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Radiobiology of Normal Tissues
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
It is now accepted that individual radiosensitivity is a genetically determined trait. Following the identification of ataxia telangiectasia, a number of other inherited syndromes were shown to be associated with an increased risk of damage by radiotherapy. These syndromes were identified because of unusually severe reactions to radiotherapy. The genes associated with these syndromes have now been identified, e.g. ataxia telangiectasia (ATM gene), Nijmegen breakage syndrome (NBS) and Ligase IV syndrome (LIG4). Patients with these syndromes cannot tolerate normal doses of radiotherapy; their cells exhibit increased radiosensitivity.
Clinical data in outcome models
Published in Issam El Naqa, A Guide to Outcome Modeling in Radiotherapy and Oncology, 2018
Nicholas J. DeNunzio, Sarah L. Kerns, Michael T. Milano
In recent years, there has been a burgeoning effort to study and understand how genetic predispositions might predict radiation toxicity. As evidenced by one early study examining skin telangiectasia after radiotherapy, 81–90% of the patient-to-patient variation in severity of post-radiotherapy telangiectasias could be explained by patient-related factors [43]. Though genetic syndromes exist that are known to predispose patients to increased radiosensitivity (e.g., ataxia telangiectasia, Nijmegen breakage syndrome, LIG4 syndrome [44], these are rare.
Nijmegen Breakage Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for NBD include several inherited disorders that also display microcephaly, growth delay, immunodeficiency, and bone marrow failure due to defective sensing, processing, and repair of DNA DSB (LIG4 syndrome [microcephaly, dysmorphic face, growth retardation, combined cellular and humoral immunodeficiency], NHEJ1 syndrome [microcephaly, dysmorphic facies, severe growth retardation, severe combined cellular and humoral immunodeficiency], Nijmegen breakage syndrome-like disorder [NBSLD or RAD50 deficiency; microcephaly, dysmorphic face, growth retardation, mild spasticity, non-progressive ataxia, normal puberty, chromosome instability at bands 7p13, 7q34, 14q11, and 14q32, absence of immunodeficiency and malignancy; due to mutation in RAD50 on chromosome 5q31.1], A-T [ovarian failure, neurodegeneration, telangiectasia, increased alpha fetal protein, immunodeficiency, cancer predisposition; due to biallelic mutations in the A-T mutated or ATM gene], A-T like disorder [ATLD; neurodegeneration, increased alpha fetal protein; due to MRE11 mutation], Fanconi anemia [occasional microcephaly, growth retardation, skeletal abnormalities—radial defect, reduced fertility—hypergonadotropic hypogonadism in males, pancytopenia, no immunodeficiency], Seckel syndrome [severe microcephaly, severe prenatal and postnatal growth retardation, developmental delay, mental retardation, pancytopenia, no immunodeficiency], Rubinstein−Taybi syndrome [microcephaly, distinctive facial features, mild growth restriction, short stature, intellectual disability, recurrent infections, defect in polysaccharide antibody response, leukemia, brain tumor], and Bloom syndrome [microcephaly, growth failure, increased cancer incidence; due to BLM mutation]) [1].
Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)
Published in Immunological Investigations, 2021
Farzaneh Rahmani, Elham Rayzan, Mohammad Reza Rahmani, Sepideh Shahkarami, Samaneh Zoghi, Arezoo Rezaei, Zahra Aryan, Mehri Najafi, Meino Rohlfs, Tim Jeske, Majid Aflatoonian, Zahra Chavoshzadeh, Fatemeh Farahmand, Farzaneh Motamed, Pejman Rohani, Hossein Alimadadi, Alireza Mahdaviani, Mahboubeh Mansouri, Marzieh Tavakol, Mirjam Vanderberg, Daniel Kotlarz, Christoph Klein, Nima Rezaei
Rag1 -/- mice transferred with naïve allogenic CD4 + T cells develop an IBD phenotype in response to gut microbiota (Stepankova et al. 2007), a model that is frequently used to study the dynamics of altered immunologic response to gut microbiota in the pathogenesis of IBD (Britton et al. 2019; Trobonjaca et al. 2001). Hypomorphic mutations in RAG1/2 genes are among frequent causes of the milder, late-onset form of combined primary immunodeficiency, i.e., atypical SCID, with a Tlow Blow phenotype (Felgentreff et al. 2011; Villa et al. 2001). Patients with atypical SCID classically present with granulomatous colitis, autoimmune cytopenia, or other autoimmune conditions but not recurrent infections (Felgentreff et al. 2011). Mutations in other genes involved in VDJ recombination, including LIG4, have also been associated with TlowBlow phenotype, atypical SCID and autoimmunity (De Azevedo Silva et al. 2014). We hypothesize that the IBD phenotype in patients P12 (with RAG1 mutation) and P13 (with LIG4 mutation) was the heralding sign for atypical SCID in them, who later developed refractory thrush (P12 and P13) and perianal abscess (in P12) and visceral leishmaniosis leading to cirrhosis (in P13). Unfortunately, neither patients survived without HSCT.
Induction of different cellular arrest and molecular responses in low EGFR expressing A549 and high EGFR expressing A431 tumor cells treated with various doses of 177Lu-Nimotuzumab
Published in International Journal of Radiation Biology, 2020
ShishuKant Suman, Rashmi Priya, Mythili Kameswaran
RT-qPCR was used to monitor the relative fold changes in transcription of the DRR genes of A431 and A549 cells treated with 177Lu-Nimotuzumab. Figures 8 and 9 depict the relative fold changes in transcription of DRR genes of A549 and A431 cells, respectively, at 0 h, 4 h, and 16 h post-treatment with 3.7 MBq, 18.5 MBq, and 37 MBq of 177Lu-Nimotuzumab. Transcription profiles demonstrated that most of the DRR genes in A431 and A549 cells showed a decrease in relative fold change of transcription at 4 h, followed by an increase in relative fold changes at 16 h post-treatment. MGMT, RAD52B, XPC, and MDM2 genes of A549 cells showed upregulation when treated with different doses over different time points. MGMT gene showed maximum upregulation at 4 h while MDM2, XPC, and ATM genes showed at 16 h in A549 cells post-treatment. LIG4 in A549 was upregulated at 4 h and 16 h in response to different doses of treatment.
Cellular vaccination of MLH1−/− mice – an immunotherapeutic proof of concept study
Published in OncoImmunology, 2018
Claudia Maletzki, Yvonne Saara Gladbach, Mohamed Hamed, Georg Fuellen, Marie-Luise Semmler, Jan Stenzel, Michael Linnebacher
With this analysis, mutations were detectable in 31 % (lysate) and 25 % (lysate + CpG ODN 1826) of analyzed markers from vaccinated tumors, respectively (vs. 15 % controls; Table 2). Increased mutation frequencies were found in genes belonging to DNA repair (Lig4), signa-ling pathways that regulate growth and metabolism (Grb14), and transcriptional repression (Bend5). The latter gene shares functional and structural similarity with its human ortholog and is mutated in 10 % of cultured MSI-H cell lines [Seltarbase.org]. Besides, NKtr1, originally described to be present on the surface of natural killer cells to facilitate target cell binding, was more frequently mutated in vaccinated than in control tumors (100% (lysate) and 20% (lysate + CpG ODN 1826), respectively, vs. 9% in controls). In contrast, APC gene mutations, originally found in every fourth MLH1−/−−associated GIT as well as in the allograft that was used for vaccination, were no longer detectable (Table 2).