Role of Insulin Use and Social Determinants of Health on Non-melanoma Skin Cancer: Results From the Behavioral Risk Factor Surveillance System.

BACKGROUND: Non-melanoma skin cancer (NMSC) is a frequent type of malignancy with a steadily increasing incidence rate worldwide. Although NMSC was shown to be associated with diabetes, no studies have addressed the extent to which insulin use influences the risk of NMSC in light of social determinants of health (SDOH). We conducted a quantitative study that examined the interplay between insulin use, SDOH, additional covariates, and NMSC among individuals with diabetes. METHODS: We based our analysis on the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a national survey conducted yearly in the US. We performed weighted chi-squared test, logistic regression, and survival analyses on 8685 eligible participants with diabetes enrolled in the BRFSS. RESULTS: Kaplan Meier survival curves showed higher probability of NMSC event-free survival for participants with diabetes using insulin compared to participants with diabetes not using insulin (log-rank test P < .001). Significant associations were detected between insulin use and reduced odds of NMSC (OR .56; 95% CI: .38-.82), and decreased hazard (HR .36; 95% CI: .21-.62), along with indices of SDOH. CONCLUSIONS: Our findings suggest that socioeconomic differences related to the healthcare system and behavioral patterns are linked to discrepancies in the use of insulin and the development of NMSC.

Cyclic AMP-regulatory element-binding protein: a novel UV-targeted transcription factor in skin cancer.

Common therapeutics in relation to melanoma and non-melanoma cancers include the use of kinase inhibitors. The long-term benefits of kinases, however, are limited by development of drug resistance. An alternative approach for treatment would be to focus on transcription factors. Cyclic AMP-regulatory element-binding protein (CREB) is a transcription factor that is commonly overactivated or overexpressed in many different cancers including skin cancer. Ultraviolet radiation (UVR), one of the main causes of skin cancer, can activate CREB in both melanocytes and keratinocytes. In addition, CREB has been found to be activated in skin cancers. Considering the prominent role that CREB plays in skin cancers, the studies reviewed herein raise the possibility of CREB as a potential prognostic and diagnostic marker of skin cancer and a novel target for therapeutic intervention.

Cutaneous squamous cell carcinoma tumor accrual rates in immunosuppressed patients with autoimmune and inflammatory conditions: A retrospective cohort study.

BACKGROUND: Immunosuppression is a known risk factor for the development of cutaneous squamous cell carcinoma (CSCC), especially in solid organ transplant recipients and chronic lymphocytic leukemia. However, this risk is less well defined in autoimmune and inflammatory conditions. OBJECTIVE: Assess the impact that disease-type, duration of immunosuppression, and systemic medications have on CSCC accrual rates, defined as the number of CSCCs a patient develops per year, in autoimmune and inflammatory conditions. METHODS: Retrospective review of 94 immunosuppressed (rheumatoid arthritis: 31[33.0%], inflammatory bowel disease: 17[18.1%], psoriasis: 11[11.7%], autoimmune other (AO): 24[25.5%], inflammatory other: 21[22.3%]) and 188 immunocompetent controls to identify all primary, invasive CSCCs diagnosed from 2010 to 2020. RESULTS: Immunosuppressed patients had higher CSCC accrual rates than immunocompetent controls (0.44 ± 0.36): total cohort (0.82 ± 0.95, P < .01), rheumatoid arthritis (0.88 ± 1.10, P < .01), inflammatory bowel disease (0.94 ± 0.88, P < .01), psoriasis (1.06 ± 1.58, P < .01), AO (0.72 ± 0.56, P < .01), and inflammatory other (0.72 ± 0.61, P < .01). There was an association between increased tumor accrual rates and exposure to systemic medications including, immunomodulators, tumor necrosis factor-alpha inhibitors, non-tumor necrosis factor inhibitor biologics, and corticosteroids, but not with number of systemic medication class exposures or duration of immunosuppression. LIMITATIONS: Retrospective, singlecenter study. CONCLUSION: Patients with autoimmune and inflammatory conditions accrue CSCCs at higher rates than immunocompetent patients.

Neoadjuvant Immunotherapy in Non-melanoma Skin Cancers of the Head and Neck.

OPINION STATEMENT: Neoadjuvant immunotherapy will change the standard of care for advanced resectable cutaneous squamous cell carcinoma (cSCC) and possibly other non-melanoma skin cancers. With pathological complete response rates around 50% for cSCC in early studies, neoadjuvant therapy allows patients the possibility of significant reduction in tumor size, de-escalation of adjuvant therapy, and improved long-term outcomes. Patients must be carefully selected to ensure that there is a margin of safety with respect to resectability, such that if a tumor progresses on neoadjuvant therapy, there remains a curative surgical option that is acceptable to the patient. The optimal treatment paradigm is an area of active research, with many researchers questioning whether adjuvant therapy, or even local therapy, is necessary in patients who seem to have a complete response. The ability to predict who will respond will become even more critical to answer, as a significant number of patients do not want to risk their disease progressing, especially in cosmetically sensitive areas of the head and neck. Recent studies in melanoma show promise for improved response rates using combination therapies, and these strategies may apply to cSCC as well. The use of LAG-3 inhibitors or mRNA vaccine technology may further improve the utility of neoadjuvant strategies.

Invasive squamous cell carcinoma within a plaque of circumscribed palmar hypokeratosis.

Circumscribed palmar hypokeratosis (CPH) is a localized disorder of epidermal keratinization that is presented as a well-delimited, depressed, erythematous plaque on the palms or on the soles. It is histopathologically characterized by an abrupt thinning of the corneal epidermal layer. CPH is considered a benign condition, but a few cases with dysplastic changes/carcinoma in situ in the hypokeratotic epidermis have been described. We report hereby a case of invasive squamous cell carcinoma developed within a plaque of CPH. The pathogenesis of the malignant changes in this disorder remains to be clarified. Clinicians should be aware of the potential for developing malignancy in CPH and carry out a closer follow-up of this disorder.

Hydrochlorothiazide Use and Risk of Skin Cancer: A Population-Based Retrospective Cohort Study.

PURPOSE: Hydrochlorothiazide (HCTZ) exposure has been linked to increased skin cancer in Caucasian (white) populations, especially squamous cell carcinoma (SCC), but not basal cell carcinoma (BCC). This study aimed to evaluate and compare skin cancer risks associated with HCTZ- and other antihypertensives use. METHODS: This retrospective cohort study utilized Taiwan's National Health Insurance Research Database. We identified patients aged 20 years and older, newly receiving antihypertensive medications between 2004 and 2015. We calculated the medication possession ratio (MPR) for the first 2 years of treatment to determine patient eligibility and treatment classification, whereby only patients with MPR above 80% were included. These were subsequently categorized by the type of antihypertensives they received, namely HCTZ, other thiazide diuretics, non-thiazide diuretics or non-diuretic antihypertensives. Cox proportional hazards model was used to evaluate skin cancer risks, and these were then classified as SCC or BCC. RESULTS: Our study included 41 086, 27 402, 19 613, and 856 782 patients receiving HCTZ, other thiazide diuretics, non-thiazide diuretics, and non-diuretic antihypertensives, respectively. We found BCC risks were similar when comparing HCTZ with other thiazides (adjusted hazard ratio: 0.84; 95% CI: 0.54-1.33), non-thiazide diuretics (0.93; 0.51-1.67), and non-diuretic antihypertensives (0.91; 0.66-1.26). We observed a higher SCC risk in the HCTZ group, compared to other thiazides (1.24; 0.74-2.08), non-thiazide diuretics (1.32; 0.70-2.51), and non-diuretic antihypertensives (1.23; 0.87-1.73), although the confidence intervals (CIs) were wide and crossed the null. CONCLUSIONS: We concluded that skin cancer need not be of major concern to physicians when prescribing antihypertensives for an Asian population.

Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer: An Interrupted Time-Series Analysis Using Swiss Claims Data.

PURPOSE: Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. METHODS: We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015-2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. RESULTS: ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300-400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. CONCLUSION: Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.

Clinician's Ability to Identify Non-Melanoma Skin Cancer on 3D-Total Body Photography Sectors that Were Initially Identified during In-Person Skin Examination with Dermoscopy.

INTRODUCTION: Non-melanoma skin cancer (NMSC) is a cause of significant morbidity and mortality in high-risk individuals. Total body photography (TBP) is currently used to monitor melanocytic lesions in patients with high risk for melanoma. The authors examined if three-dimensional (3D)-TBP could be useful for diagnosis of NMSC. METHODS: Patients (n = 129; 52 female, 77 male) with lesions suspicious for NMSC who had not yet had a biopsy underwent clinical examination followed by examination of each lesion with 3D-TBP Vectra®WB360 (Canfield Scientific, Parsippany, NJ, USA) and dermoscopy. RESULTS: The 129 patients had a total of 182 lesions. Histological examination was performed for 158 lesions; the diagnoses included basal cell carcinoma (BCC; n = 107), squamous cell carcinoma (SCC; n = 27), in-situ SCC (n = 15). Lesions were located in the head/neck region (n = 138), trunk (n = 21), and limbs (n = 23). Of the 182 lesions examined, 12 were not visible on 3D-TBP; reasons for not being visible included location under hair and on septal of nose. Two lesions appeared only as erythema in 3D-TBP but were clearly identifiable on conventional photographs. Sensitivity of 3D-TBP was lower than that of dermoscopy for BCC (73% vs. 79%, p = 0.327), higher for SCC (81% vs. 74%, p = 0.727), and lower for in-situ SCC (0% vs. 33%, p = 125). Specificity of 3D-TBP was lower than that of dermoscopy for BCC (77% vs. 82%, 0.581), lower for SCC (75% vs. 84%, p = 0.063), and higher for in-situ SCC (97% vs. 94%, p = 0.344). Diagnostic accuracy of 3D-TBP was lower than that of dermoscopy for BCC (75% vs. 80%), lower for SCC (76% vs. 82%), and lower for in-situ SCC (88% vs. 89%). Lesion location was not associated with diagnostic confidence in dermoscopy (p = 0.152) or 3D-TBP (p = 0.353). If only lesions with high confidence were included in the calculation, diagnostic accuracy increased for BCC (n = 27; sensitivity 85%, specificity 85%, diagnostic accuracy 85%), SCC (n = 10; sensitivity 90%, specificity 80%, diagnostic accuracy 83%), and for in-situ SCC (n = 2; sensitivity 0%, specificity 100%, diagnostic accuracy 95%). CONCLUSION: Diagnostic accuracy appears to be slightly lower for 3D-TBP in comparison to dermoscopy. However, there is no statistically significant difference in the sensitivity and specificity of 3D-TBP and dermoscopy for NMSC. Diagnostic accuracy increases, if only lesions with high confidence are included in the calculation. Further studies are necessary to determine if 3D-TBP can improve management of NMSC.

High Risk of Non-Melanoma Skin Cancer in Actinic Keratosis Patients with Skin of Color: A Nationwide Register-Based Cohort Study.

INTRODUCTION: Actinic keratoses (AKs) are rough, scaly patches from UV exposure, increasing the risk of non-melanoma skin cancer (NMSC). This study examines AK incidence in Korea and its role as a risk factor for NMSC. METHODS: A retrospective nationwide register-based cohort study analyzed 2,917 AK patients and 14,585 controls from 2002 to 2019. Patients diagnosed with AK were followed until NMSC occurrence, death, emigration, or December 2019. RESULTS: AK incidence reached 44.8 per 100,000 person-years in 2019. The adjusted hazard ratio for NMSC in AK patients was 8.91 (95% confidence interval, 5.72-13.90). Higher NMSC risk was observed in female AK patients, those under 60 years, and those with lower income levels. The 16-year cumulative incidence of NMSC was 4.19% in AK patients versus 0.44% in controls. CONCLUSION: AK significantly increases the risk of NMSC in Koreans, highlighting the need for tailored surveillance and treatment strategies.

The causal relationships of granulocytes and melanoma skin cancer: A univariable and multivariable Mendelian randomization study.

BACKGROUND: Increasing evidence has revealed that granulocyte has a critical role in tumorigenesis and progression. In this study, Mendelian randomization (MR) analysis was utilized for estimating the causal association between neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer, basophil percentage and melanoma skin cancer, respectively. METHODS: The Genome-Wide Association Study (GWAS) ids for melanoma skin cancer, neutrophil percentage, eosinophil percentage and basophil percentage were derived from Integrative Epidemiology Unit (IEU) Open GWAS database. The univariable MR (UVMR) analysis was conducted to estimate the risk using MR-Egger, weighted median, inverse variance weighted (IVW). In addition, sensitivity analysis was conducted to assess the reliability of UVMR results. Finally, the multivariable MR (MVMR) analysis was performed to investigate causality between neutrophil percentage and eosinophil percentage in the presence of both and melanoma skin cancer. RESULTS: The UVMR indicated that neutrophil percentage and eosinophil percentage were significantly and causally related to melanoma skin cancer, with neutrophil percentage [p = 0.025, odds ratio (OR) = 1.002] as a risk factor and eosinophil percentage (p = 7.04E-06, OR = 0.997) as a protective factor. Moreover, MVMR analysis indicated eosinophil percentage remained the protective factor (p = 0.003, OR = 0.998), while the causality of neutrophil percentage and melanoma skin cancer became insignificant (p > 0.05). CONCLUSION: The causal relationships of neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer were shown by this study, which provided a reference for subsequent research and treatment related to melanoma skin cancer.

Transmission of Genetic Material and Malignant Cells of Cutaneous Origin via Surgical Sutures.

BACKGROUND: Seeding of skin cancer cells following diagnostic or therapeutic surgical procedures can occur and might cause local recurrences. As current preferred therapy for skin malignancy is surgical excision, seeding of tumour cells by manipulating malignant tissue or suturing can be another factor leading to recurrences. OBJECTIVE: To evaluate whether genetic material and malignant cells adhere to standard suture materials. METHODS: This prospective study included patients who underwent excision of skin lesions. Monofilament and braided sutures were examined. Sutures were passed through the observed tumour or healthy skin margins and were examined for DNA material and cells by cytological analysis, cell culture and characterization, and DNA analysis. RESULTS: Twenty-two patients and 148 sutures were included. DNA quantification showed DNA material on all sutures, with no significant difference between braided and monofilament sutures. Cytological analysis showed that all slides prepared from cell blocks contained normal squamous and atypical cells. Cell culture and characterization showed viable cells adhering to the sutures under direct light microscopy. Cell cultures showed rapid proliferation of epithelial cells from squamous cell carcinoma specimens. CONCLUSION: Suture materials carry DNA material and cells, including malignant cells of cutaneous origin and may seed them at distant sites.

Mohs micrographic technique in high-risk basal cell carcinoma: a 3D prediction of safety margins.

OBJECTIVE: Compared with standard excision with a two-dimensional histological examination, Mohs micrographic surgery offers a lower recurrence rate and a greater extent of healthy tissue sparing for the treatment of high-risk basal cell carcinoma (BCC). The aims of this study were to first quantify the healthy tissue spared through the micrographic technique compared to traditional surgery for high-risk tumours. Then, to speculate, through the analysis of the distal micrographic resection margin, the adequate width of safety margins for standard excision. METHOD: A cohort of patients with high-risk BCC was treated with Mohs surgery. Safety margins, tumours residual final breach and hypothetical standard excision safety margins areas were recorded. RESULTS: A total of 96 patients were included. A reduction of 27.96% (95% Confidence Interval (CI): 17.90-38.02) of healthy skin removed was observed using a micrographic method compared to the standard approach. Standard excision with a 6mm safety margin was associated with 86.46% (95% CI: 79.62-93.30) of complete excision. Greater margins were not associated with a statistically significant improvement of complete excision. CONCLUSION: Mohs surgery should be considered the gold standard operative treatment for high-risk BCC. However, if micrographic techniques are not feasible, the standard excision with a predetermined margin of 6 mm, should be considered as the best option.

The Anticancer Activities of Natural Terpenoids That Inhibit Both Melanoma and Non-Melanoma Skin Cancers.

The prevalence of two major types of skin cancer, melanoma and non-melanoma skin cancer, has been increasing worldwide. Skin cancer incidence is estimated to rise continuously over the next 20 years due to ozone depletion and an increased life expectancy. Chemotherapeutic agents could affect healthy cells, and thus may be toxic to them and cause numerous side effects or drug resistance. Phytochemicals that are naturally occurring in fruits, plants, and herbs are known to possess various bioactive properties, including anticancer properties. Although the effects of phytochemicals are relatively milder than chemotherapeutic agents, the long-term intake of phytochemicals may be effective and safe in preventing tumor development in humans. Diverse phytochemicals have shown anti-tumorigenic activities for either melanoma or non-melanoma skin cancer. In this review, we focused on summarizing recent research findings of the natural and dietary terpenoids (eucalyptol, eugenol, geraniol, linalool, and ursolic acid) that have anticancer activities for both melanoma and non-melanoma skin cancers. These terpenoids may be helpful to protect skin collectively to prevent tumorigenesis of both melanoma and nonmelanoma skin cancers.

Micro RNA Dysregulation in Keratinocyte Carcinomas: Clinical Evidence, Functional Impact, and Future Directions.

The keratinocyte carcinomas, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC), are the most common cancers in humans. Recently, an increasing body of literature has investigated the role of miRNAs in keratinocyte carcinoma pathogenesis, progression and their use as therapeutic agents and targets, or biomarkers. However, there is very little consistency in the literature regarding the identity of and/or role of individual miRNAs in cSCC (and to a lesser extent BCC) biology. miRNA analyses that combine clinical evidence with experimental elucidation of targets and functional impact provide far more compelling evidence than studies purely based on clinical findings or bioinformatic analyses. In this study, we review the clinical evidence associated with miRNA dysregulation in KCs, assessing the quality of validation evidence provided, identify gaps, and provide recommendations for future studies based on relevant studies that investigated miRNA levels in human cSCC and BCC. Furthermore, we demonstrate how miRNAs contribute to the regulation of a diverse network of cellular functions, and that large-scale changes in tumor cell biology can be attributed to miRNA dysregulation. We highlight the need for further studies investigating the role of miRNAs as communicators between different cell types in the tumor microenvironment. Finally, we explore the clinical benefits of miRNAs as biomarkers of keratinocyte carcinoma prognosis and treatment.

Extracellular Vesicles as Novel Diagnostic and Therapeutic Agents for Non-Melanoma Skin Cancer: A Systematic Review.

Standard non-melanoma skin cancer (NMSC) treatment involves surgery, recently combined with chemotherapy or immunotherapy in cases of advanced tumors. EVs, including exosomes, are integral to carcinogenesis, and are found in NMSC releasing mediators impacting tumor progression. Nevertheless, the precise intercellular signaling role of NMSC-derived EVs remains unclear. This review aims to elucidate their potential role in NMSC diagnosis and treatment. This systematic review encompassed literature searches in electronic databases from inception to September 2023, based on certain inclusion and exclusion criteria, addressing NMSC-derived EVs, their molecular cargo, and their implications in the diagnosis, prognosis, and treatment of NMSC. Key components were identified. Extracellular vesicle (EV) proteins and RNA have emerged as diagnostic biomarkers in EV-based liquid biopsy. Circular RNA CYP24A1, known for its molecular stability, holds promise as a diagnostic biomarker. Long noncoding RNAs (lincRNA-PICSAR) and Desmoglein 2 (DSg2) are linked to drug resistance, serving as prognostic biomarkers. EV mediators are being actively investigated for their potential role as drug delivery agents. In conclusion, this systematic review showed that NMSC-derived EVs display promise as therapeutic targets and diagnostic biomarkers. Further research is imperative to fully comprehend EV mechanisms and explore their potential in cancer diagnosis and treatment.

Evidence of Neutrophils and Neutrophil Extracellular Traps in Human NMSC with Regard to Clinical Risk Factors, Ulceration and CD8+ T Cell Infiltrate.

Non-melanoma skin cancers (NMSC), including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), are increasingly common and present significant healthcare challenges. Neutrophil extracellular traps (NETs), chromatin fibers expulsed by neutrophil granulocytes, can promote immunotherapy resistance via an impairment of CD8+ T cell-mediated cytotoxicity. Here, to identify a potential therapeutic target, we investigate the expulsion of NETs and their relation to CD8+ T cell infiltration in NMSC. Immunofluorescence staining for neutrophils (CD15) and NETs (H3cit), as well as immunohistochemistry for cytotoxic T cells (CD8+) on human cSCCs (n = 24), BCCs (n = 17) and MCCs (n = 12), revealed a correlation between neutrophil infiltration and ulceration diameter in BCC and MCC, but not in cSCC. In BCC and cSCC, neutrophil infiltration also correlated with the cross-sectional area (CSA). NETs were not associated with established risk factors but with the presence of an ulceration, and, in cSCC, with abscess-like structures. CD8+ T cell infiltration was not reduced in tumors that were NET-positive nor in those with a denser neutrophil infiltration. This study is the first to report and characterize NETs in NMSC. Thus, it gives an incentive for further research in this relevant yet understudied topic.

Therapeutic Approaches for Non-Melanoma Skin Cancer: Standard of Care and Emerging Modalities.

Skin cancer encompasses a range of cutaneous malignancies, with non-melanoma skin cancers (NMSCs) being the most common neoplasm worldwide. Skin exposure is the leading risk factor for initiating NMSC. Ultraviolet (UV) light induces various genomic aberrations in both tumor-promoting and tumor-suppressing genes in epidermal cells. In conjunction with interactions with a changed stromal microenvironment and local immune suppression, these aberrations contribute to the occurrence and expansion of cancerous lesions. Surgical excision is still the most common treatment for these lesions; however, locally advanced or metastatic disease significantly increases the chances of morbidity or death. In recent years, numerous pharmacological targets were found through extensive research on the pathogenic mechanisms of NMSCs, leading to the development of novel treatments including Hedgehog pathway inhibitors for advanced and metastatic basal cell carcinoma (BCC) and PD-1/PD-L1 inhibitors for locally advanced cutaneous squamous cell carcinoma (cSCC) and Merkel cell carcinoma (MCC). Despite the efficacy of these new drugs, drug resistance and tolerability issues often arise with long-term treatment. Ongoing studies aim to identify alternative strategies with reduced adverse effects and increased tolerability. This review summarizes the current and emerging therapies used to treat NMSC.

Natural Compounds in Non-Melanoma Skin Cancer: Prevention and Treatment.

The elevated occurrence of non-melanoma skin cancer (NMSC) and the adverse effects associated with available treatments adversely impact the quality of life in multiple dimensions. In connection with this, there is a necessity for alternative approaches characterized by increased tolerance and lower side effects. Natural compounds could be employed due to their safety profile and effectiveness for inflammatory and neoplastic skin diseases. These anti-cancer drugs are often derived from natural sources such as marine, zoonotic, and botanical origins. Natural compounds should exhibit anti-carcinogenic actions through various pathways, influencing apoptosis potentiation, cell proliferation inhibition, and metastasis suppression. This review provides an overview of natural compounds used in cancer chemotherapies, chemoprevention, and promotion of skin regeneration, including polyphenolic compounds, flavonoids, vitamins, alkaloids, terpenoids, isothiocyanates, cannabinoids, carotenoids, and ceramides.

Photosensitizing antihypertensive medication and risk of skin cancer among postmenopausal women.

BACKGROUND: Few prospective studies exist with an evaluation of a dose-response relationship between use of some photosensitizing antihypertensive medications and skin cancer. PATIENT AND METHODS: We used prospective data from the Women's Health Initiative Observational Study to investigate the association between antihypertensive use and risk of non-melanoma skin cancer (NMSC) and melanoma in postmenopausal women aged 50-79 years at baseline (n  =  64,918). Multivariable Cox proportional hazards regression models were used and hazard ratios (HRs) and 95 confidence intervals (CIs) were calculated. RESULTS: 8,777 NMSC and 1,227 melanoma cases were observed. Use of antihypertensives (HR [95% CI]: 1.12 [1.07-1.18]), ACE inhibitors (1.09 [1.01-1.18]), calcium channel blockers (1.13 [1.05-1.22]), diuretics (1.20 [1.12-1.27]), loop diuretics (1.17 [1.07-1.28]), and thiazides (1.17 [1.03-1.33]) were each associated with higher NMSC risk. NMSC risk linearly increased with use of multiple antihypertensives (p-trend  =  0.02) and with longer duration of use (p-trend < 0.01). Antihypertensives (1.15 [1.00-1.31]), angiotensin-II receptor blockers (1.82 [1.05-3.15]), and diuretics (1.34 [1.13-1.59]) were each associated with elevated melanoma risk. Effect modification by solar radiation exposure was found between antihypertensive use and incidence of melanoma (p-interaction  =  0.02). CONCLUSIONS: Use of antihypertensives overall, and several individual classes thereof, were associated with higher incidence of NMSC and melanoma with dose-response relationship.

Exploring the impact of TGF-ß family gene mutations and expression on skin wound healing and tissue repair.

Transforming Growth Factor-Beta (TGF-ß) signalling pathway is of paramount importance in the processes of wound healing, epidermal integrity maintenance and development of skin cancer. The objective of this research endeavour was to clarify the impact of gene mutations and variations in expression within TGF-ß family on mechanisms of tissue repair, as well as to identify potential targets for therapeutic purposes in non-melanoma skin cancer (NMSC). The methods utilized in this study involved obtaining RNA-seq data from 224 NMSC patients and paired normal skin tissues from the PRJNA320473 and PRJEB27606 databases. The purpose of the differential gene expression analysis was to identify genes whose expression had changed significantly. In order to evaluate the effects and interrelationships of identified gene variants, structural analysis with AlphaFold and PDB data and network analysis with the STRING database were both utilized. Critical gene expression was externally validated through the utilization of the GEPIA database. Tumour tissues exhibited a notable upregulation of genes associated with the TGF-ß pathway, specifically MMP1, MMP3, MMP9, EGF, COL3A1 and COL1A2, in comparison with normal tissues. As indicated by the central node status of these genes in the network analysis, they play a crucial role in the progression of NMSCs. The results of the structural analysis suggested that mutations might cause functional disruptions. External validation of the upregulation confirmed the expression trends and emphasized the biomarker potential of the upregulated genes. In conclusion, this research offered thorough examination of molecular modifications that occur in TGF-ß family genes, which are linked to cutaneous wound healing and NMSC. The modified expression of the identified hub genes may represent innovative targets for therapeutic intervention.