Simon Tobi | Central Manchester NHS (original) (raw)

Papers by Simon Tobi

Journal of Medical Genetics, 2020

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germl... more ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.MethodsCases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.ResultsAge at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patien...

Journal of neurology, neurosurgery, and psychiatry, Jan 16, 2018

Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal ... more Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on , and on blood and tumour DNA samples when available. Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. -associated schwannomatosis also causes a small number of cases that are misdiagnosed wit...

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, Jan 8, 2016

Journal of Cystic Fibrosis, 2015

Biochemical Society Transactions, 1990

Pharmacogenomics, 2009

Aims: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemothera... more Aims: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. Materials & methods: Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m2, twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. Results: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carryin...

Mutation Research Letters, 1994

Journal of Medical Genetics, 1990

Journal of Cystic Fibrosis, 2013

International Journal of Radiation Biology, 1993

We have previously found that radiation-induced chromosome aberrations (dicentrics) are more nume... more We have previously found that radiation-induced chromosome aberrations (dicentrics) are more numerous in lymphocytes from Alzheimer's disease (AD) patients than in those from age-matched normal individuals (Tobi et al. 1990). To investigate this further, we have examined double-strand breaks (dsb) produced by gamma-irradiation in the DNA of AD and normal lymphocytes by using pulsed-field gel electrophoresis. The percentage of DNA migrating into the gels is an indirect measure of the number of dsb; we have assayed the DNA content of sequential slices of the gel by direct fluorometry and have found that the percentage migrating is dose dependent. Our results show that the level of damage is similar in AD and normal lymphocytes and preliminary assays of the rate of repair suggest that the half-time is also similar, the value being > 1 h. The latter is consistent with the known rate of rejoining of chromosome fragments in interphase lymphocytes (Pantelias and Maillie 1985). The results suggest that at a gross level dsb repair is not impaired in AD cells; however, we cannot exclude the possibility that there is misrepair or non-repair of a small fraction of the dsb, which might account for the greater radiosensitivity of the AD cells.

Hormone Research in Paediatrics, 2008

Aims: To determine the incidence of classical 21-hydroxylase deficiency (21-OHD) in Estonia from ... more Aims: To determine the incidence of classical 21-hydroxylase deficiency (21-OHD) in Estonia from 1978 to 2004, and describe their phenotype and genotype. Methods: All Estonian endocrinologists informed us about their patients with 21-OHD. The diagnosis was confirmed in 20 patients, who were all screened for 8 common mutations of the CYP21A2 gene. Results: The 27-year period incidence was 1:25,500. The incidence from 1992 was 1:16,100, which more accurately reflects the real situation in Estonia. The salt-wasting form (SW) was diagnosed in 14 (7 males) and the simple virilizing form in 6 patients (1 male). The median age at diagnosis of the SW form was 30 days in males and 2 days in females. The investigation of 34 unrelated alleles showed that a common deletion/conversion was the most frequent mutation in our group (7/34). Six other mutations were present: p.Ile172Asn (5/34), 8-bp deletion (3/34), intron-2 splice mutation (3/34), p.Arg356Trp (3/34), p.Gln318X (3/34) and a small conv...

Gerontology, 1993

We have previously shown that lymphocytes from Alzheimer's disease (AD) patients are hype... more We have previously shown that lymphocytes from Alzheimer's disease (AD) patients are hypersensitive to ionising radiation, as revealed by their higher levels of dicentrics than those from age-matched, normal individuals. We have now examined the sensitivity of these cells to N-methyl-N-nitrosourea or methyl methanesulphonate, using a variety of assays, namely unscheduled DNA synthesis, viability, sister chromatid exchange and, via high performance liquid chromatography, level of methylation and repair of the adducts, 7-methylguanine, 0(6)-methylguanine and 3-methyladenine. We have found that AD lymphocytes and age-matched normal lymphocytes respond similarly to methylation damage, as assessed by all these techniques.

Annals of the New York Academy of Sciences, 1992

... Proficient Repair of Alkylation Damage in Alzheimer's Disease Lymphocytes. SE TOBI 1... more ... Proficient Repair of Alkylation Damage in Alzheimer's Disease Lymphocytes. SE TOBI 1 ,; DC LLOYD 2 ,; D. NEARY 3 ,; RF ITZHAKI 1. Article first published online: 17 DEC 2006. DOI: 10.1111/j.1749-6632.1992.tb38693.x. Issue. Annals of the New York Academy of Sciences. ...

European Journal of Human Genetics, 2011

Journal of Photochemistry and Photobiology B: Biology, 2000

We have developed an assay to detect reactive oxygen species (ROS) generated by UVA radiation uti... more We have developed an assay to detect reactive oxygen species (ROS) generated by UVA radiation utilising chemical probes which become fluorescent upon oxidation. Using a human bladder carcinoma cell line (MGH-U1) and spontaneously immortalised keratinocytes (HaCaT), we have shown a UVA (narrow band 365+/-5 nm) dose-dependent increase in fluorescence by flow cytometry following loading of the cells with either dihydrorhodamine 123 (DHR) or 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The UVA response of both DHR and DCFH was enhanced by elevation of intracellular levels of the photosensitiser protoporphyrin IX by incubation for 2.5 h with 5-aminolaevulinic acid. Depletion of the antioxidant glutathione (GSH) using the inhibitor D,L-buthionine-sulphoximine (BSO), resulted in an increase in the UVA-induced fluorescence of DCF but not of rhodamine 123. Conversely, raising intracellular GSH levels with N-acetyl cysteine (NAC) had relatively little protective effect in terms of degree of induced fluorescence.

Journal of Pharmacy and Pharmacology, 2008

UVA should receive significant consideration as a human health risk as it is a large proportion o... more UVA should receive significant consideration as a human health risk as it is a large proportion of the solar spectrum that reaches the earth's surface and because of its ability to penetrate human skin. It is only relatively recently that this has been recognized and this previously under-researched part of the UV spectrum is becoming increasingly well characterized at doses that are quite low in relation to those experienced by humans. Absorption of UVA in a cell leads to the production of reactive oxygen and nitrogen species that can damage major biomolecules including DNA and membrane lipids. Various types of damage induced in these molecules lead to significant biological effects including cytotoxicity, mutations and alterations in cell signalling pathways. Longer-term effects such as persistent genomic instability and bystander effects have also been observed following UVA treatment of mammalian cells and, as with ionizing radiation, this changes some of the fundamental thi...