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Kuender D Yang - One of the best experts on this subject based on the ideXlab platform.
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dexamethasone induction of Keloid regression through effective suppression of vegf expression and Keloid fibroblast proliferation
Journal of Investigative Dermatology, 2006Co-Authors: Fengsheng Wang, Kuender D Yang, Chaocheng Huang, Yurren KuoAbstract:The biological mechanism underlying steroid therapy for treating Keloids remains unclear. Analytical results demonstrated that topical intra-lesional steroid injections suppress vascular endothelial growth factor (VEGF) expression in Keloid tissue and induce its regression in vivo. This study investigated whether glucocorticoid (dexamethasone) downregulates VEGF expression and hinders Keloid fibroblast (KF) proliferation in Keloid regression. Primary KF cultures were treated with various concentrations of dexamethasone, glucocorticoid receptor (GR) antagonist (mifeprostone, RU-486), VEGF-A antibody, VEGF receptor-2 (VEGF-R2) antagonist (SU-5416), and VEGF protein. Analytical results demonstrated that dexamethasone retarded KFs proliferation. However, suppression of fibroblast proliferation by dexamethasone pre-treatment was reduced by adding exogenous VEGF protein. Dexamethasone suppressed endogenous VEGF mRNA induction, protein expressed by KFs, and angiogenesis activity detected by a tube-forming assay of human umbilical vein endothelial cells co-cultured fibroblasts. These effects were reversed by pre-treatment with RU-486, and not by pre-treatment with SU-5416. Thus, dexamethasone induces Keloid regression via interaction with the GR and suppresses endogenous VEGF expression and fibroblast proliferation. However, exogenous VEGF promotes fibroblast proliferation through the GR-independent pathway. Modulation of VEGF production may comprise a valuable treatment modality for Keloids.
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suppressed tgf β1 expression is correlated with up regulation of matrix metalloproteinase 13 in Keloid regression after flashlamp pulsed dye laser treatment
Lasers in Surgery and Medicine, 2005Co-Authors: Wenshan Wu, Sengfeng Jeng, Fengsheng Wang, Huichen Huang, Kuender D YangAbstract:Background and Objectives Flashlamp pulsed-dye lasers (PDLs) has shown effectiveness in the treatment of Keloids. In this study, we investigated whether PDL treatments decreased transforming growth factor-β1 (TGF-β1)—induction and up-regulation of matrix metalloproteinase (MMP) expression in Keloid regression. Study Design/Materials and Methods Keloid tissues obtained from 10 patients with intra-lesional or punch biopsies before and 7 days after PDL treatments [fluence per pulse was 10–18 J/cm2 (mean 14.0 J/cm2)]. Immunohistochemical (IHC) staining of TGF-β1 and MMP-1 and MMP-13 expressions in Keloid tissue was performed. Western blot analysis of MMP-1 and MMP-13 expressions in extracellular matrix was evaluated. Results IHC staining indicated that expression of TGF-β1 was significantly reduced in Keloid tissues after PDL irradiation. MMP-13 but not MMP-1 expression on IHC staining significantly increased in extracellular matrix of Keloid tissues after PDL treatment. Western blot analysis also showed MMP-13 but not MMP-1 significant increased in Keloid tissues after PDL treatment. Conclusions Regression of Keloids regressed after PDL treatments are associated with down-regulation of TGF-β1 expression and up-regulation of MMP-13 activity. Lasers Surg. Med. 36:38–42, 2005. © 2005 Wiley-Liss, Inc.
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suppressed tgf beta1 expression is correlated with up regulation of matrix metalloproteinase 13 in Keloid regression after flashlamp pulsed dye laser treatment
Lasers in Surgery and Medicine, 2005Co-Authors: Yurren Kuo, Sengfeng Jeng, Fengsheng Wang, Huichen Huang, Kuender D Yang, Chazon LinAbstract:Background and Objectives Flashlamp pulsed-dye lasers (PDLs) has shown effectiveness in the treatment of Keloids. In this study, we investigated whether PDL treatments decreased transforming growth factor-β1 (TGF-β1)—induction and up-regulation of matrix metalloproteinase (MMP) expression in Keloid regression. Study Design/Materials and Methods Keloid tissues obtained from 10 patients with intra-lesional or punch biopsies before and 7 days after PDL treatments [fluence per pulse was 10–18 J/cm2 (mean 14.0 J/cm2)]. Immunohistochemical (IHC) staining of TGF-β1 and MMP-1 and MMP-13 expressions in Keloid tissue was performed. Western blot analysis of MMP-1 and MMP-13 expressions in extracellular matrix was evaluated. Results IHC staining indicated that expression of TGF-β1 was significantly reduced in Keloid tissues after PDL irradiation. MMP-13 but not MMP-1 expression on IHC staining significantly increased in extracellular matrix of Keloid tissues after PDL treatment. Western blot analysis also showed MMP-13 but not MMP-1 significant increased in Keloid tissues after PDL treatment. Conclusions Regression of Keloids regressed after PDL treatments are associated with down-regulation of TGF-β1 expression and up-regulation of MMP-13 activity. Lasers Surg. Med. 36:38–42, 2005. © 2005 Wiley-Liss, Inc.
Yurren Kuo - One of the best experts on this subject based on the ideXlab platform.
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low grade myofibroblastic sarcoma arising from Keloid scar on the chest wall after thoracic surgery
The Annals of Thoracic Surgery, 2020Co-Authors: Yurren Kuo, Chihkai Yang, Austin D Chen, Savitha Ramachandran, Sindaw LinAbstract:Keloids are considered as benign fibroproliferative skin tumors, and rare cases of malignancies have been reported. We present a case of low-grade myofibroblastic sarcoma arising from a recurrent painful Keloid scar on the right chest wall after video-assisted thoracic surgery for pneumothorax in a 77-year-old man. Wide composite excision of the Keloid, surrounding ribs, and partial diaphragm were performed. The chest wall pleural defect was reconstructed with Teflon (Chemours, Wilmington, DE), and soft tissue was reconstructed with a transverse rectus abdominis myocutaneous flap. This case highlights that refractory Keloids may be considered a harbinger of malignancy.
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dexamethasone induction of Keloid regression through effective suppression of vegf expression and Keloid fibroblast proliferation
Journal of Investigative Dermatology, 2006Co-Authors: Fengsheng Wang, Kuender D Yang, Chaocheng Huang, Yurren KuoAbstract:The biological mechanism underlying steroid therapy for treating Keloids remains unclear. Analytical results demonstrated that topical intra-lesional steroid injections suppress vascular endothelial growth factor (VEGF) expression in Keloid tissue and induce its regression in vivo. This study investigated whether glucocorticoid (dexamethasone) downregulates VEGF expression and hinders Keloid fibroblast (KF) proliferation in Keloid regression. Primary KF cultures were treated with various concentrations of dexamethasone, glucocorticoid receptor (GR) antagonist (mifeprostone, RU-486), VEGF-A antibody, VEGF receptor-2 (VEGF-R2) antagonist (SU-5416), and VEGF protein. Analytical results demonstrated that dexamethasone retarded KFs proliferation. However, suppression of fibroblast proliferation by dexamethasone pre-treatment was reduced by adding exogenous VEGF protein. Dexamethasone suppressed endogenous VEGF mRNA induction, protein expressed by KFs, and angiogenesis activity detected by a tube-forming assay of human umbilical vein endothelial cells co-cultured fibroblasts. These effects were reversed by pre-treatment with RU-486, and not by pre-treatment with SU-5416. Thus, dexamethasone induces Keloid regression via interaction with the GR and suppresses endogenous VEGF expression and fibroblast proliferation. However, exogenous VEGF promotes fibroblast proliferation through the GR-independent pathway. Modulation of VEGF production may comprise a valuable treatment modality for Keloids.
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suppressed tgf beta1 expression is correlated with up regulation of matrix metalloproteinase 13 in Keloid regression after flashlamp pulsed dye laser treatment
Lasers in Surgery and Medicine, 2005Co-Authors: Yurren Kuo, Sengfeng Jeng, Fengsheng Wang, Huichen Huang, Kuender D Yang, Chazon LinAbstract:Background and Objectives Flashlamp pulsed-dye lasers (PDLs) has shown effectiveness in the treatment of Keloids. In this study, we investigated whether PDL treatments decreased transforming growth factor-β1 (TGF-β1)—induction and up-regulation of matrix metalloproteinase (MMP) expression in Keloid regression. Study Design/Materials and Methods Keloid tissues obtained from 10 patients with intra-lesional or punch biopsies before and 7 days after PDL treatments [fluence per pulse was 10–18 J/cm2 (mean 14.0 J/cm2)]. Immunohistochemical (IHC) staining of TGF-β1 and MMP-1 and MMP-13 expressions in Keloid tissue was performed. Western blot analysis of MMP-1 and MMP-13 expressions in extracellular matrix was evaluated. Results IHC staining indicated that expression of TGF-β1 was significantly reduced in Keloid tissues after PDL irradiation. MMP-13 but not MMP-1 expression on IHC staining significantly increased in extracellular matrix of Keloid tissues after PDL treatment. Western blot analysis also showed MMP-13 but not MMP-1 significant increased in Keloid tissues after PDL treatment. Conclusions Regression of Keloids regressed after PDL treatments are associated with down-regulation of TGF-β1 expression and up-regulation of MMP-13 activity. Lasers Surg. Med. 36:38–42, 2005. © 2005 Wiley-Liss, Inc.
George P Yang - One of the best experts on this subject based on the ideXlab platform.
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increased transcriptional response to mechanical strain in Keloid fibroblasts due to increased focal adhesion complex formation
Journal of Cellular Physiology, 2006Co-Authors: Zhen Wang, Kenton Fong, Toanthang Phan, Ivor J Lim, Michael T Longaker, George P YangAbstract:Clinicians have observed that Keloids preferentially form in body areas subject to increased skin tension. We hypothesized a difference exists in the transcriptional response of Keloid fibroblasts to mechanical strain compared with normal fibroblasts. Normal and Keloid fibroblasts were seeded in a device calibrated to deliver a known level of equibiaxial strain. We examined the transcriptional response of TGF-beta isoforms and collagen Ialpha, genes differentially expressed in Keloids. Keloid fibroblasts produced more mRNA for TGF-beta1, TGF-beta2, and collagen Ialpha after mechanical strain compared to normals, and this was correlated with protein production. Inhibiting the major mechanical signal transduction pathway with the ERK inhibitor, U0126, blocked upregulation of gene expression. In addition, Keloid fibroblasts formed more focal adhesion complexes as measured by immunofluorescence for focal adhesion kinase, integrin beta1, and vinculin. Finally, there is increased activation of focal adhesion kinase when we detected the phosphorylated form of focal adhesion kinase with immunofluorescence and immunoblotting. In summary, Keloid fibroblasts have an exaggerated response to mechanical strain compared to normal fibroblasts leading to increased production of pro-fibrotic growth factors. This may be one molecular mechanism for the development of Keloids.
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complex epithelial mesenchymal interactions modulate transforming growth factor beta expression in Keloid derived cells
Wound Repair and Regeneration, 2004Co-Authors: Wei Xia, Toanthang Phan, Ivor J Lim, Michael T Longaker, George P YangAbstract:Keloids are proliferative dermal growths representing a pathologic wound healing response. We have previously demonstrated that coculture of fibroblasts derived from either Keloid or normal skin have an elevated proliferation rate when cocultured with Keloid-derived keratinocytes vs. normal keratinocytes. In these studies, we examined the contribution of transforming growth factor-beta (TGF-beta) to this phenomenon using a two-chamber coculture system. Fibroblast proliferation in coculture was slower with the addition of a pan-TGF-beta neutralizing antibody. Keloid keratinocytes in coculture expressed more TGF-beta1, -beta3, and TGF-beta receptor 1 than normal keratinocytes. Keloid fibroblasts cocultured with Keloid keratinocytes expressed more mRNA for TGF-beta1, -beta2, TGF-beta receptor 1, and Smad2. Keloid fibroblasts also produced more type I collagen, connective tissue growth factor, and insulin-like growth factor-II/mannose-6-phosphate receptor when cocultured with Keloid keratinocytes vs. normal keratinocytes. Levels of total and activated TGF-beta activity increased when fibroblasts were cocultured with keratinocytes, correlating with the changes in transcriptional activity of TGF-beta. In conclusion, we find a complex paracrine interaction regulates TGF-beta mRNA expression and activation between keratinocytes and fibroblasts. These data suggest that Keloid pathogenesis may result from both an increased TGF-beta production and activation by the Keloid keratinocyte, and elevated TGF-beta expression, utilization, and signaling in Keloid fibroblasts.
Fengsheng Wang - One of the best experts on this subject based on the ideXlab platform.
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dexamethasone induction of Keloid regression through effective suppression of vegf expression and Keloid fibroblast proliferation
Journal of Investigative Dermatology, 2006Co-Authors: Fengsheng Wang, Kuender D Yang, Chaocheng Huang, Yurren KuoAbstract:The biological mechanism underlying steroid therapy for treating Keloids remains unclear. Analytical results demonstrated that topical intra-lesional steroid injections suppress vascular endothelial growth factor (VEGF) expression in Keloid tissue and induce its regression in vivo. This study investigated whether glucocorticoid (dexamethasone) downregulates VEGF expression and hinders Keloid fibroblast (KF) proliferation in Keloid regression. Primary KF cultures were treated with various concentrations of dexamethasone, glucocorticoid receptor (GR) antagonist (mifeprostone, RU-486), VEGF-A antibody, VEGF receptor-2 (VEGF-R2) antagonist (SU-5416), and VEGF protein. Analytical results demonstrated that dexamethasone retarded KFs proliferation. However, suppression of fibroblast proliferation by dexamethasone pre-treatment was reduced by adding exogenous VEGF protein. Dexamethasone suppressed endogenous VEGF mRNA induction, protein expressed by KFs, and angiogenesis activity detected by a tube-forming assay of human umbilical vein endothelial cells co-cultured fibroblasts. These effects were reversed by pre-treatment with RU-486, and not by pre-treatment with SU-5416. Thus, dexamethasone induces Keloid regression via interaction with the GR and suppresses endogenous VEGF expression and fibroblast proliferation. However, exogenous VEGF promotes fibroblast proliferation through the GR-independent pathway. Modulation of VEGF production may comprise a valuable treatment modality for Keloids.
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suppressed tgf β1 expression is correlated with up regulation of matrix metalloproteinase 13 in Keloid regression after flashlamp pulsed dye laser treatment
Lasers in Surgery and Medicine, 2005Co-Authors: Wenshan Wu, Sengfeng Jeng, Fengsheng Wang, Huichen Huang, Kuender D YangAbstract:Background and Objectives Flashlamp pulsed-dye lasers (PDLs) has shown effectiveness in the treatment of Keloids. In this study, we investigated whether PDL treatments decreased transforming growth factor-β1 (TGF-β1)—induction and up-regulation of matrix metalloproteinase (MMP) expression in Keloid regression. Study Design/Materials and Methods Keloid tissues obtained from 10 patients with intra-lesional or punch biopsies before and 7 days after PDL treatments [fluence per pulse was 10–18 J/cm2 (mean 14.0 J/cm2)]. Immunohistochemical (IHC) staining of TGF-β1 and MMP-1 and MMP-13 expressions in Keloid tissue was performed. Western blot analysis of MMP-1 and MMP-13 expressions in extracellular matrix was evaluated. Results IHC staining indicated that expression of TGF-β1 was significantly reduced in Keloid tissues after PDL irradiation. MMP-13 but not MMP-1 expression on IHC staining significantly increased in extracellular matrix of Keloid tissues after PDL treatment. Western blot analysis also showed MMP-13 but not MMP-1 significant increased in Keloid tissues after PDL treatment. Conclusions Regression of Keloids regressed after PDL treatments are associated with down-regulation of TGF-β1 expression and up-regulation of MMP-13 activity. Lasers Surg. Med. 36:38–42, 2005. © 2005 Wiley-Liss, Inc.
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suppressed tgf beta1 expression is correlated with up regulation of matrix metalloproteinase 13 in Keloid regression after flashlamp pulsed dye laser treatment
Lasers in Surgery and Medicine, 2005Co-Authors: Yurren Kuo, Sengfeng Jeng, Fengsheng Wang, Huichen Huang, Kuender D Yang, Chazon LinAbstract:Background and Objectives Flashlamp pulsed-dye lasers (PDLs) has shown effectiveness in the treatment of Keloids. In this study, we investigated whether PDL treatments decreased transforming growth factor-β1 (TGF-β1)—induction and up-regulation of matrix metalloproteinase (MMP) expression in Keloid regression. Study Design/Materials and Methods Keloid tissues obtained from 10 patients with intra-lesional or punch biopsies before and 7 days after PDL treatments [fluence per pulse was 10–18 J/cm2 (mean 14.0 J/cm2)]. Immunohistochemical (IHC) staining of TGF-β1 and MMP-1 and MMP-13 expressions in Keloid tissue was performed. Western blot analysis of MMP-1 and MMP-13 expressions in extracellular matrix was evaluated. Results IHC staining indicated that expression of TGF-β1 was significantly reduced in Keloid tissues after PDL irradiation. MMP-13 but not MMP-1 expression on IHC staining significantly increased in extracellular matrix of Keloid tissues after PDL treatment. Western blot analysis also showed MMP-13 but not MMP-1 significant increased in Keloid tissues after PDL treatment. Conclusions Regression of Keloids regressed after PDL treatments are associated with down-regulation of TGF-β1 expression and up-regulation of MMP-13 activity. Lasers Surg. Med. 36:38–42, 2005. © 2005 Wiley-Liss, Inc.
Michael T Longaker - One of the best experts on this subject based on the ideXlab platform.
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increased transcriptional response to mechanical strain in Keloid fibroblasts due to increased focal adhesion complex formation
Journal of Cellular Physiology, 2006Co-Authors: Zhen Wang, Kenton Fong, Toanthang Phan, Ivor J Lim, Michael T Longaker, George P YangAbstract:Clinicians have observed that Keloids preferentially form in body areas subject to increased skin tension. We hypothesized a difference exists in the transcriptional response of Keloid fibroblasts to mechanical strain compared with normal fibroblasts. Normal and Keloid fibroblasts were seeded in a device calibrated to deliver a known level of equibiaxial strain. We examined the transcriptional response of TGF-beta isoforms and collagen Ialpha, genes differentially expressed in Keloids. Keloid fibroblasts produced more mRNA for TGF-beta1, TGF-beta2, and collagen Ialpha after mechanical strain compared to normals, and this was correlated with protein production. Inhibiting the major mechanical signal transduction pathway with the ERK inhibitor, U0126, blocked upregulation of gene expression. In addition, Keloid fibroblasts formed more focal adhesion complexes as measured by immunofluorescence for focal adhesion kinase, integrin beta1, and vinculin. Finally, there is increased activation of focal adhesion kinase when we detected the phosphorylated form of focal adhesion kinase with immunofluorescence and immunoblotting. In summary, Keloid fibroblasts have an exaggerated response to mechanical strain compared to normal fibroblasts leading to increased production of pro-fibrotic growth factors. This may be one molecular mechanism for the development of Keloids.
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complex epithelial mesenchymal interactions modulate transforming growth factor beta expression in Keloid derived cells
Wound Repair and Regeneration, 2004Co-Authors: Wei Xia, Toanthang Phan, Ivor J Lim, Michael T Longaker, George P YangAbstract:Keloids are proliferative dermal growths representing a pathologic wound healing response. We have previously demonstrated that coculture of fibroblasts derived from either Keloid or normal skin have an elevated proliferation rate when cocultured with Keloid-derived keratinocytes vs. normal keratinocytes. In these studies, we examined the contribution of transforming growth factor-beta (TGF-beta) to this phenomenon using a two-chamber coculture system. Fibroblast proliferation in coculture was slower with the addition of a pan-TGF-beta neutralizing antibody. Keloid keratinocytes in coculture expressed more TGF-beta1, -beta3, and TGF-beta receptor 1 than normal keratinocytes. Keloid fibroblasts cocultured with Keloid keratinocytes expressed more mRNA for TGF-beta1, -beta2, TGF-beta receptor 1, and Smad2. Keloid fibroblasts also produced more type I collagen, connective tissue growth factor, and insulin-like growth factor-II/mannose-6-phosphate receptor when cocultured with Keloid keratinocytes vs. normal keratinocytes. Levels of total and activated TGF-beta activity increased when fibroblasts were cocultured with keratinocytes, correlating with the changes in transcriptional activity of TGF-beta. In conclusion, we find a complex paracrine interaction regulates TGF-beta mRNA expression and activation between keratinocytes and fibroblasts. These data suggest that Keloid pathogenesis may result from both an increased TGF-beta production and activation by the Keloid keratinocyte, and elevated TGF-beta expression, utilization, and signaling in Keloid fibroblasts.
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differential expression of transforming growth factor beta receptors i and ii and activation of smad 3 in Keloid fibroblasts
Plastic and Reconstructive Surgery, 2001Co-Authors: Gyu S Chin, Wei Liu, Ziv M Peled, Thomas Y Lee, Douglas S Steinbrech, Meier Hsu, Michael T LongakerAbstract:Keloids represent a dysregulated response to cutaneous wounding that results in an excessive deposition of extracellular matrix, especially collagen. However, the molecular mechanisms regulating this pathologic collagen deposition still remain to be elucidated. A previous study by this group demonstrated that transforming growth factor (TGF)-beta1 and -beta2 ligands were expressed at greater levels in Keloid fibroblasts when compared with normal human dermal fibroblasts (NHDFs), suggesting that TGF-beta may play a fibrosis-promoting role in Keloid pathogenesis.To explore the biomolecular mechanisms of TGF-beta in Keloid formation, the authors first compared the expression levels of the type I and type II TGF-beta receptors in Keloid fibroblasts and NHDFs. Next, they investigated the phosphorylation of Smad 3, an intracellular TGF-beta signaling molecule, in Keloid fibroblasts and NHDFs. Finally, they examined the regulation of TGF-beta receptor II by TGF-beta1, TGF-beta2, and TGF-beta3 ligands. Our findings demonstrated an increased expression of TGF-beta receptors (types I and II) and increased phosphorylation of Smad 3 in Keloid fibroblasts relative to NHDFs. These data support a possible role of TGF-beta and its receptors as fibrosis-inducing growth factors in Keloids. In addition, all three isoforms of recombinant human TGF-beta proteins could further stimulate the expression of TGF-beta receptor II in both Keloids and NHDFs. Taken together, these results substantiate the hypothesis that the elevated levels of TGF-beta ligands and receptors present in Keloids may support increased signaling and a potential role for TGF-beta in Keloid pathogenesis.
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downregulation of apoptosis related genes in Keloid tissues
Journal of Surgical Research, 1999Co-Authors: David N Sayah, Michael T Longaker, Chia Soo, William W Shaw, James P Watson, Diana V Messadi, Xinli Zhang, Kang TingAbstract:Abstract Background. Physiologically programmed cell death or apoptosis occurs during the natural balance between cellular proliferation and demise. Materials and Methods. We compared the expression of 64 apoptosis-related genes in Keloids and normal scars to investigate the potential role of apoptosis in Keloid formation. Two sets of mRNA were isolated from Keloids excised from four previously untreated patients and four normal scar patients separately. Human cDNA arrayed hybridization was performed to compare the apoptosis-related gene expression between these two groups. In addition, TUNEL assays were performed to evaluate the percentage of apoptotic cells in Keloids (center and periphery) versus normal scars. Results. Eight of the sixty-four apoptosis-related genes studied were significantly underexpressed in Keloid tissue. The underexpressed genes and their relative expression compared with normal scar were defender against cell death 1 (DAD-1) (34.1% of normal scar); nucleoside diphosphate kinase B (c- myc transcription factor) (24.7%); glutathione S -transferase (17.9%); glutathione S -transferase microsomal (28.1%); glutathione peroxidase (47.2%); tumor necrosis factor receptor 1-associated protein (TRADD) (51.0%); 19-kDa interacting protein 3 (NIP3) (36.0%); and cytoplasmic dynein light chain 1 (HDLC1) (47.7%). Spatial analysis of apoptosis using TUNEL assays revealed apoptosis indices of 0.83 for Keloid periphery and 0.63 for Keloid center. Conclusions. In this study we demonstrated underexpression of apoptosis-related genes in human Keloid tissue and decreased apoptotic activity in fibroblasts derived from Keloids versus normal scars. We hypothesized that Keloid fibroblasts fail to undergo physiologically programmed cell death and, thus, continue to produce and secrete connective tissue beyond the period expected in normal scar formation, accounting for the progressive and hypertrophic nature of Keloids. This mechanism leads to new possibilities for treatment of Keloids through induction of apoptosis.