scholarly journals The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8877
Author(s):  
Quinn Storozynsky ◽  
Mary M. Hitt
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Treatment Strategies ◽  
Cytotoxic T Cell ◽  
Innate Immune Signaling ◽  
Therapeutic Outcomes ◽  
Wide Range ◽  
Radiation Induced ◽  
Nuanced Understanding ◽  
The Impact

Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

scholarly journals The RhoA-ROCK pathway in the regulation of T and B cell responses

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2295 ◽  
Author(s):  
Edd Ricker ◽  
Luvana Chowdhury ◽  
Woelsung Yi ◽  
Alessandra B. Pernis
Keyword(s):  
Immune Responses ◽  
Biological Processes ◽  
Dynamic Interactions ◽  
Cell Responses ◽  
Important Mediator ◽  
Downstream Effectors ◽  
Wide Range ◽  
Response To Stress ◽  
The Impact ◽  
Rho Kinases

Effective immune responses require the precise regulation of dynamic interactions between hematopoietic and non-hematopoietic cells. The Rho subfamily of GTPases, which includes RhoA, is rapidly activated downstream of a diverse array of biochemical and biomechanical signals, and is emerging as an important mediator of this cross-talk. Key downstream effectors of RhoA are the Rho kinases, or ROCKs. The ROCKs are two serine-threonine kinases that can act as global coordinators of a tissue’s response to stress and injury because of their ability to regulate a wide range of biological processes. Although the RhoA-ROCK pathway has been extensively investigated in the non-hematopoietic compartment, its role in the immune system is just now becoming appreciated. In this commentary, we provide a brief overview of recent findings that highlight the contribution of this pathway to lymphocyte development and activation, and the impact that dysregulation in the activation of RhoA and/or the ROCKs may exert on a growing list of autoimmune and lymphoproliferative disorders.

scholarly journals Protective Activity of C-Geranylflavonoid Analogs from Paulownia tomentosa against DNA Damage in 137Cs Irradiated AHH-1Cells

2014 ◽  
Vol 9 (9) ◽  
pp. 1934578X1400900
Author(s):  
Hyung-In Moon ◽  
Min Ho Jeong ◽  
Wol Soon Jo
Keyword(s):  
Dna Damage ◽  
Protective Effects ◽  
Strand Breaks ◽  
Human Lymphoblastoid Cell ◽  
Wide Range ◽  
Radiation Induced ◽  
Anti Oxidant ◽  
Dna Strand ◽  
Cellular Dna

Radiotherapy is an important form of treatment for a wide range of cancers, but it can damage DNA and cause adverse effects. We investigated if the diplacone analogs of P. tomentosa were radio-protective in a human lymphoblastoid cell line (AHH-1). Four geranylated flavonoids, diplacone, 3′- O-methyl-5′-hydroxydiplacone, 3′- O-methyl-5′- O-methyldiplacone and 3′- O-methyldiplacol, were tested for their antioxidant and radio-protective effects. Diplacone analogs effectively scavenged free radicals and inhibited radiation-induced DNA strand breaks in vitro. They significantly decreased levels of reactive oxygen species and cellular DNA damage in 2 Gy-irradiated AHH-1 cells. Glutathione levels and superoxide dismutase activity in irradiated AHH-1 cells increased significantly after treatment with these analogs. The enhanced biological anti-oxidant activity and radioprotective activity of diplacone analogs maintained the survival of irradiated AHH-1 cells in a clonogenic assay. These data suggest that diplacone analogs may protect healthy tissue surrounding tumor cells during radiotherapy to ensure better control of radiotherapy and allow higher doses of radiotherapy to be employed.

scholarly journals Radiation-induced DNA damage and repair effects on 3D genome organization

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jacob T. Sanders ◽  
Trevor F. Freeman ◽  
Yang Xu ◽  
Rosela Golloshi ◽  
Mary A. Stallard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Gene Expression Regulation ◽  
Genome Structure ◽  
Cell Types ◽  
Dimensional Structure ◽  
X Rays ◽  
3D Genome ◽  
Radiation Induced ◽  
The Impact ◽  
3D Genome Structure

AbstractThe three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. We irradiate fibroblasts, lymphoblasts, and ATM-deficient fibroblasts with 5 Gy X-rays and perform Hi-C at 30 minutes, 24 hours, or 5 days after irradiation. We observe that 3D genome changes after irradiation are cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.

scholarly journals Management of atraumatic shoulder instability in physiotherapy (MASIP): a survey of physiotherapy practice

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Caroline Coulthard ◽  
Mindy C Cairns ◽  
Deborah Williams ◽  
Ben Hughes ◽  
Anju Jaggi
Keyword(s):  
Shoulder Instability ◽  
Treatment Strategies ◽  
Management Approach ◽  
Free Text ◽  
National Guidelines ◽  
Cross Sectional ◽  
Physiotherapy Practice ◽  
Treatment Techniques ◽  
Wide Range ◽  
The Impact

Abstract Background The impact of atraumatic shoulder instability (ASI) on patients can be extensive, its management complex, with a biopsychosocial approach recommended. Currently how physiotherapists manage ASI is unknown or the extent to which current clinical practice aligns with existing evidence. At the time of this study no national guidelines or consensus to direct practice existed. Methods A cross-sectional electronic survey was distributed between July-September 2018, targeting UK-based physiotherapists managing shoulder pathology. Respondents were invited to describe their management of ASI, and rate their awareness and utilisation of various treatment techniques on a Likert-scale; median and interquartile ranges were calculated. Free text survey items were analysed using quantitative content analysis (QCA) to identify codes and categories. Means and percentages were calculated to summarise QCA and descriptive data. Results Valid survey responses were analysed (n = 135). Respondents had between 2 and 39 years of physiotherapy experience (mean = 13.9 years); the majority (71.1 %) reported that ASI made up < 10 % of their caseload. Only 22.9 % (n = 31/135) of respondents reported feeling ‘very confident’ in managing ASI; the majority feeling ‘somewhat confident’ (70.4 %, n = 95/135) or ‘not confident’ (6.7 %, n = 9/135). The majority of respondents (59.3 %) used an ASI classification system, > 90 % citing the Stanmore Classification. Physiotherapists adapted their management according to clinical presentation, responding to differing biopsychosocial needs of the patient scenario. Most respondents (> 80 %) did not use a protocol to guide their management. Exercise was the most utilised management approach for ASI, followed by education; novel treatment strategies, including cortical rehabilitation, were also reported. Conclusion Findings indicate physiotherapists utilise a wide range of treatment strategies and respond to biopsychosocial cues when managing patients with ASI. The majority reported not being very confident in managing this condition, however only a minority use rehabilitation protocols to support their management. Some interventions that respondents reported using lacked evidence to support their use in ASI management and further research regarding effectiveness is required. Guidelines have been published since this survey; the impact of these will need evaluating to determine their effectiveness in the future.

scholarly journals Antibiotics Against COVID-19 and Mitochondria? Urgent Thinking Out of the Box

2020 ◽  
Author(s):  
Jaroslaw Tyszka ◽  
Karolina Kobos ◽  
Aleksandra Tyszka
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Viral Infections ◽  
Treatment Strategies ◽  
Local Health ◽  
Antiviral Immune Response ◽  
Health Authorities ◽  
Treatment Data ◽  
The Moment ◽  
The Impact

Italian, Spanish, French vs German, Austrian or Norwegian COVID-19 tracks? Antibiotics might have a partial impact on COVID-19 death rates in various countries. Our working hypotheses based on recent publications is that that antibiotics may be a major factor that negatively affects patients&rsquo; immune system during viral infections. We are all aware that there is no specific and effective medical treatment for COVID-19 so far. However, we know that our immune system is the only efficient weapon that fights against this syndrome right now. In fact, antibiotics are very often prescribed to prevent secondary infections following an antiviral immune response. Various antibiotic therapies have also been commonly applied to support COVID-19 treatments in China and Italy. Unfortunately, the frequent antibiotic off-site targets include mitochondria that are genetically and evolutionary closely linked to bacteria. Mitochondria are multifunctional organelles responsible for bioenergetics in nearly all our cells, acting as signaling hubs in antiviral and antibacterial immune responses. Several studies have demonstrated that mitochondria are vulnerable to antibacterial treatments, interrupting their physiology. Inhibition of these processes by antibiotics might render the immune system less capable of fighting acute COVID-19 viral infections. Some antibiotics, including those prescribed for COVID-19 in Wuhan, have been shown to inhibit the synthesis of mitochondrial DNA. The question is whether antibiotics support such a treatment or weaken patient immune responses in this case. This hypothesis should be evaluated based on comparative clinical data that seem to be unavailable at the moment. Possibly the COVID-19 risk group should be extended to all patients being treated with antibiotics, including those who finished antibiotic therapies days up to several months before SARS-CoV-2 infection. We therefore urge health service response groups to evaluate the impact of antibiotics on COVID-19 recovery vs death retrospective data. We would like to motivate international, national and local health authorities to share available clinical treatment data, discuss and optimize treatment strategies.

NCOG-41. HISTOLOGICAL ANALYSIS OF SLEEP AND CIRCADIAN BRAIN CIRCUITRY IN CRANIAL RADIATION-INDUCED HYPERSOMNOLENCE (C-RIH) MOUSE MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi161-vi161
Author(s):  
Dorela Shuboni-Mulligan ◽  
Demarrius Young Jr. ◽  
Julianie De La Cruz Minyety ◽  
Nicole Briceno ◽  
Amanda King ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mouse Model ◽  
Radiation Effects ◽  
Long Term Effects ◽  
Brain Volumes ◽  
Cranial Radiation ◽  
Radiation Induced ◽  
The Impact ◽  
The Brain

Abstract BACKGROUND Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving cranial radiation-induced hypersomnolence (C-RIH) remain unclear but we hypothesize this may result from damage to neural circuits controlling sleep behavior. We developed a mouse model of C-RIH to explore the impact of radiation on the brain: examining region-specific differences in acute DNA damage response and neuroanatomic structure. METHODS Mice received whole brain radiation then behaviors were monitored using PhenoTyper® cages to determine optimal dose and long-term effects. To test short-term neurologic effects, brains were collected 1hr post-radiation then stained for γH2AX, a signal for DNA damage. Long-term effects were quantified 1-month post-treatment using neuroimaging to determine brain volume and T1 mapping changes in regions associated with sleep, circadian rhythms, and cognition. RESULTS Mice displayed decreased general activity and increased daytime sleep in a dose-dependent and sustained manner. Histologic staining demonstrated that DNA damage following radiation varies across the brain, with homeostatic sleep regions and cognitive regions expressing higher levels of γH2AX than the circadian suprachiasmatic nucleus. These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes using both trypan blue (F(1,18)=235.937, p&lt; 0.001) and clonogenic assays (F(1,24)=40.796, &lt; 0.001). Brain volumes were significantly smaller in irradiated than sham animals in the hippocampus (t(4)=3.833, p=0.019) and the pontine central grey (t(4)=3.504, p=0.025). T1 maps also showed significant changes in relaxation times in many cognitive regions but not sleep or circadian areas. CONCLUSIONS These findings suggest that the homeostatic sleep region and cognitive circuits are vulnerable to radiation and may be relevant to the development of treatment plans in patients. We plan to introduce intracranial tumor to the model to evaluate the impact of timing of treatment and C-RIH on survival.

scholarly journals Biology of E1-Deleted Adenovirus Vectors in Nonhuman Primate Muscle

2001 ◽  
Vol 75 (11) ◽  
pp. 5222-5229 ◽  
Author(s):  
Philip W. Zoltick ◽  
Narendra Chirmule ◽  
Michael A. Schnell ◽  
Guang-ping Gao ◽  
Joseph V. Hughes ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Transgene Expression ◽  
Adenovirus Vector ◽  
T Cell Response ◽  
Intramuscular Administration ◽  
Cytotoxic T Cell ◽  
Adenovirus Vectors ◽  
The Impact

ABSTRACT Adenovirus vectors have been studied as vehicles for gene transfer to skeletal muscle, an attractive target for gene therapies for inherited and acquired diseases. In this setting, immune responses to viral proteins and/or transgene products cause inflammation and lead to loss of transgene expression. A few studies in murine models have suggested that the destructive cell-mediated immune response to virally encoded proteins of E1-deleted adenovirus may not contribute to the elimination of transgene-expressing cells. However, the impact of immune responses following intramuscular administration of adenovirus vectors on transgene stability has not been elucidated in larger animal models such as nonhuman primates. Here we demonstrate that intramuscular administration of E1-deleted adenovirus vector expressing rhesus monkey erythropoietin or growth hormone to rhesus monkeys results in generation of a Th1-dependent cytotoxic T-cell response to adenovirus proteins. Transgene expression dropped significantly over time but was still detectable in some animals after 6 months. Systemic levels of adenovirus-specific neutralizing antibodies were generated, which blocked vector readministration. These studies indicate that the cellular and humoral immune response generated to adenovirus proteins, in the context of transgenes encoding self-proteins, hinders long-term transgene expression and readministration with first-generation vectors.

The role of Pirh2 C-terminal residues and ubiquitin lysine chains in ubiquitination mechanism.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11110-11110
Author(s):  
Rami Mahmoud Abou Zeinab ◽  
Roger Leng
Keyword(s):  
Dna Damage ◽  
Degradation Mechanism ◽  
Fine Tuning ◽  
P53 Family ◽  
E3 Ligases ◽  
Wide Range ◽  
Lysine Residues ◽  
Main Regulator ◽  
The Impact

11110 Background: Pirh2, a p53 inducible gene, is proposed to be a main regulator of p53 family proteins fine tuning the DNA damage response by acting as an E3 ligase. A negative feedback loop between Pirh2 and p53 exists where under unstressed conditions, Pirh2 induces p53 ubiquitination followed by proteosomal degradation. In case of cellular stress when the activity of tumor suppressors is essential, Pirh2 is self-ubiquitinated releasing p53 continuous repression. Interestingly among all E3 ligases, Pirh2 is the only one to be over-expressed in a wide range of human tumors. This over-expression indicates a disruption in the self-ubiquitination mechanism or a defect in the degradation mechanism post ubiquitination. Based on that, we aimed to analyze Pirh2 ubiquitination mechanism through mapping Pirh2 domains to reveal the essential residues for this process and the ubiquitin chains utilized. Methods: Pirh2 constructs deleting major residues in the three domains were designed, and also ubiquitin mutant constructs were designed through single/multiple mutations at specific positions where lysine residues are mutated to arginine. Using these constructs and in comparison to WT proteins, we tested Pirh2 in-vitro self and p53 ubiquitination activity. Results: Regarding Pirh2, we were able to reveal that residues 240-250 of the c-terminal along with the ring domain are essential for self-ubiquitination.K63R and K48R ubiquitin did not affect Pirh2 self-ubiquitination minimizing the impact of ubiquitin mutations on Pirh2 self-ubiquitination. However, KO, which had all lysine residues mutated to arginine, showed total inhibition of Pirh2 self-ubiquitination confirming the importance of lysine residues. Interestingly, Pirh2 self-ubiquitination reaction showed no difference in the presence or absence of p53 proteins. Concerning Pirh2-p53 ubiquitination, K48 was found to be critical for E3 ubiquitin ligase activity because K48R and not K36R showed defective ubiquitination. All results were confirmed by quantifying ubiquitin. Conclusions: Our data added knowledge to the Pirh2 self-ubiquitination mechanism that can resolve the constant overexpression of Pirh2 proteins hence maximizing p53 response to DNA damage.

Sign in / Sign up

Export Citation Format

Share Document