Promoter-Level Transcriptome Identifies Stemness Associated With Relatively High Proliferation in Pancreatic Cancer Cells

Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a-Cre; KrasG12D; p53f/+ and Ptf1a-Cre; KrasG12D; and Brg1f/f pancreatic ductal adenocarcinomas (PDAs). The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome. Two RNA samples extracted from three individual subcutaneous tumors generated by the transplantation of PanIN or IPMN cancer cell lines were used to generate libraries and Illumina Seq, with four RNA samples in total, to depict discrete transcriptional network between IPMN and PanIN. Moreover, in IPMN cells, the transcriptome tended to be enriched for suppressive and inhibitory biological processes. In contrast, the transcriptome of PanIN cells exhibited properties of stemness. Notably, the proliferation capacity of the latter cells in culture was only minimally constrained by well-known chemotherapy drugs such as GSK690693 and gemcitabine. The various transcriptional factor network systems detected in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. Further, we hope that these findings will enhance our mechanistic understanding of the characteristic molecular alterations underlying pancreatic cancer precursors. These data may provide a promising direction for therapeutic research

Nowcast and forecast of galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes in magnetosphere and ionosphere – Extension of WASAVIES to Earth orbit

Real-time estimation of cosmic-ray fluxes on satellite orbits is one of the greatest challenges in space weather research. Therefore, we develop a system for nowcasting and forecasting the galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes at any location in the magnetosphere and ionosphere during ground-level enhancement (GLE) events. It is an extended version of the WArning System for AVIation Exposure to SEP (WASAVIES), which can determine event profiles by using real-time data of the count rates of several neutron monitors (NMs) at the ground level and high-energy proton fluxes observed by Geostationary Operational Environmental Satellites (GOES) satellites. The extended version, called WASAVIES-EO, can calculate the GCR and SEP fluxes outside a satellite based on its two-line element (TLE) data. Moreover, organ absorbed-dose and dose-equivalent rates of astronauts in the International Space Station (ISS) can be estimated using the system, considering its shielding effect. The accuracy of WASAVIES-EO was validated based on the dose rates measured in ISS, as well as based on high-energy proton fluxes observed by POES satellites during large GLEs that have occurred in the 21st century. Agreement between the nowcast and forecast dose rates in ISS, especially in terms of their temporal structures, indicates the usefulness of the developed system for future mission operations

Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants

遺伝性乳癌の遺伝学的・臨床学的特徴を解明 --BRCA1/2 変異乳癌は両アレルの不活化の有無により異なった特徴を持つ--. 京都大学プレスリリース. 2020-10-26.The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1, 995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants

Subcellular distribution of human RDM1 protein isoforms and their nucleolar accumulation in response to heat shock and proteotoxic stress

The RDM1 gene encodes a RNA recognition motif (RRM)-containing protein involved in the cellular response to the anti-cancer drug cisplatin in vertebrates. We previously reported a cDNA encoding the full-length human RDM1 protein. Here, we describe the identification of 11 human cDNAs encoding RDM1 protein isoforms. This repertoire is generated by alternative pre-mRNA splicing and differential usage of two translational start sites, resulting in proteins with long or short N-terminus and a great diversity in the exonic composition of their C-terminus. By using tagged proteins and fluorescent microscopy, we examined the subcellular distribution of full-length RDM1 (renamed RDM1α), and other RDM1 isoforms. We show that RDM1α undergoes subcellular redistribution and nucleolar accumulation in response to proteotoxic stress and mild heat shock. In unstressed cells, the long N-terminal isoforms displayed distinct subcellular distribution patterns, ranging from a predominantly cytoplasmic to almost exclusive nuclear localization, suggesting functional differences among the RDM1 proteins. However, all isoforms underwent stress-induced nucleolar accumulation. We identified nuclear and nucleolar localization determinants as well as domains conferring cytoplasmic retention to the RDM1 proteins. Finally, RDM1 null chicken DT40 cells displayed an increased sensitivity to heat shock, compared to wild-type (wt) cells, suggesting a function for RDM1 in the heat-shock response

Discovery of fossil asteroidal ice in primitive meteorite Acfer 094

隕石中に小惑星の氷の痕跡を発見 --氷が抜けてできた空間を放射光X線CTで発見--. 京都大学プレスリリース. 2019-11-25.Carbonaceous chondrites are meteorites believed to preserve our planet’s source materials, but the precise nature of these materials still remains uncertain. To uncover pristine planetary materials, we performed synchrotron radiation–based x-ray computed nanotomography of a primitive carbonaceous chondrite, Acfer 094, and found ultraporous lithology (UPL) widely distributed in a fine-grained matrix. UPLs are porous aggregates of amorphous and crystalline silicates, Fe─Ni sulfides, and organics. The porous texture must have been formed by removal of ice previously filling pore spaces, suggesting that UPLs represent fossils of primordial ice. The ice-bearing UPLs formed through sintering of fluffy icy dust aggregates around the H2O snow line in the solar nebula and were incorporated into the Acfer 094 parent body, providing new insight into asteroid formation by dust agglomeration

Nowcast and forecast of galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes in magnetosphere and ionosphere – Extension of WASAVIES to Earth orbit

Real-time estimation of cosmic-ray fluxes on satellite orbits is one of the greatest challenges in space weather research. Therefore, we develop a system for nowcasting and forecasting the galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes at any location in the magnetosphere and ionosphere during ground-level enhancement (GLE) events. It is an extended version of the WArning System for AVIation Exposure to SEP (WASAVIES), which can determine event profiles by using real-time data of the count rates of several neutron monitors (NMs) at the ground level and high-energy proton fluxes observed by Geostationary Operational Environmental Satellites (GOES) satellites. The extended version, called WASAVIES-EO, can calculate the GCR and SEP fluxes outside a satellite based on its two-line element (TLE) data. Moreover, organ absorbed-dose and dose-equivalent rates of astronauts in the International Space Station (ISS) can be estimated using the system, considering its shielding effect. The accuracy of WASAVIES-EO was validated based on the dose rates measured in ISS, as well as based on high-energy proton fluxes observed by POES satellites during large GLEs that have occurred in the 21st century. Agreement between the nowcast and forecast dose rates in ISS, especially in terms of their temporal structures, indicates the usefulness of the developed system for future mission operations

Correction Notice to: Nowcast and forecast of galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes in magnetosphere and ionosphere – Extension of WASAVIES to Earth orbit

Real-time estimation of cosmic-ray fluxes on satellite orbits is one of the greatest challenges in space weather research. Therefore, we develop a system for nowcasting and forecasting the galactic cosmic ray (GCR) and solar energetic particle (SEP) fluxes at any location in the magnetosphere and ionosphere during ground-level enhancement (GLE) events. It is an extended version of the WArning System for AVIation Exposure to SEP (WASAVIES), which can determine event profiles by using real-time data of the count rates of several neutron monitors (NMs) at the ground level and high-energy proton fluxes observed by Geostationary Operational Environmental Satellites (GOES) satellites. The extended version, called WASAVIES-EO, can calculate the GCR and SEP fluxes outside a satellite based on its two-line element (TLE) data. Moreover, organ absorbed-dose and dose-equivalent rates of astronauts in the International Space Station (ISS) can be estimated using the system, considering its shielding effect. The accuracy of WASAVIES-EO was validated based on the dose rates measured in ISS, as well as based on high-energy proton fluxes observed by POES satellites during large GLEs that have occurred in the 21st century. Agreement between the nowcast and forecast dose rates in ISS, especially in terms of their temporal structures, indicates the usefulness of the developed system for future mission operations