Systems Analysis of ATF3 in Stress Response and Cancer Reveals Opposing Effects on Pro-Apoptotic Genes in p53 Pathway

Stress-inducible transcription factors play a pivotal role in cellular adaptation to environment to maintain homeostasis and integrity of the genome. Activating transcription factor 3 (ATF3) is induced by a variety of stress and inflammatory conditions and is over-expressed in many kinds of cancer cells. However, molecular mechanisms underlying pleiotropic functions of ATF3 have remained elusive. Here we employed systems analysis to identify genome-wide targets of ATF3 that is either induced by an alkylating agent methyl methanesulfonate (MMS) or over-expressed in a prostate tumour cell line LNCaP. We show that stress-induced and cancer-associated ATF3 is recruited to 5,984 and 1,423 targets, respectively, in the human genome, 89% of which are common. Notably, ATF3 targets are highly enriched for not only ATF/CRE motifs but also binding sites of several other stress-inducible transcription factors indicating an extensive network of stress response factors in transcriptional regulation of target genes. Further analysis of effects of ATF3 knockdown on these targets revealed that stress-induced ATF3 regulates genes in metabolic pathways, cell cycle, apoptosis, cell adhesion, and signalling including insulin, p53, Wnt, and VEGF pathways. Cancer-associated ATF3 is involved in regulation of distinct sets of genes in processes such as calcium signalling, Wnt, p53 and diabetes pathways. Notably, stress-induced ATF3 binds to 40% of p53 targets and activates pro-apoptotic genes such as TNFRSF10B/DR5 and BBC3/PUMA. Cancer-associated ATF3, by contrast, represses these pro-apoptotic genes in addition to CDKN1A/p21. Taken together, our data reveal an extensive network of stress-inducible transcription factors and demonstrate that ATF3 has opposing, cell context-dependent effects on p53 target genes in DNA damage response and cancer development

Fish oil-enriched nutrition combined with systemic chemotherapy for gastrointestinal cancer patients with cancer cachexia

Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2)

Causal assessment of smoking and tooth loss: A systematic review of observational studies

<p>Abstract</p> <p>Background</p> <p>Tooth loss impairs oral function. The aim of the present review was to evaluate the causal association between smoking and tooth loss on the basis of high-quality studies.</p> <p>Methods</p> <p>Relevant literature was searched and screened, and the methodological quality was assessed. Information on the strength of the association between smoking and tooth loss, the dose-response relationship and natural experimental data was collected and evaluated with respect to consistency and study design.</p> <p>Results</p> <p>Our literature search yielded 496 citations, and 6 cross-sectional and 2 cohort high-quality studies examining 58,755 subjects in four countries. All studies reported significant associations, although the strength of the association was usually moderate. Four studies reported dose-response relationships between exposure to smoking and the risk of developing tooth loss. A decrease in the risk of tooth loss for former smokers was evident in six studies. Interpretation of evidence for each element was consistent, despite some shortcomings regarding study type and population.</p> <p>Conclusions</p> <p>Based on the consistent evidence found with the existing biological plausibility, a causal association between smoking and tooth loss is highly likely. Further studies using a cohort design and different populations are necessary to confirm this association.</p

Genetic analysis of typical wet-type age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese population

Age-related macular degeneration (AMD) is a common cause of blindness in the elderly. Caucasian patients are predominantly affected by the dry form of AMD, whereas Japanese patients have predominantly the wet form of AMD and/or polypoidal choroidal vasculopathy (PCV). Although genetic association in the 10q26 (ARMS2/HTRA1) region has been established in many ethnic groups for dry-type AMD, typical wet-type AMD, and PCV, the contribution of the 1q32 (CFH) region seem to differ among these groups. Here we show a single nucleotide polymorphism (SNP) in the ARMS2/HTRA1 locus is associated in the whole genome for Japanese typical wet-type AMD (rs10490924: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p = 4.1 \times 10 ^{ - 4}$$\end{document}, OR = 4.16) and PCV (rs10490924: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p = 3.7 \times 10 ^{ -8}$$\end{document}, OR = 2.72) followed by CFH (rs800292: \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p = 7.4 \times 10 ^{ -5}$$\end{document}, OR = 2.08; \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p = 2.6 \times {10^{ - 4}}$$\end{document}, OR = 2.00), which differs from previous studies in Caucasian populations. Moreover, a SNP (rs2241394) in complement component C3 gene showed significant association with PCV (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p = 2.5 \times {10^{ - 3}}$$\end{document}, OR = 3.47). We conclude that dry-type AMD, typical wet-type AMD, and PCV have both common and distinct genetic risks that become apparent when comparing Japanese versus Caucasian populations

Vascular smooth muscle RhoA counteracts abdominal aortic aneurysm formation by modulating MAP4K4 activity

Whether a small GTPase RhoA plays a role in the pathology of abdominal aortic aneurysm (AAA) has not been determined. We show here that RhoA expression is reduced in human AAA lesions, compared with normal areas. Furthermore, incidence of AAA formation is increased in vascular smooth muscle cell (VSMC)-specific RhoA conditional knockout (cKO) mice. The contractility of the aortic rings and VSMCs from RhoA cKO mice is reduced, and expression of genes related to the VSMC contractility is attenuated by loss of RhoA. RhoA depletion activates the mitogen-activated protein (MAP) kinase signaling, including MAP4K4, in the aorta and VSMCs. Inhibition of MAP4K4 activity by DMX-5804 decreases AAA formation. Set, a binding protein to active RhoA, functions as an activator of MAP4K4 by sequestering PP2A, an inhibitor of MAP4K4, in the absence of RhoA. In conclusion, RhoA counteracts AAA formation through inhibition of MAP4K4 in cooperation with Set

Search for Cosmic-ray Boosted Sub-GeV Dark Matter using Recoil Protons at Super-Kamiokande

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton$\times$years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross-section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross-section between $10^{-33}\text{ cm}^{-2}$ and $10^{-27}\text{ cm}^{-2}$ for dark matter mass from 10 MeV/$c^2$ to 1 GeV/$c^2$.Comment: With 1-page appendi

Search for astrophysical electron antineutrinos in Super-Kamiokande with 0.01wt% gadolinium-loaded water

We report the first search result for the flux of astrophysical electron antineutrinos for energies O(10) MeV in the gadolinium-loaded Super-Kamiokande (SK) detector. In June 2020, gadolinium was introduced to the ultra-pure water of the SK detector in order to detect neutrons more efficiently. In this new experimental phase, SK-Gd, we can search for electron antineutrinos via inverse beta decay with efficient background rejection and higher signal efficiency thanks to the high efficiency of the neutron tagging technique. In this paper, we report the result for the initial stage of SK-Gd with a $22.5\times552$ $\rm kton\cdot day$ exposure at 0.01% Gd mass concentration. No significant excess over the expected background in the observed events is found for the neutrino energies below 31.3 MeV. Thus, the flux upper limits are placed at the 90% confidence level. The limits and sensitivities are already comparable with the previous SK result with pure-water ($22.5 \times 2970 \rm kton\cdot day$) owing to the enhanced neutron tagging