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

Biological Toxicity and Inflammatory Response of Semi-Single-Walled Carbon Nanotubes

The toxicological studies on carbon nanotubes (CNTs) have been urgently needed from the emerging diverse applications of CNTs. Physicochemical properties such as shape, diameter, conductance, surface charge and surface chemistry of CNTs gained during manufacturing processes play a key role in the toxicity. In this study, we separated the semi-conductive components of SWCNTs (semi-SWCNTs) and evaluated the toxicity on days 1, 7, 14 and 28 after intratracheal instillation in order to determine the role of conductance. Exposure to semi-SWCNTs significantly increased the growth of mice and significantly decreased the relative ratio of brain weight to body weight. Recruitment of monocytes into the bloodstream increased in a time-dependent manner, and significant hematological changes were observed 28 days after exposure. In the bronchoalveolar lavage (BAL) fluid, secretion of Th2-type cytokines, particularly IL-10, was more predominant than Th1-type cytokines, and expression of regulated on activation normal T cell expressed and secreted (RANTES), p53, transforming growth factor (TGF)-β, and inducible nitric oxide synthase (iNOS) increased in a time-dependent manner. Fibrotic histopathological changes peaked on day 7 and decreased 14 days after exposure. Expression of cyclooxygenase-2 (COX-2), mesothelin, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) also peaked on day 7, while that of TGF-β peaked on days 7 and 14. Secretion of histamine in BAL fluid decreased in a time-dependent manner. Consequently, we suggest that the brain is the target organ of semi-SWCNTs brought into the lung, and conductance as well as length may be critical factors affecting the intensity and duration of the inflammatory response following SWCNT exposure

Wireless thin film transistor based on micro magnetic induction coupling antenna

A wireless thin film transistor (TFT) structure in which a source/drain or a gate is connected directly to a micro antenna to receive or transmit signals or power can be an important building block, acting as an electrical switch, a rectifier or an amplifier, for various electronics as well as microelectronics, since it allows simple connection with other devices, unlike conventional wire connections. An amorphous indium gallium zinc oxide (α-IGZO) TFT with magnetic antenna structure was fabricated and studied for this purpose. To enhance the induction coupling efficiency while maintaining the same small antenna size, a magnetic core structure consisting of Ni and nanowires was formed under the antenna. With the micro-antenna connected to a source/drain or a gate of the TFT, working electrical signals were well controlled. The results demonstrated the device as an alternative solution to existing wire connections which cause a number of problems in various fields such as flexible/wearable devices, body implanted devices, micro/nano robots, and sensors for the 'internet of things' (IoT).1

A Carcinoembryonic Antigen-Secreting Adenocarcinoma Arising in Tailgut Cyst : Clinical Implications of Carcinoembryonic Antigen

Tailgut cysts (TGCs) are rare congenital cysts that occur in the retrorectal or presacral spaces. Although most tailgut cysts have been reported as benign, there have been at least 9 cases associated with malignant change. We report herein on an unusual case of a 40-year-old woman with a carcinoembryonic antigen (CEA)-producing adenocarcinoma arising within a TGC who underwent surgical resection and local radiation therapy. Despite the complete resection, metastatic adenocarcinoma developed five months after surgery. CEA-producing adenocarcinoma from a TGC is extremely rare and only two cases, including this case, have been reported in the English medical literature. Besides CEA, the serum levels of CA 19-9 became markedly elevated in this patient. Given that the serum CEA level decreased to the normal range after complete resection of tumor and that the tumor recurrence was associated with a rebound of the CEA serum level, our case shows that serial measurements of serum CEA can be used for treatment planning and for assessing the patient's treatment response for this rare disease