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Article ; Online: Porcine-derived collagen peptides promote re-epithelialisation through activation of integrin signalling.

Mistry, Krishan / Richardson, Grant / Vleminckx, Sara / Smith, Robert / Gevaert, Elien / Lovat, Penny E

Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society

2024

Abstract: Chronic non-healing cutaneous wounds represent a major burden to patients and healthcare providers worldwide, emphasising the continued unmet need for credible and efficacious therapeutic approaches for wound healing. We have recently shown the potential ...

Abstract	Chronic non-healing cutaneous wounds represent a major burden to patients and healthcare providers worldwide, emphasising the continued unmet need for credible and efficacious therapeutic approaches for wound healing. We have recently shown the potential for collagen peptides to promote proliferation and migration during cutaneous wound healing. In the present study, we demonstrate that the application of porcine-derived collagen peptides significantly increases keratinocyte and dermal fibroblast expression of integrin α2β1 and activation of an extracellular signal-related kinase (ERK)-focal adhesion kinase (FAK) signalling cascade during wound closure in vitro. SiRNA-mediated knockdown of integrin β1 impaired porcine-derived collagen peptide-induced wound closure and activation of ERK-FAK signalling in keratinocytes but did not impair ERK or FAK signalling in dermal fibroblasts, implying the activation of differing downstream signalling pathways. Studies in ex vivo human 3D skin equivalents subjected to punch biopsy-induced wounding confirmed the ability of porcine-derived collagen peptides to promote wound closure by enhancing re-epithelialisation. Collectively, these data highlight the translational and clinical potential for porcine-derived collagen peptides as a viable therapeutic approach to promote re-epithelialisation of superficial cutaneous wounds.
Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1174873-4
ISSN	1524-475X ; 1067-1927
ISSN (online)	1524-475X
ISSN	1067-1927
DOI	10.1111/wrr.13177
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Article ; Online: Health professional and patient views of a novel prognostic test for melanoma: A theoretically informed qualitative study.

Lecouturier, Jan / Bosomworth, Helen / Labus, Marie / Ellis, Rob A / Lovat, Penny E

PloS one

2022 Volume 17, Issue 4, Page(s) e0265048

Abstract: Objectives: Cutaneous melanoma rates are steadily increasing. Up to 20% of patients diagnosed with AJCC Stage I/II melanomas will develop metastatic disease. To date there are no consistently reliable means to accurately identify truly high versus low- ... ...

Abstract	Objectives: Cutaneous melanoma rates are steadily increasing. Up to 20% of patients diagnosed with AJCC Stage I/II melanomas will develop metastatic disease. To date there are no consistently reliable means to accurately identify truly high versus low-risk patient subpopulations. There is hence an urgent need for more accurate prediction of prognosis to determine appropriate clinical management. Validation of a novel prognostic test based on the immunohistochemical expression of two protein biomarkers in the epidermal microenvironment of primary melanomas was undertaken; loss of these biomarkers had previously been shown to be associated with a higher risk of recurrence or metastasis. A parallel qualitative study exploring secondary care health professional and patient views of the test was undertaken and this paper reports the perceived barriers and enablers to its implementation into the melanoma care pathway. Methods: Qualitative methods were employed drawing upon the Theoretical Domains Framework (TDF) in the exploration and analysis. An inductive-deductive analysis was performed, with all data coded using a thematic then TDF framework. Findings: 20 dermatologists, plastic surgeons, cancer nurse specialists, oncologists and histopathologists participated. Nine TDF domains were relevant to all health professional groups and the 'Skills' and 'Beliefs about Capabilities' domains were relevant only to histopathologists. 'Optimism' and 'Beliefs about consequences' were strong enablers particularly for clinicians. 'Environmental context and resources' (impact on pathology services) and 'Knowledge' (the need for robust evidence about the test reliability) were the main perceived barriers. 19 patients and one carer were interviewed. For the patients eight domains were relevant. ('Knowledge', 'Emotions', 'Beliefs about consequences', 'Social Role and identity', 'Behavioural regulation', 'Memory, attention and decision processes', 'Reinforcement' and 'Skills'). The consequences of the implementation of the test were reassurance about future risk, changes to the follow-up pathway on which there were mixed views, and the need to ensure they maintained self-surveillance (Beliefs about consequences). The test was acceptable to all patient interviewees but the resultant changes to management would need to be supported by mechanisms for fast-track back into the clinic, further information on self-surveillance and clear management plans at the time the result is conveyed (Behavioural regulation). Conclusions: Health professionals and patients perceived positive consequences-for patients and for health services-of adopting the test. However, its implementation would require exploration of the resource implications for pathology services, psychological support for patients with a high-risk test result and mechanisms to reassure and support patients should the test lead to reduced frequency or duration of follow-up. Exploring implementation at an early stage with health professionals presented challenges related to the provision of specific details of the test and its validation.
MeSH term(s)	Humans ; Melanoma/diagnosis ; Professional Role ; Prognosis ; Qualitative Research ; Reproducibility of Results ; Skin Neoplasms/diagnosis ; Tumor Microenvironment ; Melanoma, Cutaneous Malignant
Language	English
Publishing date	2022-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0265048
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Article ; Online: Health professional and patient views of a novel prognostic test for melanoma

Jan Lecouturier / Helen Bosomworth / Marie Labus / Rob A Ellis / Penny E Lovat

PLoS ONE, Vol 17, Iss 4, p e

A theoretically informed qualitative study.

2022 Volume 0265048

Abstract: Objectives Cutaneous melanoma rates are steadily increasing. Up to 20% of patients diagnosed with AJCC Stage I/II melanomas will develop metastatic disease. To date there are no consistently reliable means to accurately identify truly high versus low- ... ...

Abstract	Objectives Cutaneous melanoma rates are steadily increasing. Up to 20% of patients diagnosed with AJCC Stage I/II melanomas will develop metastatic disease. To date there are no consistently reliable means to accurately identify truly high versus low-risk patient subpopulations. There is hence an urgent need for more accurate prediction of prognosis to determine appropriate clinical management. Validation of a novel prognostic test based on the immunohistochemical expression of two protein biomarkers in the epidermal microenvironment of primary melanomas was undertaken; loss of these biomarkers had previously been shown to be associated with a higher risk of recurrence or metastasis. A parallel qualitative study exploring secondary care health professional and patient views of the test was undertaken and this paper reports the perceived barriers and enablers to its implementation into the melanoma care pathway. Methods Qualitative methods were employed drawing upon the Theoretical Domains Framework (TDF) in the exploration and analysis. An inductive-deductive analysis was performed, with all data coded using a thematic then TDF framework. Findings 20 dermatologists, plastic surgeons, cancer nurse specialists, oncologists and histopathologists participated. Nine TDF domains were relevant to all health professional groups and the 'Skills' and 'Beliefs about Capabilities' domains were relevant only to histopathologists. 'Optimism' and 'Beliefs about consequences' were strong enablers particularly for clinicians. 'Environmental context and resources' (impact on pathology services) and 'Knowledge' (the need for robust evidence about the test reliability) were the main perceived barriers. 19 patients and one carer were interviewed. For the patients eight domains were relevant. ('Knowledge', 'Emotions', 'Beliefs about consequences', 'Social Role and identity', 'Behavioural regulation', 'Memory, attention and decision processes', 'Reinforcement' and 'Skills'). The consequences of the implementation of the test were ...
Keywords	Medicine ; R ; Science ; Q
Subject code	150
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Programmed cell death-1 receptor-mediated regulation of Tbet

Lim, Jing Xuan / Lai, Chester Y / Mallett, Grace E / McDonald, David / Hulme, Gillian / Laba, Stephanie / Shapanis, Andrew / Payne, Megan / Patterson, Warren / Alexander, Michael / Coxhead, Jonathan / Filby, Andrew / Plummer, Ruth / Lovat, Penny E / Sciume, Giuseppe / Healy, Eugene / Amarnath, Shoba

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 18, Page(s) e2216587120

Abstract: Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are ... ...

Abstract	Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet
MeSH term(s)	Mice ; Animals ; Humans ; Lymphocytes ; Immunity, Innate ; Programmed Cell Death 1 Receptor/genetics ; Programmed Cell Death 1 Receptor/metabolism ; Tumor Microenvironment ; Neoplasms/metabolism ; Apoptosis ; Mammals/metabolism
Chemical Substances	Programmed Cell Death 1 Receptor
Language	English
Publishing date	2023-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2216587120
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Article: Prognostic Impact of Autophagy Biomarkers for Cutaneous Melanoma.

Tang, Diana Y L / Ellis, Robert A / Lovat, Penny E

Frontiers in oncology

2016 Volume 6, Page(s) 236

Abstract: Prognosis and survival for malignant melanoma is highly dependent on early diagnosis and treatment. While the American Joint Committee on Cancer (AJCC) criterion provides a means of staging melanomas and guiding treatment approaches, it is unable to ... ...

Abstract	Prognosis and survival for malignant melanoma is highly dependent on early diagnosis and treatment. While the American Joint Committee on Cancer (AJCC) criterion provides a means of staging melanomas and guiding treatment approaches, it is unable to identify the risk of disease progression of early stage tumors or provide reliable stratification for novel adjuvant therapies. The demand for credible prognostic/companion biomarkers able to identify high-risk melanoma subgroups as well as guide more effective personalized/precision-based therapy is therefore of paramount importance. Autophagy, the principle lysosomal-mediated process for the degradation/recycling of cellular debris, is a hot topic in cancer medicine, and observations of its deregulation in melanoma have brought its potential as a prognostic biomarker to the forefront of current research. Key regulatory proteins, including Atg8/microtubule-associated light chain 3 (LC3) and BECN1 (Beclin 1), have been proposed as potential prognostic biomarkers. However, given the dynamic nature of autophagy, their expression
Language	English
Publishing date	2016-11-09
Publishing country	Switzerland
Document type	Review ; Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2016.00236
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Article ; Online: Cell-type variation in stress responses as a consequence of manipulating GRP78 expression in neuroectodermal cells.

Martin, Shaun / Lovat, Penny E / Redfern, Chris P F

Journal of cellular biochemistry

2015 Volume 116, Issue 3, Page(s) 438–449

Abstract: Glucose-regulated protein 78 (GRP78) is a stress sensor which interacts with unfolded protein response (UPR) activators in the endoplasmic reticulum (ER). The aim of this study was to test the hypothesis that GRP78 has distinct functional roles in ... ...

Abstract	Glucose-regulated protein 78 (GRP78) is a stress sensor which interacts with unfolded protein response (UPR) activators in the endoplasmic reticulum (ER). The aim of this study was to test the hypothesis that GRP78 has distinct functional roles in mediating the effects of ER stress in neuroblastoma compared to other neuroectodermal cancer types. GRP78 was knocked down or overexpressed in neuroectodermal tumor cell lines. Protein and transcript expression were measured using Western blotting, confocal microscopy, and real-time polymerase chain reaction; cell stress was assessed by measurement of oxidative stress and accumulation of ubiquitinated proteins and cell response by measurement of apoptosis and cell viability. Neuroblastoma cells were more sensitive to ER stress than melanoma and glioblastoma cells. GRP78 knockdown increased stress sensitivity of melanoma and glioblastoma cells, but not neuroblastoma cells. Over-expression of GRP78 decreased the stress sensitivity of melanoma and glioblastoma cells but, in contrast, increased the stress sensitivity of neuroblastoma cells by activation of caspase-3-independent cell death and substantially increased the expression of UPR activators, particularly inositol-requiring element 1 (IRE1). The results from this study suggest that cell-type specific differences in the relationships between GRP78 and the UPR activators, particularly IRE1, may determine differential sensitivity to ER stress.
MeSH term(s)	Biomarkers/metabolism ; Boronic Acids/pharmacology ; Bortezomib ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Shape/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Fenretinide/pharmacology ; Gene Knockdown Techniques ; Heat-Shock Proteins/metabolism ; Humans ; Neural Plate/cytology ; Neural Plate/metabolism ; Pyrazines/pharmacology ; RNA, Small Interfering/metabolism ; Stress, Physiological/drug effects ; Unfolded Protein Response/drug effects
Chemical Substances	Biomarkers ; Boronic Acids ; Heat-Shock Proteins ; Pyrazines ; RNA, Small Interfering ; molecular chaperone GRP78 ; Fenretinide (187EJ7QEXL) ; Bortezomib (69G8BD63PP)
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.24996
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Zs.A 1114: Show issues

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Article: Established and Emerging Biomarkers in Cutaneous Malignant Melanoma.

Verykiou, Stamatina / Ellis, Robert A / Lovat, Penny E

Healthcare (Basel, Switzerland)

2014 Volume 2, Issue 1, Page(s) 60–73

Abstract: In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, ... ...

Abstract	In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, especially in patients under 35-years of age. Despite the excellent prognosis for patients diagnosed with early stage disease, metastatic disease still carries significant overall mortality. Biomarkers aim not only to identify high-risk patients, but also to provide potential therapeutic targets for differing patient subgroups. Furthermore, accessibility to tissue samples from a range of disease stages in malignant melanoma, unlike most other solid tissue tumours, provides the unique opportunity to explore the biology of tumour progression that may be relevant in the biology of cancer as a whole. Over the past decade, there have been major advances in targeted therapies, providing new avenues and hope to patients with this devastating disease. This review will focus on most up to date histological, serological and molecular biomarkers in malignant melanoma.
Language	English
Publishing date	2014-01-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2721009-1
ISSN	2227-9032
ISSN	2227-9032
DOI	10.3390/healthcare2010060
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Article ; Online: Induction of endoplasmic reticulum stress as a strategy for melanoma therapy: is there a future?

Hill, David S / Lovat, Penny E / Haass, Nikolas K

Melanoma management

2014 Volume 1, Issue 2, Page(s) 127–137

Abstract: Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced ... ...

Abstract	Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced apoptosis, while upregulation of ER chaperone proteins and antiapoptotic BCL-2 family members increases the protein folding capacity of the cell and the threshold for the induction of ER stress-induced apoptosis, respectively. Modulation of unfolded protein response signaling, inhibition of the protein folding machinery and/or active induction of ER stress may thus represent potential strategies for the therapeutic management of melanoma. To this aim, the present article focuses on the current understanding of how melanoma cells avoid or overcome ER stress-induced apoptosis, as well as therapeutic strategies through which to harness ER stress for therapeutic benefit.
Language	English
Publishing date	2014-12-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2786852-7
ISSN	2045-0893 ; 2045-0893
ISSN (online)	2045-0893
ISSN	2045-0893
DOI	10.2217/mmt.14.16
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Article ; Online: Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca

Zummo, Francesco P / Krishnanda, Stanislaus I / Georgiou, Merilin / O'Harte, Finbarr Pm / Parthsarathy, Vadivel / Cullen, Kirsty S / Honkanen-Scott, Minna / Shaw, James Am / Lovat, Penny E / Arden, Catherine

Autophagy

2021 Volume 18, Issue 4, Page(s) 799–815

Abstract: Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R ( ... ...

Abstract	Macroautophagy/autophagy is critical for the regulation of pancreatic β-cell mass and its deregulation has been implicated in the pathogenesis of type 2 diabetes (T2D). We have previously shown that treatment of pancreatic β-cells with the GLP1R (glucagon like peptide 1 receptor) agonist exendin-4 stimulates autophagic flux in a setting of chronic nutrient excess. The aim of this study was to identify the underlying pathways contributing to enhanced autophagic flux.Pancreatic β-cells (INS-1E),mouse and human islets were treated with glucolipotoxic stress (0.5 mM palmitate and 25 mM glucose) in the presence of exendin-4. Consistent with our previous work, exendin-4 stimulated autophagic flux. Using chemical inhibitors and siRNA knockdown, we identified RAPGEF4/EPAC2 (Rap guanine nucleotide exchange factor 4) and downstream calcium signaling to be essential for regulation of autophagic flux by exendin-4. This pathway was independent of AMPK and MTOR signaling. Further analysis identified PPP3/calcineurin and its downstream regulator TFEB (transcription factor EB) as key proteins mediating exendin-4 induced autophagy. Importantly, inhibition of this pathway prevented exendin-4-mediated cell survival and overexpression of TFEB mimicked the cell protective effects of exendin-4 in INS-1E and human islets. Moreover, treatment of
MeSH term(s)	AMP-Activated Protein Kinases ; Animals ; Autophagy ; Calcineurin/metabolism ; Calcium/metabolism ; Diabetes Mellitus, Type 2 ; Exenatide/pharmacology ; Glucagon-Like Peptide-1 Receptor ; Guanine Nucleotide Exchange Factors ; Mice ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Epac protein, mouse ; Glucagon-Like Peptide-1 Receptor ; Guanine Nucleotide Exchange Factors ; Exenatide (9P1872D4OL) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Calcineurin (EC 3.1.3.16) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1956123
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Zs.A 6741: Show issues

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Article ; Online: Established and Emerging Biomarkers in Cutaneous Malignant Melanoma

Stamatina Verykiou / Robert A Ellis / Penny E Lovat

Healthcare, Vol 2, Iss 1, Pp 60-

2014 Volume 73

Abstract	In an era of personalized medicine, disease specific biomarkers play an increasing role in the stratification of high-risk patient groups. Cutaneous malignant melanoma is the most deadly form of skin cancer with an ever-increasing global incidence, especially in patients under 35-years of age. Despite the excellent prognosis for patients diagnosed with early stage disease, metastatic disease still carries significant overall mortality. Biomarkers aim not only to identify high-risk patients, but also to provide potential therapeutic targets for differing patient subgroups. Furthermore, accessibility to tissue samples from a range of disease stages in malignant melanoma, unlike most other solid tissue tumours, provides the unique opportunity to explore the biology of tumour progression that may be relevant in the biology of cancer as a whole. Over the past decade, there have been major advances in targeted therapies, providing new avenues and hope to patients with this devastating disease. This review will focus on most up to date histological, serological and molecular biomarkers in malignant melanoma.
Keywords	cutaneous melanoma ; malignancy ; biomarkers ; Medicine ; R
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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