Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

Development of an ELISA-array for simultaneous detection of five encephalitis viruses

Japanese encephalitis virus(JEV), tick-borne encephalitis virus(TBEV), and eastern equine encephalitis virus (EEEV) can cause symptoms of encephalitis. Establishment of accurate and easy methods by which to detect these viruses is essential for the prevention and treatment of associated infectious diseases. Currently, there are still no multiple antigen detection methods available clinically. An ELISA-array, which detects multiple antigens, is easy to handle, and inexpensive, has enormous potential in pathogen detection. An ELISA-array method for the simultaneous detection of five encephalitis viruses was developed in this study. Seven monoclonal antibodies against five encephalitis-associated viruses were prepared and used for development of the ELISA-array. The ELISA-array assay is based on a "sandwich" ELISA format and consists of viral antibodies printed directly on 96-well microtiter plates, allowing for direct detection of 5 viruses. The developed ELISA-array proved to have similar specificity and higher sensitivity compared with the conventional ELISAs. This method was validated by different viral cultures and three chicken eggs inoculated with infected patient serum. The results demonstrated that the developed ELISA-array is sensitive and easy to use, which would have potential for clinical use

Cosmic Rays during BBN as Origin of Lithium Problem

There may be non-thermal cosmic rays during big-bang nucleosynthesis (BBN) epoch (dubbed as BBNCRs). This paper investigated whether such BBNCRs can be the origin of Lithium problem or not. It can be expected that BBNCRs flux will be small in order to keep the success of standard BBN (SBBN). With favorable assumptions on the BBNCR spectrum between 0.09 -- 4 MeV, our numerical calculation showed that extra contributions from BBNCRs can account for the $^7$Li abundance successfully. However $^6$Li abundance is only lifted an order of magnitude, which is still much lower than the observed value. As the deuteron abundance is very sensitive to the spectrum choice of BBNCRs, the allowed parameter space for the spectrum is strictly constrained. We should emphasize that the acceleration mechanism for BBNCRs in the early universe is still an open question. For example, strong turbulent magnetic field is probably the solution to the problem. Whether such a mechanism can provide the required spectrum deserves further studies.Comment: 34 pages, 21 figures, published versio

Modulating the charge injection in organic field-effect transistors: fluorinated oligophenyl self-assembled monolayers for high work function electrodes

Financial support from the ERC project SUPRAFUNCTION (GA-257305), the EC Marie-Curie projects IEF-MULTITUDES (PIEF-GA-2012-326666) and ITN iSwitch (GA no. 642196), the Agence Nationale de la Recherche through the LabEx project Chemistry of Complex Systems (ANR-10-LABX-0026_CSC), and the International Center for Frontier Research in Chemistry (icFRC). The computational work was supported by the Interuniversity Attraction Pole Programme (P7/05) initiated by the Belgian Science Policy Office, and by the Belgian National Fund for Scientific Research (FNRS). J.C. is an FNRS research director. Colin Van Dyck is a recipient of a Gustave Boël – Sofina Fellowship of the Belgian American Educational Foundation (BAEF). K.M., F.R. and M.M. acknowledge financial support by the Swiss National Science Foundation (SNF) and the Swiss Nanoscience Institute (SNI)