Mast cells and wound healing: Still an open question.

Mast cells, which originate from the bone marrow, possess the ability to secrete a diverse array of active molecules. These molecules include mediators (histamine, heparin), which have been identified for decades and are stored in specific granules, as well as small molecules generated instantaneously in response to stimulation (membrane lipid derivatives, nitric oxide), and a multitude of multifunctional cytokines that are secreted constitutively. Activated mast cells participate in the regulation of the local immune response and exert control over critical events of inflammation and healing with the assistance of a vast array of mediators. The involvement of these cell types in inflammatory states suggests that mast cells may function as sentinels that activate local immune processes in response to various types of stimuli and the entry of antigens. Moreover, due to their proximity to nerve fibers and reactivity to a variety of neurotransmitters, mast cells are among the cells that may facilitate local neuroimmune interactions. With this in mind, it is necessary to consider their participation in the repair of injuries in both acute and chronic conditions.

Unlocking the Power of Light on the Skin: A Comprehensive Review on Photobiomodulation.

Photobiomodulation (PBM) is a procedure that uses light to modulate cellular functions and biological processes. Over the past decades, PBM has gained considerable attention for its potential in various medical applications due to its non-invasive nature and minimal side effects. We conducted a narrative review including articles about photobiomodulation, LED light therapy or low-level laser therapy and their applications on dermatology published over the last 6 years, encompassing research studies, clinical trials, and technological developments. This review highlights the mechanisms of action underlying PBM, including the interaction with cellular chromophores and the activation of intracellular signaling pathways. The evidence from clinical trials and experimental studies to evaluate the efficacy of PBM in clinical practice is summarized with a special emphasis on dermatology. Furthermore, advancements in PBM technology, such as novel light sources and treatment protocols, are discussed in the context of optimizing therapeutic outcomes and improving patient care. This narrative review underscores the promising role of PBM as a non-invasive therapeutic approach with broad clinical applicability. Despite the need for further research to develop standard protocols, PBM holds great potential for addressing a wide range of medical conditions and enhancing patient outcomes in modern healthcare practice.

Clinical and Real-World Effectiveness of Mogamulizumab: A Narrative Review.

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid.

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.

Treatment Strategies in Neutrophilic Dermatoses: A Comprehensive Review.

Neutrophilic dermatoses (NDs) are a group of noninfectious disorders characterized by the presence of a sterile neutrophilic infiltrate without vasculitis histopathology. Their physiopathology is not fully understood. The association between neutrophilic dermatoses and autoinflammatory diseases has led some authors to propose that both are part of the same spectrum of diseases. The classification of NDs depends on clinical and histopathological features. This review focuses on the recent developments of treatments in these pathologies.

Cellular and Molecular Processes in Wound Healing.

This review summarizes the recent knowledge of the cellular and molecular processes that occur during wound healing. However, these biological mechanisms have yet to be defined in detail; this is demonstrated by the fact that alterations of events to pathological states, such as keloids, consisting of the excessive formation of scars, have consequences yet to be defined in detail. Attention is also dedicated to new therapies proposed for these kinds of pathologies. Awareness of these scientific problems is important for experts of various disciplines who are confronted with these kinds of presentations daily.

Anti-Fibrotic Effects of RF Electric Currents.

Hypertrophic scars and keloids are two different manifestations of excessive dermal fibrosis and are caused by an alteration in the normal wound-healing process. Treatment with radiofrequency (RF)-based therapies has proven to be useful in reducing hypertrophic scars. In this study, the effect of one of these radiofrequency therapies, Capacitive Resistive Electrical Transfer Therapy (CRET) on biomarkers of skin fibrosis was investigated. For this, in cultures of human myofibroblasts treated with CRET therapy or sham-treated, proliferation (XTT Assay), apoptosis (TUNEL Assay), and cell migration (Wound Closure Assay) were analyzed. Furthermore, in these cultures the expression and/or localization of extracellular matrix proteins such as α-SMA, Col I, Col III (immunofluorescence), metalloproteinases MMP1 and MMP9, MAP kinase ERK1/2, and the transcription factor NFκB were also investigated (immunoblot). The results have revealed that CRET decreases the expression of extracellular matrix proteins, modifies the expression of the metalloproteinase MMP9, and reduces the activation of NFκB with respect to controls, suggesting that this therapy could be useful for the treatment of fibrotic pathologies.

The Role of Physical Therapies in Wound Healing and Assisted Scarring.

Wound healing (WH) is a complex multistep process in which a failure could lead to a chronic wound (CW). CW is a major health problem and includes leg venous ulcers, diabetic foot ulcers, and pressure ulcers. CW is difficult to treat and affects vulnerable and pluripathological patients. On the other hand, excessive scarring leads to keloids and hypertrophic scars causing disfiguration and sometimes itchiness and pain. Treatment of WH includes the cleaning and careful handling of injured tissue, early treatment and prevention of infection, and promotion of healing. Treatment of underlying conditions and the use of special dressings promote healing. The patient at risk and risk areas should avoid injury as much as possible. This review aims to summarize the role of physical therapies as complementary treatments in WH and scarring. The article proposes a translational view, opening the opportunity to develop these therapies in an optimal way in clinical management, as many of them are emerging. The role of laser, photobiomodulation, photodynamic therapy, electrical stimulation, ultrasound therapy, and others are highlighted in a practical and comprehensive approach.

Methyl Aminolaevulinic Acid versus Aminolaevulinic Acid Photodynamic Therapy of Actinic Keratosis with Low Doses of Red-Light LED Illumination: Results of Long-Term Follow-Up.

Photodynamic therapy (PDT) treatment for multiple actinic keratosis (AK) has been found effective when lower doses of red light were used with methyl aminolaevulinic acid (MAL). The aim of this study was to compare the results of lower doses of red light conventional PDT (h-PDT, 16 J/cm2) with MAL and aminolaevulinic acid (ALA) in a long-term follow-up. Patients with more than five symmetrical AK on the scalp who were candidates for PDT were selected and divided randomly between MAL and ALA treatment and patients were followed at 3 and 12 months. The responses were assessed by counting the total AK and the AK per patient. Pain and adverse events were also compiled. A total of 46 patients were treated, 24 with MAL, and 22 with ALA. The two groups were comparable at baseline (p > 0.005). No significant differences were found in the results of both treatments at 12 months, despite ALA exhibiting slightly better results at 3 months. No differences in pain and adverse events were assessed. Both ALA and MAL were effective when lower doses of red light were used in c-PDT. Long term efficacy was also documented. Further studies are necessary to determine the inferior point of red-light illumination without losing efficacy.

Pure Bullous Pyoderma Gangrenosum, a Challenging Clinico-Pathological Diagnosis: Critical Literature Review with Emphasis on Diagnostic Criteria.

Pyoderma gangrenosum (PG) is an uncommon, idiopathic, neutrophilic dermatosis characterised by large necrotic ulcers. Occasionally, patients develop atypical presentations, including pustular, bullous, and vegetative lesions. Bullous pyoderma gangrenosum (BPG) is considered an extremely rare form. We describe a case of BPG in a 76-year-old man, with active oncological history, including a recent diagnosis of hairy cell leukemia. Diagnosis of PG was delayed because of atypical clinical presentation that mimicked necrotising fasciitis. The patient was treated with diverse intravenous antibiotics and several surgical procedures. The suspicion of neutrophilic dermatosis arose from the histopathological studies. In the setting of mandatory clinico-pathological correlation, the aim of this report is to point out the morphological characteristics that allow recognition of this uncommon variant of pyoderma gangrenosum.

TGFß1 Secreted by Cancer-Associated Fibroblasts as an Inductor of Resistance to Photodynamic Therapy in Squamous Cell Carcinoma Cells.

As an important component of tumor microenvironment, cancer-associated fibroblasts (CAFs) have lately gained prominence owing to their crucial role in the resistance to therapies. Photodynamic therapy (PDT) stands out as a successful therapeutic strategy to treat cutaneous squamous cell carcinoma. In this study, we demonstrate that the transforming growth factor ß1 (TGFß1) cytokine secreted by CAFs isolated from patients with SCC can drive resistance to PDT in epithelial SCC cells. To this end, CAFs obtained from patients with in situ cSCC were firstly characterized based on the expression levels of paramount markers as well as the levels of TGFß1 secreted to the extracellular environment. On a step forward, two established human cSCC cell lines (A431 and SCC13) were pre-treated with conditioned medium obtained from the selected CAF cultures. The CAF-derived conditioned medium effectively induced resistance to PDT in A431 cells through a reduction in the cell proliferation rate. This resistance effect was recapitulated by treating with recombinant TGFß1 and abolished by using the SB525334 TGFß1 receptor inhibitor, providing robust evidence of the role of TGFß1 secreted by CAFs in the development of resistance to PDT in this cell line. Conversely, higher levels of recombinant TGFß1 were needed to reduce cell proliferation in SCC13 cells, and no induction of resistance to PDT was observed in this cell line in response to CAF-derived conditioned medium. Interestingly, we probed that the comparatively higher intrinsic resistance to PDT of SCC13 cells was mediated by the elevated levels of TGFß1 secreted by this cell line. Our results point at this feature as a promising biomarker to predict both the suitability of PDT and the chances to optimize the treatment by targeting CAF-derived TGFß1 in the road to a more personalized treatment of particular cSCC tumors.

Cytoplasmic Increase in Hsp70 Protein: A Potential New Biomarker of Early Infiltration of Cutaneous Squamous Cell Carcinoma Arising from Actinic Keratosis.

BACKGROUND: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non-melanoma skin cancer and is the second leading cause of death by skin cancer in Caucasian populations. However, at present it is difficult to predict patients with poor SCC prognosis. OBJECTIVE: To identify proteins with expression levels that could predict SCC infiltration in SCC arising from actinic keratosis (SCC-AK). METHODS: A total of 20 biopsies from 20 different patients were studied; 10 were SCC-AK samples and 10 were taken from normal skin. Early infiltrated SCC-AK samples were selected based on histological examination, and to determine the expression of proteins, fresh skin samples were processed by two-dimensional electrophoresis. RESULTS: The expression levels of three proteins, namely alpha hemoglobin and heat shock proteins 27 and 70 (Hsp27 and Hsp70, respectively) were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immunohistological examination suggested that increased expression of Hsp70 proteins seemed to mainly occur in the cytoplasm of keratinocytes. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western blot experiments. CONCLUSION: Cytoplasmic expression of Hsp70 could be a potential biomarker of early infiltration of SCC arising from AK.