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1.
Oncogene ; 39(21): 4170-4182, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277233

RESUMO

Nonmelanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared with normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.

4.
Biomed Opt Express ; 10(7): 3497-3505, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31360602

RESUMO

We have developed a low-cost, near-infrared (NIR) reflectance confocal microscope (RCM) to overcome challenges in the imaging depth and speed found in our previously-reported smartphone confocal microscope. In the new NIR RCM device, we have used 840 nm superluminescent LED (sLED) to increase the tissue imaging depth and speed. A new confocal detection optics has been developed to maintain high lateral resolution even when a relatively large slit width was used. The material cost of the NIR RCM device was still low, ~$5,200. The lateral resolution was 1.1 µm and 1.3 µm along the vertical and horizontal directions, respectively. Axial resolution was measured as 11.2 µm. In vivo confocal images of human forearm skin obtained at the imaging speed of 203 frames/sec clearly visualized characteristic epidermal and dermal cellular features of the human skin.

5.
JAMA Dermatol ; 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31290958

RESUMO

Importance: To date, no concerted effort has been made to date to evaluate the literature on number-needed-to-biopsy (NNB) metrics, particularly to account for the differences in clinician type and melanoma prevalence in certain geographic locations. Objective: To review and synthesize worldwide data for NNB for the diagnosis of cutaneous melanoma. Data Source: MEDLINE, Embase, and PubMed databases were searched for English-language articles published worldwide from January 1, 2000, to November 28, 2018. Study Selection: A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia. Data Extraction and Synthesis: Articles were screened for eligibility, and possible overlapping data sets were resolved. Data extracted included clinician specialization, use of dermoscopy, geographic region and location-specific health care system, study design, number of benign tumors, number of melanomas, and NNB. The review followed the PRISMA guidelines. Main Outcome and Measures: The NNB for the diagnosis of cutaneous melanoma. Results: A total of 46 studies were included that addressed NNB for at least 3681 clinicians worldwide and included 455 496 biopsied tumors and 29 257 melanomas; primary care practitioner (PCP) data were only available from Australia. The reported NNB ranged from 2.2 to 287, and the weighted mean NNB for all included publications was 15.6. The exclusion of publications structured as all biopsied tumors, owing to variable data characterization, resulted in reported NNB ranging from 2.2 to 30.5, with a global weighted mean NNB of 14.8 for all clinicians, 7.5 for all dermatologists, 14.6 for Australian PCPs, and 13.2 for all US-based dermatological practitioners, including dermatologists and advanced practice professionals. The summary effect size (ES) demonstrates that a mean 4% of biopsies demonstrated melanoma for study stratum A (all biopsied skin tumors, ES, 0.04; 95% CI, 0.03-0.05), and a mean 12% of biopsies demonstrated melanoma for study strata B (melanocytic tumors on pathology review, ES, 0.12; 95% CI, 0.10-0.14) and C (clinical concern for melanoma, ES; 0.12; 95% CI, 0.09-0.14). Conclusions and Relevance: The existing NNB for cutaneous melanoma appeared to vary widely worldwide, lacking standardization in the metric and its reporting, and according to clinician characteristics as well; the NNB of US-based clinicians may warrant further exploration.

6.
Digit Health ; 5: 2055207619828225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30792879

RESUMO

Objective: The aim of the study is to evaluate healthcare practitioners' views on and satisfaction with (i) digital image acquisition and storage and (ii) store-and-forward teledermoscopy services for the diagnosis of skin cancer in their clinical practice. Methods: An online survey was conducted among 59 healthcare practitioners (GPs (n=17), dermatologists (n=22), dermatology registrars (n=18), a dermatology research fellow (n=1) and a plastic surgeon (n=1)) to assess usability of digital image acquisition and storage for when the imaging process is conducted by the healthcare practitioners themselves, or by their patients. The study identifies the enablers and barriers of this emerging mode of medical practice. A thematic analysis was used to extract key themes from open-ended responses, which involved identifying themes and patterns within and across participants. Results: Thirty-four healthcare practitioners (58%) had previously used a mobile dermatoscope within their practice. Participants most appreciated its use in their practice for lesion monitoring (59%) and record keeping (39%). Challenges reported were the increased time to support the additional workload (45%), technical issues (33%) and cost of equipment (27%). Practitioners were unsure (36%) or did not advocate teledermoscopy for direct-to-consumer use (41%). Only 23% supported the use of direct-to-consumer teledermoscopy. Conclusion: While most practitioners are receptive to mobile teledermoscopy, there was less support for patient-initiated use, whereby the patient controls the imaging process. As technology improves rapidly it is important to evaluate practitioners' acceptance and satisfaction of evolving telehealth services, moving forward with models of practice where healthcare practitioners and other healthcare providers will feel comfortable engaging in telehealth services.

7.
JAMA Dermatol ; 155(1): 22-28, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30477000

RESUMO

Importance: A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. Objective: To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. Design, Setting, and Participants: For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. Main Outcomes and Measures: The PFS life-years and PFS quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. Results: In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAFV600E mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response. Conclusions and Relevance: The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated.


Assuntos
Produtos Biológicos/administração & dosagem , Custos de Medicamentos , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Pele/patologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/economia , Produtos Biológicos/economia , Análise Custo-Benefício , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Herpesvirus Humano 1 , Humanos , Injeções Intravenosas , Ipilimumab/economia , Melanoma/diagnóstico , Melanoma/economia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/economia , Resultado do Tratamento , Estados Unidos
8.
J Am Acad Dermatol ; 80(1): 208-250, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30392755

RESUMO

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.


Assuntos
Melanoma/terapia , Neoplasias Cutâneas/terapia , Humanos
9.
Cancer ; 125(1): 18-44, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30281145

RESUMO

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.


Assuntos
Melanoma/prevenção & controle , Protetores contra Radiação/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Animais , Anticarcinógenos/uso terapêutico , Quimioprevenção , Ensaios Clínicos Fase III como Assunto , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Feminino , Humanos , Masculino , Neoplasias Cutâneas/tratamento farmacológico
11.
JAMA Dermatol ; 154(12): 1401-1408, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304348

RESUMO

Importance: Little evidence exists to guide the management of moderately dysplastic nevi excisionally biopsied without residual clinical pigmentation but with positive histologic margins (hereafter referred to as moderately dysplastic nevi with positive histologic margins). Objective: To determine outcomes and risk for the development of subsequent cutaneous melanoma (CM) from moderately dysplastic nevi with positive histologic margins observed for 3 years or more. Design, Setting, and Participants: A multicenter (9 US academic dermatology sites) retrospective cohort study was conducted of patients 18 years or older with moderately dysplastic nevi with positive histologic margins and 3 years or more of follow-up data collected consecutively from January 1, 1990, to August 31, 2014. Records were reviewed for patient demographics, biopsy type, pathologic findings, and development of subsequent CM at the biopsy site or elsewhere on the body. The χ2 test, the Fisher exact test, and analysis of variance were used to assess univariate association for risk of subsequent CMs, in addition to multivariable logistic regression models. To confirm histologic grading, each site submitted 5 random representative slide cases for central dermatopathologic review. Statistical analysis was performed from October 1, 2017, to June 22, 2018. Main Outcomes and Measures: Development of CM at a biopsy site or elsewhere on the body where there were moderately dysplastic nevi with positive histologic margins. Results: A total of 467 moderately dysplastic nevi with positive histologic margins from 438 patients (193 women and 245 men; mean [SD] age, 46.7 [16.1] years) were evaluated. No cases developed into CM at biopsy sites, with a mean (SD) follow-up time of 6.9 (3.4) years. However, 100 patients (22.8%) developed a CM at a separate site. Results of multivariate analyses revealed that history of CM was significantly associated with the risk of development of subsequent CM at a separate site (odds ratio, 11.74; 95% CI, 5.71-24.15; P < .001), as were prior biopsied dysplastic nevi (odds ratio, 2.55; 95% CI, 1.23-5.28; P = .01). The results of a central dermatopathologic review revealed agreement in 35 of 40 cases (87.5%). Three of 40 cases (7.5%) were upgraded in degree of atypia; of these, 1 was interpreted as melanoma in situ. That patient remains without recurrence or evidence of CM after 5 years of follow-up. Conclusions and Relevance: This study suggests that close observation with routine skin surveillance is a reasonable management approach for moderately dysplastic nevi with positive histologic margins. However, having 2 or more biopsied dysplastic nevi (with 1 that is a moderately dysplastic nevus) appears to be associated with increased risk for subsequent CM at a separate site.


Assuntos
Procedimentos Cirúrgicos Dermatológicos/métodos , Síndrome do Nevo Displásico/diagnóstico , Margens de Excisão , Melanoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Síndrome do Nevo Displásico/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Melanoma/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Pele , Neoplasias Cutâneas/cirurgia , Adulto Jovem
14.
Oncogene ; 37(42): 5633-5647, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29904102

RESUMO

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar-simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization, and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1, and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.


Assuntos
Carcinogênese/metabolismo , Carcinoma de Células Escamosas/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Cutâneas/enzimologia , Animais , Valerato de Betametasona/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinoma de Células Escamosas/patologia , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Pelados , Rocurônio/farmacologia , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversos
15.
Cancer Prev Res (Phila) ; 11(5): 265-278, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29437671

RESUMO

An urgent need exists for the development of more efficacious molecular strategies targeting nonmelanoma skin cancer (NMSC), the most common malignancy worldwide. Inflammatory signaling downstream of Toll-like receptor 4 (TLR4) has been implicated in several forms of tumorigenesis, yet its role in solar UV-induced skin carcinogenesis remains undefined. We have previously shown in keratinocyte cell culture and SKH-1 mouse epidermis that topical application of the specific TLR4 antagonist resatorvid (TAK-242) blocks acute UV-induced AP-1 and NF-κB signaling, associated with downregulation of inflammatory mediators and MAP kinase phosphorylation. We therefore explored TLR4 as a novel target for chemoprevention of UV-induced NMSC. We selected the clinical TLR4 antagonist resatorvid based upon target specificity, potency, and physicochemical properties. Here, we confirm using ex vivo permeability assays that topical resatorvid can be effectively delivered to skin, and using in vivo studies that topical resatorvid can block UV-induced AP-1 activation in mouse epidermis. We also report that in a UV-induced skin tumorigenesis model, topical resatorvid displays potent photochemopreventive activity, significantly suppressing tumor area and multiplicity. Tumors harvested from resatorvid-treated mice display reduced activity of UV-associated signaling pathways and a corresponding increase in apoptosis compared with tumors from control animals. Further mechanistic insight on resatorvid-based photochemoprevention was obtained from unsupervised hierarchical clustering analysis of protein readouts via reverse-phase protein microarray revealing a significant attenuation of key UV-induced proteomic changes by resatorvid in chronically treated high-risk SKH-1 skin prior to tumorigenesis. Taken together, our data identify TLR4 as a novel molecular target for topical photochemoprevention of NMSC. Cancer Prev Res; 11(5); 265-78. ©2018 AACRSee related editorial by Sfanos, p. 251.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Cutâneas/prevenção & controle , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Raios Ultravioleta/efeitos adversos , Administração Cutânea , Animais , Carcinogênese/efeitos da radiação , Avaliação Pré-Clínica de Medicamentos , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/efeitos da radiação , Feminino , Humanos , Camundongos , Camundongos Pelados , Camundongos Transgênicos , NF-kappa B/metabolismo , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/prevenção & controle , Permeabilidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Neoplasias Cutâneas/etiologia , Sulfonamidas/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição AP-1/metabolismo
17.
J Digit Imaging ; 31(4): 568-577, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29344752

RESUMO

Imaging is increasingly being used in dermatology for documentation, diagnosis, and management of cutaneous disease. The lack of standards for dermatologic imaging is an impediment to clinical uptake. Standardization can occur in image acquisition, terminology, interoperability, and metadata. This paper presents the International Skin Imaging Collaboration position on standardization of metadata for dermatologic imaging. Metadata is essential to ensure that dermatologic images are properly managed and interpreted. There are two standards-based approaches to recording and storing metadata in dermatologic imaging. The first uses standard consumer image file formats, and the second is the file format and metadata model developed for the Digital Imaging and Communication in Medicine (DICOM) standard. DICOM would appear to provide an advantage over using consumer image file formats for metadata as it includes all the patient, study, and technical metadata necessary to use images clinically. Whereas, consumer image file formats only include technical metadata and need to be used in conjunction with another actor-for example, an electronic medical record-to supply the patient and study metadata. The use of DICOM may have some ancillary benefits in dermatologic imaging including leveraging DICOM network and workflow services, interoperability of images and metadata, leveraging existing enterprise imaging infrastructure, greater patient safety, and better compliance to legislative requirements for image retention.


Assuntos
Dermatologia/normas , Diagnóstico por Imagem/métodos , Metadados/normas , Sistemas de Informação em Radiologia/normas , Dermatopatias/diagnóstico por imagem , Dermatologia/tendências , Dermoscopia/métodos , Humanos , Internacionalidade , Reprodutibilidade dos Testes , Dermatopatias/patologia , Estados Unidos
18.
Artigo em Inglês | MEDLINE | ID: mdl-29167824

RESUMO

Ultraviolet radiation is an important etiologic factor in skin cancer and a better understanding of how solar stimulated light (SSL) affects signal transduction pathways in human skin which is needed in further understanding activated networks that could be targeted for skin cancer prevention. We utilized Reverse Phase Protein Microarray Analysis (RPPA), a powerful technology that allows for broad-scale and quantitative measurement of the activation/phosphorylation state of hundreds of key signaling proteins and protein pathways in sun-protected skin after an acute dose of two minimal erythema dose (MED) of SSL. RPPA analysis was used to map the altered cell signaling networks resulting from acute doses of solar simulated radiation (SSL). To that end, we exposed sun-protected skin in volunteers to acute doses of two MED of SSL and collected biopsies pre-SSL and post-SSL irradiation. Frozen biopsies were subjected to laser capture microdissection (LCM) and then assessed by RPPA. The activation/phosphorylation or total levels of 128 key signaling proteins and drug targets were selected for statistical analysis. Coordinate network-based analysis was performed on specific signaling pathways that included the PI3k/Akt/mTOR and Ras/Raf/MEK/ERK pathways. Overall, we found early and sustained activation of the PI3K-AKT-mTOR and MAPK pathways. Cell death and apoptosis-related proteins were activated at 5 and 24 h. Ultimately, expression profile patterns of phosphorylated proteins in the epidermal growth factor receptor (EGFR), AKT, mTOR, and other relevant pathways may be used to determine pharmacodynamic activity of new and selective topical chemoprevention agents administered in a test area exposed to SSL to determine drug-induced attenuation or reversal of skin carcinogenesis pathways.

19.
Melanoma Manag ; 4(1): 13-37, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28758010

RESUMO

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening.

20.
Mol Cancer Ther ; 16(9): 1843-1854, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28655782

RESUMO

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. ©2017 AACR.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos da radiação , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/metabolismo , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Expressão Gênica , Genes Reporter , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/química , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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