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

다자이 오사무 “황금풍경”

太宰治『黄金風景』Translations Korea

Fundamental Bounds in Measurements for Estimating Quantum States

Quantum measurement unavoidably disturbs the state of a quantum system if any information about the system is extracted. Recently, the concept of reversing quantum measurement has been introduced and has attracted much attention. Numerous efforts have thus been devoted to understanding the fundamental relation of the amount of information obtained by measurement to either state disturbance or reversibility. Here, we experimentally prove the trade-off relations in quantum measurement with respect to both state disturbance and reversibility. By demonstrating the quantitative bound of the trade-off relations, we realize an optimal measurement for estimating quantum systems with minimum disturbance and maximum reversibility. Our results offer fundamental insights on quantum measurement and practical guidelines for implementing various quantum information protocols

2-Bromo-p-terphen­yl

In the title compound, C18H13Br, the dihedral angles between the mean planes of the central benzene ring and the mean planes of the outer phenyl and bromo­phenyl rings are 33.47 (8) and 66.35 (8)°, respectively. In the crystal, weak C—H⋯π and inter­molecular Br⋯Br [3.5503 (15) Å] inter­actions contribute to the stabilization of the packing

Properties of Central Caustics in Planetary Microlensing

To maximize the number of planet detections, current microlensing follow-up observations are focusing on high-magnification events which have a higher chance of being perturbed by central caustics. In this paper, we investigate the properties of central caustics and the perturbations induced by them. We derive analytic expressions of the location, size, and shape of the central caustic as a function of the star-planet separation, $s$, and the planet/star mass ratio, $q$, under the planetary perturbative approximation and compare the results with those based on numerical computations. While it has been known that the size of the planetary caustic is \propto \sqrt{q}, we find from this work that the dependence of the size of the central caustic on $q$ is linear, i.e., \propto q, implying that the central caustic shrinks much more rapidly with the decrease of $q$ compared to the planetary caustic. The central-caustic size depends also on the star-planet separation. If the size of the caustic is defined as the separation between the two cusps on the star-planet axis (horizontal width), we find that the dependence of the central-caustic size on the separation is \propto (s+1/s). While the size of the central caustic depends both on $s$ and q, its shape defined as the vertical/horizontal width ratio, R_c, is solely dependent on the planetary separation and we derive an analytic relation between R_c and s. Due to the smaller size of the central caustic combined with much more rapid decrease of its size with the decrease of q, the effect of finite source size on the perturbation induced by the central caustic is much more severe than the effect on the perturbation induced by the planetary caustic. Abridged.Comment: 5 pages, 4 figures, ApJ accepte

Anti-inflammatory activity of cinnamon water extract in vivo and in vitro LPS-induced models

BACKGROUND: Cinnamon bark is one of the most popular herbal ingredients in traditional oriental medicine and possesses diverse pharmacological activities including anti-bacterial, anti-viral, and anti-cancer properties. The goal of this study is to investigate the in vivo and in vitro inhibitory effect of cinnamon water extract (CWE) on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and its underlying intracellular mechanisms. METHODS: CWE was orally administrated to mice for 6 days prior to intraperitoneal injection of LPS. Serum levels of TNF-α and interleukin (IL)-6 were determined 1 hour after LPS stimulation. Peritoneal macrophages from thioglycollate-injected mice were isolated and assayed for viability, cytokine expression and signaling molecules upon LPS stimulation. CWE was further fractioned according to molecular size, and the levels of total polyphenols and biological activities of each fraction were measured. RESULTS: The oral administration of CWE to mice significantly decreased the serum levels of TNF-α and IL-6. CWE treatment in vitro decreased the mRNA expression of TNF-α. CWE blocked the LPS-induced degradation of IκBα as well as the activation of JNK, p38 and ERK1/2. Furthermore, size-based fractionation of CWE showed that the observed inhibitory effect of CWE in vitro occurred in the fraction containing the highest level of total polyphenols. CONCLUSIONS: Treatment with CWE decreased LPS-induced TNF-α in serum. In vitro inhibition of TNF-α gene by CWE may occur via the modulation of IκBα degradation and JNK, p38, and ERK1/2 activation. Our results also indicate that the observed anti-inflammatory action of CWE may originate from the presence of polyphenols

Impacts of Detailed Land-Use Types and Urban Heat in an Urban Canopy Model on Local Meteorology and Ozone Levels for Air Quality Modeling in a Coastal City, Korea

An urban canopy model (UCM), with detailed urban land-use and anthropogenic heat information, is required to reproduce and understand the urbanization process and its impact on regional climate and urban air quality. This study investigates the UCM impact on simulated meteorology and surface ozone in the coastal city of Busan using the WRF-SMOKE-CMAQ model coupled with (UCM case), and without the UCM (NOUCM case). The UCM and NOUCM case results suggest that UCM case generally produces warmer temperatures and deeper planetary boundary layer (PBL) heights, especially in the early morning and night time, than the NOUCM case. Owing to urban heating and enhanced turbulent mixing incorporation in the center of the city, the sea breeze in the UCM case tends to penetrate faster and more strongly than in the NOUCM case. After sea breeze arrival at the urban center, the urban heat island effect prevents its penetration further inland. In the UCM case in the late afternoon, local meteorological changes induce remarkable increases in simulated O3 concentrations over the downwind (up to 17.1 ppb) and downtown (up to 10.6 ppb) areas. This is probably due to an increase in temperature in the urban areas and the wind convergence zone movement due to the sea breeze interaction and offshore flows. The increase in O3 concentration in the late afternoon results in the model bias reduction under previously underestimated O3 conditions due to high NOx emissions. The simulated O3 concentrations in the UCM case are more similar to the observed O3 concentrations compared to those of the NOUCM case

Anesthetic experiences of myxoma removal surgery in two patients with Carney complex -A report of two cases-

Carney complex is an autosomal dominant disorder that occurs due to a mutation in PRKAR1A, which encodes protein kinase A. The clinical features are multiple endocrine gland neoplasms, skin tumors, pigmented skin lesions, myxomas, and schwannomas. In Carney complex, the cardiac myxoma is a common co-morbidity. It occurs in multiples, during young age, regardless of gender and cardiac chamber and is known to recur frequently. Therefore there are high risks of adhesion and massive bleeding due to repeated surgeries. Such surgical risks account for over 50% of disease-specific mortality of Carney complex patients. Here, we present anesthetic experiences of myxoma removal surgery in two patients with Carney complex