Background & Aims Over-expression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras-regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. Methods We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1-siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. Results Ras-driven tumors over-express FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1-deleted HCC cells. Moreover, FoxM1-deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS-regulation and survival. Conclusion Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS.

Actinic keratoses (AKs) are atypical, precancerous proliferations of keratinocytes that develop because of chronic exposure to ultraviolet (UV) radiation. Treatment of AK can be lesion-directed or field-directed. Field cancerization theory postulates that the skin surrounding AK is also at increased risk for possible malignant transformation since it has been exposed to the same chronic UV light. Field-directed therapies thus have the potential to address subclinical damage, reduce AK recurrence rates, and potentially reduce the risk of squamous cell carcinoma (SCC) development. Published clinical studies have found lesion clearance rates ranging from 81 to 91% for photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL). Clinical studies have also been published on various topical treatments. Complete clinical clearance (CCC) was significantly higher in patients treated with a combination of 5-fluorouracil and salicylic acid (5-FU-SA) than in the vehicle group across multiple studies, and CCC ranged between 46 and 48% following treatment with imiquimod. Additionally, treatment with diclofenac sodium (DFS) found reduction in lesion sizes to range from 67 to 75%. Reported results have been similar for another non-steroidal anti-inflammatory drug (NSAID), piroxicam, which has more cyclooxygenase (COX)-1 activity than DFS. Active treatments with ingenol mebutate were also significantly more effective than vehicle at clearing AK lesions. All treatments resulted in mild, localized skin reactions. PDT using conventional light sources was associated with increased severity of pain and/or discomfort, while PDT using daylight as the light source was associated with less pain and occasionally no pain at all. Though no widely accepted algorithm for the treatment of AKs exists, field-directed therapy can be particularly useful for treating photo-exposed areas containing multiple AKs. Additional research with more direct comparisons between these field-directed therapies will help clinicians determine the best therapeutic approach. Here, we provide a balanced and comprehensive narrative review of the literature, considering both light-based and topical therapies with a focus on their field-therapy aspects, and propose a therapeutic algorithm for selecting an appropriate treatment in the clinical setting.

Background Moisturizers traditionally function to replenish both the intercellular lipid lamella and natural moisturizing factors, and form a hydrolipid film on the skin surface to decrease transepidermal water loss and improve hydration. As we continue to identify epidermal lipid imbalance in patients with atopic dermatitis, we turn to the use of bioactive ingredients in moisturizers for improving barrier repair and function. Methods This review aims to explore the modern use of moisturizers in targeting various components of the skin barrier, dampening immune response, and restoring microbial balance. We conducted a balanced and comprehensive narrative review of the literature. Studies were identified by searching electronic databases (MEDLINE and PubMed), focusing on studies and trials regarding moisturizers that include endocannabinoids, bioactive lipids, anti‐inflammatory agents, antioxidants, and microbiome modulators. Only articles published in English language were included. Results The aforementioned ingredients exert additional biological effects to improve skin function by upregulating lipid synthesis, decreasing neurosensory transmission of itch signals, reversing oxidative stress, decreasing inflammatory cell activity and cytokine release, and modulating skin microbiota. The shift from traditional moisturizers to those with bioactive ingredients, anti‐inflammatory agents, and microbiome modulating effects opens a realm of possible therapeutic options for patients with barrier‐defective cutaneous conditions. Conclusion Focusing on the disrupted skin barrier as a target for both prevention and treatment and incorporating a combined strategy that utilizes the aforementioned agents to tackle barrier dysfunction from different angles remains a promising area for clinical impact in dermatology.