Can We Miniaturize CT Technology for a Successful Mobile Stroke Unit Roll-Out?

Mortality from stroke remains high in Australia, especially for patients located outside the metropolitan cities. This is because they have limited access to specialized stroke facilities for optimal stroke treatment. Mobile stroke units have the capability to take CT scanners out to the patient however current CT commercial scanner designs are large and heavy. As such, this paper aims to design and develop a lightweight CT scanner for use in a mobile stroke unit (either road-based or air-based ambulance) to bring healthcare solution to patients in the rural and remote areas. We used the engineering design optimization approach to redesign and reduce the weight of the existing CT scanner with without compromised it structural performance. We managed to reduce the weight the CT scanner by three-fold while reducing design costs by allowing numerous simulations to be performed using computer software to achieve our design goals. The results are not only useful to optimize CT scanner structure to retrofit on a mobile stroke unit, but also bring the medical device solution to the market and support scalable solution to the larger community. Such an advance will allow for improved equity in healthcare whereby patients can be treated irrespective of location.

Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation.

Smoking, inflammation and depression commonly co-occur and may be mechanistically linked. However, key questions remain around the direction of association and the influence of residual confounding. We aimed to characterize the association between lifetime smoking and depression, as well as to assess the role that genetically-predicted C-reactive protein (CRP) level, (an archetypal generalized inflammatory marker) and/or IL-6 activity, as a potential explanation for this association. We performed inverse variance weighted Mendelian randomization (MR) analyses using recently published summary-level GWAS data for lifetime smoking index, CRP levels, and depression. A subset of inflammatory-related genetic variants from the lifetime smoking GWAS were also used to assess the potential inflammatory causal pathways between smoking and depression. The analysis indicated reciprocal relationships of lifetime smoking with depression (ORSmk-Dep = 2.01, 95% CI 1.71-2.37, p < 0.001; ORDep-Smk = 1.09, 95% CI 1.06-1.13, p < 0.001), CRP levels and IL-6 activity (ORSmk-CRP = 1.40, 95% CI 1.21-1.55, p < 0.001; ORCRP-Smk = 1.03, 95% CI 1.02-1.05, p < 0.001, ORIL-6/CRP-Smk = 1.06 (1.03-1.09), p < 0.001). These associations were also supported by the majority of the robust MR methods performed. We did not find evidence for a reciprocal relationship between CRP levels (using > 500 genetic instruments for CRP) and depression (ORCRP-Dep = 1.01, 95% CI 0.99-1.04; ORDep-CRP = 1.03, 95% CI 0.99-1.07). We observed little variation in the IVW estimates between smoking and depression when we limited the genetic variants assessed to those related to measures of generalized inflammation, but we found evidence for an attenuation of the smoking-depression association in multivariable mendelian randomization when adjusting for IL-6 activity, suggesting that the IL-6 pathway may be at least in part responsible for the association of smoking and depression. Our study supports potential bidirectional causal associations between lifetime smoking and depression which may be at least in part explained by the IL-6 signalling pathway. The IL-6 pathway may represent a putative therapeutic target for smoking and to mitigate the effects of smoking on depression.

Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells.

Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory elements with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is critical for B-cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing regulatory B cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor transmembrane activator and cyclophilin ligand interactor. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL.

Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-ß and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.

BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface.

BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions. METHODS: We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting. RESULTS: We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions. CONCLUSION: All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/.

Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues.

PURPOSE: Recent work has demonstrated an important decrease in breast cancers for women with systemic lupus erythematosus (SLE). The reason behind this phenomenon is unknown. Our purpose was to explore whether the single nucleotide polymorphisms (SNPs) predisposing to SLE might be protective against breast cancer (in women in the general population). METHODS: We focused on loci relevant to 10 SNPs associated with SLE (with a p value of <10(-9)). We determined whether we could establish a decreased frequency of these SNPs in breast cancer cases versus controls, within the general population. To do this we used a large breast cancer genome-wide association study (GWAS) dataset, involving 3,659 breast cancer cases and 4,897 controls. These subjects were all primarily of European ancestry. RESULTS: The population-based GWAS breast cancer data we examined suggested little evidence for important associations between breast cancer and SLE-related SNPs. Within the general population GWAS data, a cytosine(C) nucleotide substitution at rs9888739 (on chromosome 16p11.2) showed a very weak inverse association with breast cancer. The odds ratio (OR) for the rs9888739-C allele was 0.907551 (p value 0.049899) in the GWAS breast cancer sample, compared to controls. There was a slightly stronger, positive, association with breast cancer for rs6445975-G (Guanine) on chromosome 3p14.3, with a breast cancer OR of 1.0911 (p value 0.0097). CONCLUSIONS: Within this large breast cancer dataset, we did not demonstrate important associations with 10 lupus-associated SNPs. If decreased breast cancer risk in SLE is influenced by genetic profiles, this may be due to complex interactions and/or epigenetic factors.

Germline BRCA1 mutations increase prostate cancer risk.

BACKGROUND: Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set. METHODS: We screened 913 cases aged 36­86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases. RESULTS: We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45%; three of the mutation carriers were affected at age 65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ~3.75-fold, (95% confidence interval 1.02­9.6) translating to a 8.6% cumulative risk by age 65. CONCLUSION: This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.

Genetic variants associated with predisposition to prostate cancer and potential clinical implications.

Prostate cancer is the commonest cancer in the developed world. There is an inherited component to this disease as shown in familial and twin studies. However, the discovery of these variants has been difficult. The emergence of genome-wide association studies has led to the identification of over 46 susceptibility loci. Their clinical utility to predict risk, response to treatment, or treatment toxicity, remains undefined. Large consortia are needed to achieve adequate statistical power to answer these genetic-clinical and genetic-epidemiological questions. International collaborations are currently underway to link genetic with clinical/epidemiological data to develop risk prediction models, which could direct screening and treatment programs.

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.

BACKGROUND: A family history of prostate cancer (PrCa) is a strong risk factor for the disease, indicating that inherited factors are important in this disease. We previously estimated that about 2% of PrCa cases diagnosed ≤ 55 years harbour a BRCA2 mutation and PrCa among BRCA2 carriers has been shown to be more aggressive, with poorer survival. METHODS: To further evaluate the role of BRCA2 in PrCa predisposition, we screened 1864 men with PrCa aged between 36 and 88 years. We analysed the BRCA2 gene using a novel high-throughput multiplex fluorescence heteroduplex detection system developed for the ABI3130xl genetic analyzer. RESULTS: We identified 19 protein-truncating mutations, 3 in-frame deletions and 69 missense variants of uncertain significance (UV) in our sample set. All the carriers of truncating mutations developed PrCa at ≤ 65 years, with a prevalence of BRCA2 mutation of 1.20% for cases in this age group. CONCLUSION: Based on the estimated frequency of BRCA2 mutations in the United Kingdom we estimate that germline mutations in the BRCA2 gene confer an ∼ 8.6-fold increased risk of PrCa by age 65, corresponding to an absolute risk of ∼ 15% by age 65. These results suggest that routine testing of early onset PrCa cases for germline BRCA2 mutations will further help to refine the prevalence and risk associated with BRCA2 mutations and may be useful for guiding management options.

Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.

BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T. METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity. RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype. CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

Polygenic susceptibility to prostate and breast cancer: implications for personalised screening.

BACKGROUND: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone. METHODS: We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively). RESULTS: Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases. CONCLUSION: Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.

Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.

Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Hand pattern indicates prostate cancer risk.

BACKGROUND: The ratio of digit lengths is fixed in utero, and may be a proxy indicator for prenatal testosterone levels. METHODS: We analysed the right-hand pattern and prostate cancer risk in 1524 prostate cancer cases and 3044 population-based controls. RESULTS: Compared with index finger shorter than ring finger (low 2D : 4D), men with index finger longer than ring finger (high 2D : 4D) showed a negative association, suggesting a protective effect with a 33% risk reduction (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.57-0.80). Risk reduction was even greater (87%) in age group <60 (OR 0.13, 95% CI 0.09-0.21). CONCLUSION: Pattern of finger lengths may be a simple marker of prostate cancer risk, with length of 2D greater than 4D suggestive of lower risk.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers.

Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.

Mutation analysis of the MSMB gene in familial prostate cancer.

BACKGROUND: MSMB, a gene coding for beta-microseminoprotein, has been identified as a candidate susceptibility gene for prostate cancer (PrCa) in two genome-wide association studies (GWAS). SNP rs10993994 is 2 bp upstream of the transcription initiation site of MSMB and was identified as an associated PrCa risk variant. The MSMB protein is underexpressed in PrCa and it was previously proposed to be an independent marker for the recurrence of cancer after radical prostatectomy. METHODS: In this study, the coding region of this gene and 1500 bp upstream of the 5'UTR has been sequenced in germline DNA in 192 PrCa patients with family history. To evaluate the possible effects of these variants we used in silico analysis. RESULTS: No deleterious mutations were identified, however, nine new sequence variants were found, most of these in the promoter and 5'UTR region. In silico analysis suggests that four of these SNPs are likely to have some effect on gene expression either by affecting ubiquitous or prostate-specific transcription factor (TF)-binding sites or modifying splicing efficiency. INTERPRETATION: We conclude that MSMB is unlikely to be a familial PrCa gene and propose that the high-risk alleles of the SNPs in the 5'UTR effect PrCa risk by modifying MSMB gene expression in response to hormones in a tissue-specific manner.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.