Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPARγ-deficient mice (Pparg-/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-/-epi and publicly available human and/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity, while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPARδ has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.

Non-melanoma skin cancer (NMSC) is the most -common skin cancer in Spain, yet national data on its incidence trends are limited. To analyse the trends in NMSC incidence in Spain from 1990 to 2019, examining variations by sex, age, period, and birth cohort. Data on NMSC incidence was sourced from the Global Health Data Exchange. Age-standardized incidence rates (ASIRs) were calculated using the direct method. Trends and average annual percentage changes were identified using Joinpoint regression analysis. Age-period-cohort analysis was applied to assess age-specific, period-specific, and cohort-specific relative risks. From 1990 to 2019, Spain reported 2,302,399 NMSC cases. ASIRs significantly declined post-2005, with men exhibiting slightly higher rates than women. Joinpoint analysis revealed distinct trends between genders, with men experiencing an initial rise followed by a decline, while women exhibited periods of increase interspersed with decline. APC analysis showed a net decrease in age-adjusted NMSC rates for both sexes. Local drift analysis showed a downward trend in most age groups, indicating a broad decrease at the population level. However, no decrease was observed in young men (20-24 years). Both sexes showed an increased risk of NMSC between 1990 and 2002, followed by a decrease. In particular, those born at the beginning of the 21st century showed a significant decrease in NMSC risk compared with earlier cohorts, suggesting a possible cohort effect. A comprehensive analysis of NMSC trends in Spain highlights the need for ongoing research and interventions to address the evolving burden.

The exact incidence of cutaneous squamous cell carcinoma (CSCC) or nonmelanoma skin cancer is unknown, and it is believed that the rate of occurrence is increasing with the growing elderly population and sun exposure, and it is more prevalent in males than in females. In this article, we describe the case of an 81-year-old woman who presented with a lesion on the right upper eyebrow. The patient had been consulting a dermatologist and undergoing treatment for three months. However, the lesion did not show any signs of improvement, and the dermatologist speculated that it might be a common wound that was healing slowly because of her diabetes. Imaging revealed an ulcerating skin lesion on the right upper eyebrow without connection to the deeper structures. Surgical intervention was chosen with the patient\'s consent. This rare case of CSCC on a woman\'s eyebrow showed that skin cancer can occur in unusual locations and in people without risk factors.

BACKGROUND: Residual tumor is not always clinically apparent following biopsy of cutaneous carcinomas, which may prompt patients to question the need for definitive treatment.
OBJECTIVE: We investigated the percentage of cases in which residual tumor was histologically present at the time of Mohs micrographic surgery (MMS) for basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) and investigated factors associated with residual tumor.
METHODS: We examined 483 MMS cases performed for biopsy-proven BCC (n=287) and SCC (n=196) between October 2022 and April 2023. Single-stage MMS specimens were step-sectioned en face to exhaust the block. Univariate and multivariable logistic regression models were created.
RESULTS: Residual tumor was identified in 83.3% of BCC and 66.8% of SCC at time of MMS (p=0.01). In patients clinically appearing tumor-free following biopsy, residual histologic tumor was identified in 68.2% of BCC and 41.5% of SCC. Residual tumor was significantly more likely in men (p=0.04), high-risk sites (p=0.002), smaller biopsy sizes (p=0.0003), and larger pre-operative sizes (p<0.0001).
CONCLUSIONS: Single center, retrospective cohort CONCLUSION: The majority of patients with BCC and SCC have residual histologic tumor at the time of MMS, oftentimes even when tumor is not clinically apparent. Multiple factors impact the presence/absence of residual tumor.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

UNASSIGNED: Prior research has shown a positive association of pseudoexfoliative glaucoma (PXG) in patients with non-melanoma skin cancer (NMSC), likely due to an increase in ultraviolet exposure associated with both. However, the role of NMSC as a genetic risk factor for PXG has not been examined. Thus, the goal of this study is to utilize Mendelian randomization with genome-wide association studies to evaluate for genetic causality while controlling for environmental confounders.
UNASSIGNED: We conducted a MR using the inverse variance weighted method (MR-IVW) as our primary analysis. Genomic data was sourced from GWASs for patients with NMSC (10,382 cases, 208,410 controls) and PXG (1,515 cases and 210,201 controls), originating from the FinnGen Biobank.
UNASSIGNED: Despite previous association of history of NMSC with occurrence of PXG, we found no evidence for a causal association between SNPs associated with NMSC and risk of PXG following MR analysis (MR-IVW, odds ratio (OR): 0.98, 95% CI: 0.85-1.14, P = 0.87).
UNASSIGNED: Here, we found no evidence for a causal association between SNPs associated with NMSC and the risk of PXG following a MR analysis.

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.

BACKGROUND: Hypertension affects 25-30% of the world population. Hydrochlorothiazide (HCTZ) is among the most used and cheapest medications but was in 2018 labeled with a warning stating increased risk of non-melanoma skin cancer (NMSC). This study describes geographical differences in the association between HCTZ and NMSC in a perspective of hypertensive heart disease (HHD).
METHODS: We conducted a systematic literature search (PubMed, Embase, Clinicaltrial.gov, and Clinicaltrial.eu) using PICO/PECO acronyms including case-control, cohort, and randomized controlled trials. We constructed a rate ratio of disability-adjusted life years (DALY) for HHD/NMSC in global burden of disease (GBD) regions.
RESULTS: No increased risk of NMSC with use of HCTZ was found in Taiwan, India, and Brazil. A small (hazard ratio (HR)/odds ratio (OR) ≤ 1.5) but significantly increased risk was seen in Canada, USA, and Korea. An increased risk (1.5 < HR/OR ≤ 2.5) in Iceland, Spain, and Japan and a highly increased risk (HR/OR > 2.5 in UK, Denmark, Netherlands, and Australia. HHD is associated with a more than 10-fold DALY rate compared with NMSC in 13 of 21 GBD regions corresponding 77.2% of the global population. In none of these 13 regions were there an increased risk of HCTZ-associated NMSC.
CONCLUSIONS: Despite limited information from many countries, our data point to large geographical differences in the association between HCTZ and NMSC. In all GBD regions, except Australasia, HHD constitutes a more than 5-fold DALY rate compared to NMSC. This disproportionate risk should be considered before avoiding HCTZ as part of the antihypertensive treatment.

Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.

Skin cancer is the most common cancer type in the USA, with over five million annually treated cases and one in five Americans predicted to develop the disease by the age of 70. Skin cancer can be classified as melanoma or non-melanoma (NMSC), the latter including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). Development of BCC and SCC is impacted by environmental, behavioral, and genetic risk factors and the incidence is on the rise, with the associated number of deaths surpassing those caused by melanoma, according to recent reports. Substantial morbidity is related to both BCC and SCC, including disfigurement, loss of function, and chronic pain, driving high treatment costs, and representing a heavy financial burden to patients and healthcare systems worldwide. Clinical presentations of BCC and SCC can be diverse, sometimes carrying considerable phenotypic similarities to benign lesions, and underscoring the need for the development of disease-specific biomarkers. Skin biomarker profiling plays an important role in deeper disease understanding, as well as in guiding clinical diagnosis and patient management, prompting the use of both invasive and non-invasive tools to evaluate specific biomarkers. In this work, we review the known and emerging biomarkers of BCC and SCC, with a focus on molecular and histologic biomarkers relevant for aspects of patient management, including prevention/risk assessments, tumor diagnosis, and therapy selection.