Radiosensitizing effect of a novel CTSS inhibitor by enhancing BRCA1 protein stability in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) patients harboring wild-type breast cancer susceptibility gene 1 (BRCA1) account for most TNBC patients but lack adequate targeted therapeutic options. Although radiotherapy (RT) is the primary treatment modality for TNBC patients, radioresistance is one of the major challenges. RT-induced increase in cathepsin S (CTSS) causes radioresistance through suppressing BRCA1-mediated apoptosis of tumor cells, which was induced by CTSS-mediated degradation of BRCA1. Targeting CTSS may provide a novel therapeutic opportunity for TNBC patients. Publicly available data and human tissue microarray slides were analyzed to investigate the relationship between CTSS and BRCA1 in breast cancer patients. A CTSS enzyme assay and in silico docking analysis were conducted to identify a novel CTSS inhibitor. RO5461111 was used first to confirm the concept of targeting CTSS for radiosensitizing effects. The MDA-MB-231 TNBC cell line was used for in vitro and in vivo assays. Western blotting, promoter assay, cell death assay, clonogenic survival assay, and immunohistochemistry staining were conducted to evaluate novel CTSS inhibitors. CTSS inhibitors were further evaluated for their additional benefit of inhibiting cell migration. A novel CTSS inhibitor, TS-24, increased BRCA1 protein levels and showed radiosensitization in TNBC cells with wild-type BRCA1 and in vivo in a TNBC xenograft mouse model. These effects were attributed by BRCA1-mediated apoptosis facilitated by TS-24. Furthermore, TS-24 demonstrated the additional effect of inhibiting cell migration. Our study suggests that employing CTSS inhibitors for the functional restoration of BRCA1 to enhance RT-induced apoptosis may provide a novel therapeutic opportunity for TNBC patients harboring wild-type BRCA1.

A novel machine learning system for identifying sleep-wake states in mice.

Research into sleep-wake behaviors relies on scoring sleep states, normally done by manual inspection of electroencephalogram (EEG) and electromyogram (EMG) recordings. This is a highly time-consuming process prone to inter-rater variability. When studying relationships between sleep and motor function, analyzing arousal states under a four-state system of active wake (AW), quiet wake (QW), nonrapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep provides greater precision in behavioral analysis but is a more complex model for classification than the traditional three-state identification (wake, NREM, and REM sleep) usually used in rodent models. Characteristic features between sleep-wake states provide potential for the use of machine learning to automate classification. Here, we devised SleepEns, which uses a novel ensemble architecture, the time-series ensemble. SleepEns achieved 90% accuracy to the source expert, which was statistically similar to the performance of two other human experts. Considering the capacity for classification disagreements that are still physiologically reasonable, SleepEns had an acceptable performance of 99% accuracy, as determined blindly by the source expert. Classifications given by SleepEns also maintained similar sleep-wake characteristics compared to expert classifications, some of which were essential for sleep-wake identification. Hence, our approach achieves results comparable to human ability in a fraction of the time. This new machine-learning ensemble will significantly impact the ability of sleep researcher to detect and study sleep-wake behaviors in mice and potentially in humans.

Effects of Surface Treatment Conditions on the Bonding Strength and Electromagnetic Pulse Shielding of Concrete Using the 85Zn-15Al Arc Thermal Metal Spraying Method.

The surface treatment of concrete enhances the bonding of its metal coatings. Therefore, in the present study, on the concrete surface, prior to the deposit of an 85Zn-15Al coating via an arc thermal spraying process, different surface treatments were considered for the effective electromagnetic pulse (EMP) shielding properties of the concrete. However, the direct coating on a concrete surface possesses lower bond adhesion, therefore it is of the utmost importance to treat the concrete surface prior to the deposition of the metal coating. Moreover, to obtain better bond adhesion and fill the defects of the coating, the concrete surface is treated by applying a surface hardener (SH), as well as a surface roughening agent (SRA) and a sealing agent (SA), respectively. The metal spraying efficiency, adhesion performance, and bonding strength under different concrete surface treatment conditions were evaluated. The EMP shielding effect was evaluated under the optimal surface treatment condition. The proposed method for EMP shielding exhibited over 60% of spraying efficiency on the treated surface and a bonding strength of up to 3.9 MPa for the SH-SRA-SA (combining surface roughening and pores/defects filling agents) specimen compared to the control one, i.e., 0.8 MPa. The EMP shielding values of the surface-treated concrete with surface hardener, surface roughening agent, and sealing agent, i.e., SH-SRA-SA specimens, exhibited 96.6 dB at 1000 MHz. This was about 12 times higher than without coated concrete.

BRCA1 deficiency in triple-negative breast cancer: Protein stability as a basis for therapy.

Mutations in breast cancer-associated 1 (BRCA1) increase the lifetime risk of developing breast cancer by up to 51% over the risk of the general population. Many aspects of this multifunctional protein have been revealed, including its essential role in homologous recombination repair, E3 ubiquitin ligase activity, transcriptional regulation, and apoptosis. Although most studies have focused on BRCA1 deficiency due to mutations, only a minority of patients carry BRCA1 mutations. A recent study has suggested an expanded definition of BRCA1 deficiency with reduced BRCA1 levels, which accounts for almost half of all triple-negative breast cancer (TNBC) patients. Reduced BRCA1 levels can result from epigenetic modifications or increased proteasomal degradation. In this review, we discuss how this knowledge of BRCA1 function and regulation of BRCA1 protein stability can help overcome the challenges encountered in the clinic and advance current treatment strategies for BRCA1-related breast cancer patients, especially focusing on TNBC.

Neuroscience: An Arousal Circuit that Senses Danger in Sleep.

Dangerous or alerting stimuli typically trigger arousal from sleep; however, the brain circuitry responsible for threat detection during sleep remains unclear. New research in mice identified a specific class of neuron in the basal forebrain that causes arousal from sleep by responding to threatening stimuli.

An Operable, Portable, and Disposable Ultrathin Endoscope for Evaluation of the Upper Gastrointestinal Tract.

BACKGROUND AND AIMS: A prototype of a disposable endoscope (DE) with easy viewing of the esophagus has been developed. The aim of this study was to develop a new version of DE with improved functionality and to assess the feasibility of DE as a screening tool for upper gastrointestinal diseases compared with conventional endoscopes. METHODS: Diagnostic accuracy and maneuverability of DE were evaluated by comparing endoscopy using DE with conventional endoscopy. Different examiners performed DE endoscopy and conventional endoscopy in a randomized order, blinded to the results. Examiners were asked to respond to a questionnaire about ease of handling and observation using DE in preformed result sheets. Tolerability of DE was also evaluated. Non-sedated participants were asked to respond to a questionnaire about the convenience and satisfaction with DE endoscopy on a nine-point Likert scale. RESULTS: The overall ease of insertion and handling of DE was excellent. The new device enabled observation and evaluation of the entire esophagus with a good agreement between DE endoscopy and conventional endoscopy in terms of endoscopic diagnosis (Kappa value; hiatal hernia; 0.910, reflux esophagitis; 0.949, Barrett's esophagus, 1.000). Participants suggested that they were more comfortable with DE endoscopy than with conventional endoscopy with a lower symptom score (p = 0.030). CONCLUSION: The new DE enabled easy observation of the entire esophagus owing to its improved maneuverability, and its diagnostic ability of esophageal diseases was comparable to that of conventional endoscopes. Non-sedated esophagoscopy with this disposable device potentially has widespread applications in outpatient clinics and areas without endoscopic facilities.

Endoscopic resection of asymptomatic, colonic, polypoid arteriovenous malformations: Two case reports and a literature review.

A colonic arteriovenous malformation (AVM) is a significant vascular lesion of the gastrointestinal tract and a common cause of lower gastrointestinal bleeding. AVMs are usually identified endoscopically as bright red, flat lesions. AVMs with a polypoid appearance are extremely rare in the large intestine. We present two cases of colonic polypoid AVM, which were detected incidentally during screening colonoscopy. Both the patients had no history of gastrointestinal bleeding such as melena or hematochezia. Colonoscopy revealed pedunculated polyps overlaid by hyperemic mucosa in the ascending colon and proximal sigmoid colon. Microscopic examination showed aberrant vessels with thickened, hypertrophic walls in the mucosa and the submucosa, and arteries were directly connected to veins without capillary beds. These features were compatible with a diagnosis of AVM with a polypoid appearance. No immediate or delayed bleeding was noted after polypectomy.