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      Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

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          Abstract

          Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.

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          mTOR Signaling in Growth, Metabolism, and Disease.

          The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
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            Aging, Cellular Senescence, and Cancer

            For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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              Chromatin modifications and their function.

              The surface of nucleosomes is studded with a multiplicity of modifications. At least eight different classes have been characterized to date and many different sites have been identified for each class. Operationally, modifications function either by disrupting chromatin contacts or by affecting the recruitment of nonhistone proteins to chromatin. Their presence on histones can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA. In this way, histone modifications have the potential to influence many fundamental biological processes, some of which may be epigenetically inherited.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                09 February 2021
                February 2021
                : 9
                : 2
                : 171
                Affiliations
                [1 ]IDI-IRCCS, Dermatological Research Hospital, via di Monti di Creta 104, 00167 Rome, Italy; f.dipietro@ 123456idi.it (F.R.D.P.); s.verkhovskaia@ 123456idi.it (S.V.); r.morese@ 123456idi.it (R.M.); francesca.ricci@ 123456idi.it (F.R.); fraric1984@ 123456gmail.com (F.R.); candi@ 123456uniroma2.it (E.C.); d.abeni@ 123456idi.it (D.A.); e.dellambra@ 123456idi.it (E.D.)
                [2 ]Department of Dermatology and Allergology, Philipps University, 35043 Marburg, Germany; didona@ 123456med.uni-marburg.de
                [3 ]Unit of Dermatology, IRCCS Ospedale San Raffaele, 20132 Milano, Italy; paolino.giovanni@ 123456hsr.it
                [4 ]Department of Pathology, University Hospital Campus Bio-Medico, 00128 Rome, Italy; micheledonati25@ 123456gmail.com
                [5 ]Sikl’s Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, 30166 Pilsen, Czech Republic
                [6 ]Institute of Dermatology, A. Gemelli University Polyclinic, IRCCS and Foundation, Sacred Heart Catholic University, 00168 Rome, Italy; cocovaleria@ 123456hotmail.it
                [7 ]Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
                Author notes
                [* ]Correspondence: l.fania@ 123456idi.it
                [†]

                Both Authors contributed equally to the work.

                Author information
                https://orcid.org/0000-0002-6119-1870
                https://orcid.org/0000-0002-4329-3312
                Article
                biomedicines-09-00171
                10.3390/biomedicines9020171
                7916193
                33572373
                b86fb4f4-c78c-472b-aa42-078aa96e07ea
                © 2021 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
                : 11 January 2021
                : 01 February 2021
                Categories
                Review

                squamous cell carcinoma,non-melanoma skin cancer,keratinocyte carcinoma,dermoscopy,therapy,radiotherapy,immunotherapy,bowen’s disease,cemiplimab

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