Family history is an important risk factor for many common chronic diseases, but it remains underutilised for diagnostic assessment and disease prevention in routine primary care.
To develop and ...validate a brief self-completed family history questionnaire (FHQ) for systematic primary care assessment for family history of diabetes, ischaemic heart disease, breast cancer, and colorectal cancer.
Two-stage diagnostic validation study in 10 general practices in eastern England. Method Participants aged 18-50 years were identified via random sampling from electronic searches of general practice records. Participants completed a FHQ then had a three-generational 'gold standard' pedigree taken, to determine disease risk category. In stage 1, the FHQ comprised 12 items; in stage 2 the shorter 6-item FHQ was validated against the same 'gold standard'.
There were 1147 participants (stage 1: 618; stage 2: 529). Overall, 32% were at increased risk of one or more marker conditions (diabetes 18.9%, ischaemic heart disease 13.3%, breast cancer 6.2%, colorectal cancer 2.2%). The shorter 6-item FHQ performed very well for all four conditions: pooled data from both stages show diabetes, sensitivity = 98%, specificity = 94%; ischaemic heart disease, sensitivity = 93%, specificity = 81%; breast cancer, sensitivity = 81%, specificity = 83%; colorectal cancer, sensitivity = 96%, specificity = 88%, with an area under the receiver operating characteristic curve of 0.90 for males and 0.89 for females.
This brief self-completed FHQ shows good diagnostic accuracy for identifying people at higher risk of four common chronic diseases. It could be used in routine primary care to identify patients who would be most likely to benefit from a more detailed pedigree and risk assessment, and consequent management strategies.
E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of ...inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.
E-cadherin germ-line mutations have recently been described as a molecular basis for early-onset familial gastric cancer in Maori kindred. We screened 18 gastric cancer families of European origin ...for germ-line mutations to determine the proportion in which E-cadherin mutations occur and the clinical characteristics of the affected families. Truncating mutations were identified in three kindred with familial diffuse gastric cancer. In these families, the age of onset of gastric cancer was variable, the penetrance was incomplete, and one kindred contained individuals with cancers at other sites. Here, we show that a proportion of diffuse gastric cancer families of European origin have germ-line E-cadherin mutations; however, these mutations are absent in intestinal gastric cancer families.
Following the success of global vaccination programmes using the live-attenuated oral and inactivated poliovirus vaccines (OPV and IPV), wild poliovirus (PV) is now only endemic in Afghanistan and ...Pakistan. However, the continued use of these vaccines poses potential risks to the eradication of PV. The production of recombinant PV virus-like particles (VLPs), which lack the viral genome offer great potential as next-generation vaccines for the post-polio world. We have previously reported production of PV VLPs using
, however, these VLPs were in the non-native conformation (C Ag), which would not produce effective protection against PV. Here, we build on this work and show that it is possible to produce wt PV-3 and thermally stabilised PV-3 (referred to as PV-3 SC8) VLPs in the native conformation (D Ag) using
. We show that the PV-3 SC8 VLPs provide a much-improved D:C antigen ratio as compared to wt PV-3, whilst exhibiting greater thermostability than the current IPV vaccine. Finally, we determine the cryo-EM structure of the yeast-derived PV-3 SC8 VLPs and compare this to previously published PV-3 D Ag structures, highlighting the similarities between these recombinantly expressed VLPs and the infectious virus, further emphasising their potential as a next-generation vaccine candidate for PV.
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