Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro.

Cilengitide is a cyclic peptide antagonist of integrins alphavbeta3 and alphavbeta5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, cilengitide (1-100 microM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by cilengitide could not be predicted by the level of expression of the cilengitide target molecules, alphavbeta3 and alphavbeta5, at the cell surface. Glioma cell death induced by cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X(L) or altering the p53 status did not modulate cilengitide-induced cell death. No consistent effects of cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from cilengitide added to temozolomide-based radiochemotherapy in patients with O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to cilengitide alone or to cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.

Biosynthesis of panaxynol and panaxydol in Panax ginseng

The natural formation of the bioactive C17-polyacetylenes (−)-(R)-panaxynol and panaxydol was analyzed by 13C-labeling experiments. For this purpose, plants of Panax ginseng were supplied with 13CO2 under field conditions or, alternatively, sterile root cultures of P. ginseng were supplemented with [U-13C6]glucose. The polyynes were isolated from the labeled roots or hairy root cultures, respectively, and analyzed by quantitative NMR spectroscopy. The same mixtures of eight doubly 13C-labeled isotopologues and one single labeled isotopologue were observed in the C17-polyacetylenes obtained from the two experiments. The polyketide-type labeling pattern is in line with the biosynthetic origin of the compounds via decarboxylation of fatty acids, probably of crepenynic acid. The 13C-study now provides experimental evidence for the biosynthesis of panaxynol and related polyacetylenes in P. ginseng under in planta conditions as well as in root cultures. The data also show that 13CO2 experiments under field conditions are useful to elucidate the biosynthetic pathways of metabolites, including those from roots.

Extratos de Piper marginatume Azadirachta indica no controle de Colletotrichum scovillei em pimentão

O objetivo deste trabalho foi avaliar o efeito de extratos de capeba (Piper marginatum) e nim (Azadirachta indica) sobre o fungo Colletotrichum scovillei e determinar o componente mais ativo no controle pós-colheita da antracnose em pimentão. A atividade de extratos metanólicos das folhas (P.marginatum e A. indica) e das sementes (A. indica) a 0, 125, 250, 500, 1.000 e 2.000 ppm, na inibição do crescimento micelial de C. scovillei in vitro foram avaliadas. O extrato metanólico de folhas de P.marginatum foi o mais ativo e, consequentemente, foi submetido ao fracionamento biomonitorado ("bioassay-guided fractionation"). Esse processo rendeu 10 frações majoritárias, obtidas por cromatografia líquida de alta performance, das quais a fração à concentração de 1,5 ppm inibiu o desenvolvimento de C. scovillei de forma mais eficiente do que o fungicida mancozeb.

Smart antennas: state of the art

Aim of this contribution is to illustrate the state of the art of smart antenna research from several perspectives. The bow is drawn from transmitter issues via channel measurements and modeling, receiver signal processing, network aspects, technological challenges towards first smart antenna applications and current status of standardization. Moreover, some future prospects of different disciplines in smart antenna research are given.

Should biomarkers be used to design personalized medicine for the treatment of glioblastoma?

Significant progress has been made in understanding the molecular pathogenesis of gliomas and in predicting general outcome depending on a limited set of clinical parameters and molecular markers. However, methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter is the only molecular marker linked to sensitivity of a specific treatment, that is, alkylating agent chemotherapy, and this predictive value may be limited to glioblastoma. Moreover, in the absence of potent alternative drugs, temozolomide chemotherapy should not be withheld from patients with newly diagnosed glioblastoma without MGMT promoter methylation in general practice. In the context of clinical trials, however, irrespective of whether classical cytotoxic drugs, tyrosine kinase inhibitors or antiangiogenic agents are used, tissue should be centrally collected. Appropriate research programs should seek to define enriched patient populations for future trials and ultimately facilitate individualized cancer treatments.

The first SEPServer event catalogue 68-MeV solar proton events observed at 1 AU in 1996-2010

SEPServer is a three-year collaborative project funded by the seventh framework programme (FP7-SPACE) of the European Union. The objective of the project is to provide access to state-of-the-art observations and analysis tools for the scientific community on solar energetic particle (SEP) events and related electromagnetic (EM) emissions. The project will eventually lead to better understanding of the particle acceleration and transport processes at the Sun and in the inner heliosphere. These processes lead to SEP events that form one of the key elements of space weather. In this paper we present the first results from the systematic analysis work performed on the following datasets: SOHO/ERNE, SOHO/EPHIN, ACE/EPAM, Wind/WAVES and GOES X-rays. A catalogue of SEP events at 1 AU, with complete coverage over solar cycle 23, based on high-energy (~68-MeV) protons from SOHO/ERNE and electron recordings of the events by SOHO/EPHIN and ACE/EPAM are presented. A total of 115 energetic particle events have been identified and analysed using velocity dispersion analysis (VDA) for protons and time-shifting analysis (TSA) for electrons and protons in order to infer the SEP release times at the Sun. EM observations during the times of the SEP event onset have been gathered and compared to the release time estimates of particles. Data from those events that occurred during the European day-time, i.e., those that also have observations from ground-based observatories included in SEPServer, are listed and a preliminary analysis of their associations is presented. We find that VDA results for protons can be a useful tool for the analysis of proton release times, but if the derived proton path length is out of a range of 1 AU < s[3 AU, the result of the analysis may be compromised, as indicated by the anti-correlation of the derived path length and release time delay from the asso ciated X-ray flare. The average path length derived from VDA is about 1.9 times the nominal length of the spiral magnetic field line. This implies that the path length of first-arriving MeV to deka-MeV protons is affected by interplanetary scattering. TSA of near-relativistic electrons results in a release time that shows significant scatter with respect to the EM emissions but with a trend of being delayed more with increasing distance between the flare and the nominal footpoint of the Earth-connected field line.

TGF-β dependent regulation of oxygen radicals during transdifferentiation of activated hepatic stellate cells to myofibroblastoid cells

Background: The activation of hepatic stellate cells (HSCs) plays a pivotal role during liver injury because the resulting myofibroblasts (MFBs) are mainly responsible for connective tissue re-assembly. MFBs represent therefore cellular targets for anti-fibrotic therapy. In this study, we employed activated HSCs, termed M1-4HSCs, whose transdifferentiation to myofibroblastoid cells (named M-HTs) depends on transforming growth factor (TGF)-β. We analyzed the oxidative stress induced by TGF-β and examined cellular defense mechanisms upon transdifferentiation of HSCs to M-HTs. Results: We found reactive oxygen species (ROS) significantly upregulated in M1-4HSCs within 72 hours of TGF-β administration. In contrast, M-HTs harbored lower intracellular ROS content than M1-4HSCs, despite of elevated NADPH oxidase activity. These observations indicated an upregulation of cellular defense mechanisms in order to protect cells from harmful consequences caused by oxidative stress. In line with this hypothesis, superoxide dismutase activation provided the resistance to augmented radical production in M-HTs, and glutathione rather than catalase was responsible for intracellular hydrogen peroxide removal. Finally, the TGF-β/NADPH oxidase mediated ROS production correlated with the upregulation of AP-1 as well as platelet-derived growth factor receptor subunits, which points to important contributions in establishing antioxidant defense. Conclusion: The data provide evidence that TGF-β induces NADPH oxidase activity which causes radical production upon the transdifferentiation of activated HSCs to M-HTs. Myofibroblastoid cells are equipped with high levels of superoxide dismutase activity as well as glutathione to counterbalance NADPH oxidase dependent oxidative stress and to avoid cellular damage.