The Immune System and Pathogenesis of Melanoma and Non-melanoma Skin Cancer.

Tumor development is the result of genetic derangement and the inability to prevent unfettered proliferation. Genetic derangements leading to tumorigenesis are variable, but the immune system plays a critical role in tumor development, prevention, and production. In this chapter, we will discuss the importance of the immune system as it relates to the development of skin cancer-both melanoma and non-melanoma skin cancers (NMSC).

Comparison of racial distribution of photodermatoses in USA academic dermatology clinics: A multicenter retrospective analysis of 1080 patients over a 10-year period.

BACKGROUND: Previous studies at single academic institutions have identified variations in the prevalence of photodermatoses among racial groups. The purpose of the study was to compare the distribution of photodermatoses between Whites and Blacks at four academic medical centers in the USA. METHODS: A retrospective chart review was performed at four institutions' general dermatology clinics using diagnoses consistent with the International Classification of Disease (ICD), Ninth and Tenth Revisions, codes related to photodermatoses between August 2006 and August 2016. A total of 9736 charts were manually reviewed and classified. Analyses were performed analyzing the frequency of photodermatoses between Whites and Blacks in the pooled data. RESULTS: There were 1,080 patients with photodermatoses identified. Statistically significant differences in the frequency of photodermatoses between Whites and Blacks were identified for polymorphous light eruption (more common in Blacks), photoallergic contact dermatitis, phototoxic drug eruption, phytophotodermatitis, porphyria, and solar urticaria (more common in Whites). The most commonly diagnosed photodermatoses were polymorphous light eruption (total 672), and photodermatitis not otherwise specified (total 189). CONCLUSION: Our study demonstrated significantly higher proportions of polymorphous light eruption in Blacks, and higher proportions of photoallergic contact dermatitis, phototoxic drug eruptions, phytophotodermatitis, porphyrias, and solar urticaria in Whites.

The Effect of Shift Work and Poor Sleep on Self-Reported Skin Conditions: A Survey of Call Center Agents in the Philippines.

Night shift workers may have a disrupted circadian rhythm, which may contribute to the development of skin disease. The purpose of this study was to determine whether there is a significant difference in the prevalence and severity of self-reported skin disease between "regular" day shift workers compared to "graveyard" night shift workers. We conducted surveys from 630 call center agents in Manila, the Philippines, and they were analyzed regarding demographics, medical history, dermatologic history, lifestyle, and sleep. No difference was found in the prevalence of skin disease between shifts. However, night shift workers were worse sleepers. When compared to good sleepers, poor sleepers had a higher prevalence of skin disease with worse severity. Graveyard shift workers with poor sleep may have increased skin disease severity.

Acne Severity and Sleep Quality in Adults.

Poor sleep quality is extremely prevalent, with about one third of adults in the USA obtaining less than the recommended amount of sleep. In addition, poor sleep quality has been linked to an increased risk of many conditions, including diabetes, hypertension, psychiatric conditions, and overall all-cause mortality. Research has shown that sleep disturbance does impact skin disease, although many details of this relationship are still unclear. The goal of this study is to determine if there is a relationship between acne severity and sleep quality in adults. Forty subjects with acne were recruited from dermatology clinics in Cleveland, OH, to participate in this study. Acne severity was assessed using the Global Acne Grading Scale (GAGS). To assess sleep quality, subjects completed the Pittsburgh Sleep Quality Index (PSQI) and completed a seven-day sleep journal. Subjects also completed the Dermatology Life Quality Index (DLQI), the Patient Health Questionnaire-2 (PHQ-2), and provided information about current and past acne treatments as well as their opinion regarding their own acne severity and exacerbating factors. Our findings support the hypothesis that there is a potential relationship between sleep quality and acne.

Effect of an Emollient on the Mycobiome of Atopic Dermatitis Patients.

INTRODUCTION: Atopic dermatitis (AD) is associated with changes in skin bacterial microbiome. Emollient treatment induces change in bacterial microbiome in AD, but its effect on fungal microbiome ("mycobiome") and their inter-kingdom correlations is unknown. We used Ion-Torrent sequencing to characterize the mycobiome of AD patients in response to emollient treatment. METHODS: Skin swabs were collected from lesional and non-lesional skin of AD patients suffering from moderate AD, after informed consent and according to GCP guidelines. Genomic DNA was extracted from each swab using the MoBio PowerSoil DNA Isolation kit and used for mycobiome sequencing analyses as described in our earlier publications. Principal coordinates analyses (PCoA), diversity, abundance, and correlations analyses were conducted in R and relevant packages using non-parametric tests (P less than .05 was significant). RESULTS: Swab samples from 10 patients (7 females, 3 males; mean age, 10.5 years) were analyzed. Emollient treatment induced a significant reduction of Scoring Atopic Dermatitis (SCORAD) score (P less than .001). PCoA showed pre-treatment and post-treatment samples clustered differently at all taxa levels. Six genera were detected in only non-lesional samples, while four were detected in only lesional samples. In non-lesional samples, Shannon diversity index was significantly increased after emollient treatment (P less than equal to .04), while lesional skin exhibited non-significant decrease. Ascomycota was the most abundant phylum and Dothideomycetes was the most abundant Class in most samples. Eight fungal species were either significantly different (P less than .05) or showed a strong trend (P less than .1) between pre- and post-treatment samples of lesional and non-lesional skin. In lesional skin, Gram-negative Pseudomonas spp. correlated significantly with pathogenic fungal species (Aspergillus, Candida spp.) in pre-treatment samples; these correlations were not detected in post-treatment samples. Moreover, lesional skin exhibited significant correlations between Gram-positive bacteria (Corynebacterium kroppenstedtiian and Staphylococcus pettenkoferi) and pathogenic Candida species in pre-treatment samples, but not in post- treated samples. DISCUSSION: Emollient treatment may induce beneficial microbial changes in the mycobiome and augment host-microbe balance on skin in AD. Clinical relevance of these results need to be investigated. J Drugs Dermatol. 2018;17(10):1039-1048.

An Acne Survey from the World's Largest Annual Gathering of Twins.

IMPORTANCE: Surveying identical twins allows us to qualitatively separate genetic and environmental factors that may contribute to acne severity. OBJECTIVE: To study a cohort of identical and fraternal twins to identify environmental factors that may influence acne severity. DESIGN, SETTING, PARTICIPANTS: A survey was administered to 139 identical and fraternal twin multiples (279 subjects) at the Annual Twins Day Festival in Twinsburg, Ohio on August 6-7, 2016. One set of triplets was included. MAIN OUTCOME(S) AND MEASURE(S): Acne incidence, severity, and triggers were analyzed using the N-1 Chi-squared test and paired, 2-tailed t test. RESULTS: The proportion of concordant pairs was significantly higher in identical (64%) vs fraternal (49%) twins (P=0.04). Acne was found to be associated with polycystic ovarian syndrome (PCOS; P=0.045), anxiety (P =0.014), and asthma (P=0.026). Identical twin pairs with acne had a higher BMI (P= 0.020) and exercised significantly less (P=0.001) than those without acne. Analyzing concordant twin pairs, the twin with more severe acne was more likely to report aggravation of acne with cosmetic product use (P=0.002) and sugar intake (P=0.048). CONCLUSIONS AND REVELANCE: This twin study further supports that there may be a genetic phenotypic link, though social and environmental factors may also have an influence in the disease process.

J Drugs Dermatol. 2018;17(4):380-382.

Topical application of ST266 reduces UV-induced skin damage.

Ultraviolet radiation (UVR) has a significant impact on human skin and is the major environmental factor for skin cancer formation. It is also believed that 80% of the signs of skin aging are attributed to UVR. UVR induces inflammatory changes in the skin via the increase in oxidative stress, DNA damage vascular permeability, and fluctuation in a myriad of cytokines. Acutely, UVR causes skin inflammation and DNA damage, which manifest as sunburn (erythema). ST266 is the secretome of proprietary amnion-derived cells that have been shown to reduce inflammation and accelerate healing of various wounds by promoting migration of keratinocytes and fibroblasts in preclinical animal studies. We hypothesized that ST266 has anti-inflammatory effects that can be used to reduce ultraviolet (UV) erythema and markers of inflammation. In this study, we examined the in vivo effects of ST266 on post UV-irradiated skin by measuring erythema, level of cyclobutane pyrimidine dimer (CPD), and expression level of xeroderma pigmentosum, complementation group A (XPA). We demonstrated that ST266 has the potential to reduce the acute effects of UV-induced skin damage when applied immediately after the initial exposure. In addition, ST266 is shown to reduce erythema, increase XPA DNA repair protein, and decrease damaged DNA.

History of UV Lamps, Types, and Their Applications.

The use of ultraviolet (UV) light, for the treatment of skin conditions, dates back to the early 1900s. It is well known that sunlight can be of therapeutic value, but it can also lead to deleterious effects such as burning and carcinogenesis. Extensive research has expanded our understanding of UV radiation and its effects in human systems and has led to the development of man-made UV sources that are more precise, safer, and more effective for the treatment of wide variety of dermatologic conditions.

Ultraviolet Photobiology in Dermatology.

The effects of ultraviolet radiation on human skin have been studied for years, and both its harmful and therapeutic effects are well known. Exposure to UV light can lead to sunburn, immunosuppression, skin aging, and carcinogenesis, and photoprotection is strongly advocated. However, when used under controlled conditions, UV radiation can also be helpful in the diagnosis and treatment of many skin conditions.

PEGylated Dendrimers as Drug Delivery Vehicles for the Photosensitizer Silicon Phthalocyanine Pc 4 for Candidal Infections.

Fungi account for billions of infections worldwide. The second most prominent causative agent for fungal infections is Candida albicans (C. albicans). As strains of fungi become resistant to antifungal medications, new treatment modalities must be investigated to combat these infections. One approach is to employ photodynamic therapy (PDT). PDT utilizes a photosensitizer, light, and cellular O2 to produce reactive oxygen species (ROS), which then induce oxidative stress resulting in apoptosis. Silicon phthalocyanine Pc 4 is a photosensitizer that has exhibited success in clinical trials for a myriad of skin diseases. The hydrophobic nature of Pc 4, however, poses significant formulation and delivery challenges in the use of this therapy. To mitigate these concerns, a drug delivery vehicle was synthesized to better formulate Pc 4 into a viable PDT agent for treating fungal infections. Utilizing poly(amidoamine) dendrimers as the framework for the vehicle, ∼13% of the amine chain ends were PEGylated to promote water solubility and deter nonspecific adsorption. In vitro studies with C. albicans demonstrate that the potency of Pc 4 was not hindered by the dendrimer vehicle. Encapsulated Pc 4 was able to effectively generate ROS and obliterate fungal pathogens upon photoactivation. The results presented within describe a nanoparticulate delivery vehicle for Pc 4 that readily kills drug-resistant C. albicans and eliminates solvent toxicity, thus, improving formulation characteristics for the hydrophobic photosensitizer.

2016 Arte Poster Competition First Place Winner: Circadian Rhythm and UV-Induced Skin Damage: An In Vivo Study.

Exposure of the skin to ultraviolet (UV) irradiation causes many detrimental effects through mechanisms related to oxidative stress and DNA damage. Excessive oxidative stress can cause apoptosis and cellular dysfunction of epidermal cells leading to cellular senescence and connective tissue degradation. Direct and indirect damage to DNA predisposes the skin to cancer formation. Chronic UV exposure also leads to skin aging manifested as wrinkling, loss of skin tone, and decreased resilience. Fortunately, human skin has several natural mechanisms for combating UV-induced damage. The mechanisms operate on a diurnal rhythm, a cycle that repeats approximately every 24 hours. It is known that the circadian rhythm is involved in many skin physiologic processes, including water regulation and epidermal stem cell function. This study evaluated whether UV damage and the skin's natural mechanisms of inflammation and repair are also affected by circadian rhythm. We looked at UV-induced erythema on seven human subjects irradiated with simulated solar radiation in the morning (at 08:00 h) versus in the afternoon (at 16:00 h). Our data suggest that the same dose of UV radiation induces significantly more inflammation in the morning than in the afternoon. Changes in protein expression relevant to DNA damage, such as xeroderma pigmentosum, complementation group A (XPA), and cyclobutane pyrimidine dimers (CPD) from skin biopsies correlated with our clinical results. Both XPA and CPD levels were higher after the morning UV exposure compared with the afternoon exposure.

J Drugs Dermatol. 2016;15(9):1124-1130.

Association of MHC region SNPs with irritant susceptibility in healthcare workers.

Irritant contact dermatitis is the most common work-related skin disease, especially affecting workers in "wet-work" occupations. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) and skin irritant response in a group of healthcare workers. 585 volunteer healthcare workers were genotyped for MHC SNPs and patch tested with three different irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH) and benzalkonium chloride (BKC). Genotyping was performed using Illumina Goldengate MHC panels. A number of SNPs within the MHC Class I (OR2B3, TRIM31, TRIM10, TRIM40 and IER3), Class II (HLA-DPA1, HLA-DPB1) and Class III (C2) genes were associated (p < 0.001) with skin response to tested irritants in different genetic models. Linkage disequilibrium patterns and functional annotations identified two SNPs in the TRIM40 (rs1573298) and HLA-DPB1 (rs9277554) genes, with a potential impact on gene regulation. In addition, SNPs in PSMB9 (rs10046277 and ITPR3 (rs499384) were associated with hand dermatitis. The results are of interest as they demonstrate that genetic variations in inflammation-related genes within the MHC can influence chemical-induced skin irritation and may explain the connection between inflamed skin and propensity to subsequent allergic contact sensitization.

Activated T cells exhibit increased uptake of silicon phthalocyanine Pc 4 and increased susceptibility to Pc 4-photodynamic therapy-mediated cell death.

Photodynamic therapy (PDT) is an emerging treatment for malignant and inflammatory dermal disorders. Photoirradiation of the silicon phthalocyanine (Pc) 4 photosensitizer with red light generates singlet oxygen and other reactive oxygen species to induce cell death. We previously reported that Pc 4-PDT elicited cell death in lymphoid-derived (Jurkat) and epithelial-derived (A431) cell lines in vitro, and furthermore that Jurkat cells were more sensitive than A431 cells to treatment. In this study, we examined the effectiveness of Pc 4-PDT on primary human CD3(+) T cells in vitro. Fluorometric analyses of lysed T cells confirmed the dose-dependent uptake of Pc 4 in non-stimulated and stimulated T cells. Flow cytometric analyses measuring annexin V and propidium iodide (PI) demonstrated a dose-dependent increase of T cell apoptosis (6.6-59.9%) at Pc 4 doses ranging from 0-300 nM. Following T cell stimulation through the T cell receptor using a combination of anti-CD3 and anti-CD28 antibodies, activated T cells exhibited increased susceptibility to Pc 4-PDT-induced apoptosis (10.6-81.2%) as determined by Pc 4 fluorescence in each cell, in both non-stimulated and stimulated T cells, Pc 4 uptake increased with Pc 4 dose up to 300 nM as assessed by flow cytometry. The mean fluorescence intensity (MFI) of Pc 4 uptake measured in stimulated T cells was significantly increased over the uptake of resting T cells at each dose of Pc 4 tested (50, 100, 150 and 300 nM, p < 0.001 between 50 and 150 nM, n = 8). Treg uptake was diminished relative to other T cells. Cutaneous T cell lymphoma (CTCL) T cells appeared to take up somewhat more Pc 4 than normal resting T cells at 100 and 150 nm Pc 4. Confocal imaging revealed that Pc 4 localized in cytoplasmic organelles, with approximately half of the Pc 4 co-localized with mitochondria in T cells. Thus, Pc 4-PDT exerts an enhanced apoptotic effect on activated CD3(+) T cells that may be exploited in targeting T cell-mediated skin diseases, such as cutaneous T cell lymphoma (CTCL) or psoriasis.

Genetic Basis of Irritant Susceptibility in Health Care Workers.

OBJECTIVE: The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within genes involved in inflammation, skin barrier integrity, signaling/pattern recognition, and antioxidant defense with irritant susceptibility in a group of health care workers. METHODS: The 536 volunteer subjects were genotyped for selected SNPs and patch tested with three model irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), and benzalkonium chloride (BKC). Genotyping was performed on genomic DNA using Illumina Goldengate custom panels. RESULTS: The ACACB (rs2268387, rs16934132, rs2284685), NTRK2 (rs10868231), NTRK3 (rs1347424), IL22 (rs1179251), PLAU (rs2227564), EGFR (rs6593202), and FGF2 (rs308439) SNPs showed an association with skin response to tested irritants in different genetic models (all at P < 0.001). Functional annotations identified two SNPs in PLAU (rs2227564) and ACACB (rs2284685) genes with a potential impact on gene regulation. In addition, EGF (rs10029654), EGFR (rs12718939), CXCL12 (rs197452), and VCAM1 (rs3917018) genes showed an association with hand dermatitis (P < 0.005). CONCLUSIONS: The results demonstrate that genetic variations in genes related to inflammation and skin homeostasis can influence responses to irritants and may explain inter-individual variation in the development of subsequent contact dermatitis.

The Response of microRNAs to Solar UVR in Skin-Resident Melanocytes Differs between Melanoma Patients and Healthy Persons.

The conversion of melanocytes into cutaneous melanoma is largely dictated by the effects of solar ultraviolet radiation (UVR). Yet to be described, however, is exactly how these cells are affected by intense solar UVR while residing in their natural microenvironment, and whether their response differs in persons with a history of melanoma when compared to that of healthy individuals. By using laser capture microdissection (LCM) to isolate a pure population of melanocytes from a small area of skin that had been intermittingly exposed or un-exposed to physiological doses of solar UVR, we can now report for the first time that the majority of UV-responsive microRNAs (miRNAs) in the melanocytes of a group of women with a history of melanoma are down-regulated when compared to those in the melanocytes of healthy controls. Among the miRNAs that were commonly and significantly down-regulated in each of these women were miR-193b (P<0.003), miR-342-3p (P<0.003), miR186 (P<0.007), miR-130a (P<0.007), and miR-146a (P<0.007). To identify genes potentially released from inhibition by these repressed UV-miRNAs, we analyzed databases (e.g., DIANA-TarBase) containing experimentally validated microRNA-gene interactions. In the end, this enabled us to construct UV-miRNA-gene regulatory networks consisting of individual genes with a probable gain-of-function being intersected not by one, but by several down-regulated UV-miRNAs. Most striking, however, was that these networks typified well-known regulatory modules involved in controlling the epithelial-to-mesenchymal transition and processes associated with the regulation of immune-evasion. We speculate that these pathways become activated by UVR resulting in miRNA down regulation only in melanocytes susceptible to melanoma, and that these changes could be partially responsible for empowering these cells toward tumor progression.

The photodynamic antibacterial effects of silicon phthalocyanine (Pc) 4.

The emergence of antibiotic-resistant strains in facultative anaerobic Gram-positive coccal bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), is a global health issue. Typically, MRSA strains are found associated with institutions like hospitals but recent data suggest that they are becoming more prevalent in community-acquired infections. It is thought that the incidence and prevalence of bacterial infections will continue to increase as (a) more frequent use of broad-spectrum antibiotics and immunosuppressive medications; (b) increased number of invasive medical procedures; and (c) higher incidence of neutropenia and HIV infections. Therefore, more optimal treatments, such as photodynamic therapy (PDT), are warranted. PDT requires the interaction of light, a photosensitizing agent, and molecular oxygen to induce cytotoxic effects. In this study, we investigated the efficacy and characterized the mechanism of cytotoxicity induced by photodynamic therapy sensitized by silicon phthalocyanine (Pc) 4 on (a) methicillin-sensitive Staphylococcus aureus (MSSA) (ATCC 25923); (b) community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) (ATCC 43300); and (c) hospital acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) (PFGE type 300). Our data include confocal image analysis, which confirmed that Pc 4 is taken up by all S. aureus strains, and viable cell recovery assay, which showed that concentrations as low as 1.0 µM Pc 4 incubated for 3 h at 37 °C followed by light at 2.0 J/cm2 can reduce cell survival by 2-5 logs. These results are encouraging, but before PDT can be utilized as an alternative treatment for eradicating resistant strains, we must first characterize the mechanism of cell death that Pc 4-based PDT employs in eliminating these pathogens.