ORCID Profile
0000-0001-6013-5220
Current Organisation
University of Sydney
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Publisher: BMJ
Date: 11-06-2013
DOI: 10.1136/JCLINPATH-2013-201607
Abstract: We assessed the diagnostic accuracy of epidermal growth factor receptor (EGFR) mutant-specific antibodies for detecting two common activating EGFR mutations. Immunohistochemical expression of mutation-specific antibodies against EGFR exon 19 deletion E746-A750 ((c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750del) and exon 21 L858R point mutation (c.2573T>G, p.Leu858Arg) were assessed in a cohort of 204 resected early stage node negative lung adenocarcinomas, and protein expression was compared with DNA analysis results from mass spectrometry analysis. Of seven cases with L858R point mutation, six were positive by immunohistochemistry (IHC). There were three false positive cases using L858R IHC (sensitivity 85.7%, specificity 98.5%, positive predictive value 66.7%, negative predictive value 99.5%). All seven E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. Four additional cases were positive for exon 19 IHC but negative by mutation analysis. The sensitivity of exon 19 IHC for E746-A750 was 100%, specificity 98.0%, positive predictive value 63.6% and negative predictive value 100%. Mutant-specific EGFR IHC has good specificity and sensitivity for identifying targeted activating EGFR mutations. Although inferior to molecular genetic analysis of the EGFR gene, IHC is highly specific and sensitive for the targeted EGFR mutations. The antibodies are likely to be of clinical value in cases where limited tumour material is available, or in situations where molecular genetic analysis is not readily available.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.NMD.2008.04.013
Abstract: Mutations in the superoxide dismutase 1 gene (SOD1) are associated with familial ALS but the role of SOD1 in sporadic ALS (SALS) is unclear. We therefore sequenced the entire SOD1 gene in 23 patients with SALS. DNA was extracted from frozen pre-frontal cerebral cortex and from blood. The 5 exons, 4 introns and 1 kb upstream and downstream of SOD1 were sequenced. Novel genetic variants were found in 30% (7 of 23) brains and known variants in 91% (21 of 23) brains from patients with SALS. Two novel variants found in SALS patients and not controls were located in the SOD1 promoter and intron 1, with the promoter variant having potential functional implications. A previously described silent variant in exon 5 in one SALS patient appears to abolish an exonic splicing enhancer. All changes found in brain DNA were also found in blood DNA. In conclusion, sequencing the entire SOD1 gene revealed 3 variants in SALS patients that were not detected in controls. Although no unequivocal mutations were found, some of these variants have potential consequences for SALS pathogenesis.
Publisher: Informa UK Limited
Date: 2010
DOI: 10.3109/17482960802572699
Abstract: Somatic mutations have been suggested as a cause of sporadic amyotrophic lateral sclerosis (SALS). These mutations can be difficult to detect since they may involve only a small percentage of cells within the tissue, so we devised a method to detect low mutation levels in brain DNA. Different proportions of a known SOD1 mutation were prepared to determine the sensitivity of DHPLC. The fraction containing the mutant signal was collected and re- lified ('enriched') to increase sensitivity and to dideoxy sequence the mutation. The combined technique was used to screen all exons and the promoter of SOD1 in 23 SALS brains. DHPLC could detect a known SOD1 mutation in 5% of a s le of brain tissue. Using our enrichment technique doubled the height of the mutant sequencing signal, which allowed identification of an unknown mutation in 10% of brain tissue. No SOD1 mutations were found in the SALS brains using this technique. In conclusion, combining DHPLC and sequencing doubles the sensitivity of sequencing alone and can detect low levels of known and unknown mutations in brain DNA. No SALS SOD1 somatic mutations were detected, but DHPLC would be useful in looking for somatic mutations in other SALS candidate genes.
Publisher: Wiley
Date: 15-06-2016
DOI: 10.1111/HIS.12992
Abstract: BRAF or NRAS mutations occur in approximately 60% of cutaneous melanomas, and the identification of such mutations underpins the appropriate selection of patients who may benefit from BRAF and MEK inhibitor targeted therapies. The utility of immunohistochemistry (IHC) to detect NRAS(Q61L) mutations is currently unknown. This study sought to assess the sensitivity and specificity of anti-BRAF(V600E) (VE1), anti-NRAS(Q61R) (SP174) and anti-NRAS(Q61L) (26193) antibodies for mutation detection in a large series of cases. Mutation status was determined using the OncoCarta assay in 754 cutaneous melanomas. IHC with the anti-BRAF(V600E) antibody was performed in all cases, and the anti-NRAS(Q61R) and anti-NRAS(Q61L) antibodies were assessed in a subset of 302 s les utilizing tissue microarrays. The staining with the anti-BRAF(V600E) and anti-NRAS(Q61R) antibodies was diffuse, homogeneous and cytoplasmic. The anti-NRAS(Q61L) antibody displayed variable intensity staining, ranging from weak to strong in NRAS(Q61L) mutant tumours. The sensitivity and specificity for anti-BRAF(V600E) was 100 and 99.3%, anti-NRAS(Q61R) was 100 and 100% and anti-NRAS(Q61L) was 82.6 and 96.2%, respectively. The use of IHC is a fast, efficient and cost-effective method to identify single specific mutations in melanoma patients. BRAF(V600E) and NRAS(Q61R) antibodies have high sensitivity and specificity however, the NRAS(Q61L) antibody appears less sensitive. IHC can help to facilitate the timely, appropriate selection and treatment of metastatic melanoma patients with targeted therapies. Detection of melanoma-associated mutations by IHC may also provide evidence for a diagnosis of melanoma in metastatic undifferentiated neoplasms lacking expression of melanoma antigens.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1038/MODPATHOL.2017.128
Abstract: Cutaneous squamous cell carcinoma is the second most prevalent malignancy, most frequently occurring in the head and neck (head and neck cutaneous squamous cell carcinoma). Treatment of locally advanced or metastatic disease is associated with functional morbidity and disfigurement. Underlying genetic mechanisms are poorly understood. Targeted sequencing of 48 clinically relevant genes was performed on DNA extracted from formalin-fixed and paraffin-embedded high-risk primary head and neck cutaneous squamous cell carcinomas that remained non-metastatic at minimum follow-up of 24 months. Associations of somatic mutations with clinicopathologic characteristics were evaluated and compared with those described in the literature for metastatic disease. Alterations in 44 cancer-associated genes were identified. TP53 was mutated in 100% of cases APC, ATM, ERBB4, GNAQ, KIT, RB1 and ABL1 were altered in 60% of cases. FGFR2 mutations (40%) were exclusively seen in patients with perineural invasion. MLH1 mutations were exclusively seen in the two younger patients (<45 years). Lower incidences of NOTCH1 mutations were observed compared with that described in metastatic head and neck cutaneous squamous cell carcinoma in the literature. Somatic mutations susceptible to EGFR inhibitors, and other small molecular targeted therapeutics were seen in 60% of cases. This study provides insights into somatic mutations in non-metastatic, high-risk head and neck cutaneous squamous cell carcinoma and identifies potential therapeutic targets. Alterations in FGFR2 and NOTCH1 may have roles in local and distant disease progression.
Publisher: Humana Press
Date: 2011
DOI: 10.1007/978-1-61779-176-5_14
Abstract: DNA sequencing is widely used for DNA diagnostics and functional studies of genes of interest. With significantly increased sequencing outputs, manual reading of sequence results can impede an efficient and accurate analysis. Mutation Surveyor is a useful in silico tool developed by SoftGenetics that assists the detection of sequence variations within Sanger sequencing traces. This tool can process up to 400 lanes of data at a time with high accuracy and sensitivity. It can effectively detect SNPs and indels in their homozygous or heterozygous states as well as mosaicism. In this chapter, we describe the general application of Mutation Surveyor for DNA sequencing analysis and its unique features.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Springer Science and Business Media LLC
Date: 20-12-2008
DOI: 10.1007/S12033-008-9134-8
Abstract: Common complex diseases remain a major health challenge and involve the interaction of multiple genes and environmental factors. Discovering the relevant genes is difficult although it is known that disease risk can originate from the variation of an in idual's genome. Application of in silico tools can significantly improve the detection of genes and variation. Data mining and automated tracking of new knowledge facilitate locus mapping. At the gene search stage, in silico prioritization of candidate genes plays an indispensable role in dealing with linked or associated loci. In silico analysis can also differentiate subtle consequences of coding DNA variants and remains the major tool to predict potential effects of non-coding DNA variants on gene transcription and/or pre-mRNA splicing.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.JNEUMETH.2011.02.028
Abstract: Rare de novo genetic variants have been detected in a number of diseases using case-parent trios. So far, trio studies have largely been confined to early-onset diseases where parent DNA s les are readily available. To test the feasibility of finding rare de novo variants in a typical late-onset neurodegenerative disease, we compared genome-wide copy number variants (CNVs) between patients with sporadic amyotrophic lateral sclerosis (SALS) and their unaffected parents. DNA from 12 SALS patients and their 24 parents was analysed for CNVs using AffyMetrix SNP 6.0 microarrays and Partek software. De novo CNVs (present in patients but not their parents) considered likely candidates for SALS were those that overlapped with CNS-related genes, were rare, or were found in multiple patients. All SALS patients had de novo CNVs. In 11 patients, 37 de novo CNVs fulfilled one or more criteria for a candidate region. Eleven de novo CNVs overlapped with genes, some of which are in pathways suspected in the pathogenesis of SALS. In conclusion, this pilot study shows that trios can be used to look for rare de novo genetic variants in patients with late adult-onset neurodegenerative disease. The results suggest that further studies of this nature with larger numbers of trios are warranted, but it is unusual to find surviving parents of offspring who have a late-onset neurodegenerative disease. An international collaborative effort will therefore be needed to collect sufficient numbers of such trios to reliably detect de novo mutations underlying these diseases.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.PATHOL.2015.12.008
Abstract: Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713) 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.JTHO.2016.09.001
Abstract: The evolution of EGFR tyrosine kinase inhibitors (TKIs) has changed the landscape of disease for a subset of patients with NSCLC. Most patients with an EGFR mutation respond to these drugs however, a proportion show limited or no tumor response. We explored the impact of co-mutation (double or multiple mutation), compared with a single mutation, of the EGFR gene on response to TKIs in a series of patients with metastatic NSCLC. We retrospectively analyzed the mutation profiles of nonsquamous NSCLC tested at Royal Prince Alfred Hospital between 2012 and 2015 by MassArray using the OncoCarta v1.0 panel. Patients with metastatic disease whose tumors had sensitizing EGFR mutation(s) were included. The primary end point was progression-free survival (PFS). We used the Kaplan-Meier method for PFS and overall survival the log rank test was used to compare groups with and without co-mutation. Multivariable analysis was done for PFS response rate was assessed using chi-square and logistic regression analysis. A total of 62 patients were included, and of these, eight (12.9%) had a co-mutation. The median PFS and overall survival times were 11.5 and 26.3 months, respectively. Patients with EGFR co-mutation had a significantly shorter median PFS than those with a single mutation (5.7 months versus 12.3 months, p = 0.02). The response rate to TKIs was significantly worse in those with co-mutation compared with in those without co-mutation (38% versus 89%, p < 0.001). Taking into account the small number of patients in this study, PFS in patients with EGFR co-mutation appeared significantly shorter, and response rate significantly lower, than in patients with a single mutation. Data from multipanel testing may identify subgroups of patients who are likely to respond poorly to standard treatment. Clarification of these subgroups may improve patient care.
Publisher: Mary Ann Liebert Inc
Date: 09-2007
Abstract: Single nucleotide polymorphisms (SNPs) can contribute to genetic predispositions or serve as genetic markers that are associated with complex diseases. So far, a few SNP arrays containing a limited number of SNPs have been used in routine genetic testing. This study described an oligochip-based method that genotypes two SNPs (-511 and -31) in the promoter region of the interleukin (IL)-1 beta gene. The sensitivity of this SNP genotyping method is derived from polymerase chain reaction (PCR)- lified allele-specific primer-probes with a biotin label incorporated from the reverse primers. The lified primer-probes can specifically hybridize with the oligonucleotides that are spotted on the oligochip. This oligochip-based method successfully discriminated the two biallelic SNPs with 9 different genotypes and all the genotyping results are in concordance with those from PCR restriction fragment length polymorphism (RFLP) analysis. Selective s les with various genotypes were also confirmed by direct sequencing. This method was applied in the genotyping of the patients with tuberculosis or gastric cancer and healthy controls. In the case control study, our genotyping data supported the reported association between gastric cancer and the genotypes of IL-1 beta -31 TT and -511 CC (p < 0.05). We also found that there is a significant difference of IL-1 beta -31 genotypes between 98 tuberculosis patients and healthy controls (p < 0.002). All of our results demonstrated that the oligochip can effectively and accurately identify SNP genotypes in the IL-1 beta promoter region.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1016/J.NEURO.2006.11.007
Abstract: Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene-environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms -909c>g, -832g>a, -162g>a and -108c>t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele -108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene-environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.
Publisher: Wiley
Date: 08-08-2011
DOI: 10.1002/MUS.22095
Abstract: Most analyses of blood DNA in sporadic neuromuscular disorders have been inconclusive. This may be because some genetic variants occur only in brain tissue. We therefore looked for copy number variants (CNVs) in both blood and brain in patients with sporadic amyotrophic lateral sclerosis (SALS). Genome-wide CNVs were compared in blood and brain from 32 SALS patients and from 26 normal (control) brains, using Affymetrix 6.0 arrays. There were 410 CNVs present in brain but not blood (somatic CNVs) in 94% of the patients (median 8 CNVs per patient). Twenty-four of the somatic CNVs were rare, were not found in control brains, and overlapped with genes. Brain-specific CNVs may be common and appear to be present in a proportion of patients with SALS. The more detailed copy number analysis that is becoming available with massively parallel sequencing may uncover brain-specific CNVs that underlie some cases of SALS.
Publisher: Informa UK Limited
Date: 2009
DOI: 10.3109/17482960802635397
Abstract: Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients have causative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, an epigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10 SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated by Affymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controls at each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylation sites (p </= 0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that genes with different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidative stress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed altered methylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initial results in a future larger whole-genome DNA methylation study.
Publisher: Wiley
Date: 05-2004
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.LUNGCAN.2015.05.007
Abstract: Immune checkpoint blockade using inhibitors of programmed death-1 have shown promise in early phase clinical trials in NSCLC and programmed death-ligand 1 (PD-L1) tumoral expression could potentially be a useful predictive marker. Data reporting the prevalence of PD-L1 expression in NSCLC and clinicopathologic associations is very limited. We sought to determine the frequency of PD-L1 expression in NSCLC and investigate associations with clinicopathologic features and patient outcome. PD-L1 expression was analyzed using immunohistochemistry (Merck clone 22C3) in 678 stages I-III NSCLC and 52 paired nodal metastases using tissue microarrays. Tumors with ≥50% cells showing positive membrane staining were considered to have high expression of PD-L1. PD-L1 expression of any intensity was identified in 32.8% of cases. High PD-L1 expression was found in 7.4% of NSCLC. Squamous cell carcinomas (8.1%) and large cell carcinomas (12.1%) showed high PD-L1 expression more commonly than adenocarcinomas (5.1%) but this was not statistically significant (p=0.072). High PD-L1 expression was associated with younger patient age and high tumor grade (p<0.05). There was no association with gender, tumor size, stage, nodal status, EGFR or KRAS mutation status. In multivariate analysis, patients with high PD-L1 expression had significantly longer overall survival (p<0.05). PD-L1 is expressed at high levels in a significant proportion of NSCLC and appears to be a favorable prognostic factor in early stage disease. As there are potential s ling limitations using tissue microarrays to assess heterogeneously expressed biomarkers, and as the results may differ in advanced stage disease, further studies are recommended.
Publisher: Public Library of Science (PLoS)
Date: 19-07-2013
Publisher: Informa UK Limited
Date: 03-2004
Abstract: DNA testing was first used in the late 1970s. Today, the indications for a DNA test have expanded to include predicting the development of genetic disorders, screening populations, confirming clinical diagnoses, prenatal testing and DNA testing to in idualize medical treatment. Apart from the wide range of indications, the next few years will see a great expansion in the number of DNA tests. This will be driven by information generated from the Human Genome Project. Improved technology will make DNA testing more accessible. In this climate, the challenges will be considerable, particularly in relation to education. The avoidance of ethical, legal and social dilemmas will require informed and wise input from professionals and the community.
Publisher: Informa UK Limited
Date: 09-2006
DOI: 10.1128/MCB.00739-06
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.PARKRELDIS.2011.08.024
Abstract: Sporadic Parkinson's disease (PD) is thought to have a major genetic component, but the variants involved remain mostly unknown. One possible reason for the difficulty in finding mutations underlying PD is that rare predominantly brain-situated somatic mutations underlie the disease these mutations would be missed by analysing blood DNA only. To test the feasibility of looking for somatic mutations in PD brain tissue, we compared copy number variants (CNVs) between 8 PD and 26 control brains using Affymetrix 6.0 arrays. The median number of CNVs per brain, and the overall proportion of lifications and deletions, were similar in PD and control brains. In 7 of the 8 PD brains, however, a total of 45 CNVs were found that were not present in control brains. Twelve of these CNVs overlapped with one or more genes, some of which are involved in pathways suspected in the pathogenesis of PD, or are rare. This study shows that PD brain CNVs can be detected, and raises the possibility that brain-situated mutations could underlie some cases of PD. A method of undertaking a definitive study of brain somatic mutations in PD, using massively parallel sequencing and multiple tissues, is suggested.
Publisher: Springer Science and Business Media LLC
Date: 29-07-1998
Abstract: Genetic markers that might contribute to the making of an elite athlete have not been identified. Potential candidate genes might be found in the renin-angiotensin pathway, which plays a key role in the regulation of both cardiac and vascular physiology. In this study, DNA polymorphisms derived from the angiotensin converting enzyme (ACE), the angiotensin type 1 receptor (AT1) and the angiotensin type 2 receptor (AT2) were studied in 64 Australian national rowers. Compared with a normal population, the rowers had an excess of the ACE I allele (P<0.02) and the ACE II genotype (P=0.03). The ACE I allele is a genetic marker that might be associated with athletic excellence. It is proposed that the underlying mechanism relates to a healthier cardiovascular system.
Publisher: Mary Ann Liebert Inc
Date: 12-2005
Abstract: Human leukocyte antigen (HLA) has been associated with Behcet's disease (BD), among which HLA-B51 is the most strongly associated genetic marker. The sandwich hybridization technique was applied in the design of the specific oligonucleotide probes to ensure the specific and accurate results. The probe-spotted chip was hybridized with the polymerase chain reaction (PCR) licons including nine suballeles (B*5101-B*5109) of exons 2 and 3 of HLA-B51 gene to determine the HLA-B51 genotypes. The results were subsequently confirmed by (PCR-SSP) and sequencing and were identical to those from polymerase chain reaction-sequencing specific primers (PCR-SSP) in 27 patients with BD and 30 healthy controls. This suggests that we successfully developed the oligochip for Behcet's-associated gene HLA-B51, which can effectively and accurately identify the HLA-B51 genotypes.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Hindawi Limited
Date: 20-03-2013
DOI: 10.1002/HUMU.22183
Publisher: Springer Science and Business Media LLC
Date: 23-04-1998
Abstract: Angelman syndrome (AS) is a rare neurodevelopmental disorder. Recently, several mutations have been found in the E6-AP ubiquitin protein ligase gene (UBE3A) in a group of patients who are nondeleted and do not have uniparental disomy or imprinting defects. Most of the reported mutations cluster within exons 9 or 16 of the UBE3A gene, and nearly all are predicted to give rise to truncated E6-AP ligases. Here, we describe two AS patients with dissimilar phenotypes. At the molecular level, they are both nondeleted, do not display uniparental disomy, and have normal imprint patterns. One has the typical AS phenotype and carries the previously reported 1344delAG de novo mutation involving a functionally significant region of UBE3A. The other expresses an atypical phenotype in that she has less severe ataxia, no inappropriate laughing, or epilepsy, and her EEG was normal at an early age. A 14-bp deletion in the 3' untranslated region of exon 16 (3'UTRdel14) adjacent to the poly(A) signal was identified. Further investigation revealed that the DNA change was a neutral polymorphism. Haplotype analysis indicated that both the AS patient and her normal sibling had inherited the same maternal UBE3A gene and its 5' flanking region. Although the 14-bp change has no functional significance, it assists with counseling to determine future risks of recurrence in this family.
Publisher: Wiley
Date: 15-11-2016
DOI: 10.1111/HIS.13076
Publisher: Cambridge University Press (CUP)
Date: 10-2004
DOI: 10.1017/S1047951104005062
Abstract: Neonatal cardiac hypertrophy associated with diabetic pregnancy is transient and regresses naturally, but is associated with increased morbidity and mortality. This study was undertaken to analyse the changes in expression of 5 cardiac genes, including atrial natriuretic peptide, α- and β-myosin heavy chain, and cardiac and skeletal α-actin genes, using a rat neonatal model, in which cardiac hypertrophy was induced via maternal diabetes. In the hypertrophied left ventricle of neonates from diabetic mothers, the levels of mRNA from all the above genes except skeletal α-actin were increased by between 1.8- and 12-fold compared with the controls at birth (p 0.05). In the first 28 days, the level of mRNA for α-myosin heavy chain increased slightly, while that for atrial natriuretic peptide and β-myosin heavy chain decreased continuously similar to the controls, but at a significantly faster rate. No significant difference between the two groups of neonates was observed in all 5 genes after 1 month, indicating complete regression. Expression of 5 cardiac genes in the neonatal cardiac hypertrophy was characterised in both hypertrophic and regressive phases. Hypertrophic regression provides a unique model for the testing of new drugs or genetic modifying factors in cardiac hypertrophy.
Publisher: Wiley
Date: 02-2011
Publisher: BMJ
Date: 12-02-2013
DOI: 10.1136/JCLINPATH-2012-201082
Abstract: Phyllodes tumours (PTs) of the breast are true biphasic neoplasms within which interactions between the epithelium and stroma are critical for tumour development and progression. Despite numerous studies reporting the results of ancillary marker investigations in PTs, the current histological grading systems remain unreliable at predicting clinical outcome even when supplemented by these markers. As a consequence, there has been much interest in the prospect of using molecular/genetic techniques to develop a more robust "grading" system. This review focuses on recent cytogenetic and molecular studies investigating the pathogenesis of PTs and those correlating molecular findings with clinicopathological features of the tumours. Recent data highlight that intratumoural genetic heterogeneity is common in PTs and may account for the reported lack of correlation between histological grading and clinical behaviour. The entire spectrum of molecular aberrations in PTs are yet to be fully defined, however recent array-based studies using comparative genomic hybridisation have reported that copy number changes increase with the progression from benign PT to malignancy. Tumour recurrence and progression is likely to reflect the presence of under-recognised subclones. p(16INK4a) (CDKN2A) inactivation also appears to be important in PT pathogenesis. Further additional studies will be required to identify and validate new prognostic markers and therapeutic targets in order to improve the diagnosis, classification, prediction of outcome and management of patients with this rare neoplasm. Data generated from modern sequencing technologies are likely to provide new insights into the disease and assist in this endeavour.
Publisher: Public Library of Science (PLoS)
Date: 17-11-2010
Publisher: Springer Science and Business Media LLC
Date: 10-08-2016
DOI: 10.1038/NCOMMS12353
Abstract: Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. A long-standing open question is why the same causal porphyria mutations exhibit widely variable penetrance and expressivity in different in iduals. Here we show that severely affected porphyria patients harbour variant alleles in the ABCB6 gene, also known as Lan , which encodes an ATP-binding cassette (ABC) transporter. Plasma membrane ABCB6 exports a variety of disease-related porphyrins. Functional studies show that most of these ABCB6 variants are expressed poorly and/or have impaired function. Accordingly, homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes in the Fech m1Pas mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury. Collectively, these studies support ABCB6 role as a genetic modifier of porphyria and suggest that porphyrin-inducing drugs may produce excessive toxicities in in iduals with the rare Lan(−) blood type.
Publisher: Springer Science and Business Media LLC
Date: 08-2002
DOI: 10.1007/S00249-002-0236-0
Abstract: Familial hypertrophic cardiomyopathy is an autosomal dominant genetic disorder caused by mutations in cardiac sarcomeric proteins. One such mutation is a six amino acid duplication of residues 1248-1253 in the C-terminal immunoglobulin domain of cardiac myosin binding protein-C, referred to as Motif X. Motif X binds the myosin rod and titin. Here we investigate the structural and functional alteration in the mutant Motif X protein to understand how sarcomeric dysfunction may occur. The cDNA encoding Motif X was cloned, mutated and expressed as wild-type and mutant proteins in a bacterial expression system. Circular dichroism spectroscopy confirmed that the normal and mutant Motif X exhibited a high beta-content, as predicted for immunoglobulin domains. Thermal denaturation curves showed that Motif X unfolded with at least two structural transitions, with the first transition occurring at 63 degrees C in the wild-type but at 40 degrees C in the mutant, consistent with the mutant being structurally less stable. Sedimentation binding studies with synthetic myosin filaments revealed no significant difference in binding to myosin between the wild-type and the mutant Motif X. Molecular modeling of this duplication mutation onto an homologous IgI structure (telokin) revealed that the duplicated residues lie within the F strand of the immunoglobulin fold, on a surface of Motif X distant from residues previously implicated in myosin binding. Taken together, these data suggest that the Motif X mutation may interfere with other, as yet unidentified, functional interactions.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.PLACENTA.2005.05.003
Abstract: The placenta is pivotal in the acceptance of the feto-placental unit by the maternal immune system. Imbalance at the maternal-fetal interface of tissue pro- and anti-inflammatory cytokines may be partly involved in disease causation. Previous work has shown conflicting levels of IL-10. IL-10 levels have been shown to increase, decrease, or remain unchanged in women with preecl sia. This study examines the difference in serum and placental IL-10 expression in women with preecl sia and investigates if the IL10 (-1082) A promoter polymorphism contributes to lower concentrations. In a prospective case-control study of 12 women with preecl sia and 31 controls we assessed serum IL-10 by ELISA, placental mRNA by quantitative PCR and protein by immunohistochemistry as well as placental IL10 promoter genotype. Comparisons were made with non-parametric tests where necessary and chi-square. We found a significant reduction in placental IL-10 mRNA and protein expression in women with preecl sia compared to controls. Women with the AA IL-10 promoter genotype expressed less placental IL-10 mRNA compared to women with AG or GG genotype. There was no difference in serum IL-10 concentrations between different genotypes. Preecl sia is associated with a deficiency of placental IL-10. Placental AA genotype in the promoter region results in significantly less placental IL-10.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Wiley
Date: 24-12-2015
DOI: 10.1002/HED.24332
Abstract: Accurate diagnosis of salivary duct carcinoma requires a high index of suspicion and clinicopathologic correlation. Hallmark genetic changes that may provide novel therapeutic options are being explored. One hundred ninety salivary gland malignancies at Royal Prince Alfred Hospital (from 1989-2014) were reviewed. Human epidermal growth factor receptor 2 (HER2) and androgen receptor status were determined along with multigene profiling. Twenty-three salivary duct carcinomas were identified, predominantly in men in their fifth to ninth decades of life. Facial nerve palsy (12%) and cervical lymph node metastases (82%) were present, and 96% received postoperative adjuvant therapy. Histologically, the tumors resembled high-grade invasive and in situ ductal carcinoma of the breast. Micropapillary, papillary, sarcomatoid, oncocytic, and mucinous variants were seen. The tumors showed androgen receptor (70%), HER2 lification (30%), and HRAS, AKT1, PIK3CA, and NRAS mutations (22% cumulative). The 5-year disease-free survival was 36%. Salivary duct carcinoma demonstrates a wide histopathologic spectrum. Treatment strategies need to take androgen receptor, HER2 lification, and PIK3CA mutation into account. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1838-E1847, 2016.
Publisher: Wiley
Date: 14-05-2007
DOI: 10.1002/AJMG.B.30543
Abstract: Environmental toxicants such as heavy metals, pesticides, and chemicals appear to be risk factors for sporadic amyotrophic lateral sclerosis (SALS). An impaired ability to break down these toxicants because of differences in detoxification genes could underlie some cases of this disease. We therefore examined the frequencies of single nucleotide polymorphisms (SNPs) in 186 SALS patients and 186 controls at the allele, genotype, and haplotype levels for the metallothionein (MT) family of genes, metal transcription factor-1 (MTF-1), and glutathione synthetase (GSS). Exposure to heavy metals, solvents/chemicals, and pesticides/herbicides was assessed by questionnaire, and gene-toxicant interactions were analyzed. An intronic SNP upstream of MT-Ie differed in SALS patients and controls at the allele and genotype levels. Haplotypes covering MT-I isoforms also differed between the two groups. Alleles and genotypes of one MTF-1 SNP differed in female SALS patients. One GSS haplotype interacted with both metals and solvents/chemicals to increase the risk of the disease. Differences in genes involved in handling toxicants, and interactions between toxicants and these genes, appear to be present in some patients with SALS. This suggests that impaired detoxification mechanisms play a role in SALS.
Publisher: The Endocrine Society
Date: 10-2008
DOI: 10.1210/JC.2008-0161
Abstract: Context: Several genome-wide association studies identified a strong association of SLC30A8 with type 2 diabetes in in iduals of European ancestry. The effect of the association of rs13266634 with type 2 diabetes or related glycemic traits has not been fully extended to non-European populations, and a comprehensive examination of common variants in the gene has not yet been carried out in Han Chinese. Objective: The objective of the study was to investigate the association of SLC30A8 with type 2 diabetes in Chinese. Design: A comprehensive gene-based association study was performed using 14 tagging single-nucleotide polymorphism (SNPs) of SLC30A8 in Han Chinese subjects with normal glucose tolerance (NGT n = 721), impaired glucose regulation (IGR n = 375), and type 2 diabetes (n = 521). Results: A significant association for SNP rs13266634 was observed between patients with type 2 diabetes and NGT controls (P = 0.016). The association was also observed between combined type 2 diabetes/IGR and NGT subjects (P = 0.002). The adjusted odds ratios for homozygote CC vs. TT at this locus were 1.71 for type 2 diabetes (95% confidence interval 1.19–2.45, P = 0.002) and 1.77 for type 2 diabetes and IGR (95% confidence interval 1.29–2.42, P = 0.0001). We further studied the genotype-phenotype correlation in 70 Han Chinese using iv glucose tolerance test and found an association between SNP rs13266634 and acute insulin response to glucose and disposition index (adjusted P = 0.012 and 0.004, respectively). Conclusions: Our results provide evidence that SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion.
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
Publisher: Informa UK Limited
Date: 06-2006
DOI: 10.1080/10284150600903594
Abstract: ST8Sia IV (polysialyltransferase IV gene) encodes a key enzyme that is required for polysialic acid synthesis. Polysialic acid is a component of the neural cell adhesion molecule and is necessary for synaptic plasticity of neural cells. We characterized 5.3 kb of pig ST8Sia IV cDNA and determined its expression profile in different organs. In hippoc us, ST8Sia IV mRNA levels were increased approximately 4.5-fold in piglets with sialic acid as a milk supplement, which suggested that exogenous sialic acid is a conditionally essential nutrient for early brain development. Extensive analyses were also performed among its orthologs from human, mouse, rat, chicken, frog and zebrafish. Our results supported that the piglet is a better animal model than other nonprimate species in the studies of ST8Sia IV related metabolism and nutrition in human infants. This pig cDNA provides a basis for uncovering the roles of ST8Sia IV during piglet development and maturation.
Publisher: Springer Science and Business Media LLC
Date: 13-12-2012
DOI: 10.1038/HR.2012.195
Publisher: Humana Press
Date: 2011
DOI: 10.1007/978-1-61779-176-5_6
Abstract: In silico PCR analysis is a useful and efficient complementary method to ensure primer specificity for an extensive range of PCR applications from gene discovery, molecular diagnosis, and pathogen detection to forensic DNA typing. In silico PCR, SNPCheck, and Primer-BLAST are commonly used web-based in silico PCR tools. Their applications are discussed here in stepwise detail along with several ex les, which aim to make it easier for the intended users to apply the tools. This virtual PCR method can assist in the selection of newly designed primers, identify potential mismatches in the primer binding sites due to known SNPs, and avoid the lification of unwanted licons so that potential problems can be prevented before any "wet bench" experiment.
Publisher: KARGER
Date: 2009
DOI: 10.1159/000235705
Abstract: Genetic research is used to identify the relative contributions made by inherent abilities (nature) versus environmental effects (nurture) in human performance. The same approach allows a better understanding of how injuries or illnesses can result from sport or physical activity. Having identified the genes involved in athletic performance, there are the intriguing possibilities of using this information for talent search, developing in idualized training programs and prevention of sports-related injuries. There are many interacting genes involved in athletic performance. This class of genes is often described as 'complex' and the mode of inheritance is called 'multifactorial'. Discovery of these genes is difficult using the conventional case control (association) studies. Recent genomic-based developments allowing high throughput SNP analysis are very promising. Potentially more exciting is the availability in the near future of cheaper and faster whole-genome sequencing technologies. Genetic research in exercise science has produced a lot of data including the ability to draw a human exercise gene map. However, progress at the genetic level has been slow because gene-based association studies are not powerful enough to detect multiple small but cumulative gene effects. In future, the more efficient genomic-based research approaches will accelerate the finding of 'sports genes'. Data generated will be enormous, making it essential to have a direct link between the laboratory researcher and bioinformatics expertise. Genetics research has moved to the genomics era, i.e. the simultaneous testing of multiple genes is now possible.
Publisher: Wiley
Date: 05-2003
DOI: 10.1046/J.1440-1681.2003.03844.X
Abstract: 1. The aim of the present study was to investigate whether pre‐ecl isa, a state of placental hypoxia, is associated with placental abnormalities in the amount, distribution and expression of enothelial nitric oxide synthase (eNOS). 2. Localization and intensity of eNOS was determined by immunohistochemistry using an antibody specific for eNOS. The amount of eNOS mRNA expression was determined by reverse transcription–polymerase chain reaction (RT‐PCR) and the densitometry of gel bands was expressed as a ratio of the band density of the housekeeping gene β 2 ‐microglobulin. 3. Endothelial NOS staining was localized to syncytiotrophoblast cells within the villi and decidual trophoblast cells. It was not present in the endothelium of terminal villous vessels. There was no significant difference in eNOS villous or decidual staining intensity between normal pregnancy (NP n = 12), pre‐ecl sia ( n = 14), or gestational hypertension (GH n = 4). Staining for eNOS was not significantly different in the decidua compared with the villi in NP, GH or pre‐ecl sia. Within the decidua, the depth of eNOS staining was similar in NP, pre‐ecl isa and GH. 4. There was no significant difference in eNOS mRNA expression between NP (0.70 ± 0.11), pre‐ecl sia (0.5 ± 0.07) or GH (0.69 ± 0.26). 5. These findings suggest that the amount of eNOS in the placenta is not deficient in pre‐ecl sia, excluding a possible pathogenic role for eNOS in this disease. Furthermore, placental hypoxia, which is associated with pre‐ecl sia, did not induce an upregulation of eNOS
Publisher: Springer Science and Business Media LLC
Date: 05-09-2017
Abstract: Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access Array™ System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA EGAS00001002200). Herein, we present analyses of this dataset using HaplotypeCaller and MuTect2 through the Broad Institute’s Genome Analysis Toolkit (GATK). We anticipate that this TP53 mutation dataset will be useful to researchers developing and testing new software to accurately determine high and low frequency variant alleles in heterogeneous aneuploid tumor tissue. Furthermore, the analysis pipeline we present provides a valuable framework for determining somatic variants more broadly in tumor tissue.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1080/00313020600561534
Abstract: Gender can influence many cardiovascular events, including cardiac hypertrophy. The presence of and dynamic changes involving androgen receptor (AR) gene expression are important confirmatory findings for androgen modulation in the pathogenesis of cardiac hypertrophy. To determine AR expression profile during neonatal hypertrophy and its regression process using a rat model. Relative mRNA levels of the AR gene were quantified at postnatal days 1, 7, 14, 21 and 28 using real time PCR. A significant 10.6-fold decrease in AR transcription levels was observed at birth in neonates with cardiac hypertrophy (p < 0.05). Our analysis also showed a significant increase in AR mRNA levels at day 28, corresponding with regression of cardiac hypertrophy. The AR gene demonstrated a noteworthy trend in its expression pattern. The initial down-regulation was most likely the result of increased testosterone levels induced by hyperinsulinaemia and hypoglycaemia, which were present in neonates from diabetic mothers during pregnancy. The paradoxical increase in AR at day 28 suggested a potential long term-effect of the in utero diabetic environment.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2005
DOI: 10.1007/S00439-005-0066-0
Abstract: EPAS1 is a gene involved in complex oxygen sensing. It is expressed in microvascular endothelial cells, lung epithelial cells, cardiac myocytes and the brain. An association study was undertaken comparing elite endurance athletes classified into two groups according to a power-time model of performance intensity: power-time-maximum (PT-MAX N=242, event duration 50 s to 10 min) and power-time-steady state (PT-SS N=151, event duration ~2-10 h), with normal controls (N=444) using 12 SNPs across EPAS1. Ordinal regression analysis of allele frequencies revealed significant differences at SNPs 2 and 3 (P=0.01). Haplotype analysis revealed the presence of haplotypes involving SNPs 2-5 that significantly differentiated (P<0.05) the groups based on an ordinal ranking using the power-time classification. These same haplotypes differentiated the PT-MAX group in which a significant decrease in a haplotype (F: G-C-C-G OR=0.57, P=0.02, 95% CI 0.36-0.92) and increase in a second haplotype (G: A-T-G-G OR=1.75, P=0.03, 95% CI 1.05-2.91) was observed compared to controls. The PT-SS group was differentiated from the PT-MAX group by a third haplotype (H: A-T-G-A OR=0.46, P=0.04, 95% CI 0.22-0.96). Since EPAS1 has a role as a sensor capable of integrating cardiovascular function, energetic demand, muscle activity and oxygen availability into physiological adaptation, we propose that DNA variants in EPAS1 influence the relative contribution of aerobic and anaerobic metabolism and hence the maximum sustainable metabolic power for a given event duration.
Publisher: Springer New York
Date: 2014
DOI: 10.1007/978-1-4939-0847-9_11
Abstract: The introduction of next-generation sequencing (NGS) technologies in research has proven to be very successful in the past 8 years. Now, there is considerable demand to apply these technologies for clinical diagnosis. The translation of research-to-clinical practice brings with it a unique set of challenges, particularly when it comes to setting up NGS in the medical laboratory. The practical issues related to infrastructure, selecting which NGS platform, and dealing with informatics requirements are discussed. Application of NGS for clinical diagnosis requires robust quality assurance at multiple levels including s le assessment, library preparation, template generation, and sequencing data which need to be generated, analyzed, and stored. The requirements for data generation, analysis, and storage are considerable.
Publisher: Elsevier BV
Date: 1997
DOI: 10.1080/00313029700169155
Abstract: Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disorder characterised predominantly by left ventricular hypertrophy and sudden cardiac death. Mutations in the cardiac beta-myosin heavy chain gene have been identified in several families and designated as "benign" or "malignant". We describe a family (family L) with a "benign" mutation in which early sudden cardiac death has occurred. The family was studied by clinical, electrocardiographic and echocardiographic assessment. DNA analysis involved screening for the six most common cardiac beta-myosin heavy chain gene mutations using allele specific oligonucleotide probes and restriction enzyme analysis. The Val606Met missense mutation was found. This mutation has been described in four families as being "benign" since it was associated with low penetrance and a near normal life span. Sudden cardiac death was an infrequent finding. In contrast, family L has a more malignant clinical picture with one sudden death in three affected in iduals. The proband died suddenly at age 14 years during exercise. Designating gene mutations in FHC as benign or malignant has major clinical implications. As these mutations have only been described in a limited number of families, caution needs to be taken when interpreting genotype-phenotype correlations in this disorder.
Publisher: Oxford University Press (OUP)
Date: 05-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-06-2012
Publisher: BMJ
Date: 12-08-2014
DOI: 10.1136/JCLINPATH-2014-202347
Abstract: Insulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase membrane receptor involved in tumourigenesis that may be a potential therapeutic target. We aimed to investigate the incidence and prognostic significance of alterations in IGF1R copy number, and IGF1R protein expression in resected primary non-small cell lung cancer (NSCLC), and lymph node metastases. IGF1R gene copy number status was evaluated by chromogenic silver in situ hybridisation and IGF1R protein expression was evaluated by immunohistochemistry in tissue microarray sections from a retrospective cohort of 309 surgically resected NSCLCs and results were compared with clinicopathological features, including EGFR and KRAS mutational status and patient survival. IGF1R gene copy number status was positive (high polysomy or lification) in 29.2% of NSCLC, and 12.1% exhibited IGF1R gene lification. High IGF1R expression was found in 28.3%. There was a modest correlation between IGF1R gene copy number and protein expression (r=0.2, p .05). Alterations of IGF1R gene copy number and protein expression in primary tumours were significantly associated with alterations in lymph node metastases (p .01). High IGF1R gene copy number and protein expression was significantly higher in squamous cell carcinomas (SCC) compared with other subtypes of NSCLC (p .05). There were no other associations between IGF1R status and other clinicopathological features including patient age, gender, smoking status, tumour size, stage, grade, EGFR or KRAS mutational status or overall survival. High IGF1R gene copy number and protein overexpression are frequent in NSCLC, particularly in SCCs, but they are not prognostically relevant.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2017
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/14660820410021249
Abstract: Metallothioneins are proteins involved in antioxidant defence, essential metal homoeostasis and heavy metal detoxification, all mechanisms implicated in sporadic amyotrophic lateral sclerosis (SALS). We therefore looked for changes in the gene for nervous system-specific metallothionein III (MT3) that might explain susceptibility to SALS. DNA was extracted from 87 sporadic ALS and 174 matched controls. The gene for MT3 was sequenced in 20 SALS and 5 control subjects to identify single nucleotide polymorphisms (SNPs). These SNPs were then screened in all subjects. Eight novel SNPs were found in the 5' untranslated region and intron 2 of MT3. No differences were found in the frequency distribution of alleles or haplotypes for these SNPs between the SALS and control groups. The genotype distribution of one SNP (A1422C) was significantly different between ALS and control groups (p<0.02) but this is not likely to be biologically relevant. We conclude that changes in the MT3 gene are unlikely to be responsible for susceptibility to SALS.
Publisher: Elsevier BV
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 10-06-2014
DOI: 10.1038/BJC.2014.287
Publisher: Springer Science and Business Media LLC
Date: 17-01-2013
DOI: 10.1007/S00125-012-2818-4
Abstract: Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease (PAD). However, the relationship between bilirubin and lower-limb utation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb utation. The relationship between baseline plasma total bilirubin levels and utation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb utation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint. Bilirubin concentrations were significantly inversely associated with lower-limb utation, with a greater than threefold risk gradient across levels. In iduals with lower bilirubin concentrations had a higher risk for first utation (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79, p = 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, γ-glutamyltransferase level, HbA1c, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, utation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81, p = 0.019). Our results identify a significant inverse relationship between bilirubin levels and total lower-limb utation, driven by major utation. Our data raise the hypothesis that bilirubin may protect against utation in type 2 diabetes.
Publisher: Elsevier BV
Date: 10-01-2007
DOI: 10.1016/J.TOXLET.2006.11.003
Abstract: Sporadic amyotrophic lateral sclerosis (SALS) results from the death of motor neurons in the brain and spinal cord. Environmental exposure to heavy metals has been implicated in SALS and impaired detoxification of these metals may cause susceptibility to the disease. The metallothionein (MT) family of proteins are the primary detoxification mechanism for heavy metals and MT-Ia and MT-IIa are the most common human isoforms. Inappropriate methylation at the promoters of these genes could lead to silencing of transcription and reduce the availability of MTs. We therefore measured the level of methylation in the promoters of MT-Ia and MT-IIa in 25 leukocyte and six brain DNA s les from SALS patients and compared these with controls. No promoter methylation was evident in any SALS or control s les. In conclusion, it is unlikely that methylation at these gene promoters is a common cause of SALS.
No related grants have been discovered for Bing Yu.