The Hyper Suprime-Cam SSP survey: Overview and survey design

Hyper Suprime-Cam (HSC) is a wide-field imaging camera on the prime focus of the 8.2-m Subaru telescope on the summit of Mauna Kea in Hawaii. A team of scientists from Japan, Taiwan, and Princeton University is using HSC to carry out a 300-night multi-band imaging survey of the high-latitude sky. The survey includes three layers: the Wide layer will cover 1400 deg2 in five broad bands (grizy), with a 5 σ point-source depth of r ≈ 26. The Deep layer covers a total of 26 deg2 in four fields, going roughly a magnitude fainter, while the UltraDeep layer goes almost a magnitude fainter still in two pointings of HSC (a total of 3.5 deg2). Here we describe the instrument, the science goals of the survey, and the survey strategy and data processing. This paper serves as an introduction to a special issue of the Publications of the Astronomical Society of Japan, which includes a large number of technical and scientific papers describing results from the early phases of this survey

Genome-Wide Mapping of Bivalent Histone Modifications in Hepatic Stem/Progenitor Cells

The “bivalent domain,” a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk+) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including Cdkn2a and Sox4, were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of Sox4 in Dlk+ cells suppressed colony propagation and resulted in increased numbers of albumin+/cytokeratin 7+ progenitor cells in colonies. These findings implicate that derepression of Sox4 expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells

Serum CXCL10 levels at the start of the second course of atezolizumab plus bevacizumab therapy predict therapeutic efficacy in patients with advanced BCLC stage C hepatocellular carcinoma: A multicenter analysis

Abstract Background & Aims Relationships of serum C‐C motif chemokine ligand 5 (CCL5) and C‐X‐C motif chemokine ligand 10 (CXCL10) levels with hot immune features have been reported in patients with hepatocellular carcinoma (HCC). Therefore, we examined the utility of their levels for predicting the efficacy of atezolizumab plus bevacizumab (Atez/Bev) in patients with HCC. Design In total, 98 patients with HCC treated with Atez/Bev were enrolled, and their initial responses were evaluated at least once via dynamic computed tomography or magnetic resonance imaging. Serum CCL5 and CXCL10 levels were assessed by enzyme‐linked immunosorbent assay before treatment and at the start of the second course of Atez/Bev therapy, and their relationships with treatment efficacy were determined. Results No analyzed factor was associated with the initial therapeutic response. Among the 56 patients with Barcelona Clinic Liver Cancer (BCLC) stage C, serum CXCL10 levels at the beginning of course two (CXCL10‐2c) tended to be higher in responders than in non‐responders in the initial evaluation, and its optimal cutoff level of 690 pg/mL could be used to stratify patients regarding overall survival (OS; high vs. low: not reached vs. 17.6 months, p = 0.034) and progression‐free survival (high vs. low: 13.6 vs. 5.1 months, p = 0.014). In multivariate analysis, high CXCL10 levels and neutrophil‐to‐lymphocyte ratios at the start of course two and Child–Pugh stage A at baseline were independent predictive factors of improved OS. Conclusions Serum CXCL10‐2c levels were predictive of Atez/Bev efficacy in patients with BCLC stage C HCC

Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

<div><p>The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (<i>IL28B</i>) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable <i>IL28B</i> genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for <i>A20, SOCS1</i>, and <i>SOCS3</i>, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as <i>IRF1</i> were significantly higher at 8 h in patients with an unfavorable <i>IL28B</i> genotype than in those with a favorable one (<i>P</i> = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of <i>IRF1</i> at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable <i>IL28B</i> genotype (<i>P</i> = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to <i>IL28B</i> genotypes, paralleling treatment efficacy.</p></div

Associations between the expression of ISGs or IFN-λ3 and treatment efficacy.

<p>Patients were divided into three groups according to <i>IL28B</i> genotype at rs8099917 and treatment outcome: TT; SVR (n = 31), TG/GG; SVR (n = 13), and TG/GG; non-SVR (n = 6). (A) Expression of <i>ISG15, IL28B</i> and suppressive genes in PBMCs at 8 hours after the initial administration of pegylated interferon, ribavirin, plus NS3/4A protease inhibitor in each group. (B) Fold-changes of mRNAs including suppressive genes at 8 hours relative to baseline in each group. Levels of mRNAs including suppressive genes and <i>ISG15</i> were normalized against glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and those for <i>IL28B</i> were measured using the calibration curves of cDNA clone. TT and TG/GG at rs8099917 is a favorable and an unfavorable <i>IL28B</i> genotype for treatment responses, respectively. Boxes represent the interquartile range of the data. The lines across the boxes and the numbers indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.</p

Fold-changes of mRNAs including suppressive genes in PBMCs at 8 hours relative to baseline in patients stratified according to <i>IL28B</i> genotype.

<p>TT and TG/GG at rs8099917 is a favorable and an unfavorable <i>IL28B</i> genotype for treatment responses, respectively. Boxes represent the interquartile range of the data. The lines across the boxes and the numbers indicate the median values. The hash marks above and below the boxes indicate the 90th and 10th percentiles for each group, respectively.</p

Baseline clinical characteristics of the 50 chronic hepatitis C patients treated with PEG-IFN, RBV and protease inhibitor.

<p>Abbreviations: ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; N.D., not determined; IFN, interferon; RBV, ribavirin; PEG-IFN, pegylated interferon; TVR, transient virological response; NVR, non-virological response.</p><p>rs8099917: TT is favorable for treatment efficacy.</p><p>Data are expressed as numbers for categorical data or the median (range) for continuous data.</p><p>Baseline clinical characteristics of the 50 chronic hepatitis C patients treated with PEG-IFN, RBV and protease inhibitor.</p