Induction of Premature Senescence by Hsp90 Inhibition in Small Cell Lung Cancer

BACKGROUND: The molecular chaperone Hsp90 is a promising new target in cancer therapy and selective Hsp90 inhibitors are currently in clinical trials. Previously these inhibitors have been reported to induce either cell cycle arrest or cell death in cancer cells. Whether the cell cycle arrest is reversible or irreversible has not generally been assessed. Here we have examined in detail the cell cycle arrest and cell death responses of human small cell lung cancer cell lines to Hsp90 inhibition. METHODOLOGY/PRINCIPAL FINDINGS: In MTT assays, small cell lung cancer cells showed a biphasic response to the Hsp90 inhibitors geldanamycin and radicicol, with low concentrations causing proliferation arrest and high concentrations causing cell death. Assessment of Hsp90 intracellular activity using loss of client protein expression showed that geldanamycin concentrations that inhibited Hsp90 correlated closely with those causing proliferation arrest but not cell death. The proliferation arrest induced by low concentrations of geldanamycin was not reversed for a period of over thirty days following drug removal and showed features of senescence. Rare populations of variant small cell lung cancer cells could be isolated that had additional genetic alterations and no longer underwent irreversible proliferation arrest in response to Hsp90 inhibitors. CONCLUSIONS/SIGNIFICANCE: We conclude that: (1) Hsp90 inhibition primarily induces premature senescence, rather than cell death, in small cell lung cancer cells; (2) small cell lung cancer cells can bypass this senescence through further genetic alterations; (3) Hsp90 inhibitor-induced cell death in small cell lung cancer cells is due to inhibition of a target other than cytosolic Hsp90. These results have implications with regard to how these inhibitors will behave in clinical trials and for the design of future inhibitors in this class

Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Ca2+ channels regulate many crucial processes within cells and their abnormal activity can be damaging to cell survival, suggesting that they might represent attractive therapeutic targets in pathogenic organisms. Parasitic diseases such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis are responsible for millions of deaths each year worldwide. The genomes of many pathogenic parasites have recently been sequenced, opening the way for rational design of targeted therapies. We analyzed genomes of pathogenic protozoan parasites as well as the genome of Schistosoma mansoni, and show the existence within them of genes encoding homologues of mammalian intracellular Ca2+ release channels: inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), two-pore Ca2+ channels (TPCs) and intracellular transient receptor potential (Trp) channels. The genomes of Trypanosoma, Leishmania and S. mansoni parasites encode IP3R/RyR and Trp channel homologues, and that of S. mansoni additionally encodes a TPC homologue. In contrast, apicomplexan parasites lack genes encoding IP3R/RyR homologues and possess only genes encoding TPC and Trp channel homologues (Toxoplasma gondii) or Trp channel homologues alone. The genomes of parasites also encode homologues of mammalian Ca2+ influx channels, including voltage-gated Ca2+ channels and plasma membrane Trp channels. The genome of S. mansoni also encodes Orai Ca2+ channel and STIM Ca2+ sensor homologues, suggesting that store-operated Ca2+ entry may occur in this parasite. Many anti-parasitic agents alter parasite Ca2+ homeostasis and some are known modulators of mammalian Ca2+ channels, suggesting that parasite Ca2+ channel homologues might be the targets of some current anti-parasitic drugs. Differences between human and parasite Ca2+ channels suggest that pathogen-specific targeting of these channels may be an attractive therapeutic prospect

Method For Producing Polymer Biomaterials Using An Infra-red Laser

A presente invenção descreve um processo de obtenção de biomateriais pela adesão entre dois materiais poliméricos, empregando laser infravermelho. Uma das inúmeras aplicações que cabem a esses biomateriais destacam-se suportes, scaffolds e recobrimentos poliméricos para uso em próteses articulares artificiais. O processo melhora as propriedades mecânicas dos polímeros, obtendo uma adesão adequada entre o hidrogel e o substrato, minimizando o desgaste sofrido pelos componentes que constituem dispositivos ortopédicos, por exemplo, um dos principais fatores que geram sua falência.The present invention describes a method for producing biomaterials by using an infra-red laser to cause two polymer materials to adhere to each other. These biomaterials have numerous uses, in particular as polymer supports, scaffolds and coatings for artificial joint prostheses. The method improves the mechanical properties of the polymers, achieving satisfactory adhesion between the hydrogel and the substrate, minimizing the wear of the components that form orthopedic devices, for example, which is one of the main causes of failure of such devices.WO2013091050 (A1)A61L27/40A61F2/02C08J7/04C08J7/18WO2012BR00502A61L27/40A61F2/02C08J7/04C08J7/18US2007207186 (A1)US2007224238 (A1)WO2011146296 (A2)US2007225823 (A1)US2007003588 (A1)US2007041952 (A1

Quantifying synergies in two-versus-one situations in team sports: an example from Rugby Union

Collective behaviors in team sports result in players forming interpersonal synergies that contribute to performance goals. Because of the huge amount of variables that continuously constrain players' behavior during a game, the way that these synergies are formed remain unclear. Our aim was to quantify interpersonal synergies in the team sport of Rugby Union. For that purpose we used the Uncontrolled Manifold Hypothesis (UCM) to identify interpersonal synergies that are formed between ball carrier and support player in two-versus-one situations in Rugby Union. The inter-player angle close to the moment of the pass was used as a performance variable and players running lines velocities as task-relevant elements. Interpersonal synergies (UCM values above 1) were found in 19 out of 55 trials under analysis, which means that on 34% of the trials, the players' running line velocities contribute to stabilizing the inter-player angle close the moment of the pass. The strength of the synergy fluctuates over time indicating the existence of a location effect during attack phases in Rugby Union. UCM analysis shows considerable promise as a performance analysis tool in team sports to discriminate between skilled sub-groups of players.info:eu-repo/semantics/publishedVersio