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https://www.readbyqxmd.com/read/29342134/chromosomal-instability-drives-metastasis-through-a-cytosolic-dna-response
#1
Samuel F Bakhoum, Bryan Ngo, Ashley M Laughney, Julie-Ann Cavallo, Charles J Murphy, Peter Ly, Pragya Shah, Roshan K Sriram, Thomas B K Watkins, Neil K Taunk, Mercedes Duran, Chantal Pauli, Christine Shaw, Kalyani Chadalavada, Vinagolu K Rajasekhar, Giulio Genovese, Subramanian Venkatesan, Nicolai J Birkbak, Nicholas McGranahan, Mark Lundquist, Quincey LaPlant, John H Healey, Olivier Elemento, Christine H Chung, Nancy Y Lee, Marcin Imielenski, Gouri Nanjangud, Dana Pe'er, Don W Cleveland, Simon N Powell, Jan Lammerding, Charles Swanton, Lewis C Cantley
Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29322423/assessing-the-cgas-cgamp-sting-activity-of-cancer-cells
#2
Geneviève Pépin, Michael P Gantier
DNA sensing by the STING pathway is emerging to be a crucial component of the antitumor immune response. Although it plays a key role in the activation of tumor immune cells, exactly how STING is activated by tumor cells is not fully understood. Recent evidence suggests that cGAS can be directly engaged and produces 2'3'-cyclic-GMP-AMP (cGAMP) within certain tumor cells upon stimulation with DNA damaging agents. Because cGAMP can transfer between adjacent cells, the capacity of tumor cells to produce cGAMP may activate tumor immune cells, even in the absence of functional STING signaling within the tumor...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29298342/the-common-haq-sting-variant-impairs-cgas-dependent-antibacterial-responses-and-is-associated-with-susceptibility-to-legionnaires-disease-in-humans
#3
Juan S Ruiz-Moreno, Lutz Hamann, Javeed A Shah, Annelies Verbon, Frank P Mockenhaupt, Monika Puzianowska-Kuznicka, Jan Naujoks, Leif E Sander, Martin Witzenrath, John C Cambier, Norbert Suttorp, Ralf R Schumann, Lei Jin, Thomas R Hawn, Bastian Opitz
ClinicalTrials.gov DRKS00005274, German Clinical Trials Register.
January 3, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29281834/sting-dependent-signaling-underlies-il-10-controlled-inflammatory-colitis
#4
Jeonghyun Ahn, Sehee Son, Sergio C Oliveira, Glen N Barber
Intestinal immune homeostasis is preserved by commensal bacteria interacting with the host to generate a balanced array of cytokines that are essential for wound repair and for combatting infection. Inflammatory bowel disease (IBD), which can lead to colitis-associated cancer (CAC), is thought to involve chronic microbial irritation following a breach of the mucosal intestinal epithelium. However, the innate immune pathways responsible for regulating these inflammatory processes remain to be fully clarified...
December 26, 2017: Cell Reports
https://www.readbyqxmd.com/read/29251796/lipotoxicity-induces-hepatic-protein-inclusions-through-tbk1-mediated-p62-sqstm1-phosphorylation
#5
Chun-Seok Cho, Hwan-Woo Park, Allison Ho, Ian A Semple, Boyoung Kim, Insook Jang, Haeli Park, Shannon Reilly, Alan R Saltiel, Jun Hee Lee
Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause non-alcoholic steatohepatitis (NASH). NASH in turn is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). The formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis...
December 18, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29250653/integrative-clinico-biological-pharmacogenetic-neuroimagistic-neuroendocrinological-and-psychological-correlations-in-depressive-and-anxiety-disorders
#6
Lavinia Maria Hogea, Laura Alexandra Nussbaum, Daniela Veronica Chiriac, LuminiŢa Ştefania Ageu, Nicoleta Ioana Andreescu, Mirela Loredana Grigoraş, Roxana Folescu, Ana Cristina Bredicean, Maria Puiu, Elena Cecilia Ildikó Roşca, Mihaela Adriana Simu, Codrina Mihaela Levai
We approach the theme of modern treatment strategies, based on clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological integrative correlations in the management of depressive and comorbid anxiety disorders. We target to evaluate the efficacy of the pharmacogenetic testing and the evolution, functioning of patients in correlation with specific neurobiological, neuroimagistic and neuroendocrinological markers. Our research was conducted between 2010-2016 on 80 children and adolescents with depressive and comorbid anxiety disorders - 40 children (G1 group), who benefited in choosing the pharmacotherapy from pharmacogenetic testing and 40 children without testing (G2 group)...
2017: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
https://www.readbyqxmd.com/read/29247853/cytosolic-sensing-of-immuno-stimulatory-dna-the-enemy-within
#7
REVIEW
Rekha Dhanwani, Mariko Takahashi, Sonia Sharma
In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I)...
December 13, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29215161/suppressive-oligodeoxynucleotides-containing-ttaggg-motifs-inhibit-cgas-activation-in-human-monocytes
#8
Folkert Steinhagen, Thomas Zillinger, Konrad Peukert, Mario Fox, Marcus Thudium, Winfried Barchet, Christian Putensen, Dennis Klinman, Eicke Latz, Christian Bode
Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutières Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes...
December 7, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29212905/cyclic-gmp-amp-synthase-is-the-cytosolic-sensor-of-plasmodium-falciparum-genomic-dna-and-activates-type-i-ifn-in-malaria
#9
Carolina Gallego-Marin, Jacob E Schrum, Warrison A Andrade, Scott A Shaffer, Lina F Giraldo, Alvaro M Lasso, Evelyn A Kurt-Jones, Kate A Fitzgerald, Douglas T Golenbock
Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP-AMP synthase (cGAS)...
December 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29209311/codevelopment-of-microbiota-and-innate-immunity-and-the-risk-for-group-b-streptococcal-disease
#10
REVIEW
Julia Kolter, Philipp Henneke
The pathogenesis of neonatal late-onset sepsis (LOD), which manifests between the third day and the third month of life, remains poorly understood. Group B Streptococcus (GBS) is the most important cause of LOD in infants without underlying diseases or prematurity and the third most frequent cause of meningitis in the Western world. On the other hand, GBS is a common intestinal colonizer in infants. Accordingly, despite its adaption to the human lower gastrointestinal tract, GBS has retained its potential virulence and its transition from a commensal to a dangerous pathogen is unpredictable in the individual...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29203515/brucella-abortus-triggers-a-cgas-independent-sting-pathway-to-induce-host-protection-that-involves-guanylate-binding-proteins-and-inflammasome-activation
#11
Miriam M Costa Franco, Fernanda Marim, Erika S Guimarães, Natan R G Assis, Daiane M Cerqueira, Juliana Alves-Silva, Jerome Harms, Gary Splitter, Judith Smith, Thirumala-Devi Kanneganti, Nina M G P de Queiroz, Delia Gutman, Glen N Barber, Sergio C Oliveira
Immunity against microbes depends on recognition of pathogen-associated molecular patterns by innate receptors. Signaling pathways triggered by Brucella abortus DNA involves TLR9, AIM2, and stimulator of IFN genes (STING). In this study, we observed by microarray analysis that several type I IFN-associated genes, such as IFN-β and guanylate-binding proteins (GBPs), are downregulated in STING knockout (KO) macrophages infected with Brucella or transfected with DNA. Additionally, we determined that STING and cyclic GMP-AMP synthase (cGAS) are important to engage the type I IFN pathway, but only STING is required to induce IL-1β secretion, caspase-1 activation, and GBP2 and GBP3 expression...
December 4, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29202128/-toll-free-pathways-for-production-of-type-i-interferons
#12
Ling Wang, Shunbin Ning
Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are recognized by different cellular pathogen recognition receptors (PRRs), which are expressed on cell membrane or in the cytoplasm of cells of the innate immune system. Nucleic acids derived from pathogens or from certain cellular conditions represent a large category of PAMPs/DAMPs that trigger production of type I interferons (IFN-I) in addition to pro-inflammatory cytokines, by specifically binding to intracellular Toll-like receptors or cytosolic receptors...
2017: AIMS allergy and immunology
https://www.readbyqxmd.com/read/29189388/cd11c-targeted-delivery-of-dna-to-dendritic-cells-leads-to-cgas-and-sting-dependent-maturation
#13
Marlene F Laursen, Esben Christensen, Laura L T Degn, Kasper Jønsson, Martin R Jakobsen, Ralf Agger, Emil Kofod-Olsen
Immunotherapeutic activation of tumor-specific T cells has proven to be an interesting approach in anticancer treatment. Particularly, anti-CTLA-4 and anti-PD-1/PD-L1 treatment looks promising, and conceivably, even better clinical results might be obtained if such treatment could be combined with boosting the existing tumor-specific T-cell response. One way to achieve this could be by increasing the level of maturation of dendritic cells locally and in the draining lymph nodes. When exposed to cancer cells, dendritic cells may spontaneously mature because of danger-associated molecular patterns derived from the tumor cells...
November 17, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29177864/detecting-release-of-bacterial-dsdna-into-the-host-cytosol-using-fluorescence-microscopy
#14
Roland Felix Dreier, José Carlos Santos, Petr Broz
Recognition of pathogens by the innate immune system relies on germline-encoded pattern recognition receptors (PRRs) that recognize unique microbial molecules, so-called pathogen-associated molecular patterns (PAMPs). Nucleic acids and their derivatives are one of the most important groups of PAMPs, and are recognized by a number of surface-associated as well as cytosolic PRRs. Cyclic GMP-AMP synthase (cGAS) recognizes the presence of pathogen- or host-derived dsDNA in the cytosol and initiates type-I-IFN production...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29176737/cgas-drives-noncanonical-inflammasome-activation-in-age-related-macular-degeneration
#15
Nagaraj Kerur, Shinichi Fukuda, Daipayan Banerjee, Younghee Kim, Dongxu Fu, Ivana Apicella, Akhil Varshney, Reo Yasuma, Benjamin J Fowler, Elmira Baghdasaryan, Kenneth M Marion, Xiwen Huang, Tetsuhiro Yasuma, Yoshio Hirano, Vlad Serbulea, Meenakshi Ambati, Vidya L Ambati, Yuji Kajiwara, Kameshwari Ambati, Shuichiro Hirahara, Ana Bastos-Carvalho, Yuichiro Ogura, Hiroko Terasaki, Tetsuro Oshika, Kyung Bo Kim, David R Hinton, Norbert Leitinger, John C Cambier, Joseph D Buxbaum, M Cristina Kenney, S Michal Jazwinski, Hiroshi Nagai, Isao Hara, A Phillip West, Katherine A Fitzgerald, SriniVas R Sadda, Bradley D Gelfand, Jayakrishna Ambati
Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion...
November 27, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29170402/publisher-correction-small-molecule-inhibition-of-cgas-reduces-interferon-expression-in-primary-macrophages-from-autoimmune-mice
#16
Jessica Vincent, Carolina Adura, Pu Gao, Antonio Luz, Lodoe Lama, Yasutomi Asano, Rei Okamoto, Toshihiro Imaeda, Jumpei Aida, Katherine Rothamel, Tasos Gogakos, Joshua Steinberg, Seth Reasoner, Kazuyoshi Aso, Thomas Tuschl, Dinshaw J Patel, J Fraser Glickman, Manuel Ascano
The previously published version of this Article contained errors in Fig. 6. In panel h the units of the x axis were incorrectly given as mM and should have been given as µM. Also, the IC50s for RU.365, RU.332 and RU.521 within panel h were incorrectly given as mM and should have been given as µM. These errors have been corrected in both the PDF and HTML versions of the Article.
November 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/29169058/cyclic-di-amp-in-host-pathogen-interactions
#17
REVIEW
Laura Devaux, Pierre-Alexandre Kaminski, Patrick Trieu-Cuot, Arnaud Firon
Cyclic di-AMP (c-di-AMP) is a bacterial signaling nucleotide synthesized by several human pathogens. This widespread and specific bacterial product is recognized by infected host cells to trigger an innate immune response. Detection of c-di-AMP in the host cytosol leads primarily to the induction of type I interferon via the STING-cGAS signaling axis, while being also entangled in the activation of the NF-κB pathway. During their long-standing interaction, host and pathogens have co-evolved to control c-di-AMP activation of innate immunity...
November 20, 2017: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/29156566/cgas-sting-pathway-in-cancer-jekyll-and-hyde-story-of-cancer-immune-response
#18
REVIEW
Debojit Bose
The last two decades have witnessed enormous growth in the field of cancer immunity. Mechanistic insights of cancer immunoediting have not only enhanced our understanding but also paved the way to target and/or harness the innate immune system to combat cancer, called cancer immunotherapy. Cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon genes(STING) pathway has recently emerged as nodal player in cancer immunity and is currently being explored as potential therapeutic target. Although therapeutic activation of this pathway has shown promising anti-tumor effects in vivo, evidence also indicates the role of this pathway in inflammation mediated carcinogenesis...
November 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29146021/symptom-dimensions-and-subgroups-in-childhood-onset-schizophrenia
#19
Kirsten E S Craddock, Xueping Zhou, Siyuan Liu, Peter Gochman, Dwight Dickinson, Judith L Rapoport
OBJECTIVE: This study investigated symptom dimensions and subgroups in the National Institute of Mental Health (NIMH) childhood-onset schizophrenia (COS) cohort and their similarities to adult-onset schizophrenia (AOS) literature. METHOD: Scores from the Scales for the Assessment of Positive and Negative Symptoms (SAPS & SANS) from 125 COS patients were assessed for fit with previously established symptom dimensions from AOS literature using confirmatory factor analysis (CFA)...
November 13, 2017: Schizophrenia Research
https://www.readbyqxmd.com/read/29142107/is-inflammatory-micronucleation-the-key-to-a-successful-anti-mitotic-cancer-drug
#20
REVIEW
T J Mitchison, J Pineda, J Shi, S Florian
Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours...
November 2017: Open Biology
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