ORCID Profile
0000-0002-1428-9373
Current Organisation
The University of Auckland
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Publisher: Frontiers Media SA
Date: 29-05-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2019
Publisher: Elsevier BV
Date: 09-2013
Publisher: BMJ
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 26-06-2012
Publisher: Frontiers Media SA
Date: 09-04-2019
Publisher: Frontiers Media SA
Date: 26-10-2018
Publisher: Springer Science and Business Media LLC
Date: 15-05-2019
DOI: 10.1038/S41390-019-0430-8
Abstract: Propranolol is the preferred treatment for problematic proliferating infantile hemangioma (IH) by targeting the renin-angiotensin system (RAS) expressed by IH endothelium. (Pro)renin receptor (PRR) is a major component of the RAS associated with the canonical wnt signaling pathway. We proposed that activation of PRR by renin causes proliferation of IH. The expression of PRR in IH tissue s les was investigated using immunohistochemical (IHC) staining and NanoString analysis. NanoString analysis was also used to confirm transcriptional expression of PRR in CD34-sorted proliferating IH-derived primary cell lines. MTT assay was utilized to determine the effect of exogenous renin on the number of viable IH cells. RT-qPCR was used to determine the effect of renin on the stem cell gene expression. NanoString analysis and IHC staining confirmed transcriptional and translational expression of PRR, which was localized to the non-endothelial and the endothelial IH cell populations. MTT assay demonstrated an increased number of viable IH cells by administration of renin and the effect was negated by the wnt receptor blocker dickkopf-1. Our results present a model for renin-induced increased proliferation of IH cells through PRR acting via the wnt signaling pathway, which may account for accumulation of cells in IH during the proliferative phase of the tumor.
Publisher: Frontiers Media SA
Date: 07-06-2018
Publisher: Wiley
Date: 10-08-2012
DOI: 10.1002/PMH.1206
Abstract: To determine if personality dysfunction is associated with poorer clinical and social indicators in patients with schizophrenia. An observational study of patients with schizophrenia in psychiatric care assessed patient satisfaction with care, social functioning and psychopathology. Analysis of the relationship between personality and these three domains quantitatively assessed differences between patients with and without comorbid personality dysfunction. Diagnostic confounding was assessed using partial correlation coefficients. Forty-five patients with schizophrenia were studied. In the schizophrenia group, personality dysfunction correlated with poorer social functioning but not poorer satisfaction with care. Linear regression found that the relationship between poorer social functioning and personality disorder in schizophrenia remained, taking other diagnoses and age into account. Partial correlation coefficients confirmed that this was no related to an overlap between personality and schizophrenia symptoms in this s le. Personality dysfunction may negatively influence social functioning in patients with schizophrenia but does not appear to impact on patients' views of the care they receive. This is not due to the potential for diagnostic confounding between schizophrenia and personality disorder. Further research using larger s les is needed to confirm this association.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2011
DOI: 10.1007/S10654-011-9634-X
Abstract: The two best known approaches to predicting cardiovascular risk are Framingham and QRISK. Both methods correctly predict less than 70% of cases, with a high ratio of false positive predictions to true predictions. Each uses a combination of predictors that is applied to the data only once. The present approach uses the Discriminant Function with multiple applications. A British s le of data on cardiovascular risk was analysed. Principal Components analysis was used to reveal the underlying structure of the data-it identified four independent determinants of the data. Discriminant Function analysis in three stages was then used to accommodate the difficulties of dealing with multiple determinants. Ninety-four percent of the cases with cardiovascular incidents (CVI) were predicted correctly up to more than 20 years ahead, with a misclassification rate overall of 2.8 errors for every one correct. When checked for likely shrinkage from s le to s le using the Jacknife method 92% of CVI's were correctly predicted. Instead of a single application of a linear combination of predictors to find those people most likely to have cardiovascular events a repeated application of the predictors to the residuals from the previous prediction stage is likely to find a much higher proportion of true predictions and with much less error. The results also allow for a simple way of conveying the risk of CVI to in idual patients.
Publisher: OAE Publishing Inc.
Date: 24-04-2019
Publisher: BMJ
Date: 11-06-2015
DOI: 10.1136/JCLINPATH-2015-203073
Abstract: Interstitial CD45+ cells and T lymphocytes have previously been demonstrated within infantile haemangioma (IH). This study investigated the expression of B and T lymphocyte markers by the CD45+ population, and the expression of Thy-1, a marker of thymocyte progenitors, which have the ability to give rise to both B and T cells. Immunohistochemical (IHC) staining was performed on proliferating and involuted IHs for the expression of CD45, CD3, CD20, CD79a, Thy-1 and CD34. The presence of mRNA corresponding to CD45, CD3G, CD20 and Thy-1 was confirmed by reverse transcriptase-polymerase chain reaction in snap-frozen IH tissues. Cell counting of 3,3-diaminobenzidine IHC-stained slides was performed on CD45+ only cells and dually stained CD45+/CD3+ cells or CD45+/CD20+ cells and analysed statistically. In situ hybridisation and mass spectrometry were also performed to confirm the presence and abundance of Thy-1, respectively. IHC staining showed a subpopulation of CD45+ interstitial cells that expressed the T lymphocyte marker, CD3, and another subpopulation that expressed the B lymphocyte marker, CD20, in proliferating and diminished in involuted IHs. The abundant expression of Thy-1 on the endothelium of proliferating, but not involuted IH, was demonstrated by IHC staining and confirmed by in situ hybridisation and mass spectrometry. Both B and T lymphocytes are present within the interstitium of proliferating and involuted IH. The expression of Thy-1 by the endothelium suggests that B and T cells in IH may have originated from within the lesion, rather than migrating from the peripheral circulation.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2019
Publisher: Frontiers Media SA
Date: 03-05-2016
Publisher: Public Library of Science (PLoS)
Date: 06-09-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2020
DOI: 10.1097/GOX.0000000000002598
Abstract: We have previously shown that the endothelium of the microvessels of infantile hemangioma (IH) exhibits a hemogenic endothelium phenotype and proposed its potential to give rise to mesenchymal stem cells, similar to the development of hematopoietic cells. This endothelial-to-mesenchymal transition (Endo-MT) process involves the acquisition of a migratory phenotype by the endothelial cells, similar to epithelial-to-mesenchymal transition that occurs during neural crest development. We hypothesized that proliferating IH expresses Endo-MT–associated proteins and investigated their expression at the mRNA, protein, and functional levels. Immunohistochemical staining of paraffin-embedded sections of proliferating IH s les from 10 patients was undertaken to investigate the expression of the Endo-MT proteins Twist1, Twist2, Snail1, and Slug. Transcriptional analysis was performed for the same markers on proliferating IH tissues and CD34 + and CD34 − cells from proliferating IH-derived primary cell lines. Adipogenic and osteogenic differentiation plasticity was determined on the CD34-sorted fractions. The endothelium of the microvessels and the cells within the interstitium of proliferating IH tissues expressed Twist1, Twist2, and Slug proteins. Twist1 was also expressed on the pericyte layer of the microvessels, whereas Snail1 was not expressed. Both CD34 + and CD34 − populations from the IH-derived primary cell lines underwent adipogenic and osteogenic differentiation. The expression of Endo-MT–associated proteins Twist1, Twist2, and Slug by both the endothelium of the microvessels and cells within the interstitium, and Twist1 on the pericyte layer of the microvessels of proliferating IH, suggest the presence of a process similar to Endo-MT. This may enable a tightly controlled primitive endothelium of proliferating IH to acquire a migratory mesenchymal phenotype with the ability to migrate away, providing a plausible explanation for the development of a fibrofatty residuum observed during involution of IH.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2018
DOI: 10.1097/GOX.0000000000001686
Abstract: The pathogenesis of Dupuytren’s disease (DD) remains unclear. An embryonic stem cell (ESC)–like population in the endothelium of the microvessels around tissues that expresses components of the renin-angiotensin system (RAS) has been reported. This study investigated if this primitive population expresses cathepsins B, D, and G, that contribute to RAS bypass loops. 3,3-Diaminobenzidine immunohistochemical (IHC) staining for cathepsins B, D, and G was performed on sections of formalin-fixed paraffin-embedded DD cords (n = 10) and nodules (n = 10). Immunofluorescence IHC staining was utilized to demonstrate co-expression of these cathepsins with ESC markers. Protein and gene expression of these cathepsins was investigated in snap-frozen DD cords (n = 3) and nodules (n = 3) by Western blotting and NanoString analysis, respectively. Enzymatic activity of these cathepsins was investigated by enzymatic activity assays. 3,3-Diaminobenzidine IHC staining demonstrated expression of cathepsins B, D, and G in DD cords and nodules. Gene expression of cathepsins B, D, and G was confirmed by NanoString analysis. Western blotting confirmed expression of cathepsins B and D, but not cathepsin G. Immunofluorescent IHC staining demonstrated high abundance of cathepsins B and D on the OCT4 + /angiotensin converting enzyme + endothelium and the smooth muscle layer of the microvessels. Cathepsin G was localized to trypase + cells within the stroma in DD cords and nodules with limited expression on the microvessels. Enzyme activity assays demonstrated functional activity of cathepsins B and D. Cathepsins B, D, and G were expressed in the DD tissues, with cathepsins B and D localized to the primitive population in the endothelium of the microvessels, whereas cathepsin G was localized to phenotypic mast cells, suggesting the presence of bypass loops for the RAS.
Publisher: Wiley
Date: 10-01-2016
DOI: 10.1111/APA.13684
Abstract: We investigated the expression of neuropeptide Y (NPY), NPY receptor 1 (NPYR1) and NPY receptor 2 (NPYR2) in infantile haemangiomas (IHs). Immunohistochemical (IHC) staining was performed on proliferating IHs from six patients aged 4-13 (mean 8.7) months and involuted IHs from six patients aged 5-59 (mean 18.7) years, for the expression of NPY, NPYR1 and NPYR2. Protein and messenger ribonucleic acid expression corresponding to these proteins was investigated by Western blotting and NanoString analysis, respectively. IHC staining, Western blotting and NanoString analysis demonstrated the presence of NPYR1, but not NPYR2, within proliferating and involuted IHs. IHC staining showed NPYR1 was expressed by B and T lymphocytes expressing CD45 and mast cells expressing tryptase. IHC staining demonstrated the presence of NPY on the NPYR1 NPYR1, but not NPYR2, was present in IHs. The localisation of NPYR1 to B and T lymphocytes and mast cells suggests its role in the biology of IHs. The demonstration of NPY on the NPYR1
Publisher: Wiley
Date: 03-09-2015
DOI: 10.1111/JPC.12720
Abstract: Propranolol, now the preferred treatment for problematic proliferating infantile haemangioma (IH), at an empirical cardiovascular dosage of 2-3 mg/kg/day is associated with variable complication rates. A meta-analysis shows complications in 31% of patients at a mean dosage of 2.12 mg/kg/day. This study reports on the minimal dosage and duration of treatment to achieve accelerated involution and side effects using a stepwise escalation regimen. Consecutive patients with problematic proliferating IH treated with propranolol were identified from our vascular anomalies database. Propranolol was commenced at 0.5 mg/kg/day in two ided doses and increased to 1 mg/kg/day after 24 h. The patients were reviewed after 1 week, and the dosage was increased to 1.5 mg/kg/day. The dosage was further increased by 0.5 mg/kg/day, if necessary, to achieve accelerated involution. Forty-four patients, aged 3 weeks to 11 months (mean, 3.8 months), received propranolol therapy for problematic proliferating IH. The minimal dosage required to achieve accelerated involution was 1.5-2 mg/kg/day. Treatment was maintained for an average of 9.3 months and discontinued at an average age of 14.2 months. Rebound growth occurred in the first patient of this series when propranolol was withdrawn at 7.5 months of age, requiring reinstitution of treatment. Slight rebound growth following cessation of treatment was observed in four other patients, but reinstitution of propranolol was not required. Minor complications were observed in three (6.8%) patients. Propranolol at 1.5-2 mg/kg/day, administered in ided doses with stepwise escalation, is safe and effective for treating problematic proliferating IH. Treatment is continued to an average age of 14.2 months.
Publisher: Frontiers Media SA
Date: 22-01-2018
Publisher: Open Access Pub
Date: 04-03-2019
DOI: 10.14302/ISSN.2576-6694.JBBS-19-2625
Abstract: Chalkley counting has been regarded as a relatively reliable method of quantifying tumor angiogenesis. In this study we investigated the reliability of Chalkley counting in quantifying tumor angiogenesis in oral tongue squamous cell carcinoma (OTSCC) using CD34 and tumor vasculogenesis using angiotensin converting enzyme, angiotensin II receptor 1 and angiotensin II receptor 2, in 32 OTSCC s les. Chalkley counting was performed by two independent observers. The averages of three ‘hot spot’ counts were compared with known prognostic factors. All four markers showed no correlation with any of the prognostic factors. When comparing the results from the two independent observers, the only marker shown to have a significant moderate correlation was CD34. The other three markers showed no significant correlation. The lack of statistical significance between the independent observers, and known prognostic factors with the four markers used, shows that Chalkley counting is not a reliable prognostic tool in OTSCC.
Publisher: Frontiers Media SA
Date: 19-05-2015
Publisher: Frontiers Media SA
Date: 09-02-2016
Publisher: Mary Ann Liebert Inc
Date: 10-2019
Publisher: BMJ
Date: 23-02-2015
DOI: 10.1136/JCLINPATH-2014-202794
Abstract: To investigate the effect of the angiotensin peptides and their agonists and antagonists on cellular proliferation in proliferating infantile haemangioma (IH) in vitro explants. Proliferating IH s les from six patients were cultured in vitro in the presence of angiotensin I (ATI) alone, or AT1 and the ACE inhibitor, ramipril, or ATII alone, or ATII with the ATII receptor 1 (ATIIR1) blocker, losartan, or ATII with the ATIIR2 blocker, PD123319, or the ATIIR2 agonist, CGP42112. After 6 days in culture, the IH tissue pieces were harvested, formalin-fixed and paraffin-embedded. The effect of each treatment type on cellular proliferation was evaluated by immunohistochemical staining of these tissue pieces using the proliferation marker, Ki67. There was a significant increase in cellular proliferation in the ATI and ATII treated IH tissues compared with control s les. Their effect on cellular proliferation was reduced by adding ramipril and PD123319, respectively. CGP42112, but not losartan, significantly increased cellular proliferation. Our findings suggest a key regulatory role of ATI and ATII in promoting cellular proliferation in IH, and establish a role for ACE and ATIIR2 in the proliferation of this tumour.
Publisher: Elsevier BV
Date: 02-2019
Publisher: Frontiers Media SA
Date: 16-05-2019
Publisher: Frontiers Media SA
Date: 12-03-2019
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.BJPS.2015.10.020
Abstract: The role of the renin-angiotensin system (RAS) in the biology of infantile haemangioma (IH) and its accelerated involution induced by β-blockers was first proposed in 2010. This led to the first clinical trial in 2012 using low-dose captopril, an angiotensin-converting enzyme (ACE) inhibitor, demonstrating a similar response in these tumours. This study aimed to compare serial serum levels of the components of the RAS in patients before and after surgical excision, propranolol or captopril treatment for problematic proliferating IH. Patients with problematic proliferating IH underwent measurements of serum levels of plasma renin activity (PRA), ACE and angiotensin II (ATII) before, and 1-2 and 6 months following surgical excision, propranolol or captopril treatment. This study included 27 patients undergoing surgical excision (n = 8), propranolol (n = 11) and captopril (n = 8) treatment. Treatment with either surgical excision or propranolol resulted in significant decrease in the mean levels of PRA. Surgical excision or captopril treatment led to significant decline in the mean levels of ATII. All three treatment modalities had no significant effect on the mean levels of ACE. This study demonstrates the effect of surgical excision, propranolol and captopril treatment in lowering the levels of PRA and ATII, but not ACE, supporting a mechanistic role for the RAS in the biology of IH.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.BJPS.2018.11.013
Abstract: To investigate the expression of components of the renin-angiotensin system (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) by the cancer stem cell (CSC) subpopulations in moderately differentiated head and neck cutaneous squamous cell carcinoma (MDHNCSCC). 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining for PRR, ACE, ATIIR1 and ATIIR2 was performed on formalin-fixed paraffin-embedded sections of ten MDHNCSCC tissue s les. Immunofluorescence (IF) IHC staining was used to localise components of the RAS. Western blotting (WB) and RT-qPCR were performed on snap-frozen MDHNCSCC tissue s les and MDHNCSCC-derived primary cell lines to investigate protein transcription expression of these proteins, respectively. DAB IHC staining demonstrated the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten MDHNCSCC tissue s les. IF IHC staining showed expression of PRR and ATIIR2 by the OCT4 PRR, ACE, ATIIR1 and ATIIR2 are expressed by the CSC subpopulations within the TNs, the PTS, and the endothelium of the microvessels within the PTS, in MDHNCSCC.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.BJOMS.2016.05.033
Abstract: There has, to our knowledge, been no previous report of changes in the prevalence and outcomes of treatment of HPV-positive (+) oropharyngeal squamous cell carcinoma (SCC) in New Zealand. We identified all affected patients in the greater Wellington region between 1 January 1994 and 30 November 2014 from the New Zealand Cancer Registry. Their personal details, characteristics of their tumours, treatment, complications, and outcomes were collected retrospectively from their casenotes and the New Zealand Death Registry, followed by p16 immunohistochemical staining. Of the 161 patients included, 131 (81%) were men. p16 immunohistochemical staining was done routinely in 13 patients during investigations, and retrospectively for 135 patients. The proportion of p16+ oropharyngeal SCC increased from 24% during 1994-1999, to 76% during 2009-2014 (p<0.001). Oropharyngeal SCC among Europeans was more likely to be p16+ than in non-Europeans (67% compared with 44%, p=0.036). Patients with p16+ disease were younger (mean (SD) 56 (10) compared with 66 (9) years, p<0.01) with fewer coexisting conditions (mean (SD) Charlson Comorbidity Index: 2.45 (0.82) compared with 2.92 (1.16), p=0.01), and less likely to have smoked (57/81(70%) compared with 38/42 (91%) p=0.035), or misused alcohol (12/81 (15%) compared with 14/42 (31%), p=0.042), or both. They were also more likely to have poorly differentiated tumours (30/52 (58%) compared with 9/34 (26%), p=0.019) with nodal metastases (74/85 (87%) compared with 17/30 (57%), p=0.001). Overall 5-year all-cause survival was more favourable for patients with p16+ disease (65/86 (76%) compared with 15/49 (31%), p=0.000). Interestingly, all-cause age at death was younger in p16+ patients (62 (11.1) compared with 71 (11.2) years, p=0.001). The prevalence of p16+ oropharyngeal SCC had tripled in this population between 1994 and 2014, and affected patients have distinct characteristics and outcomes of treatment.
Location: United Kingdom of Great Britain and Northern Ireland
Location: New Zealand
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Reginald Marsh.