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Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood–brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.

Summary: Obesity and fatty liver diseases—metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)—affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2−/− and Aldh2−/−Sptbn1+/− mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2−/− and Aldh2−/−Sptbn1+/− mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Sexual harassment and gender-based violence have become pervasive and normal within South African society. This trend is of grave concern at colleges and universities. Drawing on the social construction of the gender theory approach, this study explored the perceptions and experiences of sexual harassment among students at a South African university. The nature and causes of sexual harassment were examined. Twenty undergraduate students—twelve females, five males, one queer and two bisexual students—participated in this study. Data was generated using individual interviews and focus group discussions. Sexual harassment was prevalent at the university in the form of verbal, non-verbal and physical harassment. We argue that harassment stems from broader constructs of masculinity and patriarchal power that challenge and effectively silence victims. Non-reporting of harassment largely sanctions sexual harassment at the university. Female students were the main victims of gender-based violence with male students being the main perpetrators. LGBTQIA students were found to be vulnerable to harassment, mainly because of their sexual preference. The study revealed the need to create better awareness of what constitutes sexual harassment and gender-based violence and suggests that victims, perpetrators and university staff collaborate to tackle the scourge. We propose the necessity for focused and ongoing education and awareness campaigns on campus.

We explored the feasibility of high-speed and high-accuracy quantification of active pharmaceutical ingredient (API) content in tablet products by near-infrared (NIR) spectroscopy to improve the reliability of pharmaceuticals. For this purpose, we employed a high-power NIR time-stretch transmission spectrometer recently developed by us. By using this transmission spectrometer with a multivariate calibration model, we demonstrated the ability to quantify API content with a short measurement time of 3.9 ms per tablet for model pharmaceuticals. For the model tablet, the quantification ability of our spectrometer was comparable to that achieved by a commonly used Fourier-transform NIR (FT-NIR) spectrometer with a measurement time of several seconds. We also confirmed that the effect of irradiating tablets with the NIR pulses used in our spectrometer was negligible., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Koji Nakayama reports writing assistance was provided by Japan Agency for Medical Research and Development. Koji Nakayama has patent #JPA2020159971, JPA2023036975 issued to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Koji Nakayama has patent #EPA3951366, USA2022/0178848, CNA113614518, INA202117044615 pending to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Aya Ikarashi (Ota) has patent #JPA2020159971, JPA2023036975 issued to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. Aya Ota has patent #EPA3951366, USA2022/0178848, CNA113614518, INA202117044615 pending to Ushio Inc., TOWA PHARMACEUTICAL CO., LTD. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Although time-stretch spectroscopy is an emerging ultrafast spectroscopic technique, the applications in industrial fields have been limited due to the low output power caused by undesirable nonlinear effects occurred in a long optical fiber used for pulse chirping. Here, we developed a high-power time-stretch near infrared (NIR) spectrometer utilizing arrayed waveguide gratings (AWGs). The combination of AWGs and short optical fibers allowed large amounts of chromatic dispersion to be applied to broadband supercontinuum pulses without the power limitation imposed by employing the long optical fiber. With the proposed configuration, we achieved chirped pulses with the output power of 60 mW in the 900-1300 nm wavelength region, which is about 10 times higher than conventional time-stretch spectrometers using long optical fibers. With the developed spectrometer, the NIR absorption spectra of a standard material and liquid samples were observed with high accuracy and precision within sub-millisecond measurement time even with four orders of magnitude optical attenuation by a neutral density filter. We also confirmed the quantitative spectral analysis capability of the developed spectrometer for highly scattering samples of an oil emulsion. The qualitative comparison of the measurement precision between the developed spectrometer and the previous time-stretch spectrometer was also conducted., (© 2023. Springer Nature Limited.)

Excessive accumulation of polyamines causes cytotoxicity, including inhibition of cell growth and a decrease in viability. We investigated the mechanism of cytotoxicity caused by spermidine accumulation under various conditions using an Escherichia coli strain deficient in spermidine acetyltransferase (SAT), a key catabolic enzyme in controlling polyamine levels. Due to the excessive accumulation of polyamines by the addition of exogenous spermidine to the growth medium, cell growth and viability were markedly decreased through translational repression of specific proteins [RMF (ribosome modulation factor) and Fis (rRNA transcription factor) etc.] encoded by members of polyamine modulon, which are essential for cell growth and viability. In particular, synthesis of proteins that have unusual locations of the Shine-Dalgarno (SD) sequence in their mRNAs was inhibited. In order to elucidate the molecular mechanism of cytotoxicity by the excessive accumulation of spermidine, the spermidine-dependent structural change of the bulged-out region in the mRNA at the initiation site of the rmf mRNA was examined using NMR analysis. It was suggested that the structure of the mRNA bulged-out region is affected by excess spermidine, so the SD sequence of the rmf mRNA cannot approach initiation codon AUG.

Non-thermal atmospheric gas plasma (AGP) exhibits cytotoxicity against malignant cells with minimal cytotoxicity toward normal cells. However, the mechanisms of its tumor-selective cytotoxicity remain unclear. Here we report that AGP-activated medium increases caspase-independent cell death and mitochondrial network collapse in a panel of human cancer cells, but not in non-transformed cells. AGP irradiation stimulated reactive oxygen species (ROS) generation in AGP-activated medium, and in turn the resulting stable ROS, most likely hydrogen peroxide (H2O2), activated intracellular ROS generation and mitochondrial ROS (mROS) accumulation. Culture in AGP-activated medium resulted in cell death and excessive mitochondrial fragmentation and clustering, and these responses were inhibited by ROS scavengers. AGP-activated medium also increased dynamin-related protein 1-dependent mitochondrial fission in a tumor-specific manner, and H2O2 administration showed similar effects. Moreover, the vulnerability of tumor cells to mitochondrial network collapse appeared to result from their higher sensitivity to mROS accumulation induced by AGP-activated medium or H2O2. The present findings expand our previous observations on death receptor-mediated tumor-selective cell killing and reinforce the importance of mitochondrial network remodeling as a powerful target for tumor-selective cancer treatment.

Aim: The prognosis for non-immune hydrops fetalis (NIHF) is still poor despite progress in perinatal care. We have examined perinatal and 1-year outcomes for NIHF in relation to gestational age at diagnosis and underlying etiology in order to identify predictors of mortality., Methods: A retrospective review was conducted of 92 pregnancies with NIHF managed in hospital between 2000 and 2012. The gestational age at diagnosis, etiology, perinatal outcome, and 1-year outcome were recorded, and their associations assessed., Results: A total of 41 of 92 cases (45%) resulted in fetal death, 33 patients (36%) survived to 1 year, but only 15 of the 33 survivors were developmentally intact. Aneuploidy was the most common cause of NIHF (27%; 25/92). Of the 34 patients who were diagnosed before 22 weeks, 29 fetuses (85%) died, and four (12%) survived to 1 year without developmental delay. Meanwhile, of the 26 patients diagnosed after 30 weeks, 18 (69%) survived to 1 year. Of those 18, seven (27%) were developmentally intact. Approximately half of the pregnancies with cardiac anomalies (8/13) resulted in intrauterine fetal death (IUFD) or early neonatal death. Aneuploidy was associated with a high frequency of IUFD, and of the remaining five surviving newborns, three had developmental delay., Conclusion: The prognosis for NIHF differs according to underlying etiology and gestational age at diagnosis. NIHF diagnosed early in gestation is associated with poor outcome. Knowledge of the primary etiology is important for counseling and therapy., (© 2015 Japan Society of Obstetrics and Gynecology.)