MC1R FUNCTIONS, EXPRESSION, AND IMPLICATIONS FOR TARGETED THERAPY

The G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain

Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib

The crosstalk between Notch and MAPK pathway plays a role in MEK inhibitor resistance in BRAFV600E metastatic melanoma (MM) and promotes migration in GNAQQ209L uveal melanoma (UM) cells. We determined the cytotoxicity of combinatorial inhibition of MEK and Notch by cobimetinib and γ-secretase inhibitor (GSI) nirogacestat, in BRAFV600E and BRAF wt MM and GNAQQ209L UM cells displaying different Erk1/2 and Notch activation status, with the aim to elucidate the impact of Notch signaling in the response to MEK inhibitor. Overall the combination was synergic in BRAFV600E MM and GNAQQ209L UM cells and antagonistic in BRAF wt one. Focusing on UM cells, we found that cobimetinib resulted in G0/G1 phase arrest and apoptosis induction, whereas the combination with GSI increased treatment efficacy by inducing a senescent-like state of cells and by blocking migration towards liver cancer cells. Mechanistically, this was reflected in a strong reduction of cyclin D1, in the inactivation of retinoblastoma protein and in the increase of p27KIP1 expression levels. Of note, each drug alone prevented Notch signaling activation resulting in inhibition of c-jun(Ser63) and Hes-1 expression. The combination achieved the strongest inhibition on Notch signaling and on both c-jun(Ser63) and Erk1/2 activation level. In conclusion we unveiled a coordinate action of MAPK and Notch signaling in promoting proliferation of BRAFV600E MM and GNAQQ209L UM cells. Remarkably, the simultaneous inhibition of MEK and Notch signaling highlighted a role for the second pathway in protecting cells against senescence in GNAQQ209L UM cells treated with the MEK inhibitor

Skin above the knees: treatments for a difficult area

INTRODUCTION, OBJECTIVES, PURPOSE OF THE STUDY The interest for non-invasive techniques for skin rejuvenation is increasing. However, lax skin above the knee is often forgotten. As a matter of fact, there were not so many options for its treatment. The aim of our study is to present the application of selected rejuvenation techniques and to define their efficacy and safety. MATERIALS AND METHODS Clinical evaluation of the patient. Classification and selection of the patient and targeted therapies: from calcium hydroxyapatite to microfocused ultrasound. Inclusion criteria: people aged >18 years old; skin laxity. Exclusion criteria: severe diseases and severe skin laxity. Treatment in single or multiple sessions. Controls at T0 + T30 + T90. Measurement and analysis: standard digital photo. Evaluation of results and satisfaction of patients. RESULTS The targeted approach focused on the correction of specific morphologic variations of the skin above the knee, showing a variable grading, is effective and able to satisfy patient expectations. The treatment was well tolerated; we reported only a few adverse events: local reactions (erythema, oedema, swelling). All these effects last few days. CONCLUSIONS The treatment of the skin above the knee is challenging. Our protocols have shown good results in this difficult area and a good tolerability profile. A good selection of patients is mandatory in order to achieve the best result

Improving the aging of the neck: combined treatments

INTRODUCTION, OBJECTIVES, PURPOSE OF THE STUDY The request for less aggressive procedures to treat skin laxity of face and neck is increasing. Only a few approaches are available for aesthetic treatments of the neck. Several factors are known to be involved in aging process: skin laxity and photodamage, fat tissue deposition, variation of muscle tone. MATERIALS AND METHODS Clinical evaluation of the patient. Classification and selection of the patient and targeted therapies: from microbotox, bio-stimulation, high intensity focused ultrasound to traction thread. Inclusion criteria: people aged >18 years old; moderate skin laxity and horizontal wrinkles of the neck. Exclusion criteria: severe diseases; skin laxity showing a high grade of severity and severe fat tissue deposition. Different treatments in multiple sessions. Controls at T0 + T30 + T90. Measurement and analysis: standard digital photo. Evaluation of results and satisfaction of patients. RESULTS The targeted approach focused on the correction of specific expressions of the ageing of the neck, showing a variable grading, is effective. The association of target therapy results to satisfy patient expectations. CONCLUSIONS In the field of aesthetic medicine we have available various techniques such as microbotox, bio-stimulation, high intensity focused ultrasound and traction thread. One treatment does not exclude the others. The combination of the two treatment it is possible to optimize the results. The targeted treatment and an appropriate selection of patients are essential to reach satisfactory results in the treatment of imperfections related to the process of ageing of the neck

Permanent implants for lip augmentation: Results from a retrospective study and presentation of tips and tricks

Introduction: Lip augmentation request is increasing. Nowadays, several techniques to obtain temporary effects are available. On the other hand, permanent results can be reached through lip prosthesis implantation. This procedure represents an innovation in the field of aesthetic medicine and surgery. Material & Methods: A total of 110 women with atrophic or hypoplastic lips were treated with lip implants. The treatment was performed in a single session and controls were scheduled at fixed time intervals. A standard digital photo was used for measurement and analysis. Data concerning patient satisfaction and complications of the technique were collected and analysed. Variations to the original technique were also considered. Results: Patient evaluation revealed that a permanent and natural result without discomfort for the patient and/or the partner was reached with the implantation of silicone prosthesis in the upper and/or lower lip. Swelling, bruising, and malpositions were the most frequent adverse events. A case of severe edema was reported. Practical tricks acquired through experience were analysed to prevent complications. Conclusions: The request of permanent results for lip augmentation allowed the development of silicone prosthesis. Advantages of this prosthesis are: safety, definitive result, and reversibility considering the possibility to remove the implanted prosthesis in case of request

Competitiveness during Dual-Species Biofilm Formation of Fusarium oxysporum and Candida albicans and a Novel Treatment Strategy

During an infection, a single or multispecies biofilm can develop. Infections caused by non-dermatophyte molds, such as Fusarium spp. and yeasts, such as Candida spp., are particularly difficult to treat due to the formation of a mixed biofilm of the two species. Fusarium oxysporum is responsible for approximately 20% of human fusariosis, while Candida albicans is responsible for superficial mucosal and dermal infections and for disseminated bloodstream infections with a mortality rate above 40%. This study aims to investigate the interactions between C. albicans and F. oxysporum dual-species biofilm, considering variable formation conditions. Further, the ability of the WMR peptide, a modified version of myxinidin, to eradicate the mixed biofilm when used alone or in combination with fluconazole (FLC) was tested, and the efficacy of the combination of WMR and FLC at low doses was assessed, as well as its effect on the expression of some biofilm-related adhesin and hyphal regulatory genes. Finally, in order to confirm our findings in vivo and explore the synergistic effect of the two drugs, we utilized the Galleria mellonella infection model. We concluded that C. albicans negatively affects F. oxysporum growth in mixed biofilms. Combinatorial treatment by WMR and FLC significantly reduced the biomass and viability of both species in mature mixed biofilms, and these effects coincided with the reduced expression of biofilm-related genes in both fungi. Our results were confirmed in vivo since the synergistic antifungal activity of WMR and FLC increased the survival of infected larvae and reduced tissue invasion. These findings highlight the importance of drug combinations as an alternative treatment for C. albicans and F. oxysporum mixed biofilms

Practical Clues to recognize Melanoma incognito

Introduction & Objectives: To avoid missing melanoma, the current practice is to biopsy all lesions that are suspicious based on clinical and dermoscopic ground. Although most cases of melanoma exhibit clinical clues leading to the correct diagnosis, melanoma can mimic benign melanocytic and non-melanocytic lesions. Confocal microscopy has been shown to increase the diagnostic accuracy for melanoma diagnosis, but little is known about its ability to detect melanoma in the context of lesions that appear dermoscopically benign. Materials & Methods: We present 10 difficult-to-diagnose melanomas, in which additional clues provided by confocal microscopy increased the index of suspicion and prompt us to perform an excisional biopsy. Results: Our cases highlight the following 3 management rules. Confocal microscopy should be used: 1) in newly appearing lesions in high-risk patients; 2) lesions referred by the patient himself as growing lesions even if they are clinically banal 3) Biopsy lesions with unspecific confocal pattern that does not permit to classify the lesion as clear-cut benign. Conclusions: Our case series highlight that melanoma diagnosis is a complex process in which several factors such as patient-related information, clinical history, dermoscopic and confocal features along with “gut” feelings may influence patient’s management. Confocal microscopy in conjunction with dermoscopy can increase the index of suggestion to perform biopsy in difficult-to-diagnose melanomas

Rheological Investigation as Tool to Assess Physicochemical Stability of a Hyaluronic Acid Dermal Filler Cross-Linked with Polyethylene Glycol Diglycidyl Ether and Containing Calcium Hydroxyapatite, Glycine and L-Proline

(1) Background: Dermal fillers are commonly used in aesthetic practice and their rheological characterization is of much interest today, as well as the stability study of the finished formula against external stimuli of a different nature (biological and physicochemical). Rheological tools have been exploited to characterize the physiochemical behaviour of a hyaluronic acid (HA) based dermal filler subjected to different thermal conditions over time. The collected results provide an index of its rheological stability. (2) Methods: After a preliminary Amplitude sweep test, the Frequency sweep test was performed in order to study the stability of a HA dermal filler cross-linked with Polyethylene Glycol Diglycidyl Ether (PEGDE) and containing Calcium Hydroxyapatite (CaHA), Glycine and L-Proline subjected to different conditions. Also, a shear rate ramp test was performed in order to investigate the filler's flow behavior. (3) Results and Conclusions: G' (elastic modulus), G'' (viscous modulus) and consequentially tan delta (tangent of the phase angle) show a similar trend at different thermal conditions, underlining that the product is not affected by the storage conditions. The viscosity of the dermal filler decreases with an increasing shear rate, so a non-Newtonian shear thinning pseudoplastic behavior was demonstrated in all tested conditions

Likelihood of finding melanoma when removing a Spitzoid-looking lesion in patients aged 12 years or older

Dermoscopy improves the recognition of melanoma and Spitz nevus but occasionally melanoma may exhibit a symmetric pattern mimicking Spitz nevus