Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on ... more Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on the apocrine-rich skin of the perineum. We report 2 cases in which EMPD was initially misdiagnosed on the initial punch biopsy as melanoma-in-situ and Bowen disease respectively. Reasons for the misdiagnoses included a rare pigmented axillary variant of EMPD in the first case and atypical bowenoid features on H&E in the second. The cases are described with a critical review of the histopathological findings, along with a review of the current literature. This highlights the necessity of a comprehensive immunohistochemical panel for the assessment of intra-epithelial pagetoid atypical cells.
Journal of the European Academy of Dermatology and Venereology, 2013
Psoriasis has been linked with cardiovascular risk factors (CVRFs), including the metabolic syndr... more Psoriasis has been linked with cardiovascular risk factors (CVRFs), including the metabolic syndrome, yet many patients with psoriasis remain unscreened. To assess the reasons for lack of screening for CVRFs in psoriasis patients, and the impact of an education programme targeting these deficiencies. All patients with psoriasis, regardless of severity, and all dermatologists working at the National Skin Centre (NSC) in Singapore were surveyed over a 2-month period on their attitudes and knowledge regarding psoriasis and cardiovascular risk. This was followed by a targeted programme which was implemented over 2 months to address these identified deficiencies. Patients and doctors were surveyed a second time to assess the effects of the intervention. Obstacles to screening included lack of patient knowledge, patients not considering screening important, and lack of time during the clinic consultation. After the intervention, there was a significant increase in the proportion of patients who were aware of increased cardiovascular risk in psoriasis (33.0% to 62%), with more patients attending screening (39.1% to 63.2%). While the level of doctors' knowledge did not significantly increase, there was an increase in the proportion of patients who were screened post-intervention (37.1% to 66.2%), and more doctors reported that they were more likely to screen psoriatic patients from an earlier age (30.2% to 58.1%). The obstacles in implementing universal screening for CVRFs in psoriasis patients stem from patient, doctor and system factors. A comprehensive programme targeting all aspects of this ecosystem helps to achieve holistic care for patients with psoriasis.
We report a case of a 48-year-old Malay female who presented with multiple tumors arising from a ... more We report a case of a 48-year-old Malay female who presented with multiple tumors arising from a large nevus sebaceus on her right parieto-temporal scalp. Histologically, the tumors corresponded to a sebaceoma with carcinomatous change, a poroma and a trichoblastoma. Immunohistochemical staining of the sebaceous tumor with p53 showed strong within the areas of carcinomatous change, while there was negative to weak staining within the sebaceoma-like areas. A discussion on the potential secondary neoplasms from a nevus sebaceus ensues, with a review of this literature on multiple tumors from a nevus sebaceus.
We report a series of four patients who presented with complaints of diffuse non-scarring alopeci... more We report a series of four patients who presented with complaints of diffuse non-scarring alopecia. They had similar clinical features of alopecia, hyperseborrhea, and distinct keratinaceous hair casts that encircled the hair shafts. Propionibacterium acnes was isolated from two of the patients' scalp, and Gram-positive, Giemsa-positive bacteria were seen in the hair follicles in the scalp biopsy of one of the patients. The patients' symptoms did not respond to standard treatment for seborrheic dermatitis, but responded to a course of systemic antibiotics targeting P. acnes. We propose a role for P. acnes colonization of the terminal hair follicles in the pathogenesis of hair casts, and possibly diffuse non-scarring alopecia. Possible mechanisms of pathogenesis are discussed with a literature review.
Alopecia areata (AA) is a non-scarring autoimmune disease of the hair follicle that can present a... more Alopecia areata (AA) is a non-scarring autoimmune disease of the hair follicle that can present at any age. Pediatric cases are commonly seen in a dermatology clinic, and management can potentially be challenging, with a small proportion of cases experiencing a chronic relapsing course marked by distressing hair loss that can bring about significant psychosocial morbidity. We review the established treatments for pediatric alopecia areata, alongside second and third line therapies that have shown to be efficacious. We also offer a treatment algorithm as a guide to the treatment of pediatric AA.
F1000 - Post-publication peer review of the biomedical literature, 2012
Epithelial cancers are the most common malignancies and the greatest cause of cancer mortality wo... more Epithelial cancers are the most common malignancies and the greatest cause of cancer mortality worldwide. The incidence of keratinocyte-derived (non-melanoma) skin cancers (NMSCa) is increasing rapidly. Despite access to abundant tumor tissue and ease of observation, acceptance of NMSCa as model carcinomas has been hindered by the lack of a reliable xenograft model. Herein we describe conditions that allow routine xenoengraftment of primary human squamous cell carcinoma (SCCa) cells. Tumor development required creation of an appropriate stromal bed prior to xenografting tumor tissue onto the backs of athymic nude mice. We also demonstrate that the stromal bed must be "humanized" if primary human SCCa is to be propagated from cell suspensions. SCCa xenografts recapitulated the histological grade and phenotype of the original tumors with considerable fidelity, even after serial passage, irrespective of the histological grade of the primary human SCCa. To our knowledge this previously unreported model can be used for drug testing, as well as for studies that are relevant to the biology of primary human SCCa and other epithelial cancers.
Publisher's copyright statement: This article is licensed under a Creative Commons Attributio... more Publisher's copyright statement: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Animal development and homeostasis depend on precise temporal and spatial intercellular signaling... more Animal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebraf...
Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific ther... more Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific therapies to those that are now more targeted and rationally selected. This was achieved by means of close cooperation and communication between clinicians and basic scientists, which resulted in the elucidation and understanding of the unique pathophysiology of AA. In this review we discuss this evolution and how novel therapies for AA have changed over the decades, what we have in our current arsenal of drugs for this potentially devastating disease, and what the future holds.
Highlights d JAK-STAT5 signaling maintains quiescence in hair follicle stem cells (HFSCs) d Oncos... more Highlights d JAK-STAT5 signaling maintains quiescence in hair follicle stem cells (HFSCs) d Oncostatin M (OSM) acts upstream of JAK-STAT5 signaling to maintain HFSC quiescence d A subset of TREM2 + macrophages in the mouse skin is the source of OSM d Specific ablation of macrophages in the mouse skin is associated with anagen entry
Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with... more Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with significant skin injuries and to enable human-relevant drug screening for skin diseases; however, the incorporation of engineered skin appendages, such as hair follicles (HFs), into HSCs remains a major challenge. Here, we demonstrate a biomimetic approach for generation of human HFs within HSCs by recapitulating the physiological 3D organization of cells in the HF microenvironment using 3D-printed molds. Overexpression of Lef-1 in dermal papilla cells (DPC) restores the intact DPC transcriptional signature and significantly enhances the efficiency of HF differentiation in HSCs. Furthermore, vascularization of hairbearing HSCs prior to engraftment allows for efficient human hair growth in immunodeficient mice. The ability to regenerate an entire HF from cultured human cells will have a transformative impact on the medical management of different types of alopecia, as well as chronic wounds, which represent major unmet medical needs.
Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in... more Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in the murine hair cycle. Interestingly, others have shown that JAKinhibition is able to induce telogen-to-anagen transition in wild-type mice. This apparent contradiction highlights the complexity of interactions within the hair follicle, and encourages further discussion on the role of JAK-STAT signaling in the various stem cell niches of the hair follicle.
Purpose of Review Alopecia areata (AA) and vitiligo are dermatological autoimmune diseases that, ... more Purpose of Review Alopecia areata (AA) and vitiligo are dermatological autoimmune diseases that, until recently, have had no specifically targeted therapies. Here, we review the future of therapies specifically targeted to the treatment of alopecia areata and vitiligo, both of which have JAK-STAT signaling implicated in their pathogenesis. Recent Findings With a greater understanding of disease mechanisms and pathogenesis, we are now able to target the immune dysfunction in autoimmune diseases with more precision than topical corticosteroids and calcineurin inhibitors. Inhibition of the JAK-STAT pathway has been shown to be effective in the treatment of AA, vitiligo, and in some patients with both diseases. Summary In this review, we summarize the current molecular and immunological understanding of AA and vitiligo, how JAK inhibition is increasingly positioned as a new therapy for autoimmune diseases, and the future of topical JAK inhibitors in the field of dermatology.
Polycomb repressive complexes (PRCs) are essential chromatin regulators of cell identity. PRC1, w... more Polycomb repressive complexes (PRCs) are essential chromatin regulators of cell identity. PRC1, which is a dominant executer of Polycomb-mediated control, possesses catalyticdependent H2AK119 mono-ubiquitination and catalytic-independent activities. Despite extensive knowledge of PRC1s role in embryonic stem cells (SCs), its function in somatic SCs and tissue development is largely unknown. Here, we show that despite its well-established repressor functions, PRC1 binds to both silent and active genes in epidermal progenitors. Through loss-of-function studies, we show that global PRC1 function is essential for skin development and SC specification, whereas PRC1 catalytic activity is dispensable. By dissecting molecular mechanisms, we show that PRC1 catalytic-dependent and-independent activities repress non-skin lineage genes and attenuate expression of differentiation and proliferation genes. Interestingly, PRC1 also binds to and promotes the expression of critical skin developmental and SC genes independently of its catalytic activities. Our findings highlight PRC1s diverse roles in executing a precise developmental program.
Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on ... more Extra-mammary Paget disease (EMPD) is a rare intra-epithelial carcinoma that is usually found on the apocrine-rich skin of the perineum. We report 2 cases in which EMPD was initially misdiagnosed on the initial punch biopsy as melanoma-in-situ and Bowen disease respectively. Reasons for the misdiagnoses included a rare pigmented axillary variant of EMPD in the first case and atypical bowenoid features on H&E in the second. The cases are described with a critical review of the histopathological findings, along with a review of the current literature. This highlights the necessity of a comprehensive immunohistochemical panel for the assessment of intra-epithelial pagetoid atypical cells.
Journal of the European Academy of Dermatology and Venereology, 2013
Psoriasis has been linked with cardiovascular risk factors (CVRFs), including the metabolic syndr... more Psoriasis has been linked with cardiovascular risk factors (CVRFs), including the metabolic syndrome, yet many patients with psoriasis remain unscreened. To assess the reasons for lack of screening for CVRFs in psoriasis patients, and the impact of an education programme targeting these deficiencies. All patients with psoriasis, regardless of severity, and all dermatologists working at the National Skin Centre (NSC) in Singapore were surveyed over a 2-month period on their attitudes and knowledge regarding psoriasis and cardiovascular risk. This was followed by a targeted programme which was implemented over 2 months to address these identified deficiencies. Patients and doctors were surveyed a second time to assess the effects of the intervention. Obstacles to screening included lack of patient knowledge, patients not considering screening important, and lack of time during the clinic consultation. After the intervention, there was a significant increase in the proportion of patients who were aware of increased cardiovascular risk in psoriasis (33.0% to 62%), with more patients attending screening (39.1% to 63.2%). While the level of doctors' knowledge did not significantly increase, there was an increase in the proportion of patients who were screened post-intervention (37.1% to 66.2%), and more doctors reported that they were more likely to screen psoriatic patients from an earlier age (30.2% to 58.1%). The obstacles in implementing universal screening for CVRFs in psoriasis patients stem from patient, doctor and system factors. A comprehensive programme targeting all aspects of this ecosystem helps to achieve holistic care for patients with psoriasis.
We report a case of a 48-year-old Malay female who presented with multiple tumors arising from a ... more We report a case of a 48-year-old Malay female who presented with multiple tumors arising from a large nevus sebaceus on her right parieto-temporal scalp. Histologically, the tumors corresponded to a sebaceoma with carcinomatous change, a poroma and a trichoblastoma. Immunohistochemical staining of the sebaceous tumor with p53 showed strong within the areas of carcinomatous change, while there was negative to weak staining within the sebaceoma-like areas. A discussion on the potential secondary neoplasms from a nevus sebaceus ensues, with a review of this literature on multiple tumors from a nevus sebaceus.
We report a series of four patients who presented with complaints of diffuse non-scarring alopeci... more We report a series of four patients who presented with complaints of diffuse non-scarring alopecia. They had similar clinical features of alopecia, hyperseborrhea, and distinct keratinaceous hair casts that encircled the hair shafts. Propionibacterium acnes was isolated from two of the patients' scalp, and Gram-positive, Giemsa-positive bacteria were seen in the hair follicles in the scalp biopsy of one of the patients. The patients' symptoms did not respond to standard treatment for seborrheic dermatitis, but responded to a course of systemic antibiotics targeting P. acnes. We propose a role for P. acnes colonization of the terminal hair follicles in the pathogenesis of hair casts, and possibly diffuse non-scarring alopecia. Possible mechanisms of pathogenesis are discussed with a literature review.
Alopecia areata (AA) is a non-scarring autoimmune disease of the hair follicle that can present a... more Alopecia areata (AA) is a non-scarring autoimmune disease of the hair follicle that can present at any age. Pediatric cases are commonly seen in a dermatology clinic, and management can potentially be challenging, with a small proportion of cases experiencing a chronic relapsing course marked by distressing hair loss that can bring about significant psychosocial morbidity. We review the established treatments for pediatric alopecia areata, alongside second and third line therapies that have shown to be efficacious. We also offer a treatment algorithm as a guide to the treatment of pediatric AA.
F1000 - Post-publication peer review of the biomedical literature, 2012
Epithelial cancers are the most common malignancies and the greatest cause of cancer mortality wo... more Epithelial cancers are the most common malignancies and the greatest cause of cancer mortality worldwide. The incidence of keratinocyte-derived (non-melanoma) skin cancers (NMSCa) is increasing rapidly. Despite access to abundant tumor tissue and ease of observation, acceptance of NMSCa as model carcinomas has been hindered by the lack of a reliable xenograft model. Herein we describe conditions that allow routine xenoengraftment of primary human squamous cell carcinoma (SCCa) cells. Tumor development required creation of an appropriate stromal bed prior to xenografting tumor tissue onto the backs of athymic nude mice. We also demonstrate that the stromal bed must be "humanized" if primary human SCCa is to be propagated from cell suspensions. SCCa xenografts recapitulated the histological grade and phenotype of the original tumors with considerable fidelity, even after serial passage, irrespective of the histological grade of the primary human SCCa. To our knowledge this previously unreported model can be used for drug testing, as well as for studies that are relevant to the biology of primary human SCCa and other epithelial cancers.
Publisher's copyright statement: This article is licensed under a Creative Commons Attributio... more Publisher's copyright statement: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Animal development and homeostasis depend on precise temporal and spatial intercellular signaling... more Animal development and homeostasis depend on precise temporal and spatial intercellular signaling. Components shared between signaling pathways, generally thought to decrease specificity, paradoxically can also provide a solution to pathway coordination. Here we show that the Bone Morphogenetic Protein (BMP) and Wnt signaling pathways share Apcdd1 as a common inhibitor and that Apcdd1 is a taxon-restricted gene with novel domains and signaling functions. Previously, we showed that Apcdd1 inhibits Wnt signaling, here we find that Apcdd1 potently inhibits BMP signaling in body axis formation and neural differentiation in chicken, frog, zebrafish, and humans. Our results from experiments and modeling suggest that Apcdd1 may coordinate the outputs of two signaling pathways central to animal development and human disease.Significance StatementApcdd1is a taxon-restricted gene that inhibits both BMP and Wnt intercellular signaling pathways in multiple organisms including mice, frog, zebraf...
Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific ther... more Treatments for alopecia areata (AA) have evolved over the decades from broad and nonspecific therapies to those that are now more targeted and rationally selected. This was achieved by means of close cooperation and communication between clinicians and basic scientists, which resulted in the elucidation and understanding of the unique pathophysiology of AA. In this review we discuss this evolution and how novel therapies for AA have changed over the decades, what we have in our current arsenal of drugs for this potentially devastating disease, and what the future holds.
Highlights d JAK-STAT5 signaling maintains quiescence in hair follicle stem cells (HFSCs) d Oncos... more Highlights d JAK-STAT5 signaling maintains quiescence in hair follicle stem cells (HFSCs) d Oncostatin M (OSM) acts upstream of JAK-STAT5 signaling to maintain HFSC quiescence d A subset of TREM2 + macrophages in the mouse skin is the source of OSM d Specific ablation of macrophages in the mouse skin is associated with anagen entry
Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with... more Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with significant skin injuries and to enable human-relevant drug screening for skin diseases; however, the incorporation of engineered skin appendages, such as hair follicles (HFs), into HSCs remains a major challenge. Here, we demonstrate a biomimetic approach for generation of human HFs within HSCs by recapitulating the physiological 3D organization of cells in the HF microenvironment using 3D-printed molds. Overexpression of Lef-1 in dermal papilla cells (DPC) restores the intact DPC transcriptional signature and significantly enhances the efficiency of HF differentiation in HSCs. Furthermore, vascularization of hairbearing HSCs prior to engraftment allows for efficient human hair growth in immunodeficient mice. The ability to regenerate an entire HF from cultured human cells will have a transformative impact on the medical management of different types of alopecia, as well as chronic wounds, which represent major unmet medical needs.
Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in... more Legrand et al show that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in the murine hair cycle. Interestingly, others have shown that JAKinhibition is able to induce telogen-to-anagen transition in wild-type mice. This apparent contradiction highlights the complexity of interactions within the hair follicle, and encourages further discussion on the role of JAK-STAT signaling in the various stem cell niches of the hair follicle.
Purpose of Review Alopecia areata (AA) and vitiligo are dermatological autoimmune diseases that, ... more Purpose of Review Alopecia areata (AA) and vitiligo are dermatological autoimmune diseases that, until recently, have had no specifically targeted therapies. Here, we review the future of therapies specifically targeted to the treatment of alopecia areata and vitiligo, both of which have JAK-STAT signaling implicated in their pathogenesis. Recent Findings With a greater understanding of disease mechanisms and pathogenesis, we are now able to target the immune dysfunction in autoimmune diseases with more precision than topical corticosteroids and calcineurin inhibitors. Inhibition of the JAK-STAT pathway has been shown to be effective in the treatment of AA, vitiligo, and in some patients with both diseases. Summary In this review, we summarize the current molecular and immunological understanding of AA and vitiligo, how JAK inhibition is increasingly positioned as a new therapy for autoimmune diseases, and the future of topical JAK inhibitors in the field of dermatology.
Polycomb repressive complexes (PRCs) are essential chromatin regulators of cell identity. PRC1, w... more Polycomb repressive complexes (PRCs) are essential chromatin regulators of cell identity. PRC1, which is a dominant executer of Polycomb-mediated control, possesses catalyticdependent H2AK119 mono-ubiquitination and catalytic-independent activities. Despite extensive knowledge of PRC1s role in embryonic stem cells (SCs), its function in somatic SCs and tissue development is largely unknown. Here, we show that despite its well-established repressor functions, PRC1 binds to both silent and active genes in epidermal progenitors. Through loss-of-function studies, we show that global PRC1 function is essential for skin development and SC specification, whereas PRC1 catalytic activity is dispensable. By dissecting molecular mechanisms, we show that PRC1 catalytic-dependent and-independent activities repress non-skin lineage genes and attenuate expression of differentiation and proliferation genes. Interestingly, PRC1 also binds to and promotes the expression of critical skin developmental and SC genes independently of its catalytic activities. Our findings highlight PRC1s diverse roles in executing a precise developmental program.
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