SK channel activation potentiates auranofin-induced cell death in glio- and neuroblastoma cells

Brain tumours are among the deadliest tumours being highly resistant to currently available therapies. The proliferative behaviour of gliomas is strongly influenced by ion channel activity. Small-conductance calcium-activated potassium (SK/KCa) channels are a family of ion channels that are associated with cell proliferation and cell survival. A combined treatment of classical anti-cancer agents and pharmacological SK channel modulators has not been addressed yet. We used the gold-derivative auranofin to induce cancer cell death by targeting thioredoxin reductases in combination with CyPPA to activate SK channels in neuro- and glioblastoma cells. Combined treatment with auranofin and CyPPA induced massive mitochondrial damage and potentiated auranofin-induced toxicity in neuroblastoma cells in vitro. In particular, mitochondrial integrity, respiration and associated energy generation were impaired. These findings were recapitulated in patient-derived glioblastoma neurospheres yet not observed in non-cancerous HT22 cells. Taken together, integrating auranofin and SK channel openers to affect mitochondrial health was identified as a promising strategy to increase the effectiveness of anti-cancer agents and potentially overcome resistance

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Making the law of the jungle: the reform of forest legislation in Bolivia, Cameroon, and Indonesia

The debates over sustainable development put environmental issues squarely on the policy agendas of nations around the world. Throughout, the fate of the forest occupied center stage, and domestic and international pressure induced many developing nations to reform their forest policy, which frequently culminated in new forest legislation. Yet the process that generated those new forest laws has not received much attention and a number of questions remain unanswered. What factors determine whether governments reform forest laws in the first place? What conditions influence the direction of reform? What role does expert advice play in the process? This paper applies a political economy framework that focuses on the interplay between international structure, domestic structure and ideas to answer those questions. It argues that this approach offers the best tools for analyzing the actors and interests involved in the policy process and their power resources. Among the most significant findings are that the World Bank is not as influential in the end as is commonly perceived. Moreover, in democratic developing countries organizations that focus almost exclusively on cultivating their relationship with state ministries to influence forest policy reform usually see their efforts flounder because the legislature, especially legislative committees, is a more significant policy making arena than had been considered here before

Characterization of the hydrothermal system of the Tinguiririca Volcanic Complex, Central Chile, using structural geology and passive seismic tomography

A structural characterization of the hydrothermal–volcanic field associated with the Tinguiririca Volcanic Complex had been performed by combining passive seismic tomography and structural geology. This complex corresponds to a 20 km long succession of N25°E oriented of eruptive centers, currently showing several thermal manifestations distributed throughout the area. The structural behavior of this zone is controlled by the El Fierro–El Diablo fault system, corresponding to a high angle reverse faults of Oligocene–Miocene age. In this area, a temporary seismic network with 16 short-period stations was setup from January to April of 2010, in the context of the MSc thesis of Lira (2010), covering an area of 200 km2 that corresponds with the hydrothermal field of Tinguiririca Volcanic Complex (TVC), Central Chile, Southern Central Andes. Using P- and S- wave arrival times, a 3D seismic velocity tomography was performed. The preliminary locations of 2270 earthquakes have first been determined using an a priori 1D velocity model. Afterwards, a joint inversion of both, the 3D velocity model and final locations have been obtained. High Vp/Vs ratios are interpreted as zones with high hot fluid content and high fracturing. Meanwhile, low Vp/Vs anomalies could represent the magmatic reservoir and the conduit network associated to the fluid mobility. Based on structural information and thermal manifestations, these anomalies have been interpreted. In order to visualize the relation between local geology and the velocity model, the volume associated with the magma reservoir and the fluid circulation network has been delimited using an iso-value contour of Vp/Vs equal to 1.70. The most prominent observed feature in the obtained model is a large “V” shaped low-velocity anomaly extending along the entire study region and having the same vergency and orientation as the existing high-angle inverse faults, which corroborates that El Fierro–El Diablo fault system represents the local control for fluid mobility. This geometry coincides with surface hydrothermal manifestations and with available geochemical information of the area, which allowed us to generate a conceptual model of fluid circulation in the volcanic–hydrothermal system as well as define the location of the magmatic reservoir.Fil: Pavez, C.. Universidad de Chile; ChileFil: Tapia Silva, Felipe Fernando. Universidad de Chile; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comte, D.. Universidad de Chile; ChileFil: Gutierrez, Francisco. Universidad de Chile; ChileFil: Lira, E.. Universidad de Chile; ChileFil: Charrier González, Reynaldo. Universidad de Chile; ChileFil: Benavente, O.. Universidad de Chile; Chil

Artificial chemical nuclease and cytotoxic activity of a mononuclear copper(I) complex and a related binuclear double-stranded helicate

Copper complexes are promising candidates for anticancer drugs, because of their redox properties and the ability to generate ROS (reactive oxygen species) in the cellular media. Most of the reported complexes with anticancer properties are based on Cu(II), which must be reduced to Cu(I) to exert the therapeutic action. Here, we report on the synthesis and characterization of two novel copper(I) complexes, a mononuclear complex [Cu(L1)2](ClO4) (1) and a binuclear helicate [Cu2(L2)2](ClO4)2 (2) (L1=2-ethoxy-1,10-phenanthroline, L2=1,2-bis((1,10-phenanthrolin-2-yl)oxy)ethane), which were designed to be structurally comparable, in order to evaluate the effect of nuclearity on the artificial nuclease activity. The activity of helicate (2) was higher than that of the monometallic (1), and the DNA cleavage mechanism is through the generation of hydroxyl radical in a Fenton-like reaction, which occurs after oxidation of Cu(I) by O2. Also, helicate (2) showed a higher cytotoxic effect against different cancer cells lines, while both complexes are more active than cisplatin.Fil: Levín, Pedro. Universidad de Santiago de Chile; ChileFil: Balsa, Lucia Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Silva, Carlos P.. Universidad de Santiago de Chile; ChileFil: Herzog, Austin E.. University Johns Hopkins; Estados UnidosFil: Vega, Andrés. Universidad Andrés Bello; Chile. Centro para el Desarrollo de Nanociencias y Nanotecnología; ChileFil: Pavez, Jorge. Universidad de Santiago de Chile; Chile. Soft Matter Research and Technology Center; ChileFil: Leon, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; ArgentinaFil: Lemus, Luis. Universidad de Santiago de Chile; Chil

Making the Law of the Jungle: The Reform of Forest Legislation in Bolivia, Cameroon, Costa Rica, and Indonesia.

In the debate over the forest, policy research organizations have concentrated on uncovering the causes of deforestation and recommending measures to develop them sustainably. This article examines the conditions under which those prescriptions find their way into public policy, specifically, into reforming forest laws. We argue that this is a political rather than technocratic process that requires knowing the principal actors, their interests, and their power resources. The combination of these factors and, therefore forest policy outcomes, varies across our cases. However, similar combinations in other cases should have comparable results. We found that actors who dominated the policy process in the early stages, such as the World Bank, lost significant ground in the later stages, in part because legislatures were an important policy-making arena and legislators had significant impact on outcomes. The latter was surprising because one tends to assume the executive branch is the principal locus of policy-making in developing countries. Copyright (c) 2002 Massachusetts Institute of Technology.

Contraception With Long-acting Subdermal Implants. A Five-year Clinical Trial With Silastic Covered Rod Implants Containing Levonorgestrel

A total of 189 women volunteered to accept subdermal implants for contraception. The implants were "covered rods", consisting of a core rod containing equal parts by weight of levonorgestrel and polydimethylsiloxane and sealed inside a thin-walled tube of Silastic tubing with medical adhesive. In one study 78 women used 4 3cm rods (study 07) and in the other 111 women used 6 3cm rods. In 5 years of use there were no pregnancies in either group. Terminations because of menstrual problems were twice as frequent among the 4-rod users than among users of the 6 rods. Menstrual pattern analysis is presented for the two rod regimens and compared with the previously reported patterns for the 6-capsule regimen (NORPLANTR). Long-term in vivo release rates are also presented. © 1985.314351359Contraception with long acting subdermal implants: I. An effective and acceptable modality in international clinical trials (1978) Contraception, 18, pp. 315-333. , IThe Development of NORPLANT Implants (1983) Studies in Family Planning, 14, pp. 159-193Diaz, Pavez, Miranda, Robertson, Sivin, Croxatto, A Five-Year Clinical Trial of Levonorgestrel Silastic Implants (NORPLANT™) (1982) Contraception, 25, pp. 447-456Nash, Robertson, Moo-Young, Atkinson, Steroid Release from Silastic Capsules and Rods (1978) Contraception, 18, pp. 367-394Faundes, Mejias, DeLeon, Robertson, Alvarez, First year clinical experience with six levonorgestrel rods as subdermal contraception (1979) Contraception, 20, pp. 167-175Roy, Stanczyk, Mishell, Lumkin, Gentzschein, Clinical and Endocrinological Study of Continuous Levonorgestrel Administration from Subcutaneous Solid Polydimethylsiloxane Rods (1980) Contraception, 21, pp. 595-615Weiner, Johansson, Contraception with d-Norgestrel Silastic Rods: Plasma Levels of d-Norgestrel and Influence on the Ovarian Function (1976) Contraception, 14, pp. 551-562Robertson, Sivin, Nash, Braun, Dinh, Release Rates of Levonorgestrel from SilasticR Capsules. Homogenous Rods and covered Rods in Humans (1983) Contraception, 27, pp. 483-495Jain, Sivin, Life-Table Analysis of IUDs. Problems and Recommendations (1977) Studies in Family Planning, 8 (2)Faundes, Sivin, Stern, Long -Acting Contraceptive Implants, An Analysis of Menstrual Bleeding Patterns (1978) Contraception, 18, pp. 355-36