Terapia fotodinâmica - Aplicações em lesões cutâneas

Photodynamic therapy is a method of healing skin lesions , in addition to radiotherapy and brachytherapy are commonly used in the treatment of skin cancers , but it is still little known in Brazil , consisting of the application to the skin of a drug in the form of cream or lotion ( photosensitizer ) . It is absorbed by tumor cells and subsequently activated by light device , that wavelength of light in the order of 630 nanometers , promoting the selective destruction of cancer cells while preserving healthy cells around the lesion . It can be considered highly effective for treatment of skin cancer types of non-melanoma ( basal cell carcinoma , 85-100 % success in curing [ 3 ] , and Bowen's disease), actinic keratoses , which are precancerous lesions and still no studies that prove also action in the treatment of acne and aging caused by the sun . And the advantage of this treatment is that , when indicated , replace the surgical procedure , selectively treating the diseased cells . Thus, it offers better cosmetic results, reducing the risk of scarring [ 4 ]

Brazilian consensus on photoprotection

Brazil is a country of continental dimensions with a large heterogeneity of climates and massive mixing of the population. Almost the entire national territory is located between the Equator and the Tropic of Capricorn, and the Earth axial tilt to the south certainly makes Brazil one of the countries of the world with greater extent of land in proximity to the sun. The Brazilian coastline, where most of its population lives, is more than 8,500 km long. Due to geographic characteristics and cultural trends, Brazilians are among the peoples with the highest annual exposure to the sun. Epidemiological data show a continuing increase in the incidence of non-melanoma and melanoma skin cancers. Photoprotection can be understood as a set of measures aimed at reducing sun exposure and at preventing the development of acute and chronic actinic damage. Due to the peculiarities of Brazilian territory and culture, it would not be advisable to replicate the concepts of photoprotection from other developed countries, places with completely different climates and populations. Thus the Brazilian Society of Dermatology has developed the Brazilian Consensus on Photoprotection, the first official document on photoprotection developed in Brazil for Brazilians, with recommendations on matters involving photoprotection.

Carcinoma a cellule basali: l'esperienza della dermatologia dell'Universita' di Bologna dal 1990 al 2014

Il carcinoma a cellule basali (BCC) costituisce l'80 peercento dei tumori cutanei non-melanoma, rappresentando dunque il tumore maligno della cute più frequente nella popolazione generale. Tuttavia, non esistono ad oggi studi epidemiologici ampi ed approfonditi condotti su scala nazionale su questo tipo di neoplasia, poichè i tumori cutanei non-melanoma sono esclusi dal registro statistico dei tumori. A tale scopo presso la Dermatologia dell'Università di Bologna sono stati raccolti di tutti i casi di carcinoma basocellulare osservati dal 1 gennaio 1990 sino al 31 dicembre 2014, e sono stati rielaborati statisticamente. Il criterio di inclusione adottato è stato la positività per BCC all’esame istologico, sia in caso di biopsia semplice, sia in caso di asportazione radicale. Il progetto è stato svolto presso l’ambulatorio di chirurgia oncologica della nostra UO, così come il follow-up dei pazienti nei casi di recidività multiple o di comparsa di nuovi tumori cutanei. Ad oggi, tale neoplasia è risultata essere quella di più frequente osservazione nella Unità Operativa di Dermatologia dell’Università di Bologna. Non solo, la nostra casistica rimane quella più numerosa fino ad ora riportata in tutta Italia negli ultimi 24 anni.

Immune response to regressor and progressor tumor variants

Most skin cancers induced in mice by Ultraviolet (UV) radiation express highly immunogenic Tumor specific transplantation antigens (TSTAs) and thus exhibit a regressor phenotype. In this study, I have used cloned genes encoding tumor antigens and oncogenes in conjunction with DNA transfection technique to isolate and characterize regressor variants from progressor tumors and vice versa. The purpose of this study was (1) to determine whether the product of a cloned gene (216) from UV-1591 tumor, which encodes a novel MHC class I antigen can function as a tumor rejection antigen when expressed on unrelated, nonantigenic, murine tumor cells or whether its function is restricted to UV-induced tumors, and (2) to determine the processes by which progressor variants derived from a regressor UV-2240 cell line by transfection with an activated Ha-ras oncogene escape the immune defenses of the normal immunocompetent host.^ To answer the first question, a spontaneously transformed, nonimmunogenic cell line (10T-1) was cotransfected with DNA from p216 and pSV2-neo plasmids. Results demonstrate that the product of a cloned TSTA gene from a UV-induced murine tumor is capable of functioning as a tumor rejection antigen when expressed on unrelated, nonantigenic tumor cells. In addition, these results indicate that this approach could be used to augment the immune response against poorly antigenic tumors.^ To answer the second question, progressor variants were isolated from a highly antigenic UV radiation-induced C3H mouse regressor fibrosarcoma cell line, UV-2240, by transfection with an activated Ha-ras oncogene. Subcutaneous injection of Ha-ras-transfected UV-2240 cells into immunocompetent C3H mice produced tumors in 4 of 36 animals. In addition, the Ha-ras-induced progressor variants produced experimental lung metastasis in both normal C3H and nude mice, although they induced more lung nodules in nude mice than in normal C3H mice. Results indicate that the progressor phenotype of the Ha-ras-induced tumor variants is not due to loss of TSTAs or MHC class I antigens. This implies that some tumors can escape the immune defenses of the normal immunocompetent host by mechanisms other than the loss of TSTAs and MHC class I antigens. (Abstract shortened with permission of author.) ^

European Dermatology Forum Guidelines on topical photodynamic therapy

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, squamous cell carcinoma in-situ, superficial and certain thin basal cell carcinomas. Recurrence rates are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as a lesional or as a field therapy and has the potential to delay/reduce the development of new lesions. PDT has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immunocompetent individuals. Many additional indications have been evaluated, including photo-rejuvenation and inflammatory and infective dermatoses. This S2 guideline considers all current and emerging indications for the use of topical photodynamic therapy in Dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence. An unabridged version of this guideline is available online at: http://www.euroderm.org/edf/index.php/edf-guidelines.

Examination of synthetic retinoid -induced apoptosis in cutaneous squamous cell carcinomas: Mechanisms and implications for chemoprevention and chemotherapy with retinoids

Non-melanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (SCC), are the most common neoplasms in the United States with a lifetime risk nearly equal to all other types of cancer combined. Retinoids are naturally occurring and synthetic analogues of vitamin A that bind to nuclear retinoid receptors and modulate gene expression as a means of regulating cell proliferation and differentiation. Retinoids have been employed for many years in the treatment of various cutaneous lesions and for cancer chemoprevention and therapy. The primary drawback limiting the use of retinoids is their toxicity, which is also associated with receptor-gene interactions. In this study, the effects of the synthetic retinoids N-(4-hydroxyphenyl)retinamide (4HPR) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) were examined in cutaneous keratinocytes. Four human cutaneous SCC cell lines were examined along with normal human epidermal keratinocyte (NHEK) cells from two donors. Sensitivity to 4HPR or CD437 alone or in combination with other agents was determined via growth inhibition, cell cycle distributions, or apoptosis induction. Both synthetic retinoids were able to promote apoptosis in SCC cells more effectively than the natural retinoid all-trans retinoic acid. Apoptosis could not be inhibited by nuclear retinoic acid receptor antagonists. In NHEK cells, 4HPR induced apoptosis while CD437 promoted G1 arrest. 4HPR acted as a prooxidant by generating reactive oxygen species (ROS) in SCC and NHEK cells. 4HPR-induced apoptosis in SCC cells could be inhibited or potentiated by manipulating cellular defenses against oxidative stress, indicating an essential role for ROS in 4HPR-induced apoptosis. CD437 promoted apoptosis in SCC cells in S and G2/M phases of the cell cycle within two hours of treatment, and this rapid induction could not be blocked with cycloheximide. This study shows: (1) 4HPR- and CD437-induced apoptosis do not directly involve a traditional retinoid pathway; (2) 4HPR can act as a prooxidant as a means of promoting apoptosis; (3) CD437 induces apoptosis in SCC cells independent of protein synthesis and is potentially less toxic to NHEK cells; and (4) 4HPR and CD437 operate under different mechanisms with respect to apoptosis induction and this may potentially enhance their therapeutic index in vivo. ^

Estimativa da incidência de câncer nas redes regionais de saúde e municípios do estado de São Paulo, 2010

Introdução: Estatísticas sobre a ocorrência de casos novos de câncer são fundamentais para o planejamento e monitoramento das ações de controle da doença. No estado de São Paulo, a incidência de câncer é obtida indiretamente por meio de estimativas oficiais (para o estado como um todo e sua capital) e, de forma direta, em municípios cobertos por Registro de Câncer de Base Populacional (RCBP). Existem, atualmente, três RCBP ativos (São Paulo, Jaú e Santos), um inativo (Barretos) e um em reimplantação (Campinas). Dado o desconhecimento do panorama da incidência de câncer em áreas não cobertas por RCBP, este estudo teve como objetivo estimar a incidência de câncer, calcular taxas brutas e padronizadas por idade, específicas por sexo e localização primária do tumor para as 17 Redes Regionais de Atenção à Saúde (RRAS) de São Paulo e municípios, em 2010. Método: Utilizou-se como estimador da incidência de câncer a razão Incidência/Mortalidade (I/M), por sexo, grupo etário quinquenal dos 0 aos 80 anos e localização primária do tumor. O numerador da razão foi formado pelo número agregado de casos novos entre 2006-2010, em dois RCBP ativos (Jaú e São Paulo, respectivamente, com cobertura correspondente a 0,3 por cento e 27,3 por cento da população estadual). No denominador, o número de óbitos oficial nas respectivas áreas e período. O número estimado de casos novos resultou da multiplicação das I/M pelo número de óbitos por câncer registrados em 2010 para o conjunto de municípios formadores de cada uma das RRAS ou para cada município. O método de referência foi aquele utilizado no Globocan series, da Agência Internacional de Pesquisa contra o Câncer. O ajuste por idade das taxas de incidência ocorreu pelo método direto, tendo como padrão a população mundial. Resultados: Estimaram-se 53.476 casos novos de câncer para o sexo masculino e 55.073 casos para o feminino (excluindo-se os casos de câncer de pele não melanoma), com taxas padronizadas de 261/100.000 e 217/100.000, respectivamente. No sexo masculino, a RRAS 6 apresentou para todos os cânceres a maior taxa de incidência padronizada (285/100.000), e a RRAS 10, a menor (207/100.000). Os cânceres mais incidentes em homens foram próstata (77/100.000), cólon/reto/anus (27/100.000) e traqueia/brônquio/pulmão (16/100.000). Entre as mulheres, as taxas de incidência padronizadas por idade foram de 170/100.000 (RRAS 11) a 252/100.000 (RRAS 07); o câncer de mama foi o mais incidente (58/100.000), seguido pelos tumores de cólon/reto/anus (23/100.000) e de colo uterino (9/100.000). Conclusões: Os resultados apontaram diferentes padrões de incidência com taxas que ultrapassaram a magnitude estadual. Dados provenientes de RCBP locais podem ser usados na obtenção indireta de estimativas regionais e locais. Neste estudo, as taxas de incidência apresentadas podem estar sub ou superestimadas refletindo a qualidade, completitude e padrões observados no RCBP de maior representatividade considerado na análise.

Urinary porphyrins as biomarkers for arsenic exposure among susceptible populations in Guizhou Province, China

Coal is widely used in PR China. Unfortunately, coal from some areas in Guizhou Province contains elevated levels of arsenic. This has caused arsenicosis in individuals who use arsenic-contaminated coal for the purposes of heating, cooking and drying of food in poorly ventilated dwellings. The population at risk has been estimated to be approximately 200,000 people. Clinical symptoms of arsenicosis may include changes of skin pigmentation, hyperkeratosis of hand and feet, skin cancers, liver damage, persistent cough and chronic bronchitis. We analyzed the porphyrin excretion profile using a HPLC method in urine samples collected from 113 villagers who lived in Xing Ren district, a coal-bome arsenicosis endemic area and from 30 villagers from Xing Yi where arsenicosis is not prevalent. Urinary porphyrins were higher in the arsenic exposed group than those in the control group. The correlation between urinary arsenic and porphyrin concentrations demonstrated the effect of arsenic on heme biosynthesis resulting in increased porphyrin excretion. Both uroporphyrin and coproporphyrin III showed significant increases in the excretion profile of the younger age (< 20 years) arsenic-exposed group, suggesting that porphyrins could be used as early warning biomarkers of chronic arsenic exposure in humans. Greater increases of urinary arsenic and porphyrins in women, children and older age groups who spend much of their time indoors suggest that they might be at a higher risk. Whether elevated porphyrins could predict adverse health effects associated with both cancer and non-cancer end-points in chronically arsenic-exposed populations need further investigation. (c) 2005 Elsevier Inc. All rights reserved.

Microemulsions as topical delivery vehicles for the anti-melanoma prodrug, temozolomide hexyl ester (TMZA-HE)

A prodrug, temozolomide acid hexyl ester (TMZA-HE), was identified as a skin-deliverable congener for temozolomide (TMZ) to treat skin cancers. Poor solubility and instability of TMZA-HE rendered a serious challenge for formulation of a topical preparation. Microemulsions (ME) were chosen as a potential vehicle for TMZA-HE topical preparations. ME systems were constructed with either oleic acid (OA) or isopropyl myristate (IPM) as the oil phase and tocopheryl (vitamin E) polyethylene glycol 1000 succinate (VE-TPGS) as a surfactant. Topical formulations of OA and IPM ME systems demonstrated beneficial solubilising ability and provided a stable environment for the prodrug, TMZA-HE. Significant differences between the microstructures of OA and IPM ME systems were revealed by freeze fracture electron microscopy (FFEM) and different loading abilities and permeation potencies between the two systems were also identified. In permeation studies, IPM ME systems, with inclusion of isopropyl alcohol (IPA) as a co-surfactant, significantly increased TMZA-HE permeation through silicon membranes and rat skin resulting in less drug retention within the skin, while OA ME systems demonstrated higher solubilising ability and a higher concentration of TMZA-HE retained within the skin. Therefore IPM ME systems are promising for transdermal delivery of TMZA-HE and OA ME systems may be a suitable choice for a topical formulation of TMZA-HE. © 2007 The Authors.

UV-induced melanoma mouse model dependent on endothelin 3 over-expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.^

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Stimuli-Responsive Microneedle Arrays For On-Demand Drug Delivery

Pulsatile, or “on-demand”, delivery systems have the capability to deliver a therapeutic molecule at the right time/site of action and in the right amount (1). Pulsatile delivery systems present multiple benefits over conventional dosage forms and provide higher patient compliance. The combination of stimuli-responsive materials with the drug delivery capabilities of hydrogel-forming MN arrays (2) opens an interesting area of research. In the present work we describe, a stimuli-responsive hydrogel-forming microneedle (MN) array that enable delivery of a clinically-relevant model drug (ibuprofen) upon application of UV radiation (Figure 1A). MN arrays were prepared using a micromolding technique using a polymer prepared from 2-hydroxyethyl methacrylate (HEMA) and ethylene glycol dimethacrylate (EGDMA) (Figure 1B). The arrays were loaded with up to 5% (w/w) ibuprofen included in a light-responsible conjugate (3,5-dimethoxybenzoin conjugate) (2). The presence of the conjugate inside the MN arrays was confirmed by Raman spectroscopy measurements. MN arrays were tested in vitro showing that they were able to deliver up to three doses of 50 mg of ibuprofen after application of an optical trigger (wavelength of 365 nm) over a long period of time (up to 160 hours) (Figure 1C and 1D). The work presented here is a probe of concept and a modified version of the system should be used as UV radiation is shown to be the major etiologic agent in the development of skin cancers. Consequently, for future applications of this technology an alternative design should be developed. Based on the previous research dealing with hydrogel forming MN arrays a suitable strategy will be to use hydrogel-forming MN arrays containing a backing layer made with the material described in this work as the drug reservoir (2). Finally, a porous layer of a material that blocks UV radiation should be included between the MN array and the drug reservoir. Therefore radiation can be applied to the system without reaching the skin surface. Therefore after modification, the system described here interesting properties as “on-demand” release system for prolonged periods of time. This technology has potential for use in “on-demand” delivery of a wide range of drugs in a variety of applications relevant to enhanced patient care.

Estética do apocalipse: (re) considerações acerca da (des) arborização urbana de Natal e seu contributo à saúde pública

This study intends to establish a relation between environmental degradation, particularly the devastation of the green canopy, and public health. Utilizing a mapping of the trees included in the researched area, each individual tree was analyzed according to its age, taxonomic listing, architecture, shape and size (determined by aesthetic/convenience reasons or deformed by pruning). Initially investigated were the covert reasons lying underneath the constant aggression against trees (which many times seem to contain elements of hatred and contempt) within the urban environment. In addition to that, the aspects concerning environmental modifications and the consequent impact on public health were also assessed. Two main problems promptly emerged as a result of the removal of trees: a) without a canopy to protect the areas, they became subject to winds directly blown from SW Africa and impregnated with aerosol partic les, which are common causes for respiratory disorders and, b) direct UV solar radiation, which causes some types of skin cancers and eye disorders. To reach such results, we studied the origins and formation of UV radiation induced cancers and searched for the UV radiation spectra of action, e.g., usual intensity and quantity reaching clear and shadowed spaces in a certain area and its consequences. In a second instance, we also searched for pertinent data resources in order to confirm the increase of skin cancer cases due to exposure to UV radiation and the relation between the destruction of the green canopy and the above mentioned problems. We believe that a few significant results have been achieved by this study, namely: the relation between a culture based on medieval beliefs and its consequences on the environment; how this culture exploits and deforms nature in pursuit of financial and psychological interests to a point of transforming the landscape into a copy of something devoid of any relation to latitude and altitude; and above all, the indifference concerning the alarming results carried by these modifications

Síntese verde de nanopartículas de prata a partir de extrato aquoso do tubérculo de Curcuma longa associadas à quitosana e avaliação da atividade antitumoral in vitro em câncer de pele não melanoma (linhagem A431)

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Biológicas, Programa de Pós-Graduação Nanociência e Nanobiotecnologia, 2016.

Estética do apocalipse: (re) considerações acerca da (des) arborização urbana de Natal e seu contributo à saúde pública

This study intends to establish a relation between environmental degradation, particularly the devastation of the green canopy, and public health. Utilizing a mapping of the trees included in the researched area, each individual tree was analyzed according to its age, taxonomic listing, architecture, shape and size (determined by aesthetic/convenience reasons or deformed by pruning). Initially investigated were the covert reasons lying underneath the constant aggression against trees (which many times seem to contain elements of hatred and contempt) within the urban environment. In addition to that, the aspects concerning environmental modifications and the consequent impact on public health were also assessed. Two main problems promptly emerged as a result of the removal of trees: a) without a canopy to protect the areas, they became subject to winds directly blown from SW Africa and impregnated with aerosol partic les, which are common causes for respiratory disorders and, b) direct UV solar radiation, which causes some types of skin cancers and eye disorders. To reach such results, we studied the origins and formation of UV radiation induced cancers and searched for the UV radiation spectra of action, e.g., usual intensity and quantity reaching clear and shadowed spaces in a certain area and its consequences. In a second instance, we also searched for pertinent data resources in order to confirm the increase of skin cancer cases due to exposure to UV radiation and the relation between the destruction of the green canopy and the above mentioned problems. We believe that a few significant results have been achieved by this study, namely: the relation between a culture based on medieval beliefs and its consequences on the environment; how this culture exploits and deforms nature in pursuit of financial and psychological interests to a point of transforming the landscape into a copy of something devoid of any relation to latitude and altitude; and above all, the indifference concerning the alarming results carried by these modifications