Publications by authors named "Peter J Wilson"

45 Publications

Expression of tyrosine pathway enzymes in mice demonstrates that homogentisate 1,2-dioxygenase deficiency in the liver is responsible for homogentisic acid-derived ochronotic pigmentation.

JIMD Rep 2021 Mar 12;58(1):52-60. Epub 2020 Nov 12.

Department of Musculoskeletal & Ageing Science, Institute of Life Course and Medical Science University of Liverpool Liverpool United Kingdom.

Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase (HGD) deficiency. This study aimed to determine if HGD and other enzymes related to tyrosine metabolism are associated with the location of ochronotic pigment. Liver, kidney, skin, bone, brain, eyes, spleen, intestine, lung, heart, cartilage, and muscle were harvested from 6 AKU BALB/c (3 females, 3 males) and 4 male C57BL/6 wild type (WT) mice. , 4-hydroxyphenylpyruvate dioxygenase (-), tyrosine hydroxylase (), and tyrosinase () mRNA expression was investigated using qPCR. Adrenal gland and gonads from AKU mice were stained, followed by qPCR analysis of mRNA. The liver had the highest expression of , followed by the kidney, with none detected in cartilage or brain. Low-level expression was observed within developing male germ cells within the testis and epididymis in . 4- was most abundant in liver, with smaller amounts in kidney and low-level expression in other tissues. was expressed mainly in brain and was found primarily in the eyes. The tissue distribution of both and 4- suggest that ochronotic pigment in AKU mice is a consequence of enzymes within the liver, and not from enzymatic activity within ochronotic tissues. Excessive accumulation of HGA as ochronotic pigment in joints and other connective tissues originates from the circulation and therefore the extracellular fluid. The tissue distribution of both and suggests that these enzymes are not involved in the formation of HGA-derived ochronotic pigment.
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http://dx.doi.org/10.1002/jmd2.12184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932868PMC
March 2021

Anatomical Distribution of Ochronotic Pigment in Alkaptonuric Mice is Associated with Calcified Cartilage Chondrocytes at Osteochondral Interfaces.

Calcif Tissue Int 2021 02 14;108(2):207-218. Epub 2020 Oct 14.

Department of Musculoskeletal & Ageing Science, Institute of Life Course and Medical Science, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool, L7 8TX, UK.

Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl's staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd, Hgd tm1a), using Schmorl's staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation.
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http://dx.doi.org/10.1007/s00223-020-00764-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820185PMC
February 2021

Reversal of ochronotic pigmentation in alkaptonuria following nitisinone therapy: Analysis of data from the United Kingdom National Alkaptonuria Centre.

JIMD Rep 2020 Sep 22;55(1):75-87. Epub 2020 Jun 22.

Institute of Ageing and Chronic Disease, Musculoskeletal Biology I, William Henry Duncan Building Liverpool UK.

Background: Increased homogentisic acid (HGA) causes ochronosis. Nitisinone decreases HGA. The aim was to study the effect of nitisinone on the ochronosis progression.

Methods: Photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at V-1 (pre-baseline visit), V0 (baseline visit when 2 mg nitisinone was commenced), and yearly at V1, V2, and V3 visits. Photographs were inspected for evolution of ochronotic pigment and also scored categorically to derive eye, ear, and combined ochronosis scores. An ear cartilage biopsy was also carried out at V0 and one year after V3 (V4) and ochronotic pigment was assessed and quantitated. Visits were compared for changes in pigment. Fasting blood and 24-hour urine samples were collected for measurement of HGA.

Results: There were 80 AKU patients at V0, and 52, 47, and 40 at V1, V2, and V3 in the group with variable numbers (VAR Group) respectively; 23 patients attended once before V0, in the V-1 visit. Photographs of patients show increase in eye pigment between V-1 and V0, followed by decrease post-nitisinone at V1, V2, and V3. Ear and combined ochronosis semiquantitative scoring showed an increase between V-1 and V0 ( < .01), followed by a decrease at V1, V2, and V3, in the VAR group ( < .01). Ochronotic pigment in ear biopsy between V0 and V4 showed a 19.1% decrease ( < .05).

Conclusions: Nitisinone decreases HGA and partially reverses ochronosis.
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http://dx.doi.org/10.1002/jmd2.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463057PMC
September 2020

Seed size, number and strategies in annual plants: a comparative functional analysis and synthesis.

Ann Bot 2020 11;126(7):1109-1128

Department of Archaeology, The University, Sheffield, UK.

Background And Aims: Plants depend fundamentally on establishment from seed. However, protocols in trait-based ecology currently estimate seed size but not seed number. This can be rectified. For annuals, seed number should simply be a positive function of vegetative biomass and a negative function of seed size.

Methods: Using published values of comparative seed number as the 'gold standard' and a large functional database, comparative seed yield and number per plant and per m2 were predicted by multiple regression. Subsequently, ecological variation in each was explored for English and Spanish habitats, newly calculated C-S-R strategies and changed abundance in the British flora.

Key Results: As predicted, comparative seed mass yield per plant was consistently a positive function of plant size and competitive ability, and largely independent of seed size. Regressions estimating comparative seed number included, additionally, seed size as a negative function. Relationships differed numerically between regions, habitats and C-S-R strategies. Moreover, some species differed in life history over their geographical range. Comparative seed yield per m2 was positively correlated with FAO crop yield, and increasing British annuals produced numerous seeds. Nevertheless, predicted values must be viewed as comparative rather than absolute: they varied according to the 'gold standard' predictor used. Moreover, regressions estimating comparative seed yield per m2 achieved low precision.

Conclusions: For the first time, estimates of comparative seed yield and number for >800 annuals and their predictor equations have been produced and the ecological importance of these regenerative traits has been illustrated. 'Regenerative trait-based ecology' remains in its infancy, with work needed on determinate vs. indeterminate flowering ('bet-hedging'), C-S-R methodologies, phylogeny, comparative seed yield per m2 and changing life history. Nevertheless, this has been a positive start and readers are invited to use estimates for >800 annuals, in the Supplementary data, to help advance 'regenerative trait-based ecology' to the next level.
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http://dx.doi.org/10.1093/aob/mcaa151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751024PMC
November 2020

Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria.

Hum Mol Genet 2019 12;28(23):3928-3939

Institute of Ageing and Chronic disease, University of Liverpool, Liverpool, L7 8TX, UK.

Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype. We generated an alkaptonuria mouse model using a knockout-first design for the disruption of the HGD gene. Hgd tm1a -/- mice showed elevated HGA and ochronosis in adulthood. LacZ staining driven by the endogenous HGD promoter was localised to only liver parenchymal cells and kidney proximal tubules in adulthood, commencing at E12.5 and E15.5 respectively. Following removal of the gene trap cassette to obtain a normal mouse with a floxed 6th HGD exon, a double transgenic was then created with Mx1-Cre which conditionally deleted HGD in liver in a dose dependent manner. 20% of HGD mRNA remaining in liver did not rescue the disease, suggesting that we need more than 20% of liver HGD to correct the disease in gene therapy. Kidney HGD activity which remained intact reduced urinary HGA, most likely by increased absorption, but did not reduce plasma HGA nor did it prevent ochronosis. In addition, downstream metabolites of exogenous 13C6-HGA, were detected in heterozygous plasma, revealing that hepatocytes take up and metabolise HGA. This novel alkaptonuria mouse model demonstrated the importance of targeting liver for therapeutic intervention, supported by our observation that hepatocytes take up and metabolise HGA.
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http://dx.doi.org/10.1093/hmg/ddz234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073386PMC
December 2019

Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria.

J Inherit Metab Dis 2020 03 13;43(2):259-268. Epub 2020 Jan 13.

Department of Musculoskeletal Biology I, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 μmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813 μmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 μmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 μmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 μmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
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http://dx.doi.org/10.1002/jimd.12172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079096PMC
March 2020

Trade-offs between seed and leaf size (seed-phytomer-leaf theory): functional glue linking regenerative with life history strategies … and taxonomy with ecology?

Ann Bot 2017 11;120(5):633-652

Department of Archaeology, The University, Sheffield S10 2TN, UK.

Background And Aims: While the 'worldwide leaf economics spectrum' (Wright IJ, Reich PB, Westoby M, et al. 2004. The worldwide leaf economics spectrum. Nature : 821-827) defines mineral nutrient relationships in plants, no unifying functional consensus links size attributes. Here, the focus is upon leaf size, a much-studied plant trait that scales positively with habitat quality and components of plant size. The objective is to show that this wide range of relationships is explicable in terms of a seed-phytomer-leaf (SPL) theoretical model defining leaf size in terms of trade-offs involving the size, growth rate and number of the building blocks (phytomers) of which the young shoot is constructed.

Methods: Functional data for 2400+ species and English and Spanish vegetation surveys were used to explore interrelationships between leaf area, leaf width, canopy height, seed mass and leaf dry matter content (LDMC).

Key Results: Leaf area was a consistent function of canopy height, LDMC and seed mass. Additionally, size traits are partially uncoupled. First, broad laminas help confer competitive exclusion while morphologically large leaves can, through dissection, be functionally small. Secondly, leaf size scales positively with plant size but many of the largest-leaved species are of medium height with basally supported leaves. Thirdly, photosynthetic stems may represent a functionally viable alternative to 'small seeds + large leaves' in disturbed, fertile habitats and 'large seeds + small leaves' in infertile ones.

Conclusions: Although key elements defining the juvenile growth phase remain unmeasured, our results broadly support SPL theory in that phytometer and leaf size are a product of the size of the initial shoot meristem (≅ seed mass) and the duration and quality of juvenile growth. These allometrically constrained traits combine to confer ecological specialization on individual species. Equally, they appear conservatively expressed within major taxa. Thus, 'evolutionary canalization' sensu Stebbins (Stebbins GL. 1974. Flowering plants: evolution above the species level . Cambridge, MA: Belknap Press) is perhaps associated with both seed and leaf development, and major taxa appear routinely specialized with respect to ecologically important size-related traits.
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http://dx.doi.org/10.1093/aob/mcx084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714152PMC
November 2017

Endonasal endoscopic pituitary surgery in the elderly.

J Neurosurg 2018 02 7;128(2):429-436. Epub 2017 Apr 7.

Departments of1Neurosurgery.

OBJECTIVE Pituitary adenomas are benign, slow-growing tumors that cause symptoms either through mass effect or hormone overproduction. The decision to operate on a healthy young person is relatively straightforward. In the elderly population, however, the risks of complications may increase, rendering the decision more complex. Few studies have documented the risks of surgery using the endonasal endoscopic approach in a large number of elderly patients. The purpose of this study was to audit a single center's data regarding outcomes of purely endoscopic endonasal transsphenoidal resection of pituitary adenomas in elderly patients and to compare them to the current literature. METHODS A retrospective review of a prospectively acquired database of all endonasal endoscopic surgeries done by the senior authors was queried for patients aged 60-69 years and for those aged 70 years or older. Demographic and radiographic preoperative data were reviewed. Outcomes with respect to extent of resection and complications were examined and compared with appropriate statistical tests. RESULTS A total of 135 patents were identified (81 aged 60-69 years and 54 aged 70 years or older [70+]). The average tumor diameter was slightly larger for the patients in the 70+ age group (mean [SD] 25.7 ± 9.2 mm) than for patients aged 60-69 years (23.1 ± 9.8 mm, p = 0.056). There was no significant difference in intraoperative blood loss (p > 0.99), length of stay (p = 0.22), or duration of follow-up (p = 0.21) between the 2 groups. There was a 7.4% complication rate in patients aged 60-69 years (3 nasal and 3 medical complications) and an 18.5% complication rate in patients older than 70 years (4 cranial, 3 nasal, 1 visual, and 2 medical complications; p = 0.05 overall and 0.013 for cranial complications). Cranial complications in the 70+ age category included 2 postoperative hematomas, 1 pseudoaneurysm formation, and 1 case of symptomatic subdural hygromas. CONCLUSIONS Endonasal endoscopic surgery in elderly patients is safe, but there is a graded increase in complication rates with increasing age. The decision to operate on an asymptomatic or mildly symptomatic patient in these age groups should take this increasing complication rate into account. The use of a lumbar drain or lumbar punctures should be weighed against the risk of subdural hematoma in patients with preexisting atrophy.
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http://dx.doi.org/10.3171/2016.11.JNS162286DOI Listing
February 2018

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

c-Fos induction by gut hormones and extracellular ATP in osteoblastic-like cell lines.

Purinergic Signal 2016 12 20;12(4):647-651. Epub 2016 Jul 20.

Musculoskeletal Biology Department, Apex Building, 6 West Derby Street, Liverpool, L7 9TX, UK.

It is widely accepted that the c-Fos gene has a role in proliferation and differentiation of bone cells. ATP-induced c-Fos activation is relevant to bone homeostasis, because nucleotides that are present in the environment of bone cells can contribute to autocrine/paracrine signalling. Gut hormones have previously been shown to have an effect on bone metabolism. In this study, we used the osteoblastic Saos-2 cell line transfected with a c-Fos-driven reporter stimulated with five gut hormones: glucose inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), ghrelin and obestatin, in the presence or absence of ATP. In addition, TE-85 cells were used to determine the time course of c-Fos transcript induction following stimulation with GLP-1, and GLP-2 with or without ATP, using reverse transcription qPCR. The significant results from the experiments are as follows: higher level of c-Fos induction in presence of GIP, obestatin (p = 0.019 and p = 0.011 respectively), and GIP combined with ATP (p < 0.001) using the luciferase assay; GLP-1 and GLP-2 combined with ATP (p = 0.034 and p = 0.002, respectively) and GLP-2 alone (p < 0.001) using qPCR. In conclusion, three of the gut peptides induced c-Fos, providing a potential mechanism underlying the actions of these hormones in bone which can be directed or enhanced by the presence of ATP.
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http://dx.doi.org/10.1007/s11302-016-9526-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124003PMC
December 2016

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Functional polymorphisms in the P2X7 receptor gene are associated with stress fracture injury.

Purinergic Signal 2016 Mar 29;12(1):103-13. Epub 2016 Jan 29.

Bone and Joint Research Group, Department of Musculoskeletal Biology, Institute of Ageing and Chronic Diseases, Faculty of Health and Life Sciences, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK.

Military recruits and elite athletes are susceptible to stress fracture injuries. Genetic predisposition has been postulated to have a role in their development. The P2X7 receptor (P2X7R) gene, a key regulator of bone remodelling, is a genetic candidate that may contribute to stress fracture predisposition. The aim of this study is to evaluate the putative contribution of P2X7R to stress fracture injury in two separate cohorts, military personnel and elite athletes. In 210 Israeli Defense Forces (IDF) military conscripts, stress fracture injury was diagnosed (n = 43) based on symptoms and a positive bone scan. In a separate cohort of 518 elite athletes, self-reported medical imaging scan-certified stress fracture injuries were recorded (n = 125). Non-stress fracture controls were identified from these cohorts who had a normal bone scan or no history or symptoms of stress fracture injury. Study participants were genotyped for functional SNPs within the P2X7R gene using proprietary fluorescence-based competitive allele-specific PCR assay. Pearson's chi-squared (χ (2)) tests, corrected for multiple comparisons, were used to assess associations in genotype frequencies. The variant allele of P2X7R SNP rs3751143 (Glu496Ala-loss of function) was associated with stress fracture injury, whilst the variant allele of rs1718119 (Ala348Thr-gain of function) was associated with a reduced occurrence of stress fracture injury in military conscripts (P < 0.05). The association of the variant allele of rs3751143 with stress fractures was replicated in elite athletes (P < 0.05), whereas the variant allele of rs1718119 was also associated with reduced multiple stress fracture cases in elite athletes (P < 0.05). The association between independent P2X7R polymorphisms with stress fracture prevalence supports the role of a genetic predisposition in the development of stress fracture injury.
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http://dx.doi.org/10.1007/s11302-016-9495-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749527PMC
March 2016

Trends in Acute Primary Angle-Closure Glaucoma, Peripheral Iridotomy and Cataract Surgery in Scotland, 1998-2012.

Ophthalmic Epidemiol 2016 11;23(1):1-5. Epub 2016 Jan 11.

c Department of Ophthalmology , Queen Margaret Hospital , Dunfermline , Scotland , UK.

Purpose: We present rates of acute primary angle-closure glaucoma (APACG), peripheral iridotomy (PI) and cataract surgery in Scotland between 1998 and 2012.

Methods: The number of patients in Scotland with APACG in each of the years between 1998 and 2012 was obtained from Information Service Division (ISD) Scotland. Data was also obtained for patients who had undergone laser PI and cataract surgery. The annual rates of APACG, PI and cataract surgery were calculated using Scotland's population data during each of these years.

Results: Between 1998 and 2012 the rate of APACG in National Health Service patients decreased by 46.4% (from 46.7 to 25.0 per million, p < 0.005). The rate of PI increased overall by 116.3% (from 38.0 to 82.2 per million), but demonstrated a decrease of 48.2% (38.0 to 19.7 per million, p = 0.002) between 1998 and 2008, and an increase of 317.3% (19.7 to 82.2 per million, p = 0.005) between 2008 and 2012. Over the same 15-year period, cataract surgery increased by 73.4% (from 354.2 to 615.2 per 100,000, p < 0.005). In this timeframe, mid-year Scottish population estimates increased by 4.6%.

Conclusion: Our results demonstrate a significant reduction in the rate of APACG in the Scottish population between 1998 and 2012, along with a rising rate of PI and cataract surgery. The trend of decreasing APACG may be due to the increasing rate of cataract surgery in the same time period. This parallels patterns seen in other European countries. We discuss these findings together with other related epidemiological factors.
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http://dx.doi.org/10.3109/09286586.2015.1083035DOI Listing
August 2016

Annular Salzmann degeneration: Avoiding perturbations and pitfalls in phacoemulsification surgery.

J Cataract Refract Surg 2015 Nov;41(11):2580-3

From the Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Unlabelled: We highlight potential problems and pitfalls in cases of Salzmann nodular degeneration by reporting the case of an 84-year-old man with reduced visual acuity due to particularly extensive bilateral Salzmann nodules and moderate cataracts. Large annular Salzmann lesions were removed by superficial keratectomy in each eye. The reproducibility and accuracy of keratometry and biometry improved significantly, and uneventful phacoemulsification cataract surgery was performed 4 weeks after the keratectomy. The phacoemulsification procedures were routine other than the development of pronounced epithelial bullae in the area of Salzmann nodule excision. At final review, the uncorrected distance visual acuity was 20/20 in the right eye and 20/25 in the left eye.

Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.
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http://dx.doi.org/10.1016/j.jcrs.2015.10.037DOI Listing
November 2015

Amniotic amulet.

Clin Exp Ophthalmol 2015 Jul;43(5):403-4

Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1111/ceo.12550DOI Listing
July 2015

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

J Pathol 2015 Nov 19;237(3):363-78. Epub 2015 Aug 19.

QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.
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http://dx.doi.org/10.1002/path.4583DOI Listing
November 2015

Contemporary Treatment Paradigms in Keratoconus.

Cornea 2015 Oct;34 Suppl 10:S16-23

Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

The past 20 years have witnessed an explosion in our knowledge of keratoconus, accompanied by a radical transformation of management options. A 2-hit hypothesis proposes an underlying genetic predisposition coupled with external environmental factors, including eye rubbing and atopy. The variable prevalence and natural history have been better defined including significant cone progression in middle age. Therefore, current management must include early diagnosis, regular monitoring, and treatment of environmental cofactors. Spectacles and contact lenses remain fundamental to the optical management of keratoconus. Intrastromal corneal ring segments have been increasingly used, providing improvement in the corneal shape, corrected visual acuity, and contact lens wear. However, like contact lenses, intrastromal corneal ring segments do not treat the underlying disease process. Therefore, current approaches must also consider treatments to minimize keratoconus progression. Fortunately, there is increasing evidence that corneal collagen crosslinking will halt or slow progression in most cases. Until relatively recently, penetrating keratoplasty was the preferred intervention for advanced keratoconus, with long-term success in the region of 90%; however, the greatest risk of failure remains endothelial allograft rejection. Deep anterior lamellar keratoplasty has emerged in the new millennium as a preferred approach to conserve the host endothelium and avoid rejection. Nonetheless, the overall superiority of deep anterior lamellar keratoplasty compared with penetrating keratoplasty, in terms of optical and survival benefits, is still debated. This perspective provides an overview of our current knowledge of keratoconus and current management options. A step-ladder approach to managing keratoconus is outlined to provide the practitioner with a contemporary management paradigm.
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http://dx.doi.org/10.1097/ICO.0000000000000504DOI Listing
October 2015

A cornucopia of cornea: the challenge of being well-informed in an era of rapid change.

Asia Pac J Ophthalmol (Phila) 2015 Jan-Feb;4(1):2-4

From the Department of Ophthalmology, New Zealand National Eye Center, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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http://dx.doi.org/10.1097/APO.0000000000000113DOI Listing
March 2016

Whole-genome characterization of chemoresistant ovarian cancer.

Nature 2015 May;521(7553):489-94

Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
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http://dx.doi.org/10.1038/nature14410DOI Listing
May 2015

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

JIMD Rep 2015 5;24:45-50. Epub 2015 May 5.

Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.
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http://dx.doi.org/10.1007/8904_2015_437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582025PMC
September 2015

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator.

J Med Imaging Radiat Oncol 2015 Jun 20;59(3):371-8. Epub 2014 Nov 20.

Department of Radiation Oncology, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia.

Introduction: Primary management of prolactinomas is usually medical, with surgery a secondary option where necessary. This study is a review of a single centre's experience with focused radiotherapy where benefit was not gained by medical or surgical approaches.

Methods: Radiotherapy as an alternative and adjuvant treatment for prolactinomas has been performed at our institution with the linear accelerator since 1990. We present a retrospective review of 13 patients managed with stereotactic radiosurgery (SRS) and 5 managed with fractionated stereotactic radiotherapy (FSRT), as well as 5 managed with conventional radiotherapy, at the Prince of Wales Hospital. Patients with a histopathologically diagnosed prolactinoma were eligible. Those patients who had a confirmed pathological diagnosis of prolactinoma following surgical intervention, a prolactin level elevated above 500 μg/L, or a prolactin level persistently elevated above 200 μg/L with exclusion of other causes were represented in this review.

Results: At the end of documented follow-up (SRS median 6 years, FSRT median 2 years), no SRS patients showed an increase in tumour volume. After FSRT, 1 patient showed an increase in size, 2 showed a decrease in size and 2 patients showed no change. Prolactin levels trended towards improvement after SRS and FSRT, but no patients achieved the remission level of <20 μg/L. Seven of 13 patients in the SRS group achieved a level of <500 μg/L, whereas no patients reached this target after FSRT.

Conclusions: A reduction in prolactin level is frequent after SRS and FSRT for prolactinomas; however, true biochemical remission is uncommon. Tumour volume control in this series was excellent, but this may be related to the natural history of the disease. Morbidity and mortality after stereotactic radiation were very low in this series.
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http://dx.doi.org/10.1111/1754-9485.12257DOI Listing
June 2015

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nat Commun 2014 Oct 29;5:5224. Epub 2014 Oct 29.

QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
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http://dx.doi.org/10.1038/ncomms6224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596003PMC
October 2014

Nelson's syndrome: single centre experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy.

J Clin Neurosci 2014 Sep 11;21(9):1520-4. Epub 2014 May 11.

Department of Radiation Oncology, The Prince of Wales Cancer Centre, Level 2, High Street, Randwick, NSW 2031, Australia.

Nelson's syndrome is a unique clinical phenomenon of growth of a pituitary adenoma following bilateral adrenalectomies for the control of Cushing's disease. Primary management is surgical, with limited effective medical therapies available. We report our own institution's series of this pathology managed with radiation: prior to 1990, 12 patients were managed with conventional radiotherapy, and between 1990 and 2007, five patients underwent stereotactic radiosurgery (SRS) and two patients fractionated stereotactic radiotherapy (FSRT), both using the linear accelerator (LINAC). Tumour control was equivocal, with two of the five SRS patients having a reduction in tumour volume, one patient remaining unchanged, and two patients having an increase in volume. In the FSRT group, one patient had a decrease in tumour volume whilst the other had an increase in volume. Treatment related morbidity was low. Nelson's syndrome is a challenging clinical scenario, with a highly variable response to radiation in our series.
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http://dx.doi.org/10.1016/j.jocn.2013.12.026DOI Listing
September 2014

Differential effects of adiponectin in osteoblast-like cells.

J Recept Signal Transduct Res 2014 Oct 27;34(5):351-60. Epub 2014 Mar 27.

Escuela de Medicina, Universidad Anáhuac Mayab , Yucatán , México .

The skeleton should maintain an adequate volume, vigour and strength to carry out the role for which it is designed: to hold the whole soft tissue mass that shapes the body and to protect the vital organs. To fulfil this task a satisfactory food intake is required and regulators that are released in the feeding and fasting states, among other signals indicate how much soft mass needs to be built up. Those signals include the secretion of adipocytokines which could represent a relevant link between soft mass (adipose tissue) and skeleton. We studied the presence of adiponectin receptors (AdipoR1, AdipoR2) and its direct effects in osteosarcoma cell line Saos-2. The results indicated that adiponectin receptors were present in the osteoblastic cells with a higher expression of AdipoR1. Human recombinant globular adiponectin was able to increase viability levels and decrease cytotoxicity rates in cell cultures. Also, adiponectin significantly inhibited alkaline phosphatase activity in supernatants. Osteoprotegerin mRNA expression was significantly reduced after 72 h treatment. The FOS induction was studied and the results exhibited a significant increase caused by adiponectin. In conclusion, all these observations suggest that adiponectin influences bone metabolism decreasing the levels of bone formation. Regulators of adiponectin or its receptors could be circulating to modulate the activities of this peptide.
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http://dx.doi.org/10.3109/10799893.2014.898658DOI Listing
October 2014

Somatic point mutation calling in low cellularity tumors.

PLoS One 2013 8;8(11):e74380. Epub 2013 Nov 8.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826759PMC
March 2015
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