Newcastle upon Tyne, United Kingdom
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Palles C.,University of Oxford | Cazier J.-B.,University of Oxford | Howarth K.M.,University of Oxford | Domingo E.,University of Oxford | And 84 more authors.
Nature Genetics | Year: 2013

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ε and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain. © 2013 Nature America, Inc. All rights reserved.


Fuchs A.,Albert Ludwigs University of Freiburg | Inthal A.,Institute of Molecular Pathology | Inthal A.,Childrens Cancer Research Institute | Herrmann D.,Albert Ludwigs University of Freiburg | And 6 more authors.
Developmental Dynamics | Year: 2010

Mutations in the gene encoding the T-box transcription factor TBX22 cause X-linked cleft palate and ankyloglossia in humans. Here we show that Tbx22 expression during facial and palatal development is regulated by FGF and BMP signaling. Our results demonstrate that FGF8 induces Tbx22 in the early face while BMP4 represses and thus restricts its expression. This regulation is conserved between chicken and mouse, although the Tbx22-expression patterns differ considerably between these two species. We suggest that these species-specific differences may result at least in part from differences in the spatiotemporal patterns of BMP activity, but we exclude a direct repression of Tbx22 by the BMP-inducible transcriptional repressor MSX1. Together these findings help to integrate Tbx22 into the molecular network of factors regulating facial development. © 2010 Wiley-Liss, Inc.


Moradpourhafshejani S.,Northumbria University | Hedley J.H.,Northumbria University | Hedley J.H.,International Center for Life | Haigh A.O.,Northumbria University | And 3 more authors.
RSC Advances | Year: 2013

Proflavine diazide (PD) with amido-azide substituents on the amine groups and its N-methylated analogue (MePD) bind strongly to DNA by nearest-neighbour intercalation with little sequence selectivity, presenting reactive azide groups in the major groove. PD is neutral in aqueous solution but experiences binding-coupled protonation on interaction with DNA with an apparent pK a shift of 2.5 units. MePD can be click modified in situ on DNA with alkyne-functionalised thienyl-pyrrole as a precursor for conducting polymer synthesis, and remains intercalated after reaction with the substituents aligned in the groove. This journal is © The Royal Society of Chemistry.


Gibson B.G.,Northumbria University | Briggs M.D.,Northumbria University | Briggs M.D.,International Center for Life
Orphanet Journal of Rare Diseases | Year: 2016

The large chondroitin sulphated proteoglycan aggrecan (ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms. © 2016 The Author(s).


Lane J.P.,Northumbria University | Lane J.P.,Newcastle upon Tyne Hospitals NHS Trust | Evans P.T.G.,Northumbria University | Nademi Z.,Newcastle upon Tyne Hospitals NHS Trust | And 13 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n=11) and low-dose (n=9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3+ engraftment occurred at 92.5 and 97days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3+, CD4+, and early thymic emigrant counts at 4months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD. © 2014 American Society for Blood and Marrow Transplantation.


PubMed | Newcastle upon Tyne Hospitals NHS Trust, Northumbria University and International Center for Life
Type: Journal Article | Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation | Year: 2014

Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n=11) and low-dose (n=9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3(+) engraftment occurred at 92.5 and 97days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3(+), CD4(+), and early thymic emigrant counts at 4months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD.

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