Abstract
Objective
There are no large, longitudinal studies of thyroid function across adolescence. The aims of this study were to examine longitudinal trends in thyrotropin (TSH), free ...triiodothyronine (fT3) and free thyroxine (fT4) and determine age-specific reference ranges.
Methods
Thyroid function was assessed in 3415 participants in the Brisbane Longitudinal Twin Study at ages 12, 14, and 16, using the Abbott ARCHITECT immunoassay. Longitudinal analyses were adjusted for body mass index and puberty.
Results
In girls, mean fT4 (± SE) increased between age 12 and 14 (by 0.30 ± 0.08 pmol/L; P < 0.001), while remaining unchanged in boys; from age 14 to 16, fT4 increased in both girls (by 0.42 ± 0.07 pmol/L; P < 0.001) and boys (0.64 ± 0.07 pmol/L, P < 0.001). There was a slight increase in fT3 from age 12 to 14 years in girls (by 0.07 ± 0.03 pmol/L; P = 0.042), with a more marked increase in boys (0.29 ± 0.03 pmol/L; P < 0.001), followed by a decrease from age 14 to 16 in both sexes (girls, by 0.53 ± 0.02 pmol/L; P < 0.001; boys, by 0.62 ± 0.03 pmol/L; P < 0.001). From age 12 to 14, TSH showed no significant change in girls or boys, then levels increased from age 14 to 16 in both sexes (in girls, by 4.9%, 95% CI: 2.4%-10.3%, P = 0.020; in boys, by 7.2%, 95% CI: 3.0%-11.6%, P = 0.001). Reference ranges differed substantially from adults, particularly for fT4 and fT3.
Conclusions
Thyroid function tests in adolescents display complex, sexually dimorphic patterns. Implementation of adolescence-specific reference ranges may be appropriate.
Abstract
Context
Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their ...genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited.
Objective
To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts.
Method
We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed.
Results
We identified 2 DMPs with epigenome-wide significant (P < 2.4E−7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E−10) and cg04173586 in DOT1L (P = 2.09E−16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH.
Conclusions
This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
1. Aggregation of diluted whole blood (impedance method) and thromboxane B2 production during aggregation were measured in cigarette smokers and non-smokers, aged 41-68 years, with (n = 14) and ...without (n = 15) major symptomatic peripheral vascular disease. The plasma level of the lyso derivative of platelet activating factor (lyso-PAF) was also measured using a bioassay with 14C-serotonin labelled rabbit platelets, after extraction and acetylation to active PAF. 2. Aggregation to ADP and collagen was significantly less in non-smokers without vascular disease (n = 8) than in the other three groups (P less than 0.01; ANOVA). Thromboxane B2 production was not significantly different between the groups. There was no significant difference in plasma lyso-PAF between groups. No change was found in any variable after smokers smoked two cigarettes. 3. In these older age subjects, both vascular disease and the smoking habit were associated with greater whole blood aggregation. However, current smoking and the smoking of two cigarettes did not affect aggregation in subjects with vascular disease and plasma lyso-PAF levels were not consistently related to either smoking or vascular disease.
•Direct Skeletal Fixation represents a safe procedure for blast injury patients in the presence of previous polymicrobial colonisation.•Direct Skeletal Fixation improves quality of life outcomes and ...physical performance for bilateral above knee amputees following blast injury.•Direct Skeletal Fixation requires life long follow up and potentially revision surgery.
The aim of the study is to evaluate the clinical outcome and complications from the initial cohort of blast injured bilateral lower limb, above knee amputees who underwent Direct Skeletal Fixation (DSF).
We undertook a retrospective analysis of a prospective data base identifying patients who had undergone implantation with the Australian Osseointegration Group of Australia-Osseointegration Prosthetic Limb (OGAP-OPL) prosthesis, with minimum 24 months follow up. Patient demographics, injury profile, and polymicrobial colonisation status were recorded. Physical functional performance measures recorded were the 6 minute Walk Test (6-MWT) and patient reported outcome measures were the Short Form Health Survey-36 (SF-36). Post operatively, complications including infection, re-operation, and fracture were recorded.
7 patients (14 femora) were identified (mean age 29.8yrs), all injured by dismounted blast. Mean follow up was 46 months. All were polytrauma patients and all had previous polymicrobial colonisation. Following surgery, all patients mobilised with significant improvement in 6-minute walk time, with a mean improvement of 154 m (248 m vs 402 m, p = 0.018). The physical component score for the SF-36 demonstrated a statistically significant improvement from 34.65 to 54.5 (p = 0.018) and the mental component score demonstrated a similar improvement (41.55–58.19 p = 0.018). At follow up, no patient required explantation of the implant. Each had been prescribed a minimum of 1 course of antibiotics with no evidence of deep infection.
DSF is an option for amputees who, due to the nature of their injuries, may not be able to tolerate traditional suspension socket prostheses and have exhausted all other treatment options. At a minimum of 2 year follow up, the absence of significant infective complications suggests DSF may be utilised in the blast injured despite chronic polymicrobial colonisation. Longer term surveillance of these patients is required to assess the long-term suitability of this technique in this cohort of patients.
Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
Protein expression of integrin subunit ...beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.
High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.
Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
Integrin αvβ6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer. Protein expression of integrin subunit ...beta6 (β6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided. High expression of either the mRNA or protein for the integrin subunit β6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of β6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts. Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
Abstract
Background: Integrin αvβ6 promotes migration, invasion and survival of cancer cells, however, the relevance and role of αvβ6 has yet to be elucidated in breast cancer.
Methods: Protein ...expression of integrin subunit beta6 (β6) was measured in over 2000 breast cancers by immunohistochemistry and ITGB6 mRNA expression measured in the METABRIC dataset. Overall survival was assessed using Kaplan-Meier curves and bioinformatics statistical analyses were performed in R statistical environment v2.14.1. Using antibody (264RAD; supplied by AZ-Medimmune) blockade and siRNA knockdown of β6 in breast cell lines, the role of αvβ6 in HER2 biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT assays and Transwell invasion assays and xenografts, respectively. All statistical tests were two-sided.
Results: High expression of either the mRNA or protein for the integrin subunit β6 correlated with very poor survival (HR=1.99, P=2.9x10-6) and increased metastases to distant sites (P=0.02). Co-expression of β6 and HER2 gave a worse prognosis (HR=3.43, P=4x10-12). HER2-driven invasion was mediated by αvβ6 in an Akt2-dependent manner. Monotherapy with 264RAD or trastuzumab, slowed growth of MCF-7/HER2-18 and BT-474 xenografts to a similar degree (P<0.001) but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.
Conclusions: Targeting αvβ6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients, giving hope to the 70% of women treated who have, or develop, resistance. Moreover, routine determination of the level of expression of αvβ6 on breast cancers would stratify women into higher-risk categories, requiring enhanced therapeutic intervention.
Citation Format: Kate M. Moore, Gareth J. Thomas, Stephen W. Duffy, Jane Warwick, Rhian Gabe, Patrick Chou, Ian O. Ellis, Andrew R. Green, Syed Haider, Kellie Brouilette, Antonio Saha, Sabari Vallath, Rebecca Bowen, Claudia Chelala, Diana Eccles, William J. Tapper, Alastair M. Thompson, Phillip Quinlan, Lee Jordan, Cheryl Gillett, Adam Brentnall, Sheila Violette, Paul Weinreb, Jane Kendrew, Simon T. Barry, Ian R. Hart, Louise Jones, John F. Marshall. Therapeutic targeting of integrin αvβ6 in high-risk breast cancer. abstract. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B046.
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