RESUMEN
Epstein-Barr virus (EBV) may cause a wide spectrum of symptomatology in humans ranging from asymptomatic upper respiratory tract infection to infectious mononucleosis and in more severe cases lymphoproliferative disorders or hemophagocytic lymphohistiocytosis. Its neoplastic potential is higher in immunocompromised individuals. We describe a case of EBV-positive mucocutaneous ulcer, a more indolent clinical entity on the spectrum of EBV-driven lymphoproliferative disorders, and are one of the first to put sulfasalazine, an immunomodulatory agent, forward as the possible culprit.
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In this narrative review, we attempt to provide an overview of the evidence regarding the role of estrogen (receptors) in cutaneous melanoma (CM). We reviewed 68 studies and 4 systematic reviews and meta-analyses published from 2002 up to and including 2022. The prevailing presence of estrogen receptor ß (ERß) instead of estrogen receptor α (ERα) in CM is notable, with ERß potentially playing a protective role and being less frequently detected in progressive cases. While men with CM generally experience a less favorable prognosis, this distinction may become negligible with advancing age. The role of oral contraceptives (OC) and hormone replacement therapy (HRT) in CM remains controversial. However, recent studies tend to associate the use of these exogenous hormones with a heightened risk of CM, mostly only when using estrogen therapy and not in combination with progesterone. On the contrary, the majority of studies find no substantial influence of in vitro fertilization (IVF) treatment on CM risk. Reproductive factors, including younger age at first childbirth, higher parity, and shorter reproductive life, show conflicting evidence, with some studies suggesting a lower CM risk. We suggest an important role for estrogens in CM. More research is needed, but the integration of estrogens and targeting the estrogen receptors in melanoma therapy holds promise for future developments in the field.
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Estrógenos , Melanoma , Humanos , Melanoma/metabolismo , Estrógenos/metabolismo , Receptores de Estrógenos/metabolismo , Neoplasias Cutáneas/metabolismo , Femenino , Receptor beta de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismoRESUMEN
Phenotype switching is an emerging concept in melanoma research and deals with the cancer cell plasticity. In this paper, we present five cases of patients with metastatic malignant melanoma where the tumor underwent dramatic morphological and immunohistochemical changes thereby mimicking other types of malignancies. The diagnosis of melanoma in all these cases was based on the mutational profile of the tumor assessed by next-generation sequencing compared to the primary lesion or local regional lymph nodes. These cases highlight the importance of thorough diagnostic measures in patients with metastatic melanoma who show progressive disease and where basic pathological assessment shows a diagnostic discrepancy.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Neoplasias Cutáneas/patología , Plasticidad de la Célula , Metástasis Linfática/patología , Ganglios Linfáticos/patologíaRESUMEN
The naturally occurring skin hypoxia has emerged as a crucial host factor of the epidermal microenvironment. We wanted to systematically investigate how reduced oxygen availability of the epidermis modulates the response of keratinocytes and melanocytes to noxious ultraviolet B radiation (UVB). We report that the exposure of normal human keratinocytes (NHKs) or melanocytes (NHEMs) to mild hypoxia drastically impacts cell death responses following UVB irradiation. The hypoxic microenvironment favors survival and reduces apoptosis of UVB-irradiated NHEMs and their malignant counterparts (melanoma cells). In contrast, NHKs, but not the transformed keratinocytes, under hypoxic conditions display increased levels of reactive oxygen species (ROS) and are significantly sensitized to UVB-mediated apoptosis as compared to NHKs treated under normoxic conditions. Prolonged exposure of UVB-treated NHKs to hypoxia triggers a sustained and reactive oxygen species-dependent activation of the stress kinases p38(MAPK) and JNKs, which in turn, engage the activation of Noxa and Bim proapoptotic proteins. Combined silencing of Noxa and Bim significantly inhibits UVB-mediated apoptosis under hypoxic conditions, demonstrating that hypoxia results in an amplification of the intrinsic apoptotic pathway. Physiologically occurring skin hypoxia, by facilitating the specific removal of UVB-damaged keratinocytes, may represent a decisive host factor impeding important steps of the photocarcinogenesis process.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Hipoxia/metabolismo , Queratinocitos/metabolismo , Melanocitos/metabolismo , Melanoma/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Cutáneas/metabolismo , Apoptosis/genética , Apoptosis/efectos de la radiación , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Línea Celular Tumoral , Transformación Celular Neoplásica , Citoprotección/genética , Homeostasis , Humanos , Hipoxia/patología , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Melanocitos/patología , Melanocitos/efectos de la radiación , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Interferente Pequeño/genética , Tolerancia a Radiación/genética , Especies Reactivas de Oxígeno/metabolismo , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Rayos Ultravioleta/efectos adversosRESUMEN
The signal transduction pathways leading to apoptosis of human keratinocytes responding to UVB irradiation are complex and not completely understood. Previously, we reported that in UVB-irradiated keratinocytes, p38(MAPK) instigates Bcl-2-associated X protein (Bax) activation and mitochondrial apoptosis. However, the molecular mechanism underlying the pro-apoptotic function of p38(MAPK) remained unclear. Here, we show that in UVB-treated human primary keratinocytes the activation of p38(MAPK) is necessary to upregulate Noxa, a BH3-only pro-apoptotic dominantly induced by UVB and required for apoptosis. Whereas p53-silencing was marginally cytoprotective and poorly affected Noxa expression, p38(MAPK) inhibition in p53-silenced keratinocytes or in p53(-/-) cells could still efficiently prevent Noxa induction and intrinsic apoptosis after UVB, indicating that p38(MAPK) signals mainly through p53-independent mechanisms. Furthermore, p38(MAPK) was required for the induction and activation of hypoxia-inducible factor 1 (HIF-1) in response to UVB, and HIF-1 knockdown reduced Noxa expression and apoptosis. In UVB-irradiated keratinocytes, Noxa targeted the anti-apoptotic myeloid cell leukemia sequence 1 (Mcl-1) for degradation, and small-interfering RNA (siRNA)-mediated knockdown of Noxa or p38(MAPK) inhibition restored levels of Mcl-1 and abolished apoptosis. Thus, the pro-apoptotic mechanisms orchestrated by p38(MAPK) in human keratinocytes in response to UVB involve an HIF-1/Noxa axis, which prompts the downregulation of anti-apoptotic Mcl-1, thereby favoring Bax-mediated mitochondrial apoptosis of UVB-damaged keratinocytes.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Queratinocitos , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Rayos Ultravioleta/efectos adversos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Apoptosis/fisiología , Apoptosis/efectos de la radiación , Benzamidas , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Humanos , Queratinocitos/citología , Queratinocitos/enzimología , Queratinocitos/efectos de la radiación , Sistema de Señalización de MAP Quinasas/fisiología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias Cutáneas/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/fisiología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The p38 MAPK pathway controls critical premitochondrial events culminating in apoptosis of UVB-irradiated human keratinocytes, but the upstream mediators of this stress signal are not completely defined. This study shows that in human keratinocytes exposed to UVB the generation of reactive oxygen species (ROS) acts as a mediator of apoptosis signal regulating kinase-1 (Ask-1), a redox-sensitive mitogen-activated protein kinase kinase kinase (MAP3K) regulating p38 MAPK and JNK cascades. The NADPH oxidase antagonist diphenylene iodonium chloride and the EGFR inhibitor AG1487 prevent UVB-mediated ROS generation, the activation of the Ask-1-p38 MAPK stress response pathway, and apoptosis, evidencing the link existing between the early plasma membrane-generated ROS and the activation of a lethal cascade initiated by Ask-1. Consistent with this, Ask-1 overexpression considerably sensitizes keratinocytes to UVB-induced mitochondrial apoptosis. Although the JNK pathway is also stimulated after UVB, the killing effect of Ask-1 overexpression is reverted by p38 MAPK inhibition, suggesting that Ask-1 exerts its lethal effects mainly through the p38 MAPK pathway. Moreover, p38alpha(-/-) murine embryonic fibroblasts are protected from UVB-induced apoptosis even if JNK activation is fully preserved. These results argue for an important role of the UVB-generated ROS as mediators of the Ask-1-p38 MAPK pathway that, by culminating in apoptosis, restrains the propagation of potentially mutagenic keratinocytes.
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Apoptosis/efectos de la radiación , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , MAP Quinasa Quinasa Quinasa 5/metabolismo , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rayos Ultravioleta , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Animales , Apoptosis/fisiología , Células Cultivadas , Citometría de Flujo , Técnicas para Inmunoenzimas , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Noqueados , Transducción de Señal , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Autologous skin grafts are successfully used to close recalcitrant chronic wounds especially at the lower leg. If wound care is done in a dermato-plastic team approach using the "integrated concept," difficulties associated with harvesting the skin graft as well as the complexities associated with inducing closure at the donor and the recipient site can be minimized. In the context of wound healing, skin transplantation can be regarded as (1) a supportive procedure for epithelialization of the wound surface and (2) mechanical stability of the wound ground. By placing skin grafts on a surface, central parts are covered much faster with keratinocytes. Skin (wound) closure is the ultimate goal, as wound closure means resistance to infection. Depending on the thickness of the skin graft, different amounts of dermis are transplanted with the overlying keratinocytes. The dermal component determines the mechanical (resistance to pressure and shear forces, graft shrinkage), functional (sensibility), and aesthetic properties of the graft. Generally speaking, the thicker the graft the better the mechanical, functional, and aesthetic properties, however, the worse the neo- and revascularization. Skin grafts do depend entirely on the re- and neovascularization coming from the wound bed. If the wound bed is seen as a recipient site for tissue graft, the classification of Lexer (Die freien Transplantationen. Stuttgart: Enke; 1924) turned out to be of extreme value. Three grades can be distinguished: "good wound conditions," "moderate wound conditions," and "insufficient wound conditions." Given good wound conditions, skin grafting is feasible. Nevertheless, skin closure alone might not be sufficient to fulfill the criteria of successful defect reconstruction. In case of moderate or insufficient wound conditions, wound bed preparation is necessary. If wound bed preparation is successful and good wound conditions can be achieved, skin grafting is possible. If, however, this attempt is unsuccessful and moderate or "inadequate wound conditions" are persisting, other methods of defect reconstruction such as local flap transfer, distant flap transfer, free (microvascular) flaps, and ultimately amputation must be considered.
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Úlcera de la Pierna/cirugía , Trasplante de Piel , Colgajos Quirúrgicos , Dermatología , Humanos , Grupo de Atención al Paciente , Procedimientos de Cirugía Plástica , Cicatrización de HeridasRESUMEN
Sunburn cells are keratinocytes undergoing apoptosis after they have received a physiological UVB dose that irreversibly and severely damaged their DNA or other chromophores. If these cells would escape programmed cell death, a cancer prone phenotype could arise. On the other hand, if the decision to die is made too prematurely, the proliferative compartment of basal keratinocytes would be inevitably lost, thereby hampering normal skin homeostasis. Pro- and anti-apoptotic mediators carefully control crucial points of the cell death program by regulating complex signalling cascades originating at the cell membrane, the nucleus and the cytoplasm. The balance between survival and apoptogenic factors determines the final cell fate, and growing evidence suggests that the deregulation of this balance by chronic UVB stress, results in the development of skin malignancy. The present paper reviews recent data on the major pathways regulating UVB-induced sunburn cell formation and implicates the deregulation of these pathways in the development of skin cancer.
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Muerte Celular/fisiología , Supervivencia Celular/fisiología , Queratinocitos/citología , Quemadura Solar/patología , Humanos , Queratinocitos/efectos de la radiación , Transducción de SeñalRESUMEN
This study establishes that activation of p38 MAPK by UVB represents a crucial signal required for the conformational change and translocation of Bax to the mitochondria in human keratinocytes. UVB-induced Bax translocation and mitochondrial cytochrome c release, which precede caspase activation and other endpoints of the apoptotic program such as chromatin fragmentation and loss of mitochondrial transmembrane potential, are blocked by genetic or pharmacological inhibition of the p38alpha MAPK. Inhibition of p38 MAPK strongly reduces the UVB-induced formation of sunburn cells and blocks Bax conformational change both in cultured human keratinocytes and in human skin, providing clear evidence for the physiological role of the p38 MAPK-Bax pathway in the removal of precancerous, UVB-damaged keratinocytes. Furthermore, we show that Bcl-2 overexpression, but not the pan-caspase inhibitor zVAD-fmk, blocks Bax conformational change and its subsequent translocation downstream of p38 MAPK. These data indicate that the activation of p38 MAPK by UVB engages a caspase-independent death signal leading to mitochondrial membrane permeabilization and apoptosis in human keratinocytes and suggest that p38 MAPK might have a preventive role in the process of photocarcinogenesis.