Publications by authors named "Kate Powell"

37 Publications

Carcinosarcomas of the Uterus: Prognostic Factors and Impact of Adjuvant Treatment.

Cancer Manag Res 2021 10;13:4633-4645. Epub 2021 Jun 10.

Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, Australia.

Background: Uncertainties remain about the most effective treatment for uterine carcinosarcoma (UCS), a rare but aggressive uterine cancer, due to the limited scope for randomized trials. This study investigates whether nodal excision or adjuvant therapies after hysterectomy offer a survival benefit, using multi-institutional clinical registry data from South Australia.

Methods: Data for all consecutive cases of UCS from 1980 to 2019 were extracted from the Clinical Cancer Registry. Clinical and treatment-related factors associated with disease-specific mortality (DSM) and all-cause mortality (ACM) were determined using multivariable Cox proportional hazards regression, with subgroup analyses by stage.

Results: Median follow-up for the 140 eligible cases was 21 months. 94% underwent hysterectomy, and 72% had an additional pelvic lymph node dissection (PLND). Furthermore, 16% received adjuvant chemotherapy; 11% adjuvant radiotherapy and 16% multimodal chemoradiotherapy, with an increase in the latter two modalities over time. DSM was reduced among those who underwent PLND (HR: 0.41; 95%CI: 0.23-0.74), adjuvant chemotherapy (HR: 0.39; 95%CI: 0.18-0.84) or multimodality treatment (HR: 0.11; 95%CI: 0.06-0.30) compared with hysterectomy alone for the whole cohort and for late stage disease (FIGO III/IV) but not for earlier stage disease, except for reduced DSM with multimodal therapy. Findings were similar for ACM.

Conclusion: Our findings indicate better survival among those who received PLND, chemotherapy and multimodal adjuvant therapy, with the latter applying to early and late stage disease. However, cautious interpretation is warranted, due to potential "indication bias" and limited power. Further research into effective treatment modalities, ideally using prospective study designs, is needed.
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http://dx.doi.org/10.2147/CMAR.S309551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203298PMC
June 2021

Defining T Cell Subsets in Human Tonsils Using ChipCytometry.

J Immunol 2021 Jun 7. Epub 2021 Jun 7.

Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

ChipCytometry is a multiplex imaging method that can be used to analyze either cell suspensions or tissue sections. Images are acquired by iterative cycles of immunostaining with fluorescently labeled Abs, followed by photobleaching, which allows the accumulation of multiple markers on a single sample. In this study, we explored the feasibility of using ChipCytometry to identify and phenotype cell subsets, including rare cell types, using a combination of tissue sections and single-cell suspensions. Using ChipCytometry of tissue sections, we successfully demonstrated the architecture of human palatine tonsils, including the B and T cell zones, and characterized subcompartments such as the B cell mantle and germinal center zone, as well as intrafollicular PD1-expressing CD4 T cells. Additionally, we were able to identify the rare tonsillar T cell subsets, mucosal-associated invariant T (MAIT) and γδ-T cells, within tonsil tissue. Using single-cell suspension ChipCytometry, we further dissected human tonsillar T cell subsets via unsupervised clustering analysis as well as supervised traditional manual gating. We were able to show that PD1CD4 T cells are comprised of CXCR5BCL6 follicular Th cells and CXCR5BCL6 pre-follicular Th cells. Both supervised and unsupervised analysis approaches identified MAIT cells in single-cell suspensions, confirming a phenotype similar to that of blood-derived MAIT cells. In this study, we demonstrate that ChipCytometry is a viable method for single-cell suspension cytometry and analysis, with the additional benefit of allowing phenotyping in a spatial context using tissue sections.
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http://dx.doi.org/10.4049/jimmunol.2100063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278278PMC
June 2021

Guideline review NICE Clinical Knowledge Summary: balanitis in children.

Arch Dis Child Educ Pract Ed 2021 May 27. Epub 2021 May 27.

Surgical Department, Bristol Royal Hospital for Children, Bristol, UK.

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http://dx.doi.org/10.1136/archdischild-2020-321303DOI Listing
May 2021

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

Cell Rep 2021 Apr;35(3):109022

UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Kellogg Eye Centre, University of Michigan, 1000 Wall St., Ann Arbor, MI 48105, USA. Electronic address:

Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.
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http://dx.doi.org/10.1016/j.celrep.2021.109022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065177PMC
April 2021

Female breast cancer treatment and survival in South Australia: Results from linked health data.

Eur J Cancer Care (Engl) 2021 Mar 28:e13451. Epub 2021 Mar 28.

Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Objective: We investigated treatment and survival by clinical and sociodemographic characteristics for service evaluation using linked data.

Method: Data on invasive female breast cancers (n = 13,494) from the South Australian Cancer Registry (2000-2014 diagnoses) were linked to hospital inpatient, radiotherapy and universal health insurance data. Treatments ≤12 months from diagnosis and survival were analysed, using adjusted odds ratios (aORs) from logistic regression, and adjusted sub-hazard ratios (aSHRs) from competing risk regression.

Results And Conclusion: Five-year disease-specific survival increased to 91% for 2010-2014. Most women had breast surgery (90%), systemic therapy (72%) and radiotherapy (60%). Less treatment applied for ages 80+ vs <50 years (aOR 0.10, 95% CI 0.05-0.20) and TNM stage IV vs stage I (aOR 0.13, 95% CI 0.08-0.22). Surgical treatment increased during the study period and strongly predicted higher survival. Compared with no surgery, aSHRs were 0.31 (95% CI 0.26-0.36) for women having breast-conserving surgery, 0.49 (95% CI 0.41-0.57) for mastectomy and 0.42 (95% CI 0.33-0.52) when both surgery types were received. Patients aged 80+ years had lower survival and less treatment. More trial evidence is needed to optimise trade-offs between benefits and harms in these older women. Survival differences were not found by residential remoteness and were marginal by socioeconomic status.
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http://dx.doi.org/10.1111/ecc.13451DOI Listing
March 2021

Human intestinal tissue-resident memory T cells comprise transcriptionally and functionally distinct subsets.

Cell Rep 2021 01;34(3):108661

Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; Oxford Transplant Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK; NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.

Tissue-resident memory T (T) cells provide key adaptive immune responses in infection, cancer, and autoimmunity. However, transcriptional heterogeneity of human intestinal T cells remains undefined. Here, we investigate transcriptional and functional heterogeneity of human T cells through study of donor-derived T cells from intestinal transplant recipients. Single-cell transcriptional profiling identifies two transcriptional states of CD8 T cells, delineated by ITGAE and ITGB2 expression. We define a transcriptional signature discriminating these populations, including differential expression of cytotoxicity- and residency-associated genes. Flow cytometry of recipient-derived cells infiltrating the graft, and lymphocytes from healthy gut, confirm these CD8 T phenotypes. CD8 CD69CD103 T cells produce interleukin-2 (IL-2) and demonstrate greater polyfunctional cytokine production, whereas β2-integrinCD69CD103 T cells have higher granzyme expression. Analysis of intestinal CD4 T cells identifies several parallels, including a β2-integrin population. Together, these results describe the transcriptional, phenotypic, and functional heterogeneity of human intestinal CD4 and CD8 T cells.
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http://dx.doi.org/10.1016/j.celrep.2020.108661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816164PMC
January 2021

Power, control, communities and health inequalities. Part II: measuring shifts in power.

Health Promot Int 2020 Dec 31. Epub 2020 Dec 31.

Division of Health Research, Lancaster University, Lancaster, UK.

In the health field, there is great interest in the role empowerment might play in reducing social inequalities in health. Empowerment is understood here as the processes of developing capabilities that individuals and/or communities need to exercise control over decisions and actions impacting on their lives and health. There is a fundamental problem, however, in identifying and measuring capabilities for collective control that emerge at the level of the collective, with much of the existing literature focusing on individual measures even where community-level processes are concerned. Collective measures need to capture the dynamics of interactions within and between groups, not simply aggregate individual-level measures. This article, Part 2 in a three-part series, takes up the challenge of identifying qualitative markers of capabilities for collective control. We applied the emancipatory power framework (EPF) reported in Part 1 of the series, to qualitative data generated during a longitudinal evaluation of a major English area-based empowerment initiative, the Big Local (BL). We identified empirical 'markers' of shifts towards greater collective control pertaining to each of the 'power' dimensions in the EPF-'power within', 'power with' and 'power to'-and markers of communities exercising 'power over' other institutions/community members. These markers can usefully be applied in the evaluation planning and evaluation of empowerment initiatives. Part 3 in the series uses these markers and a second analytical framework developed during our evaluation of BL to explore how power dynamics unfold in participatory spaces in BL neighbourhoods.
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http://dx.doi.org/10.1093/heapro/daaa019DOI Listing
December 2020

Cancers of the corpus uteri treated in South Australian public hospitals: Trends in clinical management and survival across three decades.

Eur J Cancer Care (Engl) 2020 Sep 8;29(5):e13281. Epub 2020 Jul 8.

Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia.

Objective: To investigate treatment and survival over three decades.

Methods: Clinical registry data from three major public hospitals analysed using Kaplan-Meier product-limit estimates and multivariate proportional hazard regression to determine disease-specific survival.

Results: Five-year survival increased from 75% to 84%. The adjusted hazard ratio (HR, 95% CI) was 0.56 (0.41, 0.77) for 2010-2016 compared with 1984-1989 and was higher for: ages 80+ years; more advanced stages; poorly differentiated tumours; and complex mixed epithelial and mesenchymal tumours and sarcomas. Treatment was by surgery (92%), radiotherapy (33%), chemotherapy (12%) and hormone therapy (10%). Adjusted analyses showed radiotherapy and hormone therapy were less common from 1990 and chemotherapy more common for 2010-2016. Treatment likelihood was lower for ages ≥80 years, mixed epithelial and mesenchymal tumours receiving surgery and chemotherapy, but higher for radiotherapy. Advanced cancers (FIGO stage IV) had less surgery but more non-surgical treatments. Marginal evidence presented of more hormone therapy for high socio-economic areas.

Conclusions: Survival was equivalent to national figures for Australia and the United States, but potentially higher than for England and Wales. Cases aged 80+ years had less care and poorer survival. Findings illustrate the complementary roles of hospital and population-based registries in local service evaluation.
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http://dx.doi.org/10.1111/ecc.13281DOI Listing
September 2020

Monitoring TNM stage of female breast cancer and survival across the South Australian population, with national and international TNM benchmarking: A population-based cohort study.

BMJ Open 2020 06 28;10(6):e037069. Epub 2020 Jun 28.

Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Objective: Using linked cancer registry and administrative data to monitor, tumour, node and metastases (TNM) stage and survival from female breast cancer in Australia.

Method: Analysis of 2000-2014 diagnoses with linked population-based data to investigate: (1) sociodemographic predictors of advanced stage (stages III and IV), using unadjusted and adjusted logistic regression; and (2) sociodemographic factors and stage as predictors of breast cancer survival using competing risk regression.

Design: Population-based registry cohort.

Setting And Participants: 14 759 South Australian women diagnosed in 2000-2014.

Primary And Secondary Outcome Measures: Stage and survival.

Results: At diagnosis, 46% of women were classified as stage I, 39% as stage II, 12% as stage III and 4% as stage IV. After adjusting for sociodemographic factors, advanced stage was more common: (1) for ages <50 years; and although not statistically significant, for ages 80+ years; and (2) in women from socioeconomically disadvantaged areas. Compared with 2000-2004 diagnoses, stage and sociodemographic adjusted risks (sub-HRs (SHRs)) of breast cancer death were lower in 2005-2009 (SHR 0.75, 95% CI 0.67 to 0.83) and 2010-2015 (SHR 0.57, 95% CI 0.48 to 0.67). Compared with stage I, the SHR was 3.87 (95% CI 3.32 to 4.53) for stage II, 10.87 (95% CI 9.22 to 12.81) for stage III, and 41.97 (95% CI 34.78 to 50.65) for stage IV. Women aged 70+ years at diagnosis and those living in the most socioeconomically disadvantaged areas were at elevated risk of breast cancer death, independent of stage and sociodemographic factors.

Conclusions: Stage varied by age, diagnostic period and socioeconomic status, and was a stronger predictor of survival than other statistically significant sociodemographic predictors. Achieving earlier diagnosis outside the original BreastScreen target of 50-69 years (as applying <2014) and in residents of socioeconomically disadvantaged areas likely would increase cancer survival at a population level.
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http://dx.doi.org/10.1136/bmjopen-2020-037069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322288PMC
June 2020

Time from diagnosis to treatment of colorectal cancer in a South Australian clinical registry cohort: how it varies and relates to survival.

BMJ Open 2019 09 30;9(9):e031421. Epub 2019 Sep 30.

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.

Objectives: Some early studies indicated lower survival with longer time from diagnosis to cancer treatment, but others showed the reverse. We investigated time to treatment of colorectal cancer and associations with survival.

Setting And Participants: Clinical registry data for colorectal cancer cases diagnosed in 2000-2010 at four major public hospitals in South Australia and treated by surgery (n=1675), radiotherapy (n=616) and/or systemic therapy (n=1556).

Design: A historic cohort design, with rank-order tests for ordinal clinical and sociodemographic predictors and multiple logistic regression for comparing time from diagnosis to treatment. Unadjusted Kaplan-Meier estimates and adjusted Cox proportional hazards regression were used to investigate disease-specific survival by time to treatment.

Outcome Measures: Time to treatment and survival from diagnosis to death from colorectal cancer.

Results: Treatment (any type) commenced for 87% of surgical cases 60 days of diagnosis, with 80% having surgery within this period. Of those receiving radiotherapy, 59% began this treatment 60 days, and of those receiving systemic therapy, the corresponding proportion was 56%. Adjusted analyses showed treatment delay >60 days was more likely for rectal cancers, 2006-2010 diagnoses, residents of northern than other metropolitan regions and for surgery, younger ages <50 years and unexpectedly, those residing closer to metropolitan services. Adjusting for clinical and sociodemographic factors, and diagnostic year, better survival occurred in 2 years from diagnosis for time to treatment >30 days. Survival in the 3-10 years postdiagnosis generally did not differ by time to treatment, except for lower survival for any treatment >90 days for surgical cases.

Conclusions: The lower survival 2 years from diagnosis for treatment 30 days of diagnosis is consistent with other studies attributed to preferencing more complicated cases for earlier care. Lower 3-10 years survival for surgical cases first treated >90 days from diagnosis is consistent with previously reported U-shaped relationships.
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http://dx.doi.org/10.1136/bmjopen-2019-031421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797269PMC
September 2019

TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions.

Cell Rep 2019 09;28(12):3077-3091.e5

Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address:

MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8 MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8 MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.
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http://dx.doi.org/10.1016/j.celrep.2019.08.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899450PMC
September 2019

Pre-diagnostic colonoscopies reduce cancer mortality - results from linked population-based data in South Australia.

BMC Cancer 2019 Aug 29;19(1):856. Epub 2019 Aug 29.

Cancer Research Institute, University of South Australia, Adelaide, Australia.

Background: To investigate the association between pre-diagnostic colonoscopy and colorectal cancer mortality in South Australia.

Methods: Colonoscopy histories were obtained for colorectal cancer patients diagnosed in 2003-2013 using linked Medical Benefits Schedule (MBS) claims, hospital-inpatient and cancer-registry data. Colonoscopy histories included the year of colonoscopy, numbers of examinations, and the time from first colonoscopy to diagnosis. Histories of multiple exposures to colonoscopies, and exposures of greater than a year from initial colonoscopy to diagnosis, were regarded as indicators of screening or surveillance activity. Colonoscopies occurring within one year of diagnosis were regarded as more likely to be a response to cancer symptoms than those occurring > 1 year before diagnosis. Associations between colonoscopy history and post-diagnostic survival were analysed using sub-hazard ratios (SHRs) from competing risk regression adjusted for socio-demographic and cancer characteristics.

Results: Having pre-diagnostic colonoscopy was associated with an unadjusted reduction in risk of colorectal cancer death of 17% (SHR: 0.83, 95% CI 0.78-0.89). After adjusting for time period and sociodemographic characteristics, the risk of colorectal cancer death reduced by 17% for one pre-diagnostic colonoscopy examination; 27% for two pre-diagnostic colonoscopy examinations; and 45% for three or more pre-diagnostic colonoscopy examinations. Those with a time of over one year from first colonoscopy in the study window to diagnosis, when compared with less than one year, had a 17% lower risk of colorectal cancer death in this adjusted analysis. These reductions were substantially reduced or eliminated when also adjusting for less advanced stage.

Conclusions: Pre-diagnostic colonoscopy, and more so, multiple colonoscopies and first colonoscopy occurring over one year from initial colonoscopy to diagnosis, were associated with longer survival post diagnosis. This was largely explained by less advanced cancer stage at the time of diagnosis.
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http://dx.doi.org/10.1186/s12885-019-6092-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716808PMC
August 2019

SSBP1 mutations in dominant optic atrophy with variable retinal degeneration.

Ann Neurol 2019 09 31;86(3):368-383. Epub 2019 Jul 31.

School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom.

Objective: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a portion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.

Methods: Linkage analysis and sequencing were performed in multigeneration families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.

Results: We defined a new ADOA locus on 7q33-q35 and identified 3 different missense variants in SSBP1 (NM_001256510.1; c.113G>A [p.(Arg38Gln)], c.320G>A [p.(Arg107Gln)] and c.422G>A [p.(Ser141Asn)]) in affected individuals from 2 families and 2 singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 for single-strand DNA. Antisense-mediated knockdown of endogenous ssbp1 messenger RNA (mRNA) in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point toward an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in 2 multigeneration families studied.

Interpretation: SSBP1 is an essential protein for mitochondrial DNA replication and maintenance. Our data have established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. ANN NEUROL 2019;86:368-383.
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http://dx.doi.org/10.1002/ana.25550DOI Listing
September 2019

Exploring the added value of hospital-registry data for showing local service outcomes: cancers of the ovary, fallopian tube and peritoneum.

BMJ Open 2019 02 19;9(2):e024036. Epub 2019 Feb 19.

Royal Adelaide Hospital, Adelaide, South Australia, Australia.

Objectives: To explore the added value of hospital-registry data on invasive epithelial ovarian, tubal and peritoneal cancers.

Design: Historic cohort analyses.

Methods: Unadjusted and adjusted regression.

Setting: Major South Australian hospitals.

Participants: 1596 women (1984-2015 diagnoses).

Results: 5-Year and 10-year survival was 48% and 41%, respectively, equivalent to relative survival for Australia and the USA. After adjusting for age, clinical and geographic factors, risk of ovarian cancer death was 25% lower in 2010-2015 than 1984-1989. Women generally had surgical treatment (87%) in their first round of care. This was more common for younger patients (adjusted OR (95% CIs) 0.17 (0.04 to 0.65) for 80+ vs <40 years) and earlier International Federation of Gynecology and Obstetrics stages (adjusted OR 0.48 (0.13 to 1.78) for stage IIIB/C and 0.13 (0.04 to 0.45) for stage IV vs stage IA). Most (74%) had systemic therapy, which was more common for advanced stages (adjusted ORs >15.0 for stages III and IV vs stage IA). Few (9%) had radiotherapy. Women generally had systemic therapy (74%), without difference by service accessibility and socioeconomic disadvantage, suggesting equity. However, surgery was less common for residents of the most compared with least remote areas (adjusted OR 0.49 (0.24 to 0.99)); and more common prior to adjustment in the highest versus lowest socioeconomic category (unadjusted OR 1.55 (1.01 to 2.39)), but this elevation did not apply after adjustment (adjusted OR 0.19 (0.63 to 2.25)), with the difference largely explained by stage.

Conclusions: Hospital-registry data add value for assessing local service delivery. Equivalent survival to Australia-wide and USA survival, and temporal gains after adjusting for stage and other patient characteristics are reassuring. Survival gains may reflect therapeutic benefits of more extensive surgery and improved chemotherapy regimens.
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http://dx.doi.org/10.1136/bmjopen-2018-024036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367964PMC
February 2019

Using hospital registries in Australia to extend data availability on vulval cancer treatment and survival.

BMC Cancer 2018 Aug 30;18(1):858. Epub 2018 Aug 30.

Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia.

Background: The value of hospital registries for describing treatment and survival outcomes for vulval cancer was investigated. Hospital registry data from four major public hospitals in 1984-2016 were used because population-based data lacked required treatment and outcomes data. Unlike population registries, the hospital registries had recorded FIGO stage, grade and treatment.

Methods: Unadjusted and adjusted disease-specific survival and multiple logistic regression were used. Disease-specific survivals were explored using Kaplan-Meier product-limit estimates. Hazards ratios (HRs) were obtained from proportional hazards regression for 1984-1999 and 2000-2016. Repeat analyses were undertaken using competing risk regression.

Results: Five-year disease-specific survival was 70%, broadly equivalent to the five-year relative survivals reported for Australia overall (70%), the United Kingdom (70%), USA (72%), Holland (70%), and Germany (Munich) (68%). Unadjusted five-year survival tended to be lower for cancers diagnosed in 2000-2016 than 1984-1999, consistent with survival trends reported for the USA and Canada, but higher for 2000-2016 than 1984-1999 after adjusting for stage and other covariates, although differences were small and did not approach statistical significance (p ≥ 0.40). Surgery was provided as part of the primary course of treatment for 94% of patients and radiotherapy for 26%, whereas chemotherapy was provided for only 6%. Less extensive surgical procedures applied in 2000-2016 than 1984-1999 and the use of chemotherapy increased over these periods. Surgery was more common for early FIGO stages, and radiotherapy for later stages with a peak for stage III. Differences in treatment by surgery and radiotherapy were not found by geographic measures of remoteness and socioeconomic status in adjusted analyses, suggesting equity in service delivery.

Conclusions: The data illustrate the complementary value of hospital-registry data to population-registry data for informing local providers and health administrations of trends in management and outcomes, in this instance for a comparatively rare cancer that is under-represented in trials and under-reported in national statistics. Hospital registries can fill an evidence gap when clinical data are lacking in population-based registries.
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http://dx.doi.org/10.1186/s12885-018-4759-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117879PMC
August 2018

Targeted disruption of the extracellular polymeric network of biofilms by alginate oligosaccharides.

NPJ Biofilms Microbiomes 2018 29;4:13. Epub 2018 Jun 29.

1Advanced Therapies Group, Cardiff University School of Dentistry, Heath Park, Cardiff, CF14 4XY UK.

Acquisition of a mucoid phenotype by sp. in the lungs of cystic fibrosis (CF) patients, with subsequent over-production of extracellular polymeric substance (EPS), plays an important role in mediating the persistence of multi-drug resistant (MDR) infections. The ability of a low molecular weight (Mn = 3200 g mol) alginate oligomer (OligoG CF-5/20) to modify biofilm structure of mucoid (NH57388A) was studied in vitro using scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) with Texas Red (TxRd®)-labelled OligoG and EPS histochemical staining. Structural changes in treated biofilms were quantified using COMSTAT image-analysis software of CLSM z-stack images, and nanoparticle diffusion. Interactions between the oligomers, Ca and DNA were studied using molecular dynamics (MD) simulations, Fourier transform infrared spectroscopy (FTIR) and isothermal titration calorimetry (ITC). Imaging demonstrated that OligoG treatment (≥0.5%) inhibited biofilm formation, revealing a significant reduction in both biomass and biofilm height ( < 0.05). TxRd®-labelled oligomers readily diffused into established (24 h) biofilms. OligoG treatment (≥2%) induced alterations in the EPS of established biofilms; significantly reducing the structural quantities of EPS polysaccharides, and extracellular (e)DNA ( < 0.05) with a corresponding increase in nanoparticle diffusion ( < 0.05) and antibiotic efficacy against established biofilms. ITC demonstrated an absence of rapid complex formation between DNA and OligoG and confirmed the interactions of OligoG with Ca evident in FTIR and MD modelling. The ability of OligoG to diffuse into biofilms, potentiate antibiotic activity, disrupt DNA-Ca-DNA bridges and biofilm EPS matrix highlights its potential for the treatment of biofilm-related infections.
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http://dx.doi.org/10.1038/s41522-018-0056-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026129PMC
June 2018

Female breast cancer management and survival: The experience of major public hospitals in South Australia over 3 decades-trends by age and in the elderly.

J Eval Clin Pract 2017 Dec 8;23(6):1433-1443. Epub 2017 Oct 8.

Haematology and Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.

Background: Clinical registry data from major South Australian public hospitals were used to investigate trends in invasive breast-cancer treatment and survival by age.

Methods: Disease-specific survival was calculated for the 1980 to 2013 diagnostic period using Kaplan-Meier product-limit estimates, with a censoring of live cases on December 31, 2014. Cox proportional hazards regression was used to examine differences in survival by age and tumour characteristic. First-round treatments following diagnosis were analysed, using multiple logistic regression to adjust for confounding.

Results: Five-year survival increased from 75% in the 1980s to 87% in 2000 to 2013, consistent with national trends, and with increases occurring irrespective of age. There was an increased use of breast conserving surgery, radiotherapy, chemotherapy, and hormone treatments. Five-year survival was lower for women aged 80+ years, increasing from 65% in the 1980s to 74% in 2000 to 2013. Lower survival in these older women persisted after adjusting for TNM stage, other clinical variables, and diagnostic year, without evidence of a reduced disparity over time. Older women were less likely to have surgery, radiotherapy, and chemotherapy throughout 1980 to 2013. By comparison, their use of hormone therapy was elevated. The adjusted relative odds of mastectomy (as opposed to breast conserving surgery) were lower for the 80+ year age range.

Conclusions: Breast-cancer survival increases applied to all ages, including 80+ years, but poorer outcomes persisted in this older group and the gap did not reduce. A key question is whether the best trade-off now exists between optimally therapeutic cancer treatment and accommodations for frailty and co-morbidity in the aged, or whether opportunities exist for better trade-offs and better survival. Local registry data are important for describing local service activity and outcomes by age for local service providers, health administrations and consumer groups; monitoring disparities; and indicating effects of local initiatives.
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http://dx.doi.org/10.1111/jep.12819DOI Listing
December 2017

A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness.

Antimicrob Agents Chemother 2017 09 24;61(9). Epub 2017 Aug 24.

Advanced Therapies Group, Cardiff University School of Dentistry, Cardiff, United Kingdom.

In chronic respiratory disease, the formation of dense, 3-dimensional "microcolonies" by within the airway plays an important role in contributing to resistance to treatment. An biofilm model of pseudomonal microcolony formation using artificial-sputum (AS) medium was established to study the effects of low-molecular-weight alginate oligomers (OligoG CF-5/20) on pseudomonal growth, microcolony formation, and the efficacy of colistin. The studies employed clinical cystic fibrosis (CF) isolates ( = 3) and reference nonmucoid and mucoid multidrug-resistant (MDR) CF isolates ( = 7). Bacterial growth and biofilm development and disruption were studied using cell viability assays and image analysis with scanning electron and confocal laser scanning microscopy. Pseudomonal growth in AS medium was associated with increased ATP production ( < 0.05) and the formation (at 48 h) of discrete (>10-μm) microcolonies. In conventional growth medium, colistin retained an ability to inhibit growth of planktonic bacteria, although the MIC was increased (0.1 to 0.4 μg/ml) in AS medium compared to Mueller-Hinton (MH) medium. In contrast, in an established-biofilm model in AS medium, the efficacy of colistin was decreased. OligoG CF-5/20 (≥2%) treatment, however, induced dose-dependent biofilm disruption ( < 0.05) and led to colistin retaining its antimicrobial activity ( < 0.05). While circular dichroism indicated that OligoG CF-5/20 did not change the orientation of the alginate carboxyl groups, mass spectrometry demonstrated that the oligomers induced dose-dependent (>0.2%; < 0.05) reductions in pseudomonal quorum-sensing signaling. These findings reinforce the potential clinical significance of microcolony formation in the CF lung and highlight a novel approach to treat MDR pseudomonal infections.
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http://dx.doi.org/10.1128/AAC.00762-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571347PMC
September 2017

Spontaneous mutations of a model heterotrophic marine bacterium.

ISME J 2017 07 21;11(7):1713-1718. Epub 2017 Mar 21.

Simon F. S. Li Marine Science Laboratory, School of Life Sciences and Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.

Heterotrophic marine bacterioplankton populations display substantive genomic diversity that is commonly explained to be the result of selective forces imposed by resource limitation or interactions with phage and predators. Here we use a mutation-accumulation experiment followed by whole-genome sequencing of mutation lines to determine an unbiased rate and molecular spectrum of spontaneous mutations for a model heterotrophic marine bacterium in the globally important Roseobacter clade, Ruegeria pomeroyi DSS-3. We find evidence for mutational bias towards deletions over insertions, and this process alone could account for a sizable portion of genome size diversity among roseobacters and also implies that lateral gene transfer and/or selection must also play a role in maintaining roseobacters with large genome sizes. We also find evidence for a mutational bias in favor of changes from A/T to G/C nucleobases, which explains widespread occurrences of G/C-enriched Roseobacter genomes. Using the calculated mutation rate of 1.39 × 10 per base per generation, we implement a 'mutation-rate clock' approach to date the evolution of roseobacters by assuming a constant mutation rate along their evolutionary history. This approach gives an estimated date of Roseobacter genome expansion in good agreement with an earlier fossil-based estimate of ~250 million years ago and is consistent with a hypothesis of a correlated evolutionary history between roseobacters and marine eukaryotic phytoplankton groups.
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http://dx.doi.org/10.1038/ismej.2017.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584476PMC
July 2017

The interaction of wood nanocellulose dressings and the wound pathogen P. aeruginosa.

Carbohydr Polym 2017 Feb 29;157:1955-1962. Epub 2016 Nov 29.

Advanced Therapies Group, Oral and Biomedical Sciences, Cardiff University School of Dentistry, Cardiff CF14 4XY, UK.

Chronic wounds pose an increasingly significant worldwide economic burden (over £1 billion per annum in the UK alone). With the escalation in global obesity and diabetes, chronic wounds will increasingly be a significant cause of morbidity and mortality. Cellulose nanofibrils (CNF) are highly versatile and can be tailored with specific physical properties to produce an assortment of three-dimensional structures (hydrogels, aerogels or films), for subsequent utilization as wound dressing materials. Growth curves using CNF (diameter <20nm) in suspension demonstrated an interesting dose-dependent inhibition of bacterial growth. In addition, analysis of biofilm formation (Pseudomonas aeruginosa PAO1) on nanocellulose aerogels (20g/m) revealed significantly less biofilm biomass with decreasing aerogel porosity and surface roughness. Importantly, virulence factor production by P. aeruginosa in the presence of nanocellulose materials, quantified for the first time, was unaffected (p>0.05) over 24h. These data demonstrate the potential of nanocellulose materials in the development of novel dressings that may afford significant clinical potential.
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http://dx.doi.org/10.1016/j.carbpol.2016.11.080DOI Listing
February 2017

Breast cancer screening-opportunistic use of registry and linked screening data for local evaluation.

J Eval Clin Pract 2017 Jun 22;23(3):508-516. Epub 2016 Sep 22.

Centre for Population Health Research, University of South Australia, Adelaide, SA, Australia.

Rationale: Screening has been found to reduce breast cancer mortality at a population level in Australia, but these studies did not address local settings where numbers of deaths would generally have been too low for evaluation. Clinicians, administrators, and consumer groups are also interested in local service outcomes. We therefore use more common prognostic and treatment measures and survivals to gain evidence of screening effects among patients attending 4 local hospitals for treatment.

Aims And Objectives: To compare prognostic, treatment, and survival measures by screening history to determine whether expected screening effects are occurring.

Methods: Employing routine clinical registry and linked screening data to investigate associations of screening history with these measures, using unadjusted and adjusted analyses.

Results: Screened women had a 10-year survival from breast cancer of 92%, compared with 78% for unscreened women; and 79% of screened surgical cases had breast conserving surgery compared with 64% in unscreened women. Unadjusted analyses indicated that recently screened cases had earlier tumor node metastasis stages, smaller diameters, less nodal involvement, better tumor differentiation, more oestrogen and progesterone receptor positive lesions, more hormone therapy, and less chemotherapy. Radiotherapy tended to be more common in screening participants. More frequent use of adjunctive radiotherapy applied when breast conserving surgery was used.

Conclusions: Results confirm the screening effects expected from the scientific literature and demonstrate the value of opportunistic use of available registry and linked screening data for indicating to local health administrations, practitioners, and consumers whether local screening services are having the effects expected.
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http://dx.doi.org/10.1111/jep.12640DOI Listing
June 2017

Control of cerebellar granule cell output by sensory-evoked Golgi cell inhibition.

Proc Natl Acad Sci U S A 2015 Oct 2;112(42):13099-104. Epub 2015 Oct 2.

Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology, and Pharmacology, University College London, London WC1E 6BT, United Kingdom

Classical feed-forward inhibition involves an excitation-inhibition sequence that enhances the temporal precision of neuronal responses by narrowing the window for synaptic integration. In the input layer of the cerebellum, feed-forward inhibition is thought to preserve the temporal fidelity of granule cell spikes during mossy fiber stimulation. Although this classical feed-forward inhibitory circuit has been demonstrated in vitro, the extent to which inhibition shapes granule cell sensory responses in vivo remains unresolved. Here we combined whole-cell patch-clamp recordings in vivo and dynamic clamp recordings in vitro to directly assess the impact of Golgi cell inhibition on sensory information transmission in the granule cell layer of the cerebellum. We show that the majority of granule cells in Crus II of the cerebrocerebellum receive sensory-evoked phasic and spillover inhibition prior to mossy fiber excitation. This preceding inhibition reduces granule cell excitability and sensory-evoked spike precision, but enhances sensory response reproducibility across the granule cell population. Our findings suggest that neighboring granule cells and Golgi cells can receive segregated and functionally distinct mossy fiber inputs, enabling Golgi cells to regulate the size and reproducibility of sensory responses.
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http://dx.doi.org/10.1073/pnas.1510249112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620892PMC
October 2015

Synaptic representation of locomotion in single cerebellar granule cells.

Elife 2015 Jun 17;4. Epub 2015 Jun 17.

Wolfson Institute for Biomedical Research and Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.

The cerebellum plays a crucial role in the regulation of locomotion, but how movement is represented at the synaptic level is not known. Here, we use in vivo patch-clamp recordings to show that locomotion can be directly read out from mossy fiber synaptic input and spike output in single granule cells. The increase in granule cell spiking during locomotion is enhanced by glutamate spillover currents recruited during movement. Surprisingly, the entire step sequence can be predicted from input EPSCs and output spikes of a single granule cell, suggesting that a robust gait code is present already at the cerebellar input layer and transmitted via the granule cell pathway to downstream Purkinje cells. Thus, synaptic input delivers remarkably rich information to single neurons during locomotion.
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http://dx.doi.org/10.7554/eLife.07290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499793PMC
June 2015

Uptake routes and toxicokinetics of silver nanoparticles and silver ions in the earthworm Lumbricus rubellus.

Environ Toxicol Chem 2015 Oct 11;34(10):2263-70. Epub 2015 Sep 11.

Centre for Ecology and Hydrology, Crowmarsh Gifford, Wallingford, Oxfordshire, United Kingdom.

Current bioavailability models, such as the free ion activity model and biotic ligand model, explicitly consider that metal exposure will be mainly to the dissolved metal in ionic form. With the rise of nanotechnology products and the increasing release of metal-based nanoparticles (NPs) to the environment, such models may increasingly be applied to support risk assessment. It is not immediately clear, however, whether the assumption of metal ion exposure will be relevant for NPs. Using an established approach of oral gluing, a toxicokinetics study was conducted to investigate the routes of silver nanoparticles (AgNPs) and Ag(+) ion uptake in the soil-dwelling earthworm Lumbricus rubellus. The results indicated that a significant part of the Ag uptake in the earthworms is through oral/gut uptake for both Ag(+) ions and NPs. Thus, sealing the mouth reduced Ag uptake by between 40% and 75%. An X-ray analysis of the internal distribution of Ag in transverse sections confirmed the presence of increased Ag concentrations in exposed earthworm tissues. For the AgNPs but not the Ag(+) ions, high concentrations were associated with the gut wall, liver-like chloragogenous tissue, and nephridia, which suggest a pathway for AgNP uptake, detoxification, and excretion via these organs. Overall, the results indicate that Ag in the ionic and NP forms is assimilated and internally distributed in earthworms and that this uptake occurs predominantly via the gut epithelium and less so via the body wall. The importance of oral exposure questions the application of current metal bioavailability models, which implicitly consider that the dominant route of exposure is via the soil solution, for bioavailability assessment and modeling of metal-based NPs.
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http://dx.doi.org/10.1002/etc.3036DOI Listing
October 2015

Colorectal cancer treatment and survival: the experience of major public hospitals in south Australia over three decades.

Asian Pac J Cancer Prev 2015 ;16(6):2431-40

School of Population Health, University of South Australia, Adelaide, South Australia E-mail :

Background: Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010.

Materials And Methods: Kaplan-Meier product- limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends.

Results: Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased, particularly for stage C where the increase was from 8% in 1980-1986 to 60% in 2005-2010. The percentage of stage C colorectal cases less than 70 years of age having systemic therapy as part of their first treatment round increased from 3% in 1980-1986 to 81% by 1995-2010. Based on survey data on uptake of adjuvant therapy among those offered this care, it is likely that all these younger patients were offered systemic treatment.

Conclusions: We conclude that pronounced increases in survivals from colorectal cancer have occurred at major public hospitals in South Australia due to increases in stage-specific survivals. Use of adjuvant therapies has increased and the patterns of change accord with clinical guideline recommendations. Reasons for sub-optimal use of radiotherapy for rectal cases warrant further investigation, including the potential for limited rural access to impede uptake of treatments at metropolitan-based radiotherapy centres.
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http://dx.doi.org/10.7314/apjcp.2015.16.6.2431DOI Listing
February 2016

Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179.

Nat Commun 2015 Jan 23;6:6006. Epub 2015 Jan 23.

Department of Genetics, UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK.

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice.
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http://dx.doi.org/10.1038/ncomms7006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354202PMC
January 2015

Analytical approaches to support current understanding of exposure, uptake and distributions of engineered nanoparticles by aquatic and terrestrial organisms.

Ecotoxicology 2015 Mar 17;24(2):239-61. Epub 2014 Dec 17.

Centre for Ecology and Hydrology, Maclean Building, Benson Lane, Wallingford, Oxfordshire, OX10 8BB, UK.

Initiatives to support the sustainable development of the nanotechnology sector have led to rapid growth in research on the environmental fate, hazards and risk of engineered nanoparticles (ENP). As the field has matured over the last 10 years, a detailed picture of the best methods to track potential forms of exposure, their uptake routes and best methods to identify and track internal fate and distributions following assimilation into organisms has begun to emerge. Here we summarise the current state of the field, focussing particularly on metal and metal oxide ENPs. Studies to date have shown that ENPs undergo a range of physical and chemical transformations in the environment to the extent that exposures to pristine well dispersed materials will occur only rarely in nature. Methods to track assimilation and internal distributions must, therefore, be capable of detecting these modified forms. The uptake mechanisms involved in ENP assimilation may include a range of trans-cellular trafficking and distribution pathways, which can be followed by passage to intracellular compartments. To trace toxicokinetics and distributions, analytical and imaging approaches are available to determine rates, states and forms. When used hierarchically, these tools can map ENP distributions to specific target organs, cell types and organelles, such as endosomes, caveolae and lysosomes and assess speciation states. The first decade of ENP ecotoxicology research, thus, points to an emerging paradigm where exposure is to transformed materials transported into tissues and cells via passive and active pathways within which they can be assimilated and therein identified using a tiered analytical and imaging approach.
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http://dx.doi.org/10.1007/s10646-014-1387-3DOI Listing
March 2015

Do visual circuits mature without visual stimuli?

J Neurosci 2014 Nov;34(48):15833-5

Institute of Ophthalmology, UCL, London EC1V 9EL, United Kingdom, and.

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http://dx.doi.org/10.1523/JNEUROSCI.3857-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244459PMC
November 2014

The regulation of copper stress response genes in the polychaete Nereis diversicolor during prolonged extreme copper contamination.

Environ Sci Technol 2014 Nov 4;48(22):13085-92. Epub 2014 Nov 4.

Biosciences, College of Life and Environmental Sciences, University of Exeter , Exeter, EX4 4QD, U.K.

Polychaetes are frequented in toxicological studies, one reason being that some members occupy shallow burrows in sediments and are maximally exposed to the contaminants that accumulate within them. We have been studying one population of the polychaete Nereis (Hediste) diversicolor exhibiting inheritable tolerance to extreme copper contamination in estuarine sediment. Using transcriptome sequencing data we have identified a suite of genes with putative roles in metal detoxification and tolerance, and measured their regulation. Copper tolerant individuals display significantly different gene expression profiles compared to animals from a nearby population living without remarkable copper levels. Gene transcripts encoding principle copper homeostasis proteins including membrane copper ion transporters, copper ion chaperones and putative metallothionein-like proteins were significantly more abundant in tolerant animals occupying contaminated sediment. In contrast, those encoding antioxidants and cellular repair pathways were unchanged. Nontolerant animals living in contaminated sediment showed no difference in copper homeostasis-related gene expression but did have significantly elevated levels of mRNAs encoding Glutathione Peroxidase enzymes. This study represents the first use of functional genomics to investigate the copper tolerance trait in this species and provides insight into the mechanism used by these individuals to survive and flourish in conditions which are lethal to their conspecifics.
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http://dx.doi.org/10.1021/es503622xDOI Listing
November 2014

Non-invasive detection of early retinal neuronal degeneration by ultrahigh resolution optical coherence tomography.

PLoS One 2014 28;9(4):e93916. Epub 2014 Apr 28.

School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom; Department of Neurology and Ophthalmology, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Optical coherence tomography (OCT) has revolutionises the diagnosis of retinal disease based on the detection of microscopic rather than subcellular changes in retinal anatomy. However, currently the technique is limited to the detection of microscopic rather than subcellular changes in retinal anatomy. However, coherence based imaging is extremely sensitive to both changes in optical contrast and cellular events at the micrometer scale, and can generate subtle changes in the spectral content of the OCT image. Here we test the hypothesis that OCT image speckle (image texture) contains information regarding otherwise unresolvable features such as organelle changes arising in the early stages of neuronal degeneration. Using ultrahigh resolution (UHR) OCT imaging at 800 nm (spectral width 140 nm) we developed a robust method of OCT image analyses, based on spatial wavelet and texture-based parameterisation of the image speckle pattern. For the first time we show that this approach allows the non-invasive detection and quantification of early apoptotic changes in neurons within 30 min of neuronal trauma sufficient to result in apoptosis. We show a positive correlation between immunofluorescent labelling of mitochondria (a potential source of changes in cellular optical contrast) with changes in the texture of the OCT images of cultured neurons. Moreover, similar changes in optical contrast were also seen in the retinal ganglion cell- inner plexiform layer in retinal explants following optic nerve transection. The optical clarity of the explants was maintained throughout in the absence of histologically detectable change. Our data suggest that UHR OCT can be used for the non-invasive quantitative assessment of neuronal health, with a particular application to the assessment of early retinal disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093916PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002422PMC
June 2015
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