Clinical and histologic findings after use of a novel combined retinol, tripeptide, and glaucine containing cream in the treatment of photo-aged skin.

BACKGROUND: Neck skin is thinner and has a more delicate dermal layer than facial skin. The studied product was specifically formulated for the neck combining a hydrating delivery system with a trifunctional corrective technology composed of 0.2% pure retinol, 2.5% tripeptide concentrate, and 5.0% glaucine complex to help improvement in signs of aging. OBJECTIVES: To evaluate cosmetic and histologic changes 3 months after treatment using immunostains for Type I collagen, Type III collagen, and glycosaminoglycan (GAGS). In addition, overall clinical improvement in photoaged skin was measured by both Griffith's photonumeric photoaging scale, photographic improvement, and questionnaires. METHODS: This study was an open-label, blinded clinical trial evaluating a combined retinol, tripeptide, and glaucine containing cream in the treatment of photo-aged skin. The study enrolled a total of 20 healthy male or female subjects, who applied the product for 3 months to their face and neck. RESULTS: Clinical as well histologic changes were consistent with improvement in all 20 subjects. CONCLUSION: Use of a combined retinol, tripeptide, and glaucine containing cream led to both clinical and histologic improvement of phototoaging.

Correction: da Costa et al. Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells. Cancers 2020, 12, 395.

The authors wish to make the following corrections to this paper [...].

Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells.

: Lesions with driver mutations, including atypical nevi and seborrheic keratoses, are very common in dermatology, and are prone to senescence. The molecular events that prevent senescent lesions from becoming malignant are not well understood. We have developed a model of vascular proliferation using a temperaturesensitive, large T antigen and oncogenic HRas. By elevating the temperature to 39 °C, we can turn off large T antigen and study the molecular events in cells with the Ras driver mutation. To assess the signaling events associated with the switch from a proliferative to a nonproliferative state in the constant presence of a driver oncogene, SVR cells were cultivated for 24 and 48 hours and compared with SVR cells at 37 °C. Cells were evaluated by Western Blot (WB) gene chip microarray (GC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Upon evaluation, a novel phenotype was observed in endothelial cells after switching off the large T antigen. This phenotype was characterized by Notch activation, downregulation of p38 phosphorylation, downregulation of the master immune switch IRF7, and downregulation of hnRNP A0 . Switching off proliferative signaling may result in immune privilege and Notch activation, which may account, in part, for the survival of common skin lesions.

Propranolol exhibits activity against hemangiomas independent of beta blockade.

Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This has led to the widespread use of propranolol for the treatment of large and life-threatening hemangiomas of infancy. Infants receiving propranolol require monitoring to ensure that they do not suffer from side effects related to beta blockade. The exact mechanism of activity of propranolol in hemangioma of infancy is unknown. In this study, we treated hemangioma stem cells with both beta blockade active S- and inactive R-propranolol and looked for genes that were coordinately regulated by this treatment. Among the genes commonly downregulated, Angiopoietin-like 4 (ANGPTL4) was among the most regulated. We confirmed that propranolol isomers downregulated ANGPTL4 in endothelial cells, with greater downregulation of ANGPTL4 using the beta blockade inactive R-propranolol. ANGPTL4 is present in human hemangiomas of infancy. Finally, R-propranolol inhibited the growth of bEnd.3 hemangioma cells in vivo. The implication of this is that hemangioma growth can be blocked without the side effects of beta blockade. Given that humans have been exposed to racemic propranolol for decades and thus to R-propranolol, clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases is warranted.

Tris DBA palladium is an orally available inhibitor of GNAQ mutant uveal melanoma in vivo.

Uveal melanoma is a rare but often lethal malignancy and is the leading cause of death due to an ophthalmic condition. Uveal melanoma is often diagnosed at a late stage and has a strong propensity to hepatic metastasis. Recently, the most common driver mutations in uveal melanoma have been identified, predominantly in the G-proteins GNAQ. This pattern differs from that of cutaneous melanoma in which Braf and Nras predominate. There are no current clinically used agents that target GNAQ mutations, unlike the use of Braf inhibitors in cutaneous melanoma. We tested the novel agent Tris DBA palladium and found that it was markedly more effective against GNAQ mutant melanomas than wild type uveal melanomas. Given that ARF6 has recently been discovered as a node in GNAQ mutations, we evaluated the efficacy of Tris DBA palladium on ARF6 signaling and found that it was effective in inhibiting ARF6 activation. Finally, Tris DBA palladium was orally effective against GNAQ mutant melanoma in vivo. Tris DBA Palladium deserves further evaluation as a systemic agent for uveal melanoma.

Palladium based nanoparticles for the treatment of advanced melanoma.

IGF1R and CD44 are overexpressed in most advanced melanomas so we designed chemotherapeutic nanoparticles to target those receptors. Tris(dibenzylideneacetone)dipalladium (Tris DBA-Pd) is a novel inhibitor of N-myristoyltransferase 1 (NMT-1) and has proven in vivo activity against melanoma. However, poor solubility impairs its effectiveness. To improve its therapeutic efficacy and overcome drug resistance in advanced melanomas, we synthesized Tris DBA-Pd hyaluronic acid nanoparticles (Tris DBA-Pd HANP) and evaluated them against in vivo xenografts of LM36R, an aggressive BRAF mutant human melanoma resistant to BRAF inhibitors. We treated xenografted mice in four arms: empty HANPs, free Tris DBA-Pd, Tris DBA-Pd HANPs, and Tris DBA-Pd HANPs with IGF1R antibody. The Tris DBA-Pd HANP group was the most responsive to treatment and showed the greatest depletion of CD44-positive cells on IHC. Surprisingly, the HANP containing IGF1R antibody was less effective than particles without antibody, possibly due to steric hindrance of IGF1R and CD44 binding. Tris DBA-Pd nanoparticles are an effective therapy for CD44-positive tumors like melanoma, and further development of these nanoparticles should be pursued.

Selenium unmasks protective iron armor: A possible defense against cutaneous inflammation and cancer.

BACKGROUND: A link between selenium deficiency and inflammatory skin diseases have been noted by many, but this link is still not well understood. We have previously studied the efficacy of ceramide analogs, based on the fire ant venom Solenopsin A, against our psoriasis animal model. Treatment of animals with solenopsin analogs resulted in significantly improved skin as well as in a coordinate downregulation of selenoproteins, namely Glutathione Peroxidase 4 (GPX4). We thus hypothesize that ferroptosis may be a physiologic process that may protect the skin from both inflammatory and neoplastic processes. METHODS: We analyze and compare gene expression profiles in the GEO database from clinical skin samples taken from healthy patients and psoriasis patients (both involved and noninvolved skin lesions). We validated the gene expression results against a second, independent, cohort from the GEO database. RESULTS: Significant reduction in gene expression of GPX4, elevated expression of Nrf2 downstream targets, and expression profiles mirroring erastin-inhibition of Cystine/Glutamate Antiporter-System XC activity in psoriatic skin lesions, compared to both noninvolved skin and healthy patient samples, suggest an innately inducible mechanism of ferroptosis. CONCLUSIONS: We present data that may indicate selenoproteins, particularly GPX4, in resolving inflammation and skin cancer, including the novel hypothesis that the human organism may downregulate GPX4 and reactive oxygen (REDOX) regulating proteins in the skin as a way of resolving psoriasis and nonmelanoma skin cancer through increased reactive oxygen species. Further studies are needed to investigate ferroptosis as a possible physiologic mechanism for eliminating inflammatory and malignant tissues. GENERAL SIGNIFICANCE: This study provides a fresh framework for understanding the seemingly contradictory effects of selenium supplementation. In addition, it offers a novel explanation of how physiologic upregulation of ferroptosis and downregulation of selenoprotein synthesis may mediate resolution of inflammation and carcinogenesis. This is of therapeutic significance.

Regression of diffuse B-cell lymphoma of the leg with intralesional gentian violet.

In this case report, a patient of primary cutaneous diffuse B-cell lymphoma, leg type was treated with intralesional gentian violet as she was judged to be too medically fragile for conventional chemotherapy due to advanced age and multiple serious comorbidities. Gentian violet (crystal violet/hexamethyl pararosaniline) is a triphenylmethane dye. It has been shown to have an inhibitory effect on NADPH oxidase, an enzyme family which is found in abundance in reactive oxygen-driven tumors such as melanoma and lymphoma. We hypothesize that intralesional gentian violet treatment caused signalling changes in the lymphoma which allowed for immune clearance of the lymphoma. Complete resolution of the patient's lesion was noted on a follow-up visit.

Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis.

Psoriasis is a chronic inflammatory skin disease affecting 2.5-6 million patients in the United States. The cause of psoriasis remains unknown. Previous human and animal studies suggest that patients with a susceptible genetic background and some stimulus, such as barrier disruption, leads to a coordinated signaling events involving cytokines between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells. Ceramides are endogenous skin lipids essential for maintaining skin barrier function and loss of ceramides may underlie inflammatory and premalignant skin. Ceramides act as a double-edged sword, promoting normal skin homeostasis in the native state, but can be metabolized to sphingosine-1-phosphate (S1P), linked to inflammation and tumorigenesis. To overcome this difficulty, we synthesized solenopsin analogs which biochemically act as ceramides, but cannot be metabolized to S1P. We assess their in vivo bioactivity in a well-established mouse model of psoriasis, the KC-Tie2 mouse. Topical solenopsin derivatives normalized cutaneous hyperplasia in this model, decreased T cell infiltration, interleukin (IL)-22 transcription, and reversed the upregulation of calprotectin and Toll-like receptor (TLR) 4 in inflamed skin. Finally, they stimulated interleukin (IL)-12 production in skin dendritic cells. Thus suggesting barrier restoration has both a biochemical and physical component, and both are necessary for optimal barrier restoration.