ORCID Profile
0000-0002-1871-2108
Current Organisation
The University of Edinburgh
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Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2012
Publisher: Cold Spring Harbor Laboratory
Date: 23-06-2021
DOI: 10.1101/2021.06.22.449521
Abstract: Transposable elements (TEs), also known as jumping genes, are sequences able to move or copy themselves within a genome. As TEs move throughout genomes they often act as a source of genetic novelty, hence understanding TE evolution within lineages may help in understanding environmental adaptation. Studies into the TE content of lineages of mammals such as bats have uncovered horizontal transposon transfer (HTT) into these lineages, with squamates often also containing the same TEs. Despite the repeated finding of HTT into squamates, little comparative research has examined the evolution of TEs within squamates. Here we examine a erse family of Australo-Melanesian snakes (Hydrophiinae) to examine if the previously identified, order-wide pattern of variable TE content and activity holds true on a smaller scale. Hydrophiinae erged from Asian elapids ∼30 Mya and have since rapidly ersified into six hibious, ∼60 marine and ∼100 terrestrial species which fill a broad range of ecological niches. We find TE ersity and expansion differs between hydrophiines and their Asian relatives and identify multiple HTTs into Hydrophiinae, including three likely transferred into the ancestral hydrophiine from fish. These HTT events provide the first tangible evidence that Hydrophiinae reached Australia from Asia via a marine route.
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2011
DOI: 10.1158/1078-0432.CCR-11-0937
Abstract: Purpose: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects. Experimental Design: BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker. Results: Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1–18.9 mg/m2). The recommended dose level was 16 mg/m2 and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects. Conclusions: BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m2 and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced. Clin Cancer Res 17(15) 5152–60. ©2011 AACR.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2012
Abstract: Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Thirty-eight patients (22 with EFT 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
Publisher: Cold Spring Harbor Laboratory
Date: 14-04-2021
DOI: 10.1101/2021.04.13.439746
Abstract: Since the sequencing of the zebra finch genome it has become clear the avian genome, while largely stable in terms of chromosome number and gene synteny, is more dynamic at an intrachromosomal level. A multitude of intrachromosomal rearrangements and significant variation in transposable element content have been noted across the avian tree. Transposable elements (TEs) are a source of genome plasticity, because their high similarity enables chromosomal rearrangements through non-allelic homologous recombination, and they have potential for exaptation as regulatory and coding sequences. Previous studies have investigated the activity of the dominant TE in birds, CR1 retrotransposons, either focusing on their expansion within single orders, or comparing passerines to non-passerines. Here we comprehensively investigate and compare the activity of CR1 expansion across orders of birds, finding levels of CR1 activity vary significantly both between and with orders. We describe high levels of TE expansion in genera which have speciated in the last 10 million years including kiwis, geese and Amazon parrots low levels of TE expansion in songbirds across their ersification, and near inactivity of TEs in the cassowary and emu for millions of years. CR1s have remained active over long periods of time across most orders of neognaths, with activity at any one time dominated by one or two families of CR1s. Our findings of higher TE activity in species-rich clades and dominant families of TEs within lineages mirror past findings in mammals. Transposable elements (TEs) are mobile, self replicating DNA sequences within a species’ genome, and are ubiquitous sources of mutation. The dominant group of TEs within birds are chicken repeat 1 (CR1) retrotransposons, making up 7-10% of the typical avian genome. Because past research has examined the recent inactivity of CR1s within model birds such as the chicken and the zebra finch, this has fostered an erroneous view that all birds have low or no TE activity on recent timescales. Our analysis of numerous high quality avian genomes across multiple orders identified both similarities and significant differences in how CR1s expanded. Our results challenge the established view that TEs in birds are largely inactive and instead suggest that their variation in recent activity may contribute to lineage-specific changes in genome structure. Many of the patterns we identify in birds have previously been seen in mammals, highlighting parallels between the evolution of birds and mammals.
Publisher: Future Medicine Ltd
Date: 04-2012
DOI: 10.2217/CRC.12.9
Abstract: SUMMARY Clinical oncology experience with recently marketed antiangiogenic agents, which inhibit proteins important for tumor angiogenesis, has exposed significant limitations to their efficacy. Bevacizumab, a humanized neutralizing anti-VEGF-A monoclonal antibody, used in combination with cytotoxic chemotherapy for the treatment of metastatic colorectal cancer, represents the best-studied clinical ex le of targeted antiangiogenic therapy. In this context, bevacizumab provides modestly improved progression-free and overall survival in unselected patient populations via poorly understood mechanisms. Here we review concepts central to the identification and development of biomarkers in order to refine clinical use of bevacizumab in treating colorectal cancer and outline a phenotype-driven strategy for the discovery of high-value candidate biomarkers based on large-scale screening by molecular perturbation.
Publisher: MDPI AG
Date: 25-01-2022
Abstract: Transposable elements (TEs), also known as jumping genes, are sequences able to move or copy themselves within a genome. As TEs move throughout genomes they often act as a source of genetic novelty, hence understanding TE evolution within lineages may help in understanding environmental adaptation. Studies into the TE content of lineages of mammals such as bats have uncovered horizontal transposon transfer (HTT) into these lineages, with squamates often also containing the same TEs. Despite the repeated finding of HTT into squamates, little comparative research has examined the evolution of TEs within squamates. Here we examine a erse family of Australo–Melanesian snakes (Hydrophiinae) to examine if the previously identified, order-wide pattern of variable TE content and activity holds true on a smaller scale. Hydrophiinae erged from Asian elapids ~30 Mya and have since rapidly ersified into six hibious, ~60 marine and ~100 terrestrial species that fill a broad range of ecological niches. We find TE ersity and expansion differs between hydrophiines and their Asian relatives and identify multiple HTTs into Hydrophiinae, including three likely transferred into the ancestral hydrophiine from fish. These HTT events provide the first tangible evidence that Hydrophiinae reached Australia from Asia via a marine route.
Publisher: The Royal Society
Date: 09-2021
Abstract: Transposable elements (TEs) are self-replicating genetic sequences and are often described as important ‘drivers of evolution’. This driving force is because TEs promote genomic novelty by enabling rearrangement, and through exaptation as coding and regulatory elements. However, most TE insertions potentially lead to neutral or harmful outcomes, therefore host genomes have evolved machinery to suppress TE expansion. Through horizontal transposon transfer (HTT) TEs can colonize new genomes, and since new hosts may not be able to regulate subsequent replication, these TEs may proliferate rapidly. Here, we describe HTT of the Harbinger-Snek DNA transposon into sea kraits ( Laticauda ), and its subsequent explosive expansion within Laticauda genomes. This HTT occurred following the ergence of Laticauda from terrestrial Australian elapids approximately 15–25 Mya. This has resulted in numerous insertions into introns and regulatory regions, with some insertions into exons which appear to have altered UTRs or added sequence to coding exons. Harbinger-Snek has rapidly expanded to make up 8–12% of Laticauda spp. genomes this is the fastest known expansion of TEs in amniotes following HTT. Genomic changes caused by this rapid expansion may have contributed to adaptation to the hibious-marine habitat.
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2022
Publisher: Wiley
Date: 06-04-2017
DOI: 10.1111/JEB.13068
Abstract: Although it is well established theoretically that selective interference among mutations (Hill-Robertson interference) favours meiotic recombination, genomewide mean rates of mutation and strengths of selection appear too low to support this as the mechanism favouring recombination in nature. A possible solution to this discrepancy between theory and observation is that selection is at least intermittently very strong due to the antagonistic coevolution between a host and its parasites. The Red Queen theory posits that such coevolution generates fitness epistasis among loci, which generates negative linkage disequilibrium among beneficial mutations, which in turn favours recombination. This theory has received only limited support. However, Red Queen dynamics without epistasis may provide the ecological conditions that maintain strong and frequent selective interference in finite populations that indirectly selects for recombination. This hypothesis is developed here through the simulation of Red Queen dynamics. This approach required the development of a method to calculate the exact frequencies of multilocus haplotypes after recombination. Simulations show that recombination is favoured by the moderately weak selection of many loci involved in the interaction between a host and its parasites, which results in substitution rates that are compatible with empirical estimates. The model also reproduces the previously reported rapid increase in the rate of outcrossing in Caenorhabditis elegans coevolving with a bacterial pathogen.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2012
DOI: 10.1200/JCO.2012.30.4_SUPPL.665
Abstract: 665 Background: Clinical trials support the addition of bevacizumab (Bev) to first line chemotherapy for metastatic colorectal cancer (mCRC). However, given that there are alternate biological agents that can be used with chemotherapy and rare but potentially serious toxicities with Bev, there has been variable use of the drug in routine care. The purpose of this study was to prospectively explore 1 st line use of Bev in routine clinical care. Methods: A multi-site data collection was initiated in July 2009 when Bev became publicly available in Australia. A particular focus was capturing information regarding clinician decision-making that is not routinely recorded or is often poorly documented. Comprehensive comorbidity data was collected, along with specific factors, both patient (pt) and disease-related, that may impact on treatment decisions. Major adverse events that may be related to Bev were also recorded. Results: For the 2-year period from July 2009-June 2011, a database search identified 278 pts diagnosed with mCRC at five participating hospitals. 240 pts (86%) had received 1 st line chemotherapy. 102 (43%) also received Bev, the majority in combination with oxaliplatin based chemotherapy (n = 81, 79%). Bev use increased significantly from 40.4% (34/84) of all pts receiving chemotherapy in July-December 2009, to 65.8% (25/38) in January-June 2011 (p=0.0114). Overall the most frequent reasons for clinicians advising against the use of Bev were a bleeding or asymptomatic primary in situ (n=28, 23%), known hypertension (n=14, 11%), clinical trial participation (n=14, 11%), poor performance status (n=9, 7%), and perceived risk of arterial ischemic event (n=8, 6.5%). There have been four episodes of gastro-intestinal perforation, 3 in pts receiving Bev (2.9% of Bev treated patients). Conclusions: Bev use in first line mCRC has significantly increased over time, presumably as further positive safety data emerges regarding safety in older and frailer pts, and clinician prescribing experience increases. The major grounds for not using Bev in the 1 st line mCRC setting were specific clinical contexts where the risk of adverse events may be increased.
Publisher: Cold Spring Harbor Laboratory
Date: 28-02-2020
DOI: 10.1101/2020.02.27.968685
Abstract: While numerous studies have found horizontal transposon transfer (HTT) to be widespread across metazoans, few have focused on HTT in marine ecosystems. To investigate potential recent HTTs into marine species we searched for novel repetitive elements in sea snakes, a group of elapids which transitioned to a marine habitat at most 18 Mya. Our analysis uncovered repeated HTTs into sea snakes following their marine transition. Such major shifts in habitat should require significant genomic changes.The seven subfamilies of horizontally transferred LINE retrotransposons we identified in the olive sea snake ( Aipysurus laevis ) are transcribed, and hence are likely still active and expanding across the genome. A search of 600 metazoan genomes found all seven were absent from other amniotes, including terrestrial elapids, with the most similar transposons present in fish and marine invertebrates. The one exception was a similar transposon found in sea kraits, a lineage of hibious elapids which independently transitioned to a marine environment following their ergence from terrestrial species 25 Mya. Our finding of repeated horizontal transfer events into separate lineages of marine snakes greatly expands past findings of frequent horizontal transfer in the marine environment, suggesting it is ideal for the transfer of transposons.Transposons are drivers of evolution as sources of genomic sequence and hence genomic novelty. This provides evidence of the environment influencing evolution of metazoans not only through specific selection pressures, but also by contributing novel genomic material.
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2021
DOI: 10.1101/2021.06.13.448261
Abstract: Transposable elements (TEs) are self replicating genetic sequences and are often described as important “drivers of evolution”. This driving force is because TEs promote genomic novelty by enabling rearrangement, and through exaptation as coding and regulatory elements. However, most TE insertions will be neutral or harmful, therefore host genomes have evolved machinery to supress TE expansion. Through horizontal transposon transfer (HTT) TEs can colonise new genomes, and since new hosts may not be able to shut them down, these TEs may proliferate rapidly. Here we describe HTT of the Harbinger-Snek DNA transposon into sea kraits ( Laticauda ), and its subsequent explosive expansion within Laticauda genomes. This HTT occurred following the ergence of Laticauda from terrestrial Australian elapids ~15-25 Mya. This has resulted in numerous insertions into introns and regulatory regions, with some insertions into exons which appear to have altered UTRs or added sequence to coding exons. Harbinger-Snek has rapidly expanded to make up 8-12% of Laticauda spp. genomes this is the fastest known expansion of TEs in amniotes following HTT. Genomic changes caused by this rapid expansion may have contributed to adaptation to the hibious-marine habitat.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2012
DOI: 10.1200/JCO.2012.30.4_SUPPL.682
Abstract: 682 Background: Cure is potentially achievable in select patients (pts) with mCRC with limited metastatic disease to liver and/or lung. To date the peri-operative strategies undertaken by oncologists in routine practice for such pts have not been well documented. Methods: A clinical database recording information on all pts diagnosed with mCRC since July 2009 from 5 hospitals was analysed. Management strategies where a curative-intent resection had occurred was planned or was a potential option were compared with those managed with palliative intent. Results: Status at the time of first review regarding systemic chemotherapy (CT) was documented for 280 pts. 11 (4%) had already undergone curative-intent resection 31 (11%) had a resection planned 27 (10%) were considered potentially resectable if their response to treatment was good and 207 (74%) were treated with palliative intent. No pts already resected or planned for resection were ECOG 1, compared with 11% (3/27) potentially resectable and 17% (36/207) palliative pts. CT was delivered in 9 (82%) already-resected, 26 (84%) planned for resection, 26 (96%) potentially-resectable and 159 (77%) palliative-intent pts. Combination CT was the dominant strategy, although 7 of 11 (66%) already-resected pts received single agent treatment. No already-resected pts received bevacizumab with CT, compared with 27% (n=14) of planned or potentially-curative pts and 55% (n=88) of those treated with palliative intent. At the time of analysis 13 pts (42%) with a planned resection and 8 (30%) considered potentially curative have had surgery, while 3 (1.4%) where treatment was initially considered palliative have had curative-intent surgery. Conclusions: Treatment strategies for pts with mCRC differ significantly based on the treatment intent, and may be affected by surgical preference and referral pattern. Bevacizumab was less likely to be used for already-resected pts and the use of single agent therapy in this group was also not uncommon. Many pts initially considered resectable do not ultimately undergo resection, whereas occasional ‘palliative’ pts may become resectable, confirming the importance of continued consideration of this option.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.JOMS.2011.03.020
Abstract: To assess clinical behavior, response to treatment, and factors affecting survival in maxillofacial osteosarcoma treated at a tertiary referral center. Ethics-approved retrospective review of clinical and pathological records was undertaken for 15 patients managed by the Royal Melbourne Hospital Head and Neck Oncology Tumor Stream. Treatment was a combination of surgery and chemotherapy. Chemotherapy was given as adjuvant, neoadjuvant, or in combination. The overall 2-, 5-, and 15-year disease-free survival rates in this study were 92%, 74%, and 74%, respectively. Using Kaplan-Meier analysis with log rank tests, increasing T stage (P = .01) and positive margins (P = .003) were found to affect survival significantly. Neoadjuvant chemotherapy was not significantly associated with tumor necrosis or improved survival. Tumor size and adequacy of local control were found to be the most important predictors of outcome.
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2023
DOI: 10.1101/2023.08.19.550906
Abstract: Horizontal transfer of transposable elements (HTT) has been reported across many species and the impact of such events on genome structure and function has been well described. However, few studies have focused on reptilian genomes, especially HTT events in Testudines (turtles). Here, we investigated the repetitive content of Malaclemys terrapin terrapin (Diamondback turtle) and found a high similarity hAT-6 DNA transposon shared between other turtle species, ray-finned fishes, and a frog. hAT-6 was notably absent in taxa closely related to turtles, such as crocodiles and birds. Successful invasion of DNA transposons into new genomes requires the conservation of specific residues in the encoded transposase, and through structural analysis, these residues were identified indicating retention of functional transposition activity. We document a rare and recent HTT event of a DNA transposon between turtles which are known to have a low genomic evolutionary rate and ancient repeats.
Publisher: Elsevier BV
Date: 08-2023
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for James Galbraith.