RESUMEN
Fluoroscopy-induced chronic radiation dermatitis (FICRD) is a complication of fluoroscopy-guided intervention. Unlike acute radiation dermatitis, FICRD is different as delayed onset and usually appears without preexisting acute dermatitis. Unfortunately, the chronic and progressive pathology of FICRD makes it difficult to treat, and some patients need to receive wide excision and reconstruction surgery. Due to lack of standard treatment, investigating underlying mechanism is needed in order to develop an effective therapy. Herein, the Hippo pathway is specifically identified using an RNA-seq analysis in mild damaged skin specimens of patients with FICRD. Furthermore, specific increase of the Yes-associated protein (YAP1), an effector of the Hippo pathway, in skin region with mild damage plays a protective role for keratinocytes via positively regulating the numerous downstream genes involved in different biological processes. Interestingly, irradiated-keratinocytes inhibit activation of fibroblasts under TGF-ß1 treatment via remote control by an exosome containing YAP1. More importantly, targeting one of YAP1 downstream genes, nuclear receptor subfamily 3 group C member 1 (NR3C1), which encodes glucocorticoid receptor, has revealed its therapeutic potential to treat FICRD by inhibiting fibroblasts activation in vitro and preventing formation of radiation ulcers in a mouse model and in patients with FICRD. Taken together, this translational research demonstrates the critical role of YAP1 in FICRD and identification of a feasible, effective therapy for patients with FICRD. KEY MESSAGES: ⢠YAP1 overexpression in skin specimens of radiation dermatitis from FICRD patient. ⢠Radiation-induced YAP1 expression plays protective roles by promoting DNA damage repair and inhibiting fibrosis via remote control of exosomal YAP1. ⢠YAP1 positively regulates NR3C1 which encodes glucocorticoid receptor expression. ⢠Targeting glucocorticoid receptor by prednisolone has therapeutic potential for FICRD patient.
Asunto(s)
Antiinflamatorios/uso terapéutico , Fluoroscopía/efectos adversos , Glucocorticoides/uso terapéutico , Prednisolona/uso terapéutico , Radiodermatitis/metabolismo , Animales , Línea Celular , Vía de Señalización Hippo/efectos de los fármacos , Humanos , Queratinocitos/metabolismo , Ratones Endogámicos C57BL , Radiodermatitis/tratamiento farmacológico , Radiodermatitis/genética , Piel/efectos de los fármacos , Piel/metabolismo , Proteínas Señalizadoras YAP/genética , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Radiation-induced skin injury (RSI) refers to a frequently occurring complication of radiation therapy. Nearly 90% of patients having received radiation therapy underwent moderate-to-severe skin reactions, severely reducing patients' quality of life and adversely affecting their disease treatment. No gold standard has been formulated for RSIs. In the present study, the mechanism of RSI and topical medications was discussed. Besides, this study can be referenced for clinicians to treat RSIs to guide subsequent clinical medicine.
Asunto(s)
Fármacos Dermatológicos/administración & dosificación , Radiodermatitis/tratamiento farmacológico , Piel/efectos de los fármacos , Administración Cutánea , Animales , Apoptosis/efectos de los fármacos , Fármacos Dermatológicos/efectos adversos , Fibrosis , Humanos , Exposición Profesional/efectos adversos , Exposición a la Radiación/efectos adversos , Radiodermatitis/diagnóstico , Radiodermatitis/etiología , Radiodermatitis/metabolismo , Radioterapia/efectos adversos , Índice de Severidad de la Enfermedad , Piel/metabolismo , Piel/patología , Resultado del TratamientoRESUMEN
Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.
Asunto(s)
Deferoxamina/farmacología , Dermis/metabolismo , Traumatismos Experimentales por Radiación/prevención & control , Radiodermatitis/prevención & control , Animales , Dermis/patología , Femenino , Ratones , Ratones Desnudos , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Radiodermatitis/metabolismo , Radiodermatitis/patologíaRESUMEN
Radiation dermatitis (RD) is one of the most common side effects of radiotherapy; its symptoms progress from erythema to dry and moist desquamation, leading to the deterioration of the patients' quality of life. Active metabolites in brown seaweed, including phlorotannins (PTNs), show anti-inflammatory activities; however, their medical use is limited. Here, we investigated the effects of PTNs in a mouse model of RD in vivo. X-rays (36 Gy) were delivered in three fractions to the hind legs of BALB/c mice. Macroscopic RD scoring revealed that PTNs significantly mitigated RD compared with the vehicle control. Histopathological analyses of skin tissues revealed that PTNs decreased epidermal and dermal thickness compared with the vehicle control. Western blotting indicated that PTNs augmented nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) pathway activation but attenuated radiation-induced NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and inflammasome activation, suggesting the mitigation of acute inflammation in irradiated mouse skin. PTNs also facilitated fast recovery, as indicated by increased aquaporin 3 expression and decreased γH2AX (histone family member X) expression. Our results indicate that topical PTN application may alleviate RD symptoms by suppressing oxidative stress and inflammatory signaling and by promoting the healing process. Therefore, PTNs may show great potential as cosmeceuticals for patients with cancer suffering from radiation-induced inflammatory side effects such as RD.
Asunto(s)
Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Radiodermatitis/tratamiento farmacológico , Algas Marinas/química , Piel/efectos de los fármacos , Taninos/administración & dosificación , Cicatrización de Heridas/efectos de los fármacos , Administración Cutánea , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Ratones Endogámicos BALB C , Radiodermatitis/metabolismo , Radiodermatitis/patología , Transducción de Señal , Piel/metabolismo , Piel/patología , Taninos/aislamiento & purificación , Factores de TiempoRESUMEN
Radiodermatitis is a painful side effect for cancer patients undergoing radiotherapy. Irradiation of the skin causes inflammation and breakdown of the epidermis and can lead to significant morbidity and mortality in severe cases, as seen in exposure from accidents or weapons such as "dirty bombs" and ultimately leads to tissue fibrosis. However, the pathogenesis of radiodermatitis is not fully understood. Using a mouse model of radiodermatitis, we showed that the Transient Receptor Potential Melastatin 2 (TRPM2) ion channel plays a significant role in the development of dermatitis following exposure to ionizing radiation. Irradiated TRPM2-deficient mice developed less inflammation, fewer severe skin lesions and decreased fibrosis when compared to wild type mice. The TRPM2-deficient mice also showed a faster recovery period as seen by their increased weight gain post irradiation. Finally, TRPM2-deficient mice exhibited lower systemic inflammation with a reduction in inflammatory cytokines present in the serum. These findings suggest that TRPM2 may be a potential therapeutic target for reducing the severity of radiodermatitis.
Asunto(s)
Radiodermatitis/etiología , Radiodermatitis/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Relación Dosis-Respuesta en la Radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Radiodermatitis/patología , Piel/patología , Piel/efectos de la radiaciónRESUMEN
Post-radiation vascular lesions are a rare complication most commonly seen in patients previously treated for breast cancer. The main two entities include angiosarcoma (AS), which are malignant tumors that have a poor prognosis, and atypical vascular lesions (AVL), which typically behave in a benign manner and only rarely progress to angiosarcoma. The overall incidence of these lesions is low, but it appears to be increasing. Histopathologic distinction of AVL and AS is essential due to different clinical outcomes and treatment. However, due to the occasional existence of overlapping clinical and histopathologic features, it may be sometimes difficult to render a definite diagnosis, particularly in small biopsies. Ancillary techniques are, in general, of little help for separating the borderland cases but, in some instances, immunohistochemical study (IHC) for Ki67 and IHC or fluorescence in situ hybridization analysis for MYC may help in the diagnosis of angiosarcoma. Herein we discuss the clinical characteristics, histopathologic features, management strategies, and outcome of these lesions, with special emphasis on their differential diagnosis.
Asunto(s)
Neoplasias de la Mama/radioterapia , Hemangiosarcoma , Antígeno Ki-67/metabolismo , Neoplasias Inducidas por Radiación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Radiodermatitis , Neoplasias Cutáneas , Femenino , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Humanos , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/patología , Radiodermatitis/diagnóstico , Radiodermatitis/metabolismo , Radiodermatitis/patología , Radioterapia/efectos adversos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
By forming a protective barrier, epidermal keratinocytes represent the first line of defense against environmental insults. UVB radiation of the sun is a major challenge for the skin and can induce inflammation, aging, and eventually skin cancer. UVB induces an immune response in human keratinocytes resulting in activation and secretion of the proinflammatory cytokines proIL-1ß and -18. This is mediated by an assembly of protein complexes, termed inflammasomes. However, the mechanisms underlying sensing of UVB by keratinocytes, and particularly the types of inflammasomes required for cytokine secretion, are a matter of debate. To address these questions, we established a protocol that allows the generation of CRISPR/Cas9-targeted human primary keratinocytes. Our experiments showed an essential role of the NLRP1 rather than the NLRP3 inflammasome in UVB sensing and subsequent IL-1ß and -18 secretion by keratinocytes. Moreover, NLRP1 but not NLRP3 was required for inflammasome activation in response to nigericin, a potassium ionophore and well-established NLRP3 activator in immune cells. Because the CRISPR/Cas9-targeted cells retained their full differentiation capacity, genome editing of human primary keratinocytes might be useful for numerous research and medical applications.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Sistemas CRISPR-Cas , Edición Génica/métodos , Inflamasomas/metabolismo , Queratinocitos/fisiología , Radiodermatitis/genética , Rayos Ultravioleta/efectos adversos , Proteína 9 Asociada a CRISPR/genética , Células Cultivadas , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR , Nigericina/farmacología , Cultivo Primario de Células , Radiodermatitis/metabolismoRESUMEN
Radiation-induced inflammation plays an important role in radiation-induced tissue injury. 18ß-glycyrrhetinic acid (18ß-GA) has shown an anti-inflammatory activity. This study aimed to assess the activity of 18ß-GA against radiation-induced skin damage, and explore the underlying mechanisms. In vitro assay revealed 18ß-GA treatment decreased the production of IL-1ß, IL-6, PGE2 and decreased p38MAPK phosphorylation, DNA-binding activity of AP-1, and NF-κB activation in irradiated RAW264.7 macrophages. Additionally, 18ß-GA suppressed NF-κB activation by inhibiting NF-κB/p65 and IκB-α phosphorylation and alleviated ROS overproduction in irradiated RAW264.7 macrophages. In vivo assay showed 18ß-GA alleviated severity of radiation-induced skin damage, reduced inflammatory cell infiltration and TNF-α, IL-1ß and IL-6 levels in cutaneous tissues. Our findings demonstrate that 18ß-GA exhibits anti-inflammatory actions against radiation-induced skin damage probably by inhibiting NADPH oxidase activity, ROS production, activation of p38MAPK and NF-κB signaling, and the DNA binding activities of NF-κB and AP-1, consequently suppressing pro-inflammatory cytokine production.
Asunto(s)
Antiinflamatorios/administración & dosificación , Ácido Glicirretínico/análogos & derivados , NADPH Oxidasas/metabolismo , Radiodermatitis/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ácido Glicirretínico/administración & dosificación , Ácido Glicirretínico/farmacología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Células RAW 264.7 , Radiodermatitis/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND/AIM: Radiation dermatitis is observed in 95% of breast cancer patients receiving radiotherapy. The aim of this study was to explore the correlation between protein expression in tumor cells and the risk of developing radiation dermatitis. PATIENTS AND METHODS: Breast cancer patients receiving postoperative radiotherapy were included in this study. Tumor specimens from 122 patients were examined by immunohistochemistry for the expression of Ki67, ataxia telangiectasia mutated (ATM) kinase, hypoxia-inducible factor-1-alpha (HIF-1a), inducible nitric oxide synthase (iNOS), and a-glucosidase (aGluc). The findings were correlated with the occurrence and severity of radiation dermatitis (Radiation therapy oncology group-RTOG grading scale), taking into consideration body weight and skin type (Fitzpatrick system). Data were explored further via pathway and network analyses. RESULTS: Correlation of radiation dermatitis (RTOG scale) with the observed increased expression of Ki67, ATM, iNOS, HIF-1a and aGluc, failed to reach statistical significance when skin type and/or body weight were considered. Network interactions of proteins involved in tumor growth (Ki67, ATM) and/or affect the oxidation state of the cell (HIF-1a, iNOS, aGluc) were revealed, that may contribute to the risk of developing acute radiation dermatitis. CONCLUSION: Correlation of the increased expression of the studied proteins and the occurrence and severity of radiation dermatitis in women undergoing postoperative radiotherapy, failed to reach statistical significance. Pathway and network analyses predicted that vasodilation and angiogenesis may contribute to radiation-induced dermatitis via mechanisms that need to be further explored. Our strategy serves as a paradigm for coupling histopathological data to molecular findings and network analyses for risk assessment in the clinic.
Asunto(s)
Neoplasias de la Mama/radioterapia , Radiodermatitis/diagnóstico , Radioterapia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Neoplasias de la Mama/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/metabolismo , Radiodermatitis/etiología , Radiodermatitis/metabolismo , Radioterapia/efectos adversos , alfa-Glucosidasas/metabolismoRESUMEN
UV-radiations are the invisible part of light spectra having a wavelength between visible rays and X-rays. Based on wavelength, UV rays are subdivided into UV-A (320-400 nm), UV-B (280-320 nm) and UV-C (200-280 nm). Ultraviolet rays can have both harmful and beneficial effects. UV-C has the property of ionization thus acting as a strong mutagen, which can cause immune-mediated disease and cancer in adverse cases. Numbers of genetic factors have been identified in human involved in inducing skin cancer from UV-radiations. Certain heredity diseases have been found susceptible to UV-induced skin cancer. UV radiations activate the cutaneous immune system, which led to an inflammatory response by different mechanisms. The first line of defense mechanism against UV radiation is melanin (an epidermal pigment), and UV absorbing pigment of skin, which dissipate UV radiation as heat. Cell surface death receptor (e.g. Fas) of keratinocytes responds to UV-induced injury and elicits apoptosis to avoid malignant transformation. In addition to the formation of photo-dimers in the genome, UV also can induce mutation by generating ROS and nucleotides are highly susceptible to these free radical injuries. Melanocortin 1 receptor (MC1R) has been known to be implicated in different UV-induced damages such as pigmentation, adaptive tanning, and skin cancer. UV-B induces the formation of pre-vitamin D3 in the epidermal layer of skin. UV-induced tans act as a photoprotection by providing a sun protection factor (SPF) of 3-4 and epidermal hyperplasia. There is a need to prevent the harmful effects and harness the useful effects of UV radiations.
Asunto(s)
Melanoma/etiología , Neoplasias Inducidas por Radiación/etiología , Radiodermatitis/etiología , Neoplasias Cutáneas/etiología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Apoptosis/efectos de la radiación , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Humanos , Queratinocitos/inmunología , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Melaninas/metabolismo , Melanoma/genética , Melanoma/inmunología , Melanoma/metabolismo , Mutagénesis/efectos de la radiación , Neoplasias Inducidas por Radiación/genética , Neoplasias Inducidas por Radiación/inmunología , Neoplasias Inducidas por Radiación/metabolismo , Radiodermatitis/genética , Radiodermatitis/inmunología , Radiodermatitis/metabolismo , Transducción de Señal/efectos de la radiación , Piel/inmunología , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Receptor fas/metabolismoRESUMEN
Radiotherapy is a primary oncological treatment modality that also damages normal tissue, including the skin, and causes radiation dermatitis (RD). Here, we explore the mechanism of acute epidermal damage in radiation dermatitis. Two distinctive phases in the damage response were identified: an early destructive phase, where a burst of reactive oxygen species induces loss of E-cadherin-mediated cell contact, followed by a regenerative phase, during which Wnt and Hippo signaling are activated. A blocking peptide, as well as a neutralizing antibody to E-cadherin, works synergistically with ionizing radiation to promote the epidermal damage. In addition, ROS disassembles adherens junctions in epithelial cells via posttranslational mechanisms, that is, activation of Src/Abl kinases and degradation of ß-catenin/E-cadherin. The key role of tyrosine kinases in this process is further substantiated by the rescue effect of the tyrosine kinase inhibitor genistein, and the more specific Src/Abl kinase inhibitor dasatinib: both reduced ROS-induced degradation of ß-catenin/E-cadherin in vitro and ameliorated skin damage in rodent models. Finally, we confirm that the same key molecular events are also seen in human radiation dermatitis. Therefore, we propose that loss of cell contact in epidermal keratinocytes through reactive oxygen species-mediated disassembly of adherens junctions is pivotal for the acute epidermal damage in radiation dermatitis.
Asunto(s)
Cadherinas/metabolismo , Traumatismos Experimentales por Radiación/patología , Radiodermatitis/patología , Animales , Western Blotting , Células Cultivadas , Epidermis/metabolismo , Epidermis/patología , Epidermis/efectos de la radiación , Humanos , Inmunoprecipitación , Masculino , Ratones , Ratones Endogámicos C57BL , Traumatismos Experimentales por Radiación/metabolismo , Radiodermatitis/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
Coffea arabica extract (CAE) containing 48.3 ± 0.4 mg/g of chlorogenic acid and a trace amount of caffeic acid was found to alleviate photoaging activity in human skin fibroblasts. In this study, polyphenol-rich CAE was investigated for its antioxidant and antiinflammatory properties, as well as for its capability to alleviate ultraviolet B (UVB)-induced photodamage in BALB/c hairless mice. The results indicated that 500 µg/mL of CAE exhibited a reducing power of 94.7%, ferrous ion chelating activity of 46.4%, and hydroxyl radical scavenging activity of 20.3%. The CAE dose dependently reduced UVB-induced reactive oxygen species (ROS) generation in fibroblasts. Furthermore, CAE inhibited the UVB-induced expression of cyclooxygenase-2 and p-inhibitor κB, and the translocation of nuclear factor-kappa B (NF-κB) to the nucleus of fibroblasts. In addition, CAE alleviated UVB-induced photoaging and photodamage in BALB/c hairless mice by restoring the collagen content and reduced UVB-induced epidermal hyperplasia. CAE also inhibited UVB-induced NF-κB, interleukin-6, and matrix metalloproteinase-1 expression in the hairless mouse skin. The results indicated that CAE exhibits antiphotodamage activity by inhibiting UV-induced oxidative stress and inflammation. Therefore, CAE is a candidate for use in antioxidant, antiinflammatory, and antiphotodamage products.
Asunto(s)
Antiinflamatorios/administración & dosificación , Antioxidantes/administración & dosificación , Coffea/química , Fibroblastos/efectos de los fármacos , Polifenoles/administración & dosificación , Radiodermatitis/prevención & control , Administración Tópica , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Células Cultivadas , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Pelados , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Polifenoles/farmacología , Radiodermatitis/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The CDKN2A locus encodes for tumor suppressor genes p16INK4a and p14Arf which are frequently inactivated in human skin tumors. The purpose of this study was to determine the relationship between loss of INK4a/Arf activity and inflammation in the development of ultraviolet (UV) radiation-induced skin tumors. Panels of INK4a/Arf-/- mice and wild-type (WT) mice were treated with a single dose of UVB (200 mJ/cm2 ). For long-term studies, these mice were irradiated with UVB (200 mJ/cm2 ) three times weekly for 30 weeks. At the end of the experiment, tissues were harvested from mice and assayed for inflammatory biomarkers and cytokines. A single dose of UVB resulted in a significant increase in reactive oxygen species (ROS) and 8-dihydroxyguanosine (8-oxo-dG) lesions in INK4a/Arf-/- mice compared to WT mice. When subjected to chronic UVB, we found that 100% of INK4a/Arf-/- mice had tumors, whereas there were no tumors in WT controls after 24 weeks of UVB exposure. The increase in tumor development correlated with a significant increase in nuclear factor (NF)-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2 ) and its receptors both in UVB-exposed skin and in the tumors. A significant increase was seen in inflammatory cytokines in skin samples of INK4a/Arf-/- mice following treatment with chronic UVB radiation. Furthermore, significantly more CD11b+ Gr1+ myeloid cells were present in UVB-exposed INK4a/Arf-/- mice compared to WT mice. Our data indicate that by targeting UVB-induced inflammation, it may be possible to prevent UVB-induced skin tumors in individuals that carry CDKN2A mutation.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Radiodermatitis/etiología , Neoplasias Cutáneas/etiología , Rayos Ultravioleta/efectos adversos , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antígenos Ly/metabolismo , Núcleo Celular/metabolismo , Ciclooxigenasa 2/metabolismo , Citoplasma/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Dinoprostona/metabolismo , Femenino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Ratones , Ratones Noqueados , Células Mieloides/metabolismo , Células Mieloides/patología , Inhibidor NF-kappaB alfa/metabolismo , Radiodermatitis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Prostaglandina E/metabolismo , Neoplasias Cutáneas/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We have previously shown that 207-nm ultraviolet (UV) light has similar antimicrobial properties as typical germicidal UV light (254 nm), but without inducing mammalian skin damage. The biophysical rationale is based on the limited penetration distance of 207-nm light in biological samples (e.g. stratum corneum) compared with that of 254-nm light. Here we extended our previous studies to 222-nm light and tested the hypothesis that there exists a narrow wavelength window in the far-UVC region, from around 200-222 nm, which is significantly harmful to bacteria, but without damaging cells in tissues. We used a krypton-chlorine (Kr-Cl) excimer lamp that produces 222-nm UV light with a bandpass filter to remove the lower- and higher-wavelength components. Relative to respective controls, we measured: 1. in vitro killing of methicillin-resistant Staphylococcus aureus (MRSA) as a function of UV fluence; 2. yields of the main UV-associated premutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in a 3D human skin tissue model in vitro; 3. eight cellular and molecular skin damage endpoints in exposed hairless mice in vivo. Comparisons were made with results from a conventional 254-nm UV germicidal lamp used as positive control. We found that 222-nm light kills MRSA efficiently but, unlike conventional germicidal UV lamps (254 nm), it produces almost no premutagenic UV-associated DNA lesions in a 3D human skin model and it is not cytotoxic to exposed mammalian skin. As predicted by biophysical considerations and in agreement with our previous findings, far-UVC light in the range of 200-222 nm kills bacteria efficiently regardless of their drug-resistant proficiency, but without the skin damaging effects associated with conventional germicidal UV exposure.
Asunto(s)
Desinfección/métodos , Staphylococcus aureus Resistente a Meticilina/efectos de la radiación , Piel/efectos de la radiación , Rayos Ultravioleta , Animales , Diferenciación Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , ADN/efectos de la radiación , Daño del ADN , Epidermis/anatomía & histología , Epidermis/efectos de la radiación , Humanos , Queratinocitos/citología , Queratinocitos/efectos de la radiación , Masculino , Ratones , Ratones Pelados , Radiodermatitis/etiología , Radiodermatitis/metabolismo , Radiodermatitis/patología , Piel/citología , Piel/metabolismo , Piel/microbiología , Terapia UltravioletaRESUMEN
BACKGROUND: We have encountered cases of post-radiation angiosarcoma (PRAS) histologically mimicking radiation dermatitis. METHODS: Cases of PRAS from institutional/consultation archives from 2006 to 2016 were reviewed. For inclusion, tumors had to have inapparent/subtle tumor at low magnification and scattered individual tumor cells resembling radiation fibroblasts. Prior ancillary studies were reviewed, with additional immunostains performed as needed. RESULTS: 10 cases met criteria. All occurred in women treated for breast cancer (mean age 71 years). All had similar findings: in particular, scattered single atypical cells with pleomorphic nuclei associated with microscopic hemorrhage. They also had narrow, slightly wavy "worm-like" vascular channels lined by atypical endothelial cells that lacked architectural complexity. Four cases showed focal areas of more conventional angiosarcoma. One case was an excision of a large mass that showed the "radiation dermatitis-like" pattern radiating out from the central mass. All were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was demonstrated by FISH in both cases tested. In 3 of 3 cases with available re-excision specimens, more obvious angiosarcoma was seen. CONCLUSIONS: PRAS can be very subtle and histologically mimic radiation dermatitis. Careful attention to histologic features and ancillary tests allow accurate diagnosis in subtle PRAS.
Asunto(s)
Neoplasias de la Mama , Hemangiosarcoma , Neoplasias Inducidas por Radiación , Radiodermatitis , Neoplasias Cutáneas , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Humanos , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/diagnóstico , Neoplasias Inducidas por Radiación/metabolismo , Neoplasias Inducidas por Radiación/patología , Radiodermatitis/diagnóstico , Radiodermatitis/metabolismo , Radiodermatitis/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
The use of ionizing radiation is critical to cancer treatment and fluoroscopic procedures. However, despite efforts to minimize total radiation dose, many patients experience toxic cutaneous side-effects of ionizing radiation, ranging from mild erythema to subcutaneous fibrosis, telangiectasia formation, and ulceration. Extent of injury is highly variable among patients. Studying the genetic determinants of radiation injury can help develop protocols to reduce radiation toxicity, as well as drive research into effective modulators of the genes and gene products associated with radiation injury. Many studies in the past two decades have identified single-nucleotide polymorphisms that may be associated with susceptibility to cutaneous radiation injury, such as those in genes related to the following cellular responses to ionizing radiation: inflammation, DNA repair, oxidation and stress response, and cell-cycle and apoptosis. This review summarizes the current literature on potential major genes and polymorphisms, in the previously described damage response pathways, that are involved in susceptibility to cutaneous radiation injury. Potential pitfalls of current research and further avenues of discovery will be explored.
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Polimorfismo de Nucleótido Simple , Radiodermatitis/genética , Apoptosis/genética , Ciclo Celular/genética , Daño del ADN , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genómica/métodos , Humanos , Mediadores de Inflamación/metabolismo , Estrés Oxidativo/genética , Fenotipo , Radiodermatitis/diagnóstico , Radiodermatitis/metabolismo , Radiografía Intervencional/efectos adversos , Radioterapia/efectos adversos , Reproducibilidad de los Resultados , Factores de RiesgoRESUMEN
Exposure of the skin to ultraviolet (UV) irradiation causes various consequences such as inflammation and photoageing. Galanin is an active neuropeptide expressed widely in the central nervous system and peripheral tissues including the skin. Galanin promotes or inhibits inflammation in a context-dependent manner, but its role in UV irradiation-induced responses in human skin was still unknown. UV irradiation induced a substantial expression of galanin in primary epidermal keratinocytes in vitro and in human epidermis in vivo. Galanin knock-down by siRNA transfection markedly inhibited UV irradiation-induced expression of matrix metalloproteinase (MMP)-1, interleukin (IL)-1ß, IL-6 and cyclooxygenase (COX)-2. Moreover, siRNA-mediated knock-down of GAL2 , a principal galanin receptor in the skin, led to a considerable decrease in these mediators in keratinocytes. Collectively, our findings suggest that galanin is an important messenger between the neuroendocrine system and UV irradiation-damaged skin.
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Epidermis/efectos de la radiación , Galanina/metabolismo , Queratinocitos/efectos de los fármacos , Radiodermatitis/metabolismo , Epidermis/metabolismo , Humanos , Queratinocitos/metabolismo , Rayos UltravioletaRESUMEN
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor that regulates many antioxidants, and we have recently succeeded in obtaining a novel Nrf2 activator, RS9, from microbial transformation. RS9 is categorized as a triterpenoid, and well-known triterpenoids such as RTA 402 (bardoxolone methyl) and RTA 408 have been tested in clinical trials. RTA 408 lotion is currently being tested in patients at risk for radiation dermatitis. This prompted us to study the profiles of RS9 in the skin. All the above triterpenoids increased the level of an Nrf2-targeted gene, NADPH:quinone oxidoreductase-1, in normal human epidermal keratinocytes. Among them, the activity of RS9 was prominent; furthermore, the cellular toxicity was less compared with RTA compounds. BALB/c mice were irradiated with 30 Gy/day on Day 0, and compounds were topically applied on the back once daily from Day 1 to Day 30. Dermatitis scores peaked on Day 18, with a score of 2.6 in vehicle-treated mice, and topical applications of 0.1% RTA 402, RTA 408 and RS9 reduced the scores to 1.8, 2.0 and 1.4, respectively. Moreover, the percentage of animals with scores ≥2 was analyzed, and 0.1% RS9 suppressed the percentage from 100% to 47%. These results imply that RS9 has potential efficacy for treating radiation dermatitis.
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Factor 2 Relacionado con NF-E2/metabolismo , Radiodermatitis/metabolismo , Radiodermatitis/patología , Animales , Epidermis/patología , Femenino , Humanos , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Ionizing radiation is a common therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to permanent changes. We have previously demonstrated that occupancy of A2A receptor (A2AR) stimulates collagen production, so we determined whether blockade or deletion of A2AR could prevent radiation-induced fibrosis. After targeted irradiation (40 Gy) of the skin of wild-type (WT) or A2AR knockout (A2ARKO) mice, the A2AR antagonist ZM241385 was applied daily for 28 d. In irradiated WT mice treated with the A2AR antagonist, there was a marked reduction in collagen content and skin thickness, and ZM241385 treatment reduced the number of myofibroblasts and angiogenesis. After irradiation, there is an increase in loosely packed collagen fibrils, which is significantly diminished by ZM241385. Irradiation also induced an increase in epidermal thickness, prevented by ZM241385, by increasing the number of proliferating keratinocytes. Similarly, in A2ARKO mice, the changes in collagen alignment, skin thickness, myofibroblast content, angiogenesis, and epidermal hyperplasia were markedly reduced following irradiation. Radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2ARKO mice. Radiation therapy is administered to a significant number of patients with cancer, and radiation reactions may limit this therapeutic modality. Our findings suggest that topical application of an A2AR antagonist prevents radiation dermatitis and may be useful in the prevention or amelioration of radiation changes in the skin.
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Radiodermatitis/metabolismo , Receptor de Adenosina A2A/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Animales , Colágeno/metabolismo , Queratinocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Radiodermatitis/tratamiento farmacológico , Receptor de Adenosina A2A/genética , Triazinas/farmacología , Triazinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
BACKGROUND: Human papilloma virus (HPV) infection, p16 expression and hypoxia may play important roles in the carcinogenesis, treatment response and toxicities of head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to assess whether there is any correlation between pre-radiotherapy (RT) anemia, p16 expression and toxicities and local control for patients undergoing definitive therapy. METHODS: 79 HNSCC patients who had undergone radiochemotherapy (RCT) or RT-antibody therapy were retrospectively analyzed. p16 (INK4A) expression was detected by immunohistochemical analysis. Factors predisposing for acute side effects were examined by uni- and multivariate analysis. RESULTS: p16 overexpression was detected in 32 cases. Pretreatment anemia was present in one third of patients. Only 5% of patients were characterized by both pre-RT anemia and p16 overexpression. p16 expression was significantly associated with acute grade 3 toxicity. 47% of p16-positive patients developed grade ≥ 3 radiodermatitis compared to 26% of p16-negative patients (p = 0.04). A reduced risk of severe skin toxicities was noted for patients with hypoxic blood values before RT. p16 expression was significantly correlated with local control (p = 0.002). CONCLUSIONS: p16 expression is associated with better response to definitive combined treatment (RCT, RT + cetuximab), but also significantly related to acute high-grade toxicity.