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

Diffuse Alveolar Hemorrhage in a 39-year-old Woman: Unusual Initial Presentation of Microscopic Polyangiitis

Microscopic polyangiitis (MPA) is a necrotizing vasculitis involving the small vessels without granulomatous inflammation. Most MPA initially presents with renal involvement without pulmonary involvement. Isolated and initially presenting alveolar hemorrhage is very rare. The patient was a 39-year-old female with a progressive cough, dyspnea, and blood-tinged sputum for the previous 5 days. We determined that her condition was MPA though VATS lung biopsy and renal biopsy. After 2 months of steroid therapy, the chest lesions had improved. We report here a rare case of MPA with isolated and initial involvement of the lung with a review of the literature

A Case of Severe Anemia by Necator americanus Infection in Korea

This report describes clinical and parasitological findings of an 82-yr-old female patient who lived in a local rural village and suffered from severe chronic anemia for several years. She was transferred to the National Police Hospital in Seoul for management of severe dyspnea and dizziness. At admission, she showed symptoms or signs of severe anemia. Gastroduodenoscopy observed hyperemic mucosa of the duodenum and discovered numerous moving roundworms on the mucosa. Endoscopy isolated seven of them, which were identified as Necator americanus by characteristic morphology of cutting plates in the buccal cavity. The patient was treated with albendazole and supportive measures for anemia, and her physical condition much improved. This case suggests the possibility that hookworm N. americanus is still transmitted in a remote local mountainous area in Korea

Sustainable and recyclable super engineering thermoplastic from biorenewable monomer

Environmental and health concerns force the search for sustainable super engineering plastics (SEPs) that utilise bio-derived cyclic monomers, e.g. isosorbide instead of restricted petrochemicals. However, previously reported bio-derived thermosets or thermoplastics rarely offer thermal/mechanical properties, scalability, or recycling that match those of petrochemical SEPs. Here we use a phase transfer catalyst to synthesise an isosorbide-based polymer with a high molecular weight >100 kg mol−1, which is reproducible at a 1-kg-scale production. It is transparent and solvent/melt-processible for recycling, with a glass transition temperature of 212 °C, a tensile strength of 78 MPa, and a thermal expansion coefficient of 23.8 ppm K−1. Such a performance combination has not been reported before for bio-based thermoplastics, petrochemical SEPs, or thermosets. Interestingly, quantum chemical simulations show the alicyclic bicyclic ring structure of isosorbide imposes stronger geometric restraint to polymer chain than the aromatic group of bisphenol-A.11Ysciescopu

Resting-state EEG activity related to impulsivity in gambling disorder

Background and aims Impulsivity is a core feature of gambling disorder (GD) and is related to the treatment response. Thus, it is of interest to determine objective neurobiological markers associated with impulsivity in GD. We explored resting-state electroencephalographic (EEG) activity in patients with GD according to the degree of impulsivity. Methods In total, 109 GD subjects were divided into three groups according to Barratt impulsiveness scale-11 (BIS-11) scores: high (HI; 25th percentile of BIS-11 scores, n = 29), middle (MI; 26th–74th percentile, n = 57), and low-impulsivity (LI) groups (75th percentile, n = 23). We used generalized estimating equations to analyze differences in EEG absolute power considering group (HI, MI, and LI), brain region (frontal, central, and posterior), and hemisphere (left, midline, and right) for each frequency band (delta, theta, alpha, beta, and gamma). Results The results indicated that GD patients in the HI group showed decreased theta absolute power, and decreased alpha and beta absolute power in the left, right, particularly midline frontocentral regions. Discussion and conclusions This study is a novel attempt to reveal impulsive features in GD by neurophysiological methods. The results suggest different EEG patterns among GD patients according to the degree of impulsivity, raising the possibility of neurophysiological objective features in GD and helping clinicians in treating GD patients with impulsive features