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

Multi-view Cross-Modality MR Image Translation for Vestibular Schwannoma and Cochlea Segmentation

In this work, we propose a multi-view image translation framework, which can translate contrast-enhanced T1 (ceT1) MR imaging to high-resolution T2 (hrT2) MR imaging for unsupervised vestibular schwannoma and cochlea segmentation. We adopt two image translation models in parallel that use a pixel-level consistent constraint and a patch-level contrastive constraint, respectively. Thereby, we can augment pseudo-hrT2 images reflecting different perspectives, which eventually lead to a high-performing segmentation model. Our experimental results on the CrossMoDA challenge show that the proposed method achieved enhanced performance on the vestibular schwannoma and cochlea segmentation.Comment: 9 pages, 4 figure

Input of terrestrial organic matter linked to deglaciation increased mercury transport to the Svalbard fjords

Deglaciation has accelerated the transport of minerals as well as modern and ancient organic matter from land to fjord sediments in Spitsbergen, Svalbard, in the European Arctic Ocean. Consequently, such sediments may contain significant levels of total mercury (THg) bound to terrestrial organic matter. The present study compared THg contents in surface sediments from three fjord settings in Spitsbergen: Hornsund in the southern Spitsbergen, which has high annual volume of loss glacier and receives sediment from multiple tidewater glaciers, Dicksonfjorden in the central Spitsbergen, which receives sediment from glacifluvial rivers, and Wijdefjorden in the northern Spitsbergen, which receive sediments from a mixture of tidewater glaciers and glacifluvial rivers. Our results showed that the THg (52 +/- 15 ng g(-1)) bound to organic matter (OM) was the highest in the Hornsund surface sediments, where the glacier loss (0.44 km(3) yr(-1)) and organic carbon accumulation rates (9.3 similar to 49.4 g m(-2) yr(-1)) were elevated compared to other fjords. Furthermore, the delta C-13 (-27 similar to -24 parts per thousand) and delta S-34 values (-10 similar to 15 parts per thousand) of OM indicated that most of OM were originated from terrestrial sources. Thus, the temperature-driven glacial melting could release more OM originating from the meltwater or terrestrial materials, which are available for THg binding in the European Arctic fjord ecosystems.11Ysciescopu

Anti-reflective nano- and micro-structures on 4H-SiC for photodiodes

In this study, nano-scale honeycomb-shaped structures with anti-reflection properties were successfully formed on SiC. The surface of 4H-SiC wafer after a conventional photolithography process was etched by inductively coupled plasma. We demonstrate that the reflection characteristic of the fabricated photodiodes has significantly reduced by 55% compared with the reference devices. As a result, the optical response Iillumination/Idark of the 4H-SiC photodiodes were enhanced up to 178%, which can be ascribed primarily to the improved light trapping in the proposed nano-scale texturing

The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side