734 results on '"Leary S"'
Search Results
2. Association between overweight/obesity and dental outcomes in early childhood: Findings from an Australian cohort study.
- Author
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Leary, S. D., Ha, D. H., Dudding, T., and Do, L. G.
- Subjects
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PRESCHOOL children , *BODY mass index , *ORAL health , *DENTAL caries , *COHORT analysis - Abstract
Objectives Methods Results Conclusions Oral health is an important part of general health and well‐being and shares risk factors, such as poor diet, with obesity. The published literature assessing the association between obesity and oral health in early childhood is sparse and inconsistent. The objective of this study was to investigate associations between overweight/obesity (measured by body mass index) and dental outcomes (caries, plaque index and gingival index) both cross‐sectionally and longitudinally, taking account of potential confounding factors, based on data collected at age 2 and age 5 within the Australian Study of Mothers' and Infants' Life Events Affecting Oral Health (SMILE) birth cohort study.This study used data from 1174 SMILE participants. Associations between overweight/obesity and dental outcomes were assessed using generalized linear regression models for the modified Poisson family with log link to estimate prevalence ratios. Cross‐sectional and longitudinal models were fitted, after minimal and full adjustment for potential confounders.Approximately 12% of the participants were overweight/obese at 2 years and 9% at 5 years. Between 2 and 5 years, the prevalence of caries increased from approximately 4% to 24%, at least mild plaque accumulation increased from 37% to 90% and at least mild inflammation from 27% to 68%. There were no associations between overweight/obesity and the prevalence of dental caries; prevalence ratios (PR) [95% confidence interval (CI)] after adjustment for age and sex were 0.9 (0.3, 2.4) cross‐sectionally at 2 years, 1.0 (0.6, 1.5) cross‐sectionally at 5 years, and 1.0 (0.6, 1.5) for overweight/obesity at 2 years and caries at 5 years. Prevalence ratios were all around the value of 1 for the other dental outcomes and also after adjustment for additional confounders.There were no associations between overweight/obesity and dental caries, plaque index or gingival index in this cohort of preschool children. However, associations may emerge as the children become older, and it will be possible to extend analyses to include data collected at age 7 in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Assessing the validity of EQ-5D-5L in people with head & neck cancer: Does a generic quality of life measure perform as well as a disease-specific measure in a patient population?
- Author
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Davies, A., Waylen, A., Leary, S., Thomas, S., Pring, M., Janssen, B., Beynon, R., Lang, S., Schimansky, S., Hurley, K., and Ness, A.
- Published
- 2020
- Full Text
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4. Trajectories of child free sugars intake and dental caries - a population-based birth cohort study
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Ha, Diep, Nguyen, Huy, Bell, Lucinda, Devenish-Coleman, Gemma, Thomson, W.M., Manton, D., Leary, S., Scott, Jane, Spencer, A.J., Do, Loc, Ha, Diep, Nguyen, Huy, Bell, Lucinda, Devenish-Coleman, Gemma, Thomson, W.M., Manton, D., Leary, S., Scott, Jane, Spencer, A.J., and Do, Loc
- Abstract
Objectives: To investigate the association between trajectories of free sugars intake during the first five years of life and dental caries experience at five years. Methods: Data from the SMILE population-based prospective birth cohort study, collected at one, two and five years old, were used. A 3-days dietary diary and food frequency questionnaire were used to estimate free sugars intake (FSI) in grams. The primary outcomes were dental caries prevalence and experience (dmfs). The Group Based Trajectory Modelling method was used to characterize three FSI trajectories (‘Low and increasing’; ‘Mod erate and increasing’; and ‘High and increasing’), which were the main exposures. Multivariable regression models were generated to compute adjusted prevalence ratios (APR) and rate ratios (ARR) for the exposure, controlling for socioeconomic factors. Results: The prevalence of caries was 23.3%, with a mean dmfs of 1.4, and a median of 3.0 among those who had caries. There were clear gradients of caries prevalence and experience by the FSI trajectories. The ‘High and increasing’ had an APR of 2.13 (95%CI 1.23-3.70) and ARR of 2.77 (95%CI 1.45-5.32) against the ‘Low and increasing’. The ‘Moderate and increasing’ group had intermediate estimates. A quarter of the caries cases could have been prevented if the whole study sample had been in the ‘Low and increasing’ FSI trajectory. Conclusion: A sustained, high trajectory of FSI from a young age was positively associated with child dental caries. Measures to minimise consumption of free sugars must commence early in life. Clinical significance: The study has provided high level evidence to inform clinicians’ decisions in promoting a healthy dietary pattern for young children.
- Published
- 2023
5. Amino acid racemisation dating of a last interglacial estuarine deposit at Largs, New South Wales
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Murray-Wallace, C V, Leary, S P, Kimber, R W L, and BioStor
- Published
- 1996
6. CHANGES IN ORAL HEALTH BEHAVIOUR BETWEEN CHILDHOOD AND ADOLESCENCE : FINDINGS FROM A UK COHORT
- Author
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Leary, S, Graham, E, and Do, L
- Published
- 2016
7. Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study
- Author
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Do, L.G., primary, Spencer, A.J., additional, Sawyer, A., additional, Jones, A., additional, Leary, S., additional, Roberts, R., additional, and Ha, D.H., additional
- Published
- 2022
- Full Text
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8. Challenges and Novel Approaches in the Epidemiological Study of Early Life Influences on Later Disease
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Smith, G. Davey, Leary, S., Ness, A., Lawlor, D. A., Koletzko, Berthold, editor, Decsi, Tamás, editor, Molnár, Dées, editor, and de la Hunty, Anne, editor
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- 2009
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9. Garden terror—Case series of twenty‐eight serious ear injuries caused by yucca plants
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Vartanyan, M., Orimoto, K., Dragovic, A.S., Crock, C., Dobson, M., and OʼLeary, S.
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- 2018
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10. Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors
- Author
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Sooda, A., Rwandamuriye, F., Wanjalla, C.N., Jing, L., Koelle, D.M., Peters, B., Leary, S., Chopra, A., Calderwood, M.A., Mallal, S.A., Pavlos, R., Watson, M., Phillips, E.J., Redwood, A.J., Sooda, A., Rwandamuriye, F., Wanjalla, C.N., Jing, L., Koelle, D.M., Peters, B., Leary, S., Chopra, A., Calderwood, M.A., Mallal, S.A., Pavlos, R., Watson, M., Phillips, E.J., and Redwood, A.J.
- Abstract
Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.
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- 2022
11. Pediatric pineoblastoma: A pooled outcome study of North American and Australian therapeutic data.
- Author
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Hansford, JR, Huang, J, Endersby, R, Dodgshun, AJ, Li, BK, Hwang, E, Leary, S, Gajjar, A, Von Hoff, K, Wells, O, Wray, A, Kotecha, RS, Raleigh, DR, Stoller, S, Mueller, S, Schild, SE, Bandopadhayay, P, Fouladi, M, Bouffet, E, Huang, A, Onar-Thomas, A, Gottardo, NG, Hansford, JR, Huang, J, Endersby, R, Dodgshun, AJ, Li, BK, Hwang, E, Leary, S, Gajjar, A, Von Hoff, K, Wells, O, Wray, A, Kotecha, RS, Raleigh, DR, Stoller, S, Mueller, S, Schild, SE, Bandopadhayay, P, Fouladi, M, Bouffet, E, Huang, A, Onar-Thomas, A, and Gottardo, NG
- Abstract
BACKGROUND: Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. PATIENTS AND METHODS: Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher's exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses. RESULTS: We describe a pooled cohort of 178 pineoblastoma cases from Children's Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children <3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both P < .0001). Multivariable analysis showed male sex was associated with worse PFS in children <3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; P = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; P = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; P = .0016). CONCLUSION: Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.
- Published
- 2022
12. Sequencing of the viral UL111a gene directly from clinical specimens reveals variants of HCMV-encoded IL-10 that are associated with altered immune responses to HCMV
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Waters, S., Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, K., Gaudieri, S., Irish, A., Keil, A.D., Allcock, R.J.N., Price, P., Waters, S., Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, K., Gaudieri, S., Irish, A., Keil, A.D., Allcock, R.J.N., and Price, P.
- Abstract
Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ~80% of adults worldwide. Acute infections are often asymptomatic in healthy individuals but generate diverse syndromes in neonates, renal transplant recipients (RTR), and people with HIV (PWH). The HCMV gene UL111a encodes a homolog of human interleukin-10 (IL-10) that interacts with the human IL-10 receptor. Deep sequencing technologies were used to sequence UL111a directly from 59 clinical samples from Indonesian PWH and Australian RTR, healthy adults, and neonates. Overall, 93% of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous variation. Carriage of these variants differed between neonates and adults, Australians and Indonesians, and between saliva and blood leukocytes. The variant alleles of N41D and S71Y occurred together in Australian RTR and were associated with higher T-cell responses to HCMV pp65. The variant P122S was associated with lower levels of antibodies reactive with a lysate of HCMV-infected fibroblasts. L174F was associated with increased levels of antibodies reactive with HCMV lysate, immediate-early 1 (IE-1), and glycoprotein B (gB) in Australian RTR and Indonesians PWH, suggesting a higher viral burden. We conclude that variants of UL111a are common in all populations and may influence systemic responses to HCMV.
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- 2022
13. Altered subgenomic RNA abundance provides unique insight into SARS-CoV-2 B.1.1.7/Alpha variant infections
- Author
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Parker, M.D., Stewart, H., Shehata, O.M., Lindsey, B.B., Shah, D.R., Hsu, S., Keeley, A.J., Partridge, D.G., Leary, S., Cope, A., State, A., Johnson, K., Ali, N., Raghei, R., Heffer, J., Smith, N., Zhang, P., Gallis, M., Louka, S.F., Hornsby, H.R., Alamri, H., Whiteley, M., Foulkes, B.H., Christou, S., Wolverson, P., Pohare, M., Hansford, S.E., Green, L.R., Evans, C., Raza, M., Wang, D., Firth, A.E., Edgar, J.R., Gaudieri, S., Mallal, S., Collins, M.O., Peden, A.A., de Silva, T.I., Parker, M.D., Stewart, H., Shehata, O.M., Lindsey, B.B., Shah, D.R., Hsu, S., Keeley, A.J., Partridge, D.G., Leary, S., Cope, A., State, A., Johnson, K., Ali, N., Raghei, R., Heffer, J., Smith, N., Zhang, P., Gallis, M., Louka, S.F., Hornsby, H.R., Alamri, H., Whiteley, M., Foulkes, B.H., Christou, S., Wolverson, P., Pohare, M., Hansford, S.E., Green, L.R., Evans, C., Raza, M., Wang, D., Firth, A.E., Edgar, J.R., Gaudieri, S., Mallal, S., Collins, M.O., Peden, A.A., and de Silva, T.I.
- Abstract
B.1.1.7 lineage SARS-CoV-2 is more transmissible, leads to greater clinical severity, and results in modest reductions in antibody neutralization. Subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool (periscope) to ARTIC Network Oxford Nanopore Technologies genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA is significantly increased in B.1.1.7 (alpha) infections (n = 879). This increase is seen over the previous dominant lineage in the UK, B.1.177 (n = 943), which is independent of genomic reads, E cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus in vitro. We hypothesise that increased ORF9b in B.1.1.7 is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT > CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles to evaluate emerging potential variants of concern.
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- 2022
14. Single-cell multi-omic approaches define common molecular and cellular signals of dominant antigen-driven cells at the site of drug-induced Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) tissue damage
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Gibson, A., Li, Y., Thorne, M., Ram, R., Palubinsky, A., Choshi, P., Porter, M., Trubiano, J., Deshpande, P., Chopra, A., Leary, S., Gangula, R., White, K., Pilkington, M., Konvinse, K., Wang, C-W, Pan, R-Y, Hung, S-I, Chung, W-H, Peter, J., Mallal, S., Phillips, E., Gibson, A., Li, Y., Thorne, M., Ram, R., Palubinsky, A., Choshi, P., Porter, M., Trubiano, J., Deshpande, P., Chopra, A., Leary, S., Gangula, R., White, K., Pilkington, M., Konvinse, K., Wang, C-W, Pan, R-Y, Hung, S-I, Chung, W-H, Peter, J., Mallal, S., and Phillips, E.
- Abstract
Human leukocyte antigen (HLA)-restricted CD8+ T-cells expressing dominant T-cell receptor (TCR) clonotypes are recently implicated drivers of keratinocyte cell death, cutaneous blistering, and mortality in drug-induced Stevens Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN). Signatures of these effector population(s) remain undefined in affected tissue but hold utility for early diagnosis and targeted therapy.
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- 2022
15. Sequencing of the Viral UL111a Gene Directly from Clinical Specimens Reveals Variants of HCMV-Encoded IL-10 That Are Associated with Altered Immune Responses to HCMV
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Waters, Shelley, Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, Kylie, Gaudieri, S., Irish, A., Keil, A.D., Allcock, R.J.N., Price, Patricia, Waters, Shelley, Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, Kylie, Gaudieri, S., Irish, A., Keil, A.D., Allcock, R.J.N., and Price, Patricia
- Abstract
Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ~80% of adults world-wide. Acute infections are often asymptomatic in healthy individuals but generate diverse syndromes in neonates, renal transplant recipients (RTR), and people with HIV (PWH). The HCMV gene UL111a encodes a homolog of human interleukin-10 (IL-10) that interacts with the human IL-10 receptor. Deep sequencing technologies were used to sequence UL111a directly from 59 clinical samples from Indonesian PWH and Australian RTR, healthy adults, and neonates. Overall, 93% of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous variation. Carriage of these variants differed between neonates and adults, Australians and Indonesians, and between saliva and blood leukocytes. The variant alleles of N41D and S71Y occurred together in Australian RTR and were associated with higher T-cell responses to HCMV pp65. The variant P122S was associated with lower levels of antibodies reactive with a lysate of HCMV-infected fibroblasts. L174F was associated with increased levels of antibodies reactive with HCMV lysate, immediate-early 1 (IE-1), and glycoprotein B (gB) in Australian RTR and Indonesians PWH, suggesting a higher viral burden. We conclude that variants of UL111a are common in all populations and may influence systemic responses to HCMV.
- Published
- 2022
16. Group-based trajectories of maternal intake of sugar-sweetened beverage and offspring oral health from a prospective birth cohort study
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Ha, D.H., Nguyen, H., Dao, A., Golley, R.K., Thomson, D.M., Manton, D.J., Leary, S., Scott, Jane, Spencer, A.J., Do, Loc, Ha, D.H., Nguyen, H., Dao, A., Golley, R.K., Thomson, D.M., Manton, D.J., Leary, S., Scott, Jane, Spencer, A.J., and Do, Loc
- Abstract
Objectives: To investigate the trajectory of maternal intake of sugar-sweetened beverages (SSB) during the first five years of their child’s life and its effect on the child’s dental caries at five years-of-age. Methods: This is an ongoing prospective population-based birth cohort study in Adelaide, Australia. Mothers completed questionnaires on their SSB intake, socioeconomic factors and health behaviors at the birth of their child and at the ages of one, two and five years. Child dental caries measured as decayed, missing, or filled tooth surfaces was collected by oral examination. Maternal SSB intake was used to estimate the trajectory of SSB intake. The trajectories then became the main exposure of the study. Dental caries at age five years were the primary outcomes. Adjusted mean- and prevalence-ratios were estimated for dental caries, controlling for confounders. Results: 879 children had dental examinations at five years-of-age. Group-based trajectory modeling identified three trajectories of maternal SSB intake: ‘Stable low’ (40.8%), ‘Moderate but increasing’ (13.6%), and ‘High early’ trajectory (45.6%). Multivariable regression analysis found children of mothers in the ‘High early’ and ‘Moderate but increasing’ groups to have greater experience of dental caries (MR: 1.37 (95%CI 1.01-1.67), and 1.24 (95%CI 0.96-1.60) than those in the ‘Stable low’ trajectory, respectively. Conclusion: Maternal consumption of SSB during pregnancy and in the early postnatal period influenced their offspring’s oral health. It is important to create a low-sugar environment from early childhood. The results suggest that health promotion activities need to be delivered to expecting women or soon after childbirth.
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- 2022
17. sj-docx-1-jdr-10.1177_00220345221119431 – Supplemental material for Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study
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Do, L.G., Spencer, A.J., Sawyer, A., Jones, A., Leary, S., Roberts, R., and Ha, D.H.
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110599 Dentistry not elsewhere classified ,FOS: Materials engineering ,FOS: Clinical medicine ,91299 Materials Engineering not elsewhere classified - Abstract
Supplemental material, sj-docx-1-jdr-10.1177_00220345221119431 for Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study by L.G. Do, A.J. Spencer, A. Sawyer, A. Jones, S. Leary, R. Roberts and D.H. Ha in Journal of Dental Research
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- 2022
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18. An Evaluation of Current Services Available for People Diagnosed with Head and Neck Cancer in the UK (2009–2010)
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Hughes, C., Homer, J., Bradley, P., Nutting, C., Ness, A., Persson, M., Jeffreys, M., Waylen, A., Leary, S., and Thomas, S.
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- 2012
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19. Early Childhood Exposures to Fluorides and Child Behavioral Development and Executive Function: A Population-Based Longitudinal Study.
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Do, L.G., Spencer, A.J., Sawyer, A., Jones, A., Leary, S., Roberts, R., and Ha, D.H.
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FLUORIDES ,CHILD development ,WATER fluoridation ,EXECUTIVE function - Abstract
It is important to both protect the healthy development and maintain the oral health of the child population. The study examined the effect of early childhood exposures to water fluoridation on measures of school-age executive functioning and emotional and behavioral development in a population-based sample. This longitudinal follow-up study used information from Australia's National Child Oral Health Study 2012–14. Children aged 5 to 10 y at baseline were contacted again after 7 to 8 y, before they had turned 18 y of age. Percent lifetime exposed to fluoridated water (%LEFW) from birth to the age 5 y was estimated from residential history and postcode-level fluoride levels in public tap water. Measures of children's emotional and behavioral development were assessed by the Strength and Difficulties Questionnaire (SDQ), and executive functioning was measured by the Behavior Rating Inventory of Executive Function (BRIEF). Multivariable regression models were generated to compare the associations between the exposure and the primary outcomes and controlled for covariates. An equivalence test was also conducted to compare the primary outcomes of those who had 100% LEFW against those with 0% LEFW. Sensitivity analysis was also conducted. A total of 2,682 children completed the SDQ and BRIEF, with mean scores of 7.0 (95% confidence interval, 6.6–7.4) and 45.3 (44.7–45.8), respectively. Those with lower %LEFW tended to have poorer scores of the SDQ and BRIEF. Multivariable regression models reported no association between exposure to fluoridated water and the SDQ and BRIEF scores. Low household income, identifying as Indigenous, and having a neurodevelopmental diagnosis were associated with poorer SDQ/BRIEF scores. An equivalence test confirmed that the SDQ/BRIEF scores among those with 100% LEFW were equivalent to that of those who had 0% LEFW. Exposure to fluoridated water during the first 5 y of life was not associated with altered measures of child emotional and behavioral development and executive functioning. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Use of CDP-STAR in a fast and highly sensitive chemiluminescent detection procedure for VNTR loci with neutral and charged membranes
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Leary, S. L., Victor, J., Balazs, I., Carracedo, Angel, editor, Brinkmann, Bernd, editor, and Bär, Walter, editor
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- 1996
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21. Defining an adipose tissue single cell atlas to understand metabolic disease in HIV
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Bailin, SS., Ram, R., Chopra, A., Gangula, R., Leary, S., Mashayekhi, M., Gabriel, CL., Woodward, BO., Lima, M., Hannah, L., Kalams, SA., Mallal, SA., Koethe, JR., and Wanjalla, CN.
- Subjects
Adipose tissues -- Observations ,AIDS (Disease) -- Research ,AIDS research ,Immune response -- Regulation ,HIV infection -- Development and progression -- Care and treatment ,Health - Abstract
Background: Adipose tissue (AT) is a critical regulator of metabolic health and is emerging as important in HIV. Despite this, data on the complex cellular milieu and immune regulation are [...]
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- 2021
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22. Does Birth Weight Predict Childhood Diet in the Avon Longitudinal Study of Parents and Children?
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Shultis, W. A., Leary, S. D., Ness, A. R., Bain, C. J., and Emmett, P. M.
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- 2005
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23. Randomized clinical trial of postoperative chewing gum versus standard care after colorectal resection
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Atkinson, C., Penfold, C. M., Ness, A. R., Longman, R. J., Thomas, S. J., Hollingworth, W., Kandiyali, R., Leary, S. D., and Lewis, S. J.
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- 2016
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24. Structural outcomes in the Cleft Care UK study. Part 2: dento-facial outcomes
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Al-Ghatam, R., Jones, T. E. M., Ireland, A. J., Atack, N. E., Chawla, O., Deacon, S., Albery, L., Cobb, A. R. M., Cadogan, J., Leary, S., Waylen, A., Wills, A. K., Richard, B., Bella, H., Ness, A. R., and Sandy, J. R.
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- 2015
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25. Endolymphatic hydrops is prevalent in the first weeks following cochlear implantation
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Smeds, H., Eastwood, H. T., Hampson, A. J., Sale, P., Campbell, L. J., Arhatari, B. D., Mansour, S., and OʼLeary, S. J.
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- 2015
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26. Seasonal isolation of microalgae from municipal wastewater for remediation and biofuel applications
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Park, K. C., Whitney, C. G.E., Kozera, C., OʼLeary, S. J.B., and McGinn, P. J.
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- 2015
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27. Generation of a novel SARS-CoV-2 Sub-genomic RNA due to the R203K/G204R variant in Nucleocapsid: Homologous recombination has potential to change SARS-CoV-2 at both protein and RNA level
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Leary, S., Gaudieri, S., Parker, M.D., Chopra, A., James, I., Pakala, S., Alves, E., John, M., Lindsey, B.B., Keeley, A.J., Rowland-Jones, S.L., Swanson, M.S., Ostrov, D.A., Bubenik, J.L., Das, S.R., Sidney, J., Sette, A., de Silva, T.I., Phillips, E., Mallal, S., Leary, S., Gaudieri, S., Parker, M.D., Chopra, A., James, I., Pakala, S., Alves, E., John, M., Lindsey, B.B., Keeley, A.J., Rowland-Jones, S.L., Swanson, M.S., Ostrov, D.A., Bubenik, J.L., Das, S.R., Sidney, J., Sette, A., de Silva, T.I., Phillips, E., and Mallal, S.
- Abstract
Background: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host’s anti-viral immune response, in turn affecting the frequency of variants over time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. Methods: Deep-sequencing data of SARS-CoV-2 from public databases and from clinical samples were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Results: Sequence analysis suggests that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep-sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. Conclusions: The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans, resulting in both coding changes and novel sub-genomic RNA transcripts, suggests this as a mechanism for diversification and adaptation within its new host.
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- 2021
28. Visual genomics analysis studio as a tool to analyze multiomic data
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Hertzman, R.J., Deshpande, P., Leary, S., Li, Y., Ram, R., Chopra, A., Cooper, D., Watson, M., Palubinsky, A.M., Mallal, S., Gibson, A., Phillips, E.J., Hertzman, R.J., Deshpande, P., Leary, S., Li, Y., Ram, R., Chopra, A., Cooper, D., Watson, M., Palubinsky, A.M., Mallal, S., Gibson, A., and Phillips, E.J.
- Abstract
Type B adverse drug reactions (ADRs) are iatrogenic immune-mediated syndromes with mechanistic etiologies that remain incompletely understood. Some of the most severe ADRs, including delayed drug hypersensitivity reactions, are T-cell mediated, restricted by specific human leukocyte antigen risk alleles and sometimes by public or oligoclonal T-cell receptors (TCRs), central to the immunopathogenesis of tissue-damaging response. However, the specific cellular signatures of effector, regulatory, and accessory immune populations that mediate disease, define reaction phenotype, and determine severity have not been defined. Recent development of single-cell platforms bringing together advances in genomics and immunology provides the tools to simultaneously examine the full transcriptome, TCRs, and surface protein markers of highly heterogeneous immune cell populations at the site of the pathological response at a single-cell level. However, the requirement for advanced bioinformatics expertise and computational hardware and software has often limited the ability of investigators with the understanding of diseases and biological models to exploit these new approaches. Here we describe the features and use of a state-of-the-art, fully integrated application for analysis and visualization of multiomic single-cell data called Visual Genomics Analysis Studio (VGAS). This unique user-friendly, Windows-based graphical user interface is specifically designed to enable investigators to interrogate their own data. While VGAS also includes tools for sequence alignment and identification of associations with host or organism genetic polymorphisms, in this review we focus on its application for analysis of single-cell TCR–RNA–Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-seq, enabling holistic cellular characterization by unbiased transcriptome and select surface proteome. Critically, VGAS does not require user-directed coding or access to high-performance com
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- 2021
29. In chronic infection, HIV Gag-Specific CD4+ T cell receptor diversity is higher than CD8+ T cell receptor diversity and is associated with Less HIV quasispecies diversity
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Pilkinton, M.A., McDonnell, W.J., Barnett, L., Chopra, A., Gangula, R., White, K.D., Leary, S., Currenti, J., Gaudieri, S., Mallal, S.A., Kalams, S.A., Silvestri, G., Pilkinton, M.A., McDonnell, W.J., Barnett, L., Chopra, A., Gangula, R., White, K.D., Leary, S., Currenti, J., Gaudieri, S., Mallal, S.A., Kalams, S.A., and Silvestri, G.
- Abstract
Cellular immune responses to Gag correlate with improved HIV control. The full extent of cellular immune responses comprises both the number of epitopes recognized by CD4+ and CD8+ T cells and the diversity of the T cell receptor (TCR) repertoire directed against each epitope. The optimal diversity of the responsive TCR repertoire is unclear. Therefore, we evaluated the TCR diversity of CD4+ and CD8+ T cells responding to HIV-1 Gag to determine if TCR diversity correlates with clinical or virologic metrics. Previous studies of TCR repertoires have been limited primarily to CD8+ T cell responses directed against a small number of well-characterized T cell epitopes restricted by specific human leukocyte antigens. We stimulated peripheral blood mononuclear cells from 21 chronic HIV-infected individuals overnight with a pool of HIV-1 Gag peptides, followed by sorting of activated CD4+ and CD8+ T cells and TCR deep sequencing. We found Gag-reactive CD8+ T cells to be more oligoclonal, with a few dominant TCRs comprising the bulk of the repertoire, compared with the highly diverse TCR repertoires of Gag-reactive CD4+ T cells. HIV sequencing of the same donors revealed that high CD4+ T cell TCR diversity was strongly associated with lower HIV Gag genetic diversity. We conclude that the TCR repertoire of Gag-reactive CD4+ T helper cells displays substantial diversity without a clearly dominant circulating TCR clonotype, in contrast to a hierarchy of dominant TCR clonotypes in the Gag-reactive CD8+ T cells, and may serve to limit HIV diversity during chronic infection.
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- 2021
30. Subgenomic RNA identification in SARS-CoV-2 genomic sequencing data
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Parker, M.D., Lindsey, B.B., Leary, S., Gaudieri, S., Chopra, A., Wyles, M., Angyal, A., Green, L.R., Parsons, P., Tucker, R.M., Brown, R., Groves, D., Johnson, K., Carrilero, L., Heffer, J., Partridge, D.G., Evans, C., Raza, M., Keeley, A.J., Smith, N., Filipe, A.D., Shepherd, J.G., Davis, C., Bennett, S., Sreenu, V.B., Kohl, A., Aranday-Cortes, E., Tong, L., Nichols, J., Thomson, E.C., Wang, D., Mallal, S., de Silva, T.I., Parker, M.D., Lindsey, B.B., Leary, S., Gaudieri, S., Chopra, A., Wyles, M., Angyal, A., Green, L.R., Parsons, P., Tucker, R.M., Brown, R., Groves, D., Johnson, K., Carrilero, L., Heffer, J., Partridge, D.G., Evans, C., Raza, M., Keeley, A.J., Smith, N., Filipe, A.D., Shepherd, J.G., Davis, C., Bennett, S., Sreenu, V.B., Kohl, A., Aranday-Cortes, E., Tong, L., Nichols, J., Thomson, E.C., Wang, D., Mallal, S., and de Silva, T.I.
- Abstract
We have developed periscope, a tool for the detection and quantification of subgenomic RNA (sgRNA) in SARS-CoV-2 genomic sequence data. The translation of the SARS-CoV-2 RNA genome for most open reading frames (ORFs) occurs via RNA intermediates termed “subgenomic RNAs.” sgRNAs are produced through discontinuous transcription, which relies on homology between transcription regulatory sequences (TRS-B) upstream of the ORF start codons and that of the TRS-L, which is located in the 5′ UTR. TRS-L is immediately preceded by a leader sequence. This leader sequence is therefore found at the 5′ end of all sgRNA. We applied periscope to 1155 SARS-CoV-2 genomes from Sheffield, United Kingdom, and validated our findings using orthogonal data sets and in vitro cell systems. By using a simple local alignment to detect reads that contain the leader sequence, we were able to identify and quantify reads arising from canonical and noncanonical sgRNA. We were able to detect all canonical sgRNAs at the expected abundances, with the exception of ORF10. A number of recurrent noncanonical sgRNAs are detected. We show that the results are reproducible using technical replicates and determine the optimum number of reads for sgRNA analysis. In VeroE6 ACE2+/− cell lines, periscope can detect the changes in the kinetics of sgRNA in orthogonal sequencing data sets. Finally, variants found in genomic RNA are transmitted to sgRNAs with high fidelity in most cases. This tool can be applied to all sequenced COVID-19 samples worldwide to provide comprehensive analysis of SARS-CoV-2 sgRNA.
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- 2021
31. Single-cell immunopathology of systemic contact allergy associated with corticosteroids
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Hertzman, R., Deshpande, P., White, K., Gangula, R., Chopra, A., Ram, R., Leary, S., Zic, J., Zwerner, J., Gibson, A., Phillips, E., Hertzman, R., Deshpande, P., White, K., Gangula, R., Chopra, A., Ram, R., Leary, S., Zic, J., Zwerner, J., Gibson, A., and Phillips, E.
- Abstract
Rationale Allergic contact dermatitis (ACD) is a classic delayed hypersensitivity reaction commonly associated with corticosteroids that can rarely manifest as a delayed rash following systemic administration. Methods A 50-year old woman developed local edema and delayed spreading rash following interarticular injection with dexamethasone and methylprednisolone acetate (MA). 6-months following this intradermal skin testing (IDST) was positive to MA and methylprednisolone sodium succinate, and IDST and patch test negative to other corticosteroids. She tolerated dexamethasone challenge. Cells were isolated from 4-mm punch biopsies from 48-hour positive IDST and unaffected skin with liberase digestion and sorted on CD3. scTCR and scRNA-seq were performed using plate-based assays (Smart-seq-2). Data was filtered using Seurat and analysed with Visual Genomics Analysis Studio (VGAS) software. Results Histopathology showed a superficial perivascular dermatitis with epidermal spongiosis in keeping with ACD. T-cells were 18x more prevalent in affected skin and those from both affected and unaffected sites were predominantly CD8+ T-cells that expressed CD45RO and polyclonal TCR alpha beta. Differentially expressed genes (DEG) in T-cells from affected skin reflected homing (CCR7,S1PR1), T-cell activation and proliferation (TNFRS9, GRAP2, ZYG11A, ZHX1), T-cell effector differentiation (IL-21R), and stress survival (EEF1A1, IFI6) without representation of markers of T-cell residency (ITGAE) or regulation. Conclusions We demonstrate insights into the immunopathogenesis of drug-induced ACD by showing that IDST+ methylprednisolone associated ACD is corticosteroid-specific and associated with a polyclonal population of primarily CD45RO+ memory CD8+ T-cells showing upregulation of markers of homing, T-cell activation, proliferation and differentiation but lacking markers of T-cell residency and regulation.
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- 2021
32. Single-cell analysis shows that adipose tissue of persons with both HIV and diabetes is enriched for clonal, cytotoxic, and CMV-specific CD4+ T cells
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Wanjalla, C.N., McDonnell, W.J., Ram, R., Chopra, A., Gangula, R., Leary, S., Mashayekhi, M., Simmons, J.D., Warren, C.M., Bailin, S., Gabriel, C.L., Guo, L., Furch, B.D., Lima, M.C., Woodward, B.O., Hannah, L., Pilkinton, M.A., Fuller, D.T., Kawai, K., Virmani, R., Finn, A.V., Hasty, A.H., Mallal, S.A., Kalams, S.A., Koethe, J.R., Wanjalla, C.N., McDonnell, W.J., Ram, R., Chopra, A., Gangula, R., Leary, S., Mashayekhi, M., Simmons, J.D., Warren, C.M., Bailin, S., Gabriel, C.L., Guo, L., Furch, B.D., Lima, M.C., Woodward, B.O., Hannah, L., Pilkinton, M.A., Fuller, D.T., Kawai, K., Virmani, R., Finn, A.V., Hasty, A.H., Mallal, S.A., Kalams, S.A., and Koethe, J.R.
- Abstract
Persons with HIV are at increased risk for diabetes mellitus compared with individuals without HIV. Adipose tissue is an important regulator of glucose and lipid metabolism, and adipose tissue T cells modulate local inflammatory responses and, by extension, adipocyte function. Persons with HIV and diabetes have a high proportion of CX3CR1+ GPR56+ CD57+ (C-G-C+) CD4+ T cells in adipose tissue, a subset of which are cytomegalovirus specific, whereas individuals with diabetes but without HIV have predominantly CD69+ CD4+ T cells. Adipose tissue CD69+ and C-G-C+ CD4+ T cell subsets demonstrate higher receptor clonality compared with the same cells in blood, potentially reflecting antigen-driven expansion, but C-G-C+ CD4+ T cells have a more inflammatory and cytotoxic RNA transcriptome. Future studies will explore whether viral antigens have a role in recruitment and proliferation of pro-inflammatory C-G-C+ CD4+ T cells in adipose tissue of persons with HIV.
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- 2021
33. Title: Defining the clinical and prognostic landscape of embryonal tumors with multi-layered rosettes (ETMRs), a rare brain tumor registry (RBTC) study.
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Gajjar A., Leary S., Mulcahy Levy J.M., Lassaletta A., Rivas E., Reddy A., Gillespie G.Y., Gupta N., Yalon-Oren M., Amariglio L., Nakamura H., Wu K.-S., Wong T.-T., Ra Y.-S., Spina M.L., Emanuele P.V., Massimi L., Buccoliero A.M., Hansford J.R., Grundy R.G., Adamek D., Fangusaro J., Scharnhorst D., Johnston D., Lafay-Cousin L., Camelo-Piragua S., Kabbara N., Boutarbouch M., Da Costa M.J.G., Hanson D., Wood P., Al-Hussaini M., Amayiri N., Wang Y., Catchpoole D., Michaud J., Bendel A.E., Ellezam B., Gerber N., Plant A., Jeffery R., Dunham C., Moertel C., Walter A., Ziegler D., Dodgshun A., Gottardo N., Demir A., Ramanujachar R., Raabe E., Mary S., Dirks P., Taylor M., Eugene H., Lindsey H., Tihan T., Mette J., Dahl C., Low S., Smith A., Hazrati L.-N., Kresak J., Gino S., Tan E., Morales A., Santa-Maria V., Hawkins C., Bartels U., Stephens D., Nobusawa S., Dufour C., Bourdeaut F., Andre N., Bouffet E., Huang A., Khan S., Solano-Paez P., Suwal T., Al-Karmi S., Lu M., Ho B., Fouladi M., Gajjar A., Leary S., Mulcahy Levy J.M., Lassaletta A., Rivas E., Reddy A., Gillespie G.Y., Gupta N., Yalon-Oren M., Amariglio L., Nakamura H., Wu K.-S., Wong T.-T., Ra Y.-S., Spina M.L., Emanuele P.V., Massimi L., Buccoliero A.M., Hansford J.R., Grundy R.G., Adamek D., Fangusaro J., Scharnhorst D., Johnston D., Lafay-Cousin L., Camelo-Piragua S., Kabbara N., Boutarbouch M., Da Costa M.J.G., Hanson D., Wood P., Al-Hussaini M., Amayiri N., Wang Y., Catchpoole D., Michaud J., Bendel A.E., Ellezam B., Gerber N., Plant A., Jeffery R., Dunham C., Moertel C., Walter A., Ziegler D., Dodgshun A., Gottardo N., Demir A., Ramanujachar R., Raabe E., Mary S., Dirks P., Taylor M., Eugene H., Lindsey H., Tihan T., Mette J., Dahl C., Low S., Smith A., Hazrati L.-N., Kresak J., Gino S., Tan E., Morales A., Santa-Maria V., Hawkins C., Bartels U., Stephens D., Nobusawa S., Dufour C., Bourdeaut F., Andre N., Bouffet E., Huang A., Khan S., Solano-Paez P., Suwal T., Al-Karmi S., Lu M., Ho B., and Fouladi M.
- Abstract
ETMR, an aggressive disease characterised by C19MC alterations, were previously categorised as various histologic diagnoses. The clinical spectrum and impact of conventional multi-modal therapy on this new WHO diagnostic category remains poorly understood as a majority of ~200 cases reported to date lack molecular confirmation. We undertook comprehensive clinico-pathologic studies of a large molecularly confirmed cohort to improve disease recognition and treatment approaches. Amongst 623 CNSPNETs patients enrolled in the RBTC registry, 159 primary ETMRs were confirmed based on a combination of FISH (125), methylation analysis (88), SNP and RNAseq (32) analyses; 91% had C19MC amplification/gains/fusions, 9% lacked C19MC alterations but had global methylation features of ETMR NOS. ETMRs arose in young patients (median age 26 months) predominantly as localized disease (M0-72%, M2-3 -18%) at multiple locations including cerebrum (60%) cerebellum (18%), midline structures (6%); notably 10% were brainstem primaries mimicking DIPG. Uni-and multivariate analyses of clinical and treatment details of curative regimens available for 110 patients identified metastatic disease (p=0.002), brainstem locations(p=0.005), extent of surgery, receipt of multi-modal therapy including high dose chemotherapy and radiation (P<0.001) as significant treatment prognosticators, while C19MC status, age and gender were nonsignificant risk factors. Analyses of events in all patients showed respective EFS at 3 and 12 months of 84%(95%CI:77-91) and 37%(95%CI:20-41) and 4yr OS of 27%(95%CI:18-37) indicating despite intensified therapies ETMR is a rapidly progressive and fatal disease. Our comprehensive data on the largest cohort of molecularly-confirmed ETMRs provides a critical framework to guide current clinical management and development of clinical trials.
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- 2021
34. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma
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Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, Northcott, PA, Kumar, R, Smith, KS, Deng, M, Terhune, C, Robinson, GW, Orr, BA, Liu, APY, Lin, T, Billups, CA, Chintagumpala, M, Bowers, DC, Hassall, TE, Hansford, JR, Khuong-Quang, DA, Crawford, JR, Bendel, AE, Gururangan, S, Schroeder, K, Bouffet, E, Bartels, U, Fisher, MJ, Cohn, R, Partap, S, Kellie, SJ, McCowage, G, Paulino, AC, Rutkowski, S, Fleischhack, G, Dhall, G, Klesse, LJ, Leary, S, Nazarian, J, Kool, M, Wesseling, P, Ryzhova, M, Zheludkova, O, Golanov, A, McLendon, RE, Packer, RJ, Dunham, C, Hukin, J, Fouladi, M, Faria, CC, Pimentel, J, Walter, AW, Jabado, N, Cho, Y-J, Perreault, S, Croul, SE, Zapotocky, M, Hawkins, C, Tabori, U, Taylor, MD, Pfister, SM, Klimo, P, Boop, FA, Ellison, DW, Merchant, TE, Onar-Thomas, A, Korshunov, A, Jones, DTW, Gajjar, A, Ramaswamy, V, and Northcott, PA
- Abstract
PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular ta
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- 2021
35. PINEOBLASTOMA: A POOLED OUTCOME STUDY OF NORTH AMERICAN AND AUSTRALIAN THERAPEUTIC DATA
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Hansford, J, Huang, J, Dodgshun, A, Li, B, Hwang, E, Leary, S, Gajjar, A, Von Hoff, K, Endersby, R, Wells, O, Wray, A, Kotecha, R, Raleigh, D, Stoller, S, Mueller, S, Schild, S, Bandopadhayay, P, Fouladi, M, Bouffet, E, Huang, A, Onar, A, Gottardo, N, Hansford, J, Huang, J, Dodgshun, A, Li, B, Hwang, E, Leary, S, Gajjar, A, Von Hoff, K, Endersby, R, Wells, O, Wray, A, Kotecha, R, Raleigh, D, Stoller, S, Mueller, S, Schild, S, Bandopadhayay, P, Fouladi, M, Bouffet, E, Huang, A, Onar, A, and Gottardo, N
- Abstract
Background Pineoblastoma (PB) is a rare embryonal brain tumour most often diagnosed in young children. To date, no clinical trials have been conducted specific to pediatric PB. Collaborative studies performed over the past 30 years have included PB in studies accruing for other embryonal tumours, primarily medulloblastoma (MB), but also including the entity formerly known as CNS-PNET and atypical teratoid rhabdoid tumors. Each of these studies have included only a small number of children with PB, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods Published centrally reviewed series with sufficient treatment and outcome data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact and Wilcoxon-Mann-Whitney tests, and Spearman correlations were used as appropriate. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analysis. Results We describe a 30-year review of the reported clinical features of PB and a pooled centrally reviewed, cohort analysis of cases (n=178) from the Children’s Oncology Group (COG) (n=82) groups and several published, centrally reviewed institutional series (n=96). We find young children <3 years of age have a dramatically poorer outlook compared to older children (5-year OS 16.2% +/- 5.3% vs 67.3% +/- 5%) confirming new and novel approaches are needed in future clinical trials for this at risk group. Interestingly, male gender was predictive of worse outcome possibly suggestive of gender specific subgroup risks that needs validation in future studies. Assessment of radiation therapy is not possible as the vast majority of children under age three did not receive any form of radiation therapy. Conclusion Given the relative scarcity of this tumor and the emerging data on subgroups of pineoblastoma, prospective, collaborative international studies will be vital
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- 2021
36. Sequencing directly from clinical specimens reveals genetic variations in HCMV-Encoded Chemokine Receptor US28 that may influence antibody levels and interactions with human chemokines
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Waters, S., Agostino, M., Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, K., Gaudieri, S., Gaff, J., Irish, A., Keil, A.D., Price, P., Allcock, R.J.N., Campos, S.K., Waters, S., Agostino, M., Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, K., Gaudieri, S., Gaff, J., Irish, A., Keil, A.D., Price, P., Allcock, R.J.N., and Campos, S.K.
- Abstract
Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by ∼80% of the world’s population. Acute infections are asymptomatic in healthy individuals but generate diverse syndromes in neonates, solid organ transplant recipients, and HIV-infected individuals. The HCMV gene US28 encodes a homolog of a human chemokine receptor that is able to bind several chemokines and HIV gp120. Deep sequencing technologies were used to sequence US28 directly from 60 clinical samples from Indonesian HIV patients and Australian renal transplant recipients, healthy adults, and neonates. Molecular modeling approaches were used to predict whether nine nonsynonymous mutations in US28 may alter protein binding to a panel of six chemokines and two variants of HIV gp120. Ninety-two percent of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous mutation. Carriage of these variants differed between neonates and adults, Australian and Indonesian samples, and saliva samples and blood leukocytes. Two nonsynonymous mutations (N170D and R267K) were associated with increased levels of immediate early protein 1 (IE-1) and glycoprotein B (gB) HCMV-reactive antibodies, suggesting a higher viral burden. Seven of the nine mutations were predicted to alter binding of at least one ligand. Overall, HCMV variants are common in all populations and have the potential to affect US28 interactions with human chemokines and/or gp120 and alter responses to the virus. The findings relied on deep sequencing technologies applied directly to clinical samples, so the variants exist in vivo.
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- 2021
37. Cross-Reactivity to mutated viral immune targets can influence CD8+ T cell functionality: An alternative viral adaptation strategy
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Currenti, J., Law, B.M.P., Qin, K., John, M., Pilkinton, M.A., Bansal, A., Leary, S., Ram, R., Chopra, A., Gangula, R., Yue, L., Warren, C., Barnett, L., Alves, E., McDonnell, W.J., Sooda, A., Heath, S.L., Mallal, S., Goepfert, P., Kalams, S.A., Gaudieri, S., Currenti, J., Law, B.M.P., Qin, K., John, M., Pilkinton, M.A., Bansal, A., Leary, S., Ram, R., Chopra, A., Gangula, R., Yue, L., Warren, C., Barnett, L., Alves, E., McDonnell, W.J., Sooda, A., Heath, S.L., Mallal, S., Goepfert, P., Kalams, S.A., and Gaudieri, S.
- Abstract
Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. Another described, but less understood, adaptation strategy involves the selection of mutations within epitopes that retain immune recognition, suggesting a benefit for the virus despite continued immune pressure (termed non-classical adaptation). To understand this adaptation strategy, we utilized a single cell transcriptomic approach to identify features of the HIV-specific CD8+ T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes containing a non-classical adaptation. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8+ T cells of chronic (n=7) and acute (n=4) HIV-infected subjects identified by either HLA class I tetramers or upregulation of activation markers following peptide stimulation. CD8+ T cells were predominantly dual tetramer+, confirming a large proportion of cross-reactive TCR clonotypes capable of recognizing the NAE and AE form. However, single-reactive CD8+ T cells were identified in acute HIV-infected subjects only, providing the potential for the selection of T cell clones over time. The transcriptomic profile of CD8+ T cells was dependent on the autologous virus: subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an ‘effective’ immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNɣ, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8+ T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.
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- 2021
38. Defining an adipose tissue single cell atlas to understand metabolic disease in HIV
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Bailin, S.S., Ram, R., Chopra, A., Gangula, R., Leary, S., Mashayekhi, M., Gabriel, C.L., Woodward, B.O., Lima, M., Hannah, L., Kalams, S.A., Mallal, S.A., Koethe, J.R., Wanjalla, C.N., Bailin, S.S., Ram, R., Chopra, A., Gangula, R., Leary, S., Mashayekhi, M., Gabriel, C.L., Woodward, B.O., Lima, M., Hannah, L., Kalams, S.A., Mallal, S.A., Koethe, J.R., and Wanjalla, C.N.
- Abstract
Background: Adipose tissue (AT) is a critical regulator of metabolic health and is emerging as important in HIV. Despite this, data on the complex cellular milieu and immune regulation are lacking. We sought to assess the AT microenvironment in persons with HIV (PWH). Methods: We performed subcutaneous abdominal liposuction and isolated the stromal vascular fraction (SVF) from 16 HIV-negative diabetics, 16 HIV-positive non-diabetics and 16 HIV-positive diabetics on long-term ART. Cells were stained with a panel of 5’ DNA-sequence tagged antibodies (TotalSeq-C) that represented standard lineages, activation and regulatory markers (45 antibodies). For the analysis, CellRanger (version 3.0.0) was used to demultiplex the raw sequencing data, extract filter and correct barcodes and unique molecular identifiers, remove cDNA PCR duplicates and align reads to the human transcriptome (GRCh38). The resulting BAM files and filtered count matrices were used in analyses. We assessed the AT cell types and their association of these subsets with the preadipocytes (Spearman rank correlation). Results: Agnostic to metabolic disease, PWH had lower proportions of pre-adipocytes (median 20.4% in non-diabetic and 36.4% in diabetic) compared with HIV-negative diabetic participants (62.7%) (Figure 1). The proportion of CD8 T cells, monocytes and NK cells were significantly higher in PWH compared with HIV-negative participants, irrespective of metabolic disease. Pre-adipocyte and NK cells were inversely related in non-diabetic PWH (r = _0.68, p = 0.005), diabetic PWH (r = _0.70, p = 0.004) and HIV-negative diabetics (r = _0.51, p = 0.05). A similar trend was observed between CD8 T cells and pre-adipocytes. Conclusions: We have generated a detailed atlas of AT SVF by HIV and diabetes status and show that PWH have higher proportions of NK and T cells compared with diabetic HIV negative. We hypothesize that this may correlate with the HIV reservoir. Future studies will pair this data with mea
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- 2021
39. Sequencing directly from clinical specimens reveals genetic variations in HCMV-encoded chemokine receptor us28 that may influence antibody levels and interactions with human chemokines
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Waters, Shelley, Agostino, Mark, Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, Kylie, Gaudieri, S., Gaff, J., Irish, A., Keil, A.D., Price, Patricia, Allcock, R.J.N., Waters, Shelley, Agostino, Mark, Lee, S., Ariyanto, I., Kresoje, N., Leary, S., Munyard, Kylie, Gaudieri, S., Gaff, J., Irish, A., Keil, A.D., Price, Patricia, and Allcock, R.J.N.
- Abstract
Human cytomegalovirus (HCMV) is a beta-herpesvirus carried by;80% of the world’s population. Acute infections are asymptomatic in healthy individuals but generate diverse syndromes in neonates, solid organ transplant recipients, and HIV-infected individuals. The HCMV gene US28 encodes a homolog of a human chemokine receptor that is able to bind several chemokines and HIV gp120. Deep sequencing technologies were used to sequence US28 directly from 60 clinical samples from Indonesian HIV patients and Australian renal transplant recipients, healthy adults, and neonates. Molecular modeling approaches were used to predict whether nine nonsynonymous mutations in US28 may alter protein binding to a panel of six chemokines and two variants of HIV gp120. Ninety-two percent of samples contained more than one variant of HCMV, as defined by at least one nonsynonymous mutation. Carriage of these variants differed between neonates and adults, Australian and Indonesian samples, and saliva samples and blood leukocytes. Two nonsynonymous mutations (N170D and R267K) were associated with increased levels of immediate early protein 1 (IE-1) and glycoprotein B (gB) HCMV-reactive antibodies, suggesting a higher viral burden. Seven of the nine mutations were predicted to alter binding of at least one ligand. Overall, HCMV variants are common in all populations and have the potential to affect US28 interactions with human chemokines and/or gp120 and alter responses to the virus. The findings relied on deep sequencing technologies applied directly to clinical samples, so the variants exist in vivo. IMPORTANCE Human cytomegalovirus (HCMV) is a common viral pathogen of solid organ transplant recipients, neonates, and HIV-infected individuals. HCMV encodes homologs of several host genes with the potential to influence viral persistence and/ or pathogenesis. Here, we present deep sequencing of an HCMV chemokine receptor homolog, US28, acquired directly from clinical specimens. Carriage of these
- Published
- 2021
40. Obesity impairs academic attainment in adolescence: findings from ALSPAC, a UK cohort
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Booth, J N, Tomporowski, P D, Boyle, J ME, Ness, A R, Joinson, C, Leary, S D, and Reilly, J J
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- 2014
- Full Text
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41. PNS16 Capturing the Complexity of Medicare's Pharmacy Benefit Structure in a Budget Impact Model
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Alston, M., primary, Carioto, J., additional, Leary, S., additional, and Pyenson, B., additional
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- 2021
- Full Text
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42. Folic acid supplementation during pregnancy may protect against depression 21 months after pregnancy, an effect modified by MTHFR C677T genotype
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Lewis, S.J., Araya, R., Leary, S., Smith, G. Davey, and Ness, A.
- Subjects
Folic acid -- Psychological aspects ,Genotype -- Health aspects ,Postpartum depression -- Diagnosis ,Food/cooking/nutrition ,Health - Abstract
Background/Objectives: As low folate status has been implicated in depression, high folate intake, in the form of supplements, during pregnancy might offer protection against depression during pregnancy and postpartum. Subjects/Methods: We examined the association between change in self-reported depressive symptoms (Edinburgh Postnatal Depression Scale) at different timepoints during and following pregnancy and self-reported folic acid supplementation during pregnancy in a prospective cohort of 6809 pregnant women. We also tested whether there was a main effect of methylenetetrahydrofolate reductase (MTHFR) C677T genotype (which influences folate metabolism and intracellular levels of folate metabolites and homocysteine) on change in depression scores, and carried out our analysis of folic acid supplementation and depression stratifying by genotype. Results: We found no strong evidence that folic acid supplementation reduced the risk of depression during pregnancy and up to 8 months after pregnancy. However, we did find evidence to suggest that folic acid supplements during pregnancy protected against depression 21 months postpartum, and that this effect was more pronounced in those with the MTHFR C677T TT genotype (change in depression score from 8 months to 21 months postpartum among TT individuals was 0.66 (95% CI = 0.31-1.01) among those not taking supplements, compared with --1.02 (95% CI = --2.22-0.18) among those taking supplements at 18 weeks pregnancy, [p.sup.difference] = 0.01). Conclusions: Low folate is unlikely to be an important risk factor for depression during pregnancy and for postpartum depression, but may be a risk factor for depression outside of pregnancy, especially among women with the MTHFR C677T TT genotype. European journal of Clinical Nutrition (2012) 66, 97-103; doi: 10.1038/ejcn.2011.136; published online 20 July 2011 Keywords: postpartum depression; folate; MTHFR; polymorphism; folic acid; ALSPAC, Introduction Several studies have shown that low folate levels are associated with depression in the general population (Bjelland et al., 2003; Paul et al, 2004; Lewis et al., 2006; Morris [...]
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- 2012
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43. Associations between objectively measured physical activity and academic attainment in adolescents from a UK cohort
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Booth, J N, Leary, S D, Joinson, C, Ness, A R, Tomporowski, P D, Boyle, J M, and Reilly, J J
- Published
- 2014
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44. Effects of pre-weaning dietary substitutions on plasma insulin and glucose profiles in primiparous sows
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Chen, T. Y., Stott, P., OʼLeary, S., Athorn, R. Z., Bouwman, E. G., and Langendijk, P.
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- 2013
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45. Influence of Cochleostomy and Cochlear Implant Insertion on Drug Gradients following Intratympanic Application in Guinea Pigs
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King, E. B., Hartsock, J. J., OʼLeary, S. J., and Salt, A. N.
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- 2013
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46. Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs
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King, E. B., Salt, A. N., Kel, G. E., Eastwood, H. T., and OʼLeary, S. J.
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- 2013
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47. Association between body composition and blood pressure in a contemporary cohort of 9-year-old children
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Brion, M A, Ness, A R, Davey Smith, G, and Leary, S D
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- 2007
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48. Relationships of maternal and paternal birthweights to features of the metabolic syndrome in adult offspring: an inter-generational study in South India
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Veena, S. R., Geetha, S., Leary, S. D., Saperia, J., Fisher, D. J., Kumaran, K., Coakley, P., Stein, C. E., and Fall, C. H. D.
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- 2007
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49. Repair of an attenuated low-passage murine cytomegalovirus bacterial artificial chromosome identifies a novel spliced gene essential for salivary gland tropism
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Redwood, A.J., Masters, L.L., Chan, B., Leary, S., Forbes, C., Jonjic, S., Juranić Lisnić, V., Lisnić, B., Smith, L.M., Jung, J.U., Redwood, A.J., Masters, L.L., Chan, B., Leary, S., Forbes, C., Jonjic, S., Juranić Lisnić, V., Lisnić, B., Smith, L.M., and Jung, J.U.
- Abstract
The cloning of herpesviruses as bacterial artificial chromosomes (BACs) has revolutionized the study of herpesvirus biology, allowing rapid and precise manipulation of viral genomes. Several clinical strains of human cytomegalovirus (HCMV) have been cloned as BACs; however, no low-passage strains of murine CMV (MCMV), which provide a model mimicking these isolates, have been cloned. Here, the low-passage G4 strain of was BAC cloned. G4 carries an m157 gene that does not ligate the natural killer (NK) cell-activating receptor, Ly49H, meaning that unlike laboratory strains of MCMV, this virus replicates well in C57BL/6 mice. This BAC clone exhibited normal replication during acute infection in the spleen and liver but was attenuated for salivary gland tropism. Next-generation sequencing revealed a C-to-A mutation at nucleotide position 188422, located in the 3′ untranslated region of sgg1, a spliced gene critical for salivary gland tropism. Repair of this mutation restored tropism for the salivary glands. Transcriptional analysis revealed a novel spliced gene within the sgg1 locus. This small open reading frame (ORF), sgg1.1, starts at the 3′ end of the first exon of sgg1 and extends exon 2 of sgg1. This shorter spliced gene is prematurely terminated by the nonsense mutation at nt 188422. Sequence analysis of tissue culture-passaged virus demonstrated that sgg1.1 was stable, although other mutational hot spots were identified. The G4 BAC will allow in vivo studies in a broader range of mice, avoiding the strong NK cell responses seen in B6 mice with other MCMV BAC-derived MCMVs.
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- 2020
50. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
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Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, Ramaswamy, V, Nobre, L, Zapotocky, M, Khan, S, Fukuoka, K, Fonseca, A, McKeown, T, Sumerauer, D, Vicha, A, Grajkowska, WA, Trubicka, J, Li, KKW, Ng, H-K, Massimi, L, Lee, JY, Kim, S-K, Zelcer, S, Vasiljevic, A, Faure-Conter, C, Hauser, P, Lach, B, Van Veelen-Vincent, M-L, French, PJ, Van Meir, EG, Weiss, WA, Gupta, N, Pollack, IF, Hamilton, RL, Rao, AAN, Giannini, C, Rubin, JB, Moore, AS, Chambless, LB, Vibhakar, R, Ra, YS, Massimino, M, McLendon, RE, Wheeler, H, Zollo, M, Ferruci, V, Kumabe, T, Faria, CC, Sterba, J, Jung, S, Lopez-Aguilar, E, Mora, J, Carlotti, CG, Olson, JM, Leary, S, Cain, J, Krskova, L, Zamecnik, J, Hawkins, CE, Tabori, U, Huang, A, Bartels, U, Northcott, PA, Taylor, MD, Yip, S, Hansford, JR, Bouffet, E, and Ramaswamy, V
- Abstract
Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
- Published
- 2020
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