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      Advances in the Understanding of Skin Cancer: Ultraviolet Radiation, Mutations, and Antisense Oligonucleotides as Anticancer Drugs

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          Abstract

          Skin cancer has always been and remains the leader among all tumors in terms of occurrence. One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells. These mutations inactivate apoptosis, an event required to avoid the malignant transformation of healthy cells. Among these deadliest of cancers, melanoma and its ‘younger sister’, Merkel cell carcinoma, are the most lethal. The heavy toll of skin cancers stems from their rapid progression and the fact that they metastasize easily. Added to this is the difficulty in determining reliable margins when excising tumors and the lack of effective chemotherapy. Possibly the biggest problem posed by skin cancer is reliably detecting the extent to which cancer cells have spread throughout the body. The initial tumor is visible and can be removed, whereas metastases are invisible to the naked eye and much harder to eliminate. In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery.

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          Cancer chemoprevention with dietary phytochemicals.

          Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.
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            A systematic review of worldwide incidence of nonmelanoma skin cancer.

              Nonmelanoma skin cancer (NMSC) is the most common cancer affecting white-skinned individuals and the incidence is increasing worldwide. This systematic review brings together 75 studies conducted over the past half century to look at geographical variations and trends worldwide in NMSC, and specifically incidence data are compared with recent U.K. cancer registry data. Following the development of a comprehensive search strategy, an assessment tool was adapted to look at the methodological quality of the eligible studies. Most of the studies focused on white populations in Europe, the U.S.A. and Australia; however, limited data were available for other skin types in regions such as Africa. Worldwide the incidence for NMSC varies widely with the highest rates in Australia [>1000/100, 000 person-years for basal cell carcinoma (BCC)] and the lowest rates in parts of Africa (< 1/100, 000 person-years for BCC). The average incidence rates in England were 76·21/100, 000 person-years and 22·65/100, 000 person-years for BCC and squamous cell carcinoma (SCC), respectively, with highest rates in the South-West of England (121·29/100, 000 person-years for BCC and 33·02/100, 000 person-years for SCC) and lowest rates by far in London (0·24/100, 000 person-years for BCC and 14·98/100, 000 person-years for SCC). The incidence rates in the U.K. appear to be increasing at a greater rate when compared with the rest of Europe. NMSC is an increasing problem for health care services worldwide. This review highlights a requirement for prevention studies in this area and the issues surrounding incomplete NMSC registration. Registration standards of NMSC should be improved to the level of other invasive disease. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.
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              The role of BRAF V600 mutation in melanoma

              BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                17 April 2019
                April 2019
                : 24
                : 8
                : 1516
                Affiliations
                [1 ]Medical Academy named after S.I. Georgievsky, V.I. Vernadsky Crimean Federal University, Lenin Boulevard 5/7, 295051 Simferopol, Crimea; botan_icus@ 123456mail.ru (K.V.L.); wwwzzznnn333@ 123456gmail.com (Z.Z.T.); gemini_m@ 123456list.ru (T.P.M.); evgu79@ 123456mail.ru (E.Y.B.); fomochkina_i@ 123456mail.ru (I.I.F.); kubyshkin_av@ 123456mail.ru (A.V.K.)
                [2 ]Research Institute of Agriculture of Crimea, Kiyevskaya St. 150, 295493, Simferopol, Crimea
                [3 ]Taurida Academy, V.I. Vernadsky Crimean Federal University, Vernadsky Av. 4, 295007 Simferopol, Crimea; genepcr@ 123456mail.ru (V.V.O.); pcr.product@ 123456gmail.com (N.V.G.); useinovrefat@ 123456gmail.com (R.Z.U.); i.nowikow2012@ 123456mail.ru (I.A.N.)
                [4 ]Nikita Botanical Gardens—National Scientific Centre RAS, Nikitsky spusk 52, vil. Nikita, 298648 Yalta, Crimea
                [5 ]D. Mendeleev University of Chemical Technology of Russia, Miusskaya sq. 9, 125047 Moscow, Russia; mikgorlov@ 123456gmail.com (M.V.G.); sin.sad92@ 123456gmail.com (A.S.E.)
                [6 ]Centre for Genomic and Regenerative Medicine, School of Biomedicine, Far Eastern Federal University, Sukhanova St. 8, 690090 Vladivostok, Russia; nikitawayfarer@ 123456yandex.ru (N.A.S.); vkumeiko@ 123456yandex.ru (V.V.K.)
                [7 ]National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Palchevsky St. 17, 690041 Vladivostok, Russia
                [8 ]Ltd “NPF Syntol”, Timiryazevskaya St. 42, 127434 Moscow, Russia; mikki1@ 123456mail.ru
                Author notes
                Author information
                https://orcid.org/0000-0001-7832-234X
                https://orcid.org/0000-0002-5350-2392
                https://orcid.org/0000-0002-1309-4005
                Article
                molecules-24-01516
                10.3390/molecules24081516
                6514765
                30999681
                af92c440-5199-425b-ac1e-2f5fddee7293
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 March 2019
                : 15 April 2019
                Categories
                Review

                melanoma,basal cell carcinoma,squamous cell carcinoma,merkel cell carcinoma,dermatofibrosarcoma protuberans,ultraviolet radiation,mutations,skin,antisense oligonucleotides

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