Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical ...features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole-genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8
T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell-mediated disease provides hope that future therapies directed towards depleting these cells could be effective.
Objective To understand belief in a specific scientific claim by studying the pattern of citations among papers stating it.Design A complete citation network was constructed from all PubMed indexed ...English literature papers addressing the belief that β amyloid, a protein accumulated in the brain in Alzheimer’s disease, is produced by and injures skeletal muscle of patients with inclusion body myositis. Social network theory and graph theory were used to analyse this network.Main outcome measures Citation bias, amplification, and invention, and their effects on determining authority.Results The network contained 242 papers and 675 citations addressing the belief, with 220 553 citation paths supporting it. Unfounded authority was established by citation bias against papers that refuted or weakened the belief; amplification, the marked expansion of the belief system by papers presenting no data addressing it; and forms of invention such as the conversion of hypothesis into fact through citation alone. Extension of this network into text within grants funded by the National Institutes of Health and obtained through the Freedom of Information Act showed the same phenomena present and sometimes used to justify requests for funding.Conclusion Citation is both an impartial scholarly method and a powerful form of social communication. Through distortions in its social use that include bias, amplification, and invention, citation can be used to generate information cascades resulting in unfounded authority of claims. Construction and analysis of a claim specific citation network may clarify the nature of a published belief system and expose distorted methods of social citation.
DNA repair is essential to maintain genomic integrity and initiate genetic diversity. While gene conversion and classical nonhomologous end-joining are the most physiologically predominant forms of ...DNA repair mechanisms, emerging lines of evidence suggest the usage of several noncanonical homology-directed repair (HDR) pathways in both prokaryotes and eukaryotes in different contexts. Here we review how these alternative HDR pathways are executed, specifically focusing on the determinants that dictate competition between them and their relevance to cancers that display complex genomic rearrangements or maintain their telomeres by homology-directed DNA synthesis.
Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour ...microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP-AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)-cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%–15% employ a ...recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
Display omitted
•DSB responses initiate interchromosomal associations between ALT telomeres•Homology search and synapsis can be visualized in real time in mammalian cells•ALT telomeres associate via rapid directional movements of up to 5 μm•ALT telomere movement, synapsis, and recombination require Rad51 and Hop2-Mnd1
Lengthening telomeres by the so-called ALT pathway, that utilizes telomere clustering and recombination rather than telomerase activity, leverages a specialized homology searching mechanism characterized by long-range random surveillance of nuclear space prior to rapid directional movement to a homologous telomere following double-stranded breaks.
ABSTRACT
Introduction: Recent studies have identified circulating immunoglobulin (Ig) G autoantibodies against cytoplasmic 5′‐nucleotidase 1A (cN1A; NT5C1A) in patients with inclusion body myositis ...(IBM), whose detection provides for an IBM blood diagnostic test. Whether or not anti‐cN1A autoantibody isotypes other than IgG are present in IBM has not previously been reported. Methods: Plasma and serum samples from 205 patients (50 with and155 without IBM) were studied for the presence of IgM and IgA, in addition to IgG, anti‐cN1A autoantibodies using immunoblots and enzyme‐linked immunoassays (ELISAs). Results: IgM, IgA, and IgG anti‐cN1A autoantibodies were detected by ELISA with similar sensitivities (49–53%) and specificities (94–96%), but with differing patterns of autoantibody isotype presence. Combination assays of all 3 autoantibody levels improved diagnostic sensitivity to 76%. Conclusions: In addition to previously recognized IgG anti‐cN1A autoantibodies, IBM patients have circulating IgM and IgA anti‐cN1A autoantibodies. Differing patterns of these isotypes may be present and useful for diagnosis. Muscle Nerve 50: 488–492, 2014
The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent ...years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in-class BRCA-targeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy.
Tumor metastasis is a singularly important determinant of survival in most cancers. Historically, radiation therapy (RT) directed at a primary tumor mass was associated infrequently with remission of ...metastasis outside the field of irradiation. This away-from-target or "abscopal effect" received fringe attention because of its rarity. With the advent of immunotherapy, there are now increasing reports of abscopal effects upon RT in combination with immune checkpoint inhibition. This sparked investigation into underlying mechanisms and clinical trials aimed at enhancement of this effect. While these studies clearly attribute the abscopal effect to an antitumor immune response, the initial molecular triggers for its onset and specificity remain enigmatic. Here, we propose that DNA damage-induced inflammation coupled with neoantigen generation is essential during this intriguing phenomenon of systemic tumor regression and discuss the implications of this model for treatment aimed at triggering the abscopal effect in metastatic cancer.
Resolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is ...associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity.
Display omitted
•Persistent DSBs are required for ATM-dependent rDNA silencing•Non-homologous end-joining limits DSB rDNA silencing•ATM-dependent rDNA silencing drives large-scale nucleolar reorganization•Nucleolar chromatin movement promotes DSB recognition
Transcriptional silencing accompanies signaling of DNA double-strand breaks. Harding et al. show that ATM kinase drives nucleolar reorganization and transcriptional silencing in response to rDNA breaks. This silencing is reversed by ongoing repair mainly through non-homologous end-joining.
Inclusion body myositis (IBM) is a poorly understood and refractory autoimmune muscle disease. Though widely believed to have no significant humoral autoimmunity, we sought to identify novel ...autoantibodies with high specificity for this disease.
Plasma autoantibodies from 65 people, including 25 with IBM, were analyzed by immunoblots against normal human muscle. Thirteen of 25 (52%) IBM patient samples recognized an approximately 43 kDa muscle protein. No other disease (N = 25) or healthy volunteer (N = 15) samples recognized this protein.
Circulating antibodies against a 43-kDa muscle autoantigen may lead to the discovery of a novel biomarker for IBM. Its high specificity for IBM among patients with autoimmune myopathies furthermore suggests a relationship to disease pathogenesis.
PDF
