possible. Here, using a coupled ocean–atmosphere model, we show that the rise of Antarctic glaciation, rather than altered palaeogeography, is best able to explain the observed oceanographic changes. We find that growth of the Antarctic ice sheet caused enhanced northward transport of Antarctic intermediate water and invigorated the formation of Antarctic bottom water, fundamentally reorganizing ocean circulation. Conversely, gateway openings had much less impact on ocean thermal stratification and circulation. Our results support available evidence that CO2 drawdown—not gateway opening—caused Antarctic ice sheet growth, and further show that these feedbacks in turn altered ocean circulation. The precise timing and rate of glaciation, and thus its impacts on ocean circulation, reflect the balance between potentially positive feedbacks (increases in sea ice extent and enhanced primary productivity) and negative feedbacks (stronger southward heat transport and localized high-latitude warming). The Antarctic ice sheet had a complex, dynamic role in ocean circulation and heat fluxes during its initiation, and these processes are likely to operate in the future

Origin and age of the earliest Martian crust from meteorite NWA 7533

The ancient cratered terrain of the southern highlands of Mars is thought to hold clues to the planet’s early differentiation [1,2] but until now no meteoritic regolith breccias have been recovered from Mars. Here we show that the meteorite Northwest Africa (NWA) 7533 (paired with meteorite NWA 7034 [3]) is a polymict breccia consisting of a fine-grained interclast matrix containing clasts of igneous-textured rocks and fine-grained clast-laden impact melt rocks. High abundances of meteoritic siderophiles (for example nickel and iridium) found throughout the rock reach a level in the fine-grained portions equivalent to 5 per cent CI chondritic input, which is comparable to the highest levels found in lunar breccias. Furthermore, analyses of three leucocratic monzonite clasts show a correlation between nickel, iridium and magnesium consistent with differentiation from impact melts. Compositionally, all the fine-grained material is alkalic basalt, chemically identical (except for sulphur, chlorine and zinc) to soils from Gusev crater. Thus, we propose that NWA 7533 is a Martian regolith breccia. It contains zircons for which we measured an age of 4,428 ± 25 million years, which were later disturbed 1,712 ± 85 million years ago. This evidence for early crustal differentiation implies that the Martian crust, and its volatile inventory [4] formed in about the first 100 million years of Martian history, coeval with earliest crust formation on the Moon [5] and the Earth [6]. In addition, incompatible element abundances in clast-laden impact melt rocks and interclast matrix provide a geochemical estimate of the average thickness of the Martian crust (50 kilometres) comparable to that estimated geophysically [2,7]