Chronic Ultraviolet Radiation Research Articles

Granzyme B Expression in Conjunctiva of Patients with Pterygium.

Pterygium is often associated with chronic ultraviolet (UV) radiation exposure and characterized by the overgrowth of conjunctiva and extracellular matrix (ECM) remodeling. Notably, several studies in the skin have demonstrated that chronic UV radiation can upregulate Granzyme B (GrB) expression and increase ECM degradation. The aim of this study was to compare GrB expression between pterygium and healthy controls and to further link this GrB expression to mast cells. Post-mortem pterygium tissues and conjunctival tissues from age-matched controls were used to assess GrB expression via immunofluorescence and microscopy. We found a significantly higher density of GrB+ cells from pterygium specimens compared to healthy controls. Furthermore, many of the GrB+ cells in pterygium specimens co-expressed tryptase, a mast cell marker. These findings suggest a role for conjunctival mast cell-secreted GrB in the pathogenesis of pterygium and highlight GrB as a possible therapeutic target in delaying or halting pterygium progression.

Corneal Epithelial Cell Density Is Reduced in Young Adults With Conjunctival Ultraviolet Autofluorescence.

The aim of this study was to investigate the effects of chronic ultraviolet (UV) radiation exposure on the corneal microstructure using conjunctival UV autofluorescence (CUVAF) as a marker of exposure. Young healthy adults aged 18 to 35 years were recruited. Participant's demographics and sun exposure behavior were recorded using questionnaires. Images of the bulbar conjunctiva from the right eye were captured and analyzed for the CUVAF area. Corneal microstructure was assessed by in vivo confocal microscopy and anterior segment optical coherence tomography. The presence of palisades of Vogt in all 4 limbal quadrants was recorded. CUVAF was observed in 31 of 52 eyes (60%), with a mean (±SD) nasal, temporal, and total CUVAF area of 5.39 ± 4.16 mm 2 , 4.29 ± 4.27 mm 2 , and 9.67 ± 7.01 mm 2 , respectively. Individuals with CUVAF were significantly more likely to report undertaking moderate-intensity to high-intensity outdoor exercise ( P = 0.021). Individuals with CUVAF were less likely to have visible nasal and temporal palisades of Vogt ( P = 0.011). Corneal basal cell densities anterior to the nerve whorl ( P < 0.001) and nasally ( P = 0.005) were lower in individuals with CUVAF. Wing cell density anterior to the nerve whorl was lower in individuals with CUVAF ( P = 0.011). No significant changes in the central and limbal corneal epithelial thickness were observed. Significant reductions in corneal epithelial cell density were observed in individuals with CUVAF, a biomarker of chronic UV exposure. This observation suggests that chronic UV exposure is damaging to the corneal microstructure.

Cutaneous Squamous Cell Carcinoma: An Up-to-Date Comprehensive Review with a Focus on Contemporary Optical Imaging Diagnostic Modalities

Cutaneous squamous cell carcinoma (cSCC) arises from the abnormal proliferation of keratinocytes of the epidermis, most commonly due to UV-light-induced DNA damage. Although histopathological assessment is the gold standard for diagnosing cSCC, nascent optical imaging diagnostic modalities enable clinicians to perform “optical or virtual biopsy” in real-time. We aim to report advances in optical imaging diagnostics for cSCC, along with an updated review of the literature. A comprehensive literature review was performed using PubMed, Embase, and Cochrane databases for manuscripts published from 2008 to 2022. The search yielded a total of 9581 articles, out of which 136 relevant articles were included in the literature review after fulfilling screening and eligibility criteria. This review highlights the current optical imaging devices used for diagnosing cSCC and their diagnostic features. These devices include in vivo and ex vivo reflectance confocal microscopy, optical coherence tomography, line-field confocal optical coherence tomography, multiphoton tomography, and high-frequency ultrasonography. Although surgical excision or Mohs micrographic surgery is considered the gold standard, the latest developments in nonsurgical management of cSCC are discussed. Based on he review of the literature, we conclude that contemporary optical imaging devices such as confocal microscopy, optical coherence tomography, line-field confocal optical coherence tomography and multiphoton tomography have revolutionized real-time diagnostic imaging in dermatology, particularly within the realm of skin cancer. These devices enable rapid diagnoses and allow for a faster initiation of therapy. The application of newer imaging devices to cSCC management may benefit high-risk patients (e.g., chronic UV radiation exposure or organ transplant recipients) or patients with multifocal cSCC, for whom multiple biopsies would be impractical, thus avoiding unnecessary biopsies. Together with dermoscopy, optical imaging technologies can help to improve the efficiency of diagnosis by reducing the turnaround time and the need for extensive laboratory processing resources.

Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Pathogenesis of melasma

AbstractTo adequately guide future therapies, it is important to elucidate the pathogenesis of melasma. Chronic ultraviolet (UV) radiation exposure, hormonal stimulation, and genetic predisposition play a role in melasma. A widely accepted theory for the pathogenesis of melasma is the increase of melanin through UV, which leads to the upregulation of melanin stimulating receptors (MSR) such as melanocortin‐1 receptors (MC1R), resulting in increased hormone binding and melanin production. Furthermore, there are similarities between the histopathologic presentation of melasma and solar elastosis, a hallmark of photo‐aged skin. These overlaps include altered basement membrane, increased vascularization, and increased mast cell count. There is significant data showing greater degree of solar elastosis in the melasma skin compared to the perilesional skin. Additionally, an etiologic factor in the pathogenesis of melasma is hormonal exposure to estrogen. Melasma has increased prevalence among menstruating women, women on oral contraceptives, and pregnant women. In melasma lesions, studies have shown an increased number of estrogen receptors and progesterone receptors in the dermis and epidermis, respectively. Previously, increased melanogenesis was thought to be the sole contributing factor to the pathogenesis of melasma but more recently, aberrant vasodilation and angiogenesis have been found to play a role. Nitric oxide, a potent vasodilator, was found to be overexpressed at the dermal‐epidermal junction and was hypothesized to contribute to melasma through stimulation of tyrosinase and increasing vascularity. In conclusion, the various mechanisms implicated in melasma include melanocyte dysfunction, solar elastosis, mast cell dysfunction, hormonal influence, vascular transformation, and basement membrane damage.

490 Variation in epidermal mutation burden after field treatment with topical 5-fluorouracil

Cutaneous field cancerization resulting from chronic ultraviolet radiation has a high burden of clinical and subclinical actinic damage. Field treatment with topical 5-fluorouracil (5-FU) is effective in treating field cancerization. Based on the concept of field cancerization, resulting from the accumulation of genetic alterations, we hypothesised that field therapies are effective at reducing future keratinocyte cancer formation through decreasing the epidermal mutation load. In our study, adult patients aged 45 years or older with evidence of photodamaged forearms were recruited.

Exposome and Skin. Part 2. The Influential Role of the Exposome, Beyond UVR, in Actinic Keratosis, Bowen's Disease and Squamous Cell Carcinoma: A Proposal.

Actinic keratosis (AK) is the main risk factor for the development of cutaneous invasive squamous cell carcinoma (SCC). It represents the first sign of severe chronic ultraviolet radiation exposure, which has a clear significant effect. Nevertheless, the skin is exposed to many other exposome factors which should be thoroughly considered. Our aim was to assess the impact of exposome factors other than ultraviolet radiation (UVR) on the etiopathology of AK and Bowen’s disease (BD) and progression of AK to SCC and to design tailored prevention strategies. We performed an exhaustive literature search in September 2021 through PubMed on the impact of exposome factors other than UVR on AK, BD and SCC. We conducted several parallel searches combining terms of the following topics: AK, BD, SCC and microbiome, hormones, nutrition, alcohol, tobacco, viral infections, chemical contaminants and air pollution. Notably, skin microbiome studies have shown how Staphylococcus aureus infections are associated with AK and AK-to-SCC progression by the production of chronic inflammation. Nutritional studies have demonstrated how a caloric restriction in fat intake, oral nicotinamide and moderate consumption of wine significantly reduce the number of premalignant keratoses and SCC. Regarding lifestyle factors, both alcohol and smoking are associated with the development of SCC in a dose-dependent manner. Relevant environmental factors are viral infections and chemical contaminants. Human papillomavirus infections induce deregulation of cellular proliferation and are associated with AK, BD and SCC. In addition to outdoor jobs, occupations such as industrial processing and farming also increase the risk of developing keratoses and SCC. The exposome of AK will undoubtedly help the understanding of its etiopathology and possible progression to SCC and will serve as a basis to design tailored prevention strategies.

The Multidisciplinary Management of Cutaneous Squamous Cell Carcinoma: A Comprehensive Review and Clinical Recommendations by a Panel of Experts.

Simple SummaryCutaneous squamous cell carcinoma is one of the most common forms of cancer. Although most cases are cured with surgical excision, a few tumors are associated with a high risk of local or distant relapse; therefore, it is relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Recently, PD-1 inhibitor cemiplimab was approved by the regulatory authorities for the treatment of advanced cutaneous squamous cell carcinoma; subsequently, the anti-PD-1 agent pembrolizumab received the approval by the FDA only in the same setting. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of cutaneous squamous cell carcinoma.Cutaneous squamous cell carcinomas (CSCC) account for about 20% of all keratinocyte carcinomas, which are the most common form of cancer. Heterogeneity of treatments and low mortality are a challenge in obtaining accurate incidence data and consistent registration in cancer registries. Indeed, CSCC mostly presents as an indolent, low-risk lesion, with five-year cure rates greater than 90% after surgical excision, and only few tumors are associated with a high-risk of local or distant relapse; therefore, it is particularly relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Due to an etiopathogenesis largely relying on chronic UV radiation exposure, CSCC is among the tumors with the highest rate of somatic mutations, which are associated with increased response rates to immunotherapy. Thanks to such strong pre-clinical rationale, clinical trials led to the approval of anti-PD-1 cemiplimab by the FDA (Food and Drug Administration) and EMA (European Medicines Agency), and anti-PD-1 pembrolizumab by the FDA only. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of CSCC.

Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation-induced tissue damage.

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing, and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt signalling in skin, stimulation of fibroblast proliferation by epidermal β-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4- and CD8-positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro-inflammatory prostaglandins, and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress.

Topical carvedilol delivery prevents UV-induced skin cancer with negligible systemic absorption

The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10 µM) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25 weeks, topical T-CAR gel (10 µM) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100 µM), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32 mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects.

Micronodular basal cell carcinoma of the scrotum: a case report and review of the literature

IntroductionBasal cell carcinoma is the most common nonmelanotic skin cancer. It has variable clinical and histological subtypes that vary in their aggressiveness and liability to recurrence and metastasis. Chronic ultraviolet radiation exposure is considered to be the main risk factor for developing basal cell carcinoma; therefore, it typically arises on sun-exposed skin, mainly the head and neck.Case presentationWe present the case of a 55-year-old Caucasian male who presented with a lesion on the scrotum for 2 years. The lesion was clinically presumed benign and initially treated with curettage. Microscopic examination revealed an incompletely resected micronodular basal cell carcinoma with sebaceous differentiation. Therefore, a second excisional biopsy was performed to completely excise the incidentally discovered malignant tumor.ConclusionWe report the first case of micronodular basal cell carcinoma arising on the scrotum. The goal of our article is to draw clinicians’ attention to the possible involvement of unexposed skin with basal cell carcinoma, and we highlight the importance of accurate diagnosis and prompt treatment due to the aggressive nature of micronodular basal cell carcinoma.

246 Epidermal ablation reduces keratinocyte cancer occurrence by reducing skin mutation burden caused by chronic ultraviolet radiation

Ultra-Violet (UV) radiation from sunlight is the main carcinogen driving keratinocyte cancers of the skin. The accumulation of UV-induced mutations on sun-exposed areas leads to field cancerisation. Knowing the regenerative property of the skin, we investigated if epidermal ablation removes mutations on the epidermis and allows less mutated cells from the deeper part of the skin to repopulate the ablated surface. Patients with history of multiple epidermal cancers were subjected to epidermal ablation on their forearms with three different depths of laser (600nm, 400nm and fractional laser).

297 Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. Here we show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and migration.

Chronic UV radiation–induced RORγt+ IL-22–producing lymphoid cells are associated with mutant KC clonal expansion

Chronic ultraviolet (UV) radiation exposure is the greatest risk factor for cutaneous squamous cell carcinoma (cSCC) development, and compromised immunity accelerates this risk. Having previously identified that epidermal Langerhans cells (LC) facilitate the expansion of UV-induced mutant keratinocytes (KC), we sought to more fully elucidate the immune pathways critical to cutaneous carcinogenesis and to identify potential targets of intervention. Herein, we reveal that chronic UV induces and LC enhance a local immune shift toward RORγt+ interleukin (IL)-22/IL-17A-producing cells that occurs in the presence or absence of T cells while identifying a distinct RORγt+ Sca-1+ CD103+ ICOS+ CD2+/- CCR6+ intracellular CD3+ cutaneous innate lymphoid cell type-3 (ILC3) population (uvILC3) that is associated with UV-induced mutant KC growth. We further show that mutant KC clone size is markedly reduced in the absence of RORγt+ lymphocytes or IL-22, both observed in association with expanding KC clones, and find that topical application of a RORγ/γt inhibitor during chronic UV exposure reduces local expression of IL-22 and IL-17A while markedly limiting mutant p53 KC clonal expansion. We implicate upstream Toll-like receptor signaling in driving this immune response to chronic UV exposure, as MyD88/Trif double-deficient mice also show substantially reduced p53 island number and size. These data elucidate key immune components of chronic UV-induced cutaneous carcinogenesis that might represent targets for skin cancer prevention.

Changes in Phospholipid/Ceramide Profiles and Eicosanoid Levels in the Plasma of Rats Irradiated with UV Rays and Treated Topically with Cannabidiol.

Chronic UV radiation causes oxidative stress and inflammation of skin and blood cells. Therefore, in this study, we assessed the effects of cannabidiol (CBD), a natural phytocannabinoid with antioxidant and anti-inflammatory properties, on the phospholipid (PL) and ceramide (CER) profiles in the plasma of nude rats irradiated with UVA/UVB and treated topically with CBD. The results obtained showed that UVA/UVB radiation increased the levels of phosphatidylcholines, lysophospholipids, and eicosanoids (PGE2, TxB2), while downregulation of sphingomyelins led to an increase in CER[NS] and CER[NDS]. Topical application of CBD to the skin of control rats significantly upregulated plasma ether-linked phosphatidylethanolamines (PEo) and ceramides. However, CBD administered to rats irradiated with UVA/UVB promoted further upregulation of CER and PEo and led to significant downregulation of lysophospholipids. This was accompanied by the anti-inflammatory effect of CBD, manifested by a reduction in the levels of proinflammatory PGE2 and TxB2 and a dramatic increase in the level of anti-inflammatory LPXA4. It can therefore be suggested that topical application of CBD to the skin of rats exposed to UVA/UVB radiation prevents changes in plasma phospholipid profile resulting in a reduction of inflammation by reducing the level of LPE and LPC species and increasing antioxidant capacity due to upregulation of PEo species.

Overview of germline and somatic genetic alterations in basal and squamous cell carcinoma: a review of the current literature.

Non-melanoma skin cancers (NMSCs), including basal and squamous cell carcinomas, represent the most common malignancies among Caucasians. Over two million cases of NMSC occur each year in the US, with a progressive increase in incidence. There are well-known environmental risk factors, such as iatrogenic or ionizing radiation exposure, but the effect of chronic ultraviolet radiation, especially ultraviolet B radiation, is one of the main predisposing factors. Currently, based on our knowledge of the pathophysiology of most NMSCs, we have a better understanding of the associated genetic risk factors. The aim of this study was to evaluate the factors that contribute to the onset of NMSC through a comprehensive literature research.

Synergistic Effect of 300 μm Needle-Depth Fractional Microneedling Radiofrequency on the Treatment of Senescence-Induced Aging Hyperpigmentation of the Skin

Aging-associated dermatological pigmentary diseases are associated with accumulation of senescence cells and the disruption of basement membrane due to chronic ultraviolet radiation (UVR) exposure. Our study is on the synergistic effect of the novel 300 μm needle-depth fractional microneedling radiofrequency (FMR) treatment and conventional Q-switched ND:YAG laser on aging-associated hyperpigmentation of the skin. The prospective controlled clinical trial of 25 Asian women revealed significantly higher improvements not only on wrinkles, but also on hyperpigmentation. Additional ex vivo study revealed significant reduction of pro-melanogenic markers as well as senescent keratinocytes, while increased expression of collagen type IV on the epidermal basement membrane, after additional FMR treatment on UV-irradiated human tissues. These results demonstrate that 300 μm needle-depth FMR might effectively remove senescent keratinocytes that secrete pro-melanogenic markers, and repair disrupted basement membrane, therefore preventing constant hyperpigmentation of the aged skin.

119 Proteomics and lipidomics reveal the protective mechanism of dietary n-3 PUFA supplementation for photoaging

Chronic ultraviolet radiation (UVR) could induce photoaging, even carcinogenesis. Dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been proved to alleviate photoaging and cutaneous carcinoma. Whereas the exact mechanism remains poorly elucidated, accumulated evidence suggested that the alleviation effect of n-3 PUFA for photoaging is a multifactorial procession characterized by different pathways. Here, we performed a whole-genome proteomics and lipidomics analyses using a self-constructed photoaging mouse model with n-3 PUFA or n-6 PUFA supplementation. Significant alleviation of photoaging was observed and a total of 88 differentially expressed proteins and 152 differentially expressed lipids were identified in mice with n-3 PUFA supplementation. We found that n-3 PUFA may alleviate photoaging by upregulating Hmmr (hyaluronic acid receptor) expression, which can decrease Mmp9 expression, reducing collagens degradation. As most proteins were associated with lipogenesis and lipids metabolism, we further analyzed the lipidomics data, most triglyceride (93%) showed a significant increase in the n-3 PUFA supplementation group. Our proteomics and lipidomics results indicate that the protective mechanism of n-3 PUFA for photoaging is complicate, the effect of elevated triglyceride by n-3 PUFA supplementation in counteracting skin photoaging should cannot be overestimated, which will become a new prime target in fighting photoaging.

081 Ultraviolet light-induced collagen degradation inhibits melanoma invasion

Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma. The ageing, sun-exposed dermis accumulates UVR damage, and older patients develop more melanomas at UVR-exposed sites. As fibroblasts play key roles in the stromal response to UVR and in cancer progression, we investigated how long term UVR modifies dermal fibroblast function and how this affects melanoma invasion. Chronic UVR exposure on dermal fibroblasts showed that extracellular matrix pathways, particularly those involved in collagen catabolism, were upregulated in the absence of acute UVR.

Dietary table grape protects against ultraviolet photodamage in humans: 1. clinical evaluation

To the Editor: In animal models, grape polyphenols protect against acute and chronic ultraviolet (UV) radiation–induced inflammation and DNA damage.1,2 In addition, topical administration of grape seed proanthocyanidin extract reduced sunburn cell formation and prevented Langerhans cell depletion in humans.3