An immuno-wall microdevice exhibits rapid and sensitive detection of IDH1-R132H mutation specific to grade II and III gliomas

World Health Organization grade II and III gliomas most frequently occur in the central nervous system (CNS) in adults. Gliomas are not circumscribed; tumor edges are irregular and consist of tumor cells, normal brain tissue, and hyperplastic reactive glial cells. Therefore, the tumors are not fully resectable, resulting in recurrence, malignant progression, and eventual death. Approximately 69–80% of grade II and III gliomas harbor mutations in the isocitrate dehydrogenase 1 gene (IDH1), of which 83–90% are found to be the IDH1-R132H mutation. Detection of the IDH1-R132H mutation should help in the differential diagnosis of grade II and III gliomas from other types of CNS tumors and help determine the boundary between the tumor and normal brain tissue. In this study, we established a highly sensitive antibody-based device, referred to as the immuno-wall, to detect the IDH1-R132H mutation in gliomas. The immuno-wall causes an immunoreaction in microchannels fabricated using a photo-polymerizing polymer. This microdevice enables the analysis of the IDH1 status with a small sample within 15 min with substantially high sensitivity. Our results suggested that 10% content of the IDH1-R132H mutation in a sample of 0.33 μl volume, with 500 ng protein, or from 500 cells is theoretically sufficient for the analysis. The immuno-wall device will enable the rapid and highly sensitive detection of the IDH1-R132H mutation in routine clinical practice

Volcanic activity on Io and its influence on the dynamics of the Jovian magnetosphere observed by EXCEED/Hisaki in 2015

Abstract Jupiter’s moon Io, which orbits deep inside the magnetosphere, is the most geologically active object in the solar system. Kurdalagon Patera, a volcano on Io, erupted in 2015 and became a substantial source of Jovian magnetospheric plasma. Based on Earth-orbiting spacecraft observations, Io plasma torus (IPT) exhibited the peak intensity (nearly double) of ionic sulfur emissions roughly 2 month later, followed by a decay phase. This environmental change provides a unique opportunity to determine how the more heavily loaded magnetosphere behaves. Indeed, the extreme ultraviolet spectroscope for exospheric dynamics onboard the Earth-orbiting spacecraft Hisaki witnessed the whole interval via aurora and IPT observations. A simple-minded idea would be that the centrifugal force acting on fast co-rotating magnetic flux tubes loaded with heavier contents intensifies their outward transport. At the same time, there must be increased inward convection to conserve the magnetic flux. The latter could be accompanied by (1) increased inward velocity of field lines, (2) increased frequency of inward transport events, (3) increased inward flux carried per event, or (4) combinations of them. The Hisaki observations showed that the densities of major ions in the IPT increased and roughly doubled compared with pre-eruption values. The hot electron fraction, which sustains the EUV radiation from the IPT, gradually increased on a timescale of days. Pairs of intensified aurora and IPT brightening due to the enhanced supply of hot electrons from the mid-magnetosphere to the IPT upon aurora explosions observed during both quiet and active times, enabled the study of the mid-magnetosphere/IPT relationship. Hisaki observations under active Io conditions showed that: (1) the hot electron fraction in the torus gradually increased; (2) brightening pairs were more intense; (3) the energy supplied by the largest event maintained enhanced torus emission for less than a day; (4) the time delay of a torus brightening from a corresponding aurora intensification was roughly 11 h, that is, the same as during quiet times, suggesting that the inward convection speed of high-energy electrons does not change significantly. Graphical abstract

TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation

Abstract Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment

Urinary MicroRNA-Based Diagnostic Model for Central Nervous System Tumors Using Nanowire Scaffolds

There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood. Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy. Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. Urinary microRNAs from patients with CNS tumors (n = 119) and noncancer individuals (n = 100) were analyzed using a microarray to yield comprehensive microRNA expression profiles. To clarify the origin of urinary microRNAs of patients with CNS tumors, glioblastoma organoids were generated. Glioblastoma organoid-derived differentially expressed microRNAs (DEMs) included 73.4% of the DEMs in urine of patients with parental tumors but included only 3.9% of those in urine of noncancer individuals, which suggested that many CNS tumor-derived microRNAs could be identified in urine directly. We constructed the diagnostic model based on the expression of the selected microRNAs and found that it was able to differentiate patients and noncancer individuals at a sensitivity and specificity of 100 and 97%, respectively, in an independent dataset. Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors