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Oral squamous cell carcinoma (OSCC), the most frequent of head and neck cancers, has been a topic of great interest to the scientific community [...]

We would like to thank Çınar et al. for their appreciation and insightful discussions presented in their comment [...].

Background: In primary Sjögren’s Syndrome (pSS), cutaneous vasculitis lesions (CVL) are extraglandular manifestations with an important clinical and prognostic impact and their early detection might contribute to the improvement of disease control and even patients’ survival. The aim of this study was to evaluate the predictive potential of hematological elements in the development of CVL in pSS patients. Methods: In this single center, retrospective study, a total of 245 participants were included (124 pSS patients and 121 healthy controls). Complete blood count, inflammatory and immunological parameters were determined at the initial visit. pSS patients underwent a periodical follow-up program, when disease progression and response to therapy was monitored, including the emergence of CVL. Results: In pSS, leucocytes, lymphocyte, neutrophil, monocyte, erythrocyte and platelet counts are significantly decreased compared to healthy subjects (p < 0.001), whereas cellular ratios: NLR, PLR, MLR, and immunological and inflammatory parameters are significantly increased (p < 0.001). A total of 34 patients with pSS (27.41%) developed CVL during the follow-up period. The occurrence of CVL was positively correlated with neutrophil and platelet counts (p < 0.001), while for lymphocytes the correlation was negative (p < 0.001). Cellular ratios: NLR, PLR and MLR, and gammaglobulins also revealed significant positive correlations with the emergence of CVL in pSS (p < 0.001). The multivariate analysis confirmed the independent predictive character for CVL emergence in pSS for NLR (CI95% 0.053–0.2, p < 0.002), PLR (CI95% 0.001–0.003, p < 0.003), MLR (CI95% 0.086–0.935, p < 0.019), and gammaglobulins (CI95% 0.423–0.688, p < 0.001). Conclusions: Standard hematological parameters, widely used in the assessment of pSS patients, such as NLR, PLR, MLR and gammaglobulins could become valid elements that might be used for the early detection of patients at risk for the development of CVL.

Background: The oral squamous cell carcinoma (OSCC) tumor microenvironment (TME) is a complex interweb of cells and mediators balancing carcinogenesis, inflammation, and the immune response. However, cytokines are not only secreted within the TME but also released by a variety of other cells that do not comprise the TME; therefore, a thorough assessment of humoral changes in OSCC should include the measurement of serum cytokines. Methods: We assessed the role of various serum cytokines in the evolution of OSCC, before and after treatment, versus a control group. We measured the serum concentrations of MIP-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, and TNF-α. Results: Significantly higher values (p < 0.01) were noted for IL-1β, IL-6, IL-8, IL-10, and TNF-α in the OSCC group before treatment (n = 13) compared with the control group (n = 14), and the increased concentrations persisted after treatment (n = 11). Furthermore, the variations in the values of MIP-1α, IL-1β, IL-10, and TNF-α are correlated both before and after treatment (p < 0.01). In the pretherapeutic group, IL-6 and IL-8 concentrations also correlate with IL-1β and IL-10 serum levels (p < 0.01), while in the posttherapeutic group, IL-4 varies with MIP-1α and TNF-α (p < 0.01). Conclusion: In OSCC patients, serum cytokine levels are significantly higher compared with control, but they are not significantly altered by treatment, therefore implying that they are also influenced by systemic factors. The interactions between all involved cytokines and the various pathways they regulate warrant further studies to clarify their definitive roles.

Polymeric nanoparticles have been introduced as a delivery vehicle for active compounds in a broad range of medical applications due to their biocompatibility, stability, controlled release of active compounds, and reduced toxicity. The oral route is the most used approach for delivery of biologics to the body. The homeostasis and function of oral cavity tissues are dependent on the activity of stem cells. The present work focuses, for the first time, on the interaction between two types of polymeric nanoparticles, poly (lactic-co-glycolic acid) or PLGA and PLGA/chitosan, and two stem cell populations, oral keratinocyte stem cells (OKSCs) and stem cells from human exfoliated deciduous teeth (SHEDs). The main results show that statistical significance was observed in OKSCs uptake when compared with normal keratinocytes and transit amplifying cells after 24 h of incubation with 5 and 10 µg/mL PLGA/chitosan. The CD117+ SHED subpopulation incorporated more PLGA/chitosan nanoparticles than nonseparated SHED. The uptake for PLGA/chitosan particles was better than for PLGA particles with longer incubation times, yielding better results in both cell types. The present results demonstrate that nanoparticle uptake depends on stem cell type, incubation time, particle concentration, and surface properties.

Antimony has been known and used since ancient times, but its applications have increased significantly during the last two centuries. Aside from its few medical applications, it also has industrial applications, acting as a flame retardant and a catalyst. Geologically, native antimony is rare, and it is mostly found in sulfide ores. The main ore minerals of antimony are antimonite and jamesonite. The extensive mining and use of antimony have led to its introduction into the biosphere, where it can be hazardous, depending on its bioavailability and absorption. Detailed studies exist both from active and abandoned mining sites, and from urban settings, which document the environmental impact of antimony pollution and its impact on human physiology. Despite its evident and pronounced toxicity, it has also been used in some drugs, initially tartar emetics and subsequently antimonials. The latter are used to treat tropical diseases and their therapeutic potential for leishmaniasis means that they will not be soon phased out, despite the fact the antimonial resistance is beginning to be documented. The mechanisms by which antimony is introduced into human cells and subsequently excreted are still the subject of research; their elucidation will enable us to better understand antimony toxicity and, hopefully, to improve the nature and delivery method of antimonial drugs.

Background: Oral squamous cell carcinoma (OSCC) is a common cancer with high morbidity and mortality. Alterations of antitumor immune responses are involved in the development of this malignancy, and investigation of immune changes in the peripheral blood of OSCC patients has aroused the interest of researchers. Methods: In our study, we assessed the proportions of CD3+ total T lymphocytes, CD3+CD4+ helper T lymphocytes, CD3+CD8+ suppressor/cytotoxic T lymphocytes, CD3−CD19+ total B lymphocytes, and CD3−CD16+CD56+ NK cells in the peripheral blood of OSCC patients. Results: The data obtained both pre- and post-therapy showed a similar level of total CD3+ T lymphocytes in OSCC patients and control subjects, pinpointing the stability of this immune parameter. On the other hand, pre-therapeutic data showed a lower proportion of helper T lymphocytes (CD4+), a significantly higher level of cytotoxic/suppressive T lymphocytes (CD8+), and a much lower CD4+ T lymphocyte/CD8+ T lymphocyte ratio compared to control subjects. Conversely, evaluation of circulating NK (CD16+) cells showed a markedly higher pre-therapeutic level compared to the control group. Conclusions: Our results related to immune changes in the peripheral blood add new information to this complex universe of connections between immuno-inflammatory processes and carcinogenesis.

Early diagnosis is essential for completely eradicating skin cancer and maximizing patients’ clinical benefits. Emerging optical imaging modalities such as reflectance confocal microscopy (RCM), optical coherence tomography (OCT), magnetic resonance imaging (MRI), near-infrared (NIR) bioimaging, positron emission tomography (PET), and their combinations provide non-invasive imaging data that may help in the early detection of cutaneous tumors and surgical planning. Hence, they seem appropriate for observing dynamic processes such as blood flow, immune cell activation, and tumor energy metabolism, which may be relevant for disease evolution. This review discusses the latest technological and methodological advances in imaging techniques that may be applied for skin cancer detection and monitoring. In the first instance, we will describe the principle and prospective clinical applications of the most commonly used imaging techniques, highlighting the challenges and opportunities of their implementation in the clinical setting. We will also highlight how imaging techniques may complement the molecular and histological approaches in sharpening the non-invasive skin characterization, laying the ground for more personalized approaches in skin cancer patients.

Flavonoids are a category of plant-derived compounds which exhibit a large number of health-related effects. One of the most well-known and studied flavonoids is kaempferol, which can be found in a wide variety of herbs and plant families. Apart from their anticarcinogenic and anti-inflammatory effects, kaempferol and its associated compounds also exhibit antibacterial, antifungal, and antiprotozoal activities. The development of drugs and treatment schemes based on these compounds is becoming increasingly important in the face of emerging resistance of numerous pathogens as well as complex molecular interactions between various drug therapies. In addition, many of the kaempferol-containing plants are used in traditional systems all over the world for centuries to treat numerous conditions. Due to its variety of sources and associated compounds, some molecular mechanisms of kaempferol antimicrobial activity are well known while others are still under analysis. This paper thoroughly documents the vegetal and food sources of kaempferol as well as the most recent and significant studies regarding its antimicrobial applications.

We would like to thank Çınar et al. for their appreciation and insightful discussions presented in their comment [...]

Chronic obstructive pulmonary disease (COPD) and asthma are chronic respiratory diseases with high prevalence and mortality that significantly alter the quality of life in affected patients. While the cellular and molecular mechanisms engaged in the development and evolution of these two conditions are different, COPD and asthma share a wide array of symptoms and clinical signs that may impede differential diagnosis. However, the distinct signaling pathways regulating cough and airway hyperresponsiveness employ the interaction of different cells, molecules, and receptors. Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a major role in cough and airway inflammation. Consequently, its agonist, capsaicin, is of substantial interest in exploring the cellular effects and regulatory pathways that mediate these respiratory conditions. Increasingly more studies emphasize the use of capsaicin for the inhalation cough challenge, yet the involvement of TRPV1 in cough, bronchoconstriction, and the initiation of inflammation has not been entirely revealed. This review outlines a comparative perspective on the effects of capsaicin and its receptor in the pathophysiology of COPD and asthma, underlying the complex entanglement of molecular signals that bridge the alteration of cellular function with the multitude of clinical effects.

Portal vein thrombosis (PVT) is a frequent complication in cirrhotic patients, but it may also exist as a basic vascular condition even without any liver damage. Local and systemic factors play a significant role in the pathogenesis of PVT; yet, in practice, more than one factor may be identified. PVT can be considered a result of liver fibrosis and hepatic insufficiency. The JAK2 mutation has been accepted as a factor producing PVT. In general, the anticoagulants are recommended but this therapy should be used carefully in treating patients that associate coagulopathy or thrombocytopenia and esophageal varices. Acute PVT without bowel infarction has a good prognosis. In liver cirrhosis, the mortality due to hemorrhage is higher than in chronic PVT. Therefore, for the patients with PVT, the survival rate is decreased by 55% in two years, due to hepatic insufficiency. Regarding the treatment, LMWH (low molecular weight heparine) is the most utilized in patients with cirrhosis, non-malignancies, infections, or those who are awaiting a liver transplant. DOACs (direct-acting oral anticoagulants) may be used in the rest of the medical conditions, being safe and equal to LMWH.

Inflammation is deeply involved in the development of most types of cancer. Many studies focus on the interaction between immune-inflammatory mechanisms and tumorigenesis in the head and neck squamous cell carcinoma (HNSCC). In this chapter, we emphasize the complexity of processes underlying this interaction and discuss the mechanisms of carcinogenesis in HNSCC with a special focus on metabolic changes, inflammation, and the immune landscape. Unveiling complex connections between immuno-inflammatory processes and tumor initiation, promotion, and progression will open new directions in the reliable identification of predictive factors and therapeutic targets in HNSCC.

Inflammation is deeply involved in the development of most types of cancer. Many studies focus on the interaction between immune-inflammatory mechanisms and tumorigenesis in the head and neck squamous cell carcinoma (HNSCC). In this chapter, we emphasize the complexity of processes underlying this interaction and discuss the mechanisms of carcinogenesis in HNSCC with a special focus on metabolic changes, inflammation, and the immune landscape. Unveiling complex connections between immuno-inflammatory processes and tumor initiation, promotion, and progression will open new directions in the reliable identification of predictive factors and therapeutic targets in HNSCC.

Background: During the last two years, the COVID-19 pandemic led to millions of disease-related deaths worldwide. The efforts of the scientific community facing this global challenge resulted in outstanding achievements. Thus, within one year, new mRNA-based vaccines against SARS-CoV-2 viral infection were released, providing highly efficient protection and showing a very good safety profile in the general population. However, clinical data collection after vaccination is a continuous process for the long-term safety of any new medical product. The aim of our paper is to present two cases of hematological malignancies: diffuse large B-cell non-Hodgkin lymphoma and T/NK-cell lymphoma, diagnosed shortly after the administration of the mRNA COVID-19 vaccine. Methods and Results: Case 1: A female patient was admitted with a suspicious cervical mass that emerged within one week after the administration of second dose of the BNT162b2 COVID-19 vaccine. Surgical removal followed by pathology assessment of the specimen confirmed the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. Case 2: A male patient was admitted with multiple ulcerative oral lesions arising on the third day after the initial dose of the BNT162b2 COVID-19 vaccine. These lesions had a progressive character and during the following months were complicated with repetitive episodes of heavy oral bleeding, requiring blood transfusions. The incisional biopsy of the lesions and pathological assessment of the specimens confirmed the diagnosis of T/NK-cell lymphoma. Conclusions: The safety profile of the mRNA-based vaccines is an undeniable fact. In most cases, suspicions of potentially aggressive side effects were ruled out, proving to be transient post-vaccine reactions. Clinicians should remain alert to report any potentially aggressive manifestations emerging in the context of mRNA COVID-19 vaccination, such as these cases of hematological malignancies, in order to promote additional investigations on the particular mechanisms of action of COVID-19 vaccines and to provide the best medical care to the patients.

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.

Non‑melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun‑protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun‑exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well‑known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene‑related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α‑melanocyte‑stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.

Melanoma has a significant mortality and its growing incidence is associated with important social and health care costs. Thus, investigation of the complex mechanisms contributing to emergence and development of melanoma are of real interest both in scientific research and clinical practice. Estrogens play an important role in the emergence and development of certain types of cancer, such as breast cancer, endometrial cancer and ovarian cancer, but their role in development of cutaneous melanoma is still a matter of debate. Various data suggest that increased levels of endogenous estrogens during pregnancy or exposure to exogenous estrogens by use of oral contraceptives (OCs) and hormone replacement therapy (HRT) may have a potential role in melanoma development and progression. Moreover, there were revealed several intracellular pathways which can support the connection between estrogens, estrogen receptors (ER) and melanoma. While ER-β plays an antiproliferative role, ER-α promotes cell growth and cellular atypia. Thus, inhibition of ER-β activity in the skin can increase the risk for development of cutaneous melanoma and spread of metastatic cells. However, despite recent advances in this area, the exact role and clinical implications of estrogens and estrogen receptors in melanoma are still not entirely understood and require further investigations.

Impaired wound healing is an encumbering public health issue that increases the demand for developing new therapies in order to minimize health costs and enhance treatment efficacy. Available conventional therapies are still unable to maximize their potential in penetrating the skin at the target site and accelerating the healing process. Nanotechnology exhibits an excellent opportunity to enrich currently available medical treatments, enhance standard care and manage wounds. It is a promising approach, able to address issues such as the permeability and bioavailability of drugs with reduced stability or low water solubility. This paper focuses on nanosized-lipid-based drug delivery systems, describing their numerous applications in managing skin wounds. We also highlight the relationship between the physicochemical characteristics of nanosized, lipid-based drug delivery systems and their impact on the wound-healing process. Different types of nanosized-lipid-based drug delivery systems, such as vesicular systems and lipid nanoparticles, demonstrated better applicability and enhanced skin penetration in wound healing therapy compared with conventional treatments. Moreover, an improved chemically and physically stable drug delivery system, with increased drug loading capacity and enhanced bioavailability, has been shown in drugs encapsulated in lipid nanoparticles. Their applications in wound care show potential for overcoming impediments, such as the inadequate bioavailability of active agents with low solubility. Future research in nanosized-lipid-based drug delivery systems will allow the achievement of increased bioavailability and better control of drug release, providing the clinician with more effective therapies for wound care.

Background: squamous cell carcinoma (SCC) is the second most common type of malignancy worldwide. Skin and mucosa of the head and neck areas are the most frequently affected. An aggressive behavior in SCC is not easily detected, and despite all efforts, mortality in these types of cancer did not show major improvements during recent decades. In this study, we aim to determine the role of histological features available through standard pathology assessment in SCC and their relation with tumor behavior and patients’ survival. Method: in a group of one hundred patients diagnosed with SCC involving the head and neck areas, we assessed the presence of four histological features (tumor/stroma ratio, immune infiltration at the front of invasion, tumor-budding activity, and tumor necrosis), their correlations with tumor type (mucosal or cutaneous), tumor clinicopathological characteristics, and their prognostic potential. Results: the comparison between histological features in cutaneous versus mucosal SCC reveals no significant differences for any of the four parameters assessed. We found significant correlations between tumor/stroma ratio and lymphatic metastasis (p = 0.0275), perineural invasion (p = 0.0006), and clinical staging (p = 0.0116). Immune infiltration at the front of invasion revealed similar correlations with lymph node involvement (p = 0.002), perineural invasion (p = 0.0138), and clinical staging (p = 0.0043). Tumor budding and tumor necrosis correlated with the size of the tumor (p = 0.0077 and p = 0.0004) and the clinical staging (p = 0.0039 and p = 0.0143). In addition, tumor budding was significantly correlated with perineural invasion (p = 0.0454). In mucosal SCC, patients with improved outcome revealed high values for the tumor/stroma ratio (p = 0.0159) and immune infiltration at the front of invasion (p = 0.0274). However, the multivariate analysis did not confirm their independent prognostic roles. Conclusions: extended histological assessments that include features such as tumor/stroma ratio, immune infiltration at the front of invasion, tumor budding, and tumor necrosis can be an easy, accessible method to collect additional information on tumor aggressiveness in skin and mucosa SCC affecting the head and neck areas.

Simple Summary Melanoma is a very aggressive and fatal malignant tumor. While curable if diagnosed in its early stages, advanced melanoma, despite the complex therapeutic approaches, is associated with one of the highest mortality rates. Hence, more and more studies have focused on mechanisms that may contribute to melanoma development and progression. Various studies suggest a role played by neuroendocrine factors which can act directly on tumor cells, modulating their proliferation and metastasis capability, or indirectly through immune or inflammatory processes that impact disease progression. However, there are still multiple areas to explore and numerous unknown features to uncover. A detailed exploration of the mechanisms by which neuroendocrine factors can influence the clinical course of the disease could open up new areas of biomedical research and may lead to the development of new therapeutic approaches in melanoma. Abstract Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects.

(1) Background: The immune microenvironment plays an important role in carcinogenesis and has prognostic potential in many types of cancer. In this study we assess the prognostic character of tumor-infiltrating immune cells CD4+, CD8+ and CD56+ in resectable oral squamous cell carcinoma (OSCC), (2) Methods: We have evaluated the densities of CD4+, CD8+ and CD56+ in two distinct compartments, intratumor and invasion front, in 90 patients with OSCC, (3) Results: Significant differences were found between the tumor compartments for the CD4+ and CD8+ lymphocytes. An improved outcome (OS) was seen in patients with high densities of intratumor CD8+ lymphocytes (p = 0.0086), CD8+ lymphocytes at the front of invasion (p = 0.0011) and for intratumor CD56+ cells (p = 0.0016). Multivariate analysis confirmed the independent prognostic role of CD8+ at the front of invasion (OR = 3.75, CI95% 1.17–12.35, p = 0.026) and for intratumor CD56+ cells (OR = 3.669, CI95% 1.09–15.37, p = 0.035), (4) Conclusions: Tumor-infiltrating CD8+ lymphocytes at the front of invasion and CD56+ in the intratumor compartment display predictive traits in OSCC. A reach immune infiltration with these types of cells is associated with an improved patient outcome.

Basal cell carcinoma (BCC) is the world’s leading skin cancer in terms of frequency at the moment and its incidence continues to rise each year, leading to profound negative psychosocial and economic consequences. UV exposure is the most important environmental factor in the development of BCC in genetically predisposed individuals, this being reflected by the anatomical distribution of lesions mainly on sun-exposed skin areas. Early diagnosis and prompt management are of crucial importance in order to prevent local tissue destruction and subsequent disfigurement. Although various noninvasive or minimal invasive techniques have demonstrated their utility in increasing diagnostic accuracy of BCC and progress has been made in its treatment options, recurrent, aggressive, and metastatic variants of BCC still pose significant challenge for the healthcare system. Analysis of gene expression and proteomic profiling of tumor cells and of tumoral microenvironment in various tissues strongly suggests that certain molecules involved in skin cancer pathogenic pathways might represent novel predictive and prognostic biomarkers in BCC.

Cannabinoids are increasingly-used substances in the treatment of chronic pain, some neuropsychiatric disorders and more recently, skin disorders with an inflammatory component. However, various studies cite conflicting results concerning the cellular mechanisms involved, while others suggest that cannabinoids may even exert pro-inflammatory behaviors. This paper aims to detail and clarify the complex workings of cannabinoids in the molecular setting of the main dermatological inflammatory diseases, and their interactions with other substances with emerging applications in the treatment of these conditions. Also, the potential role of cannabinoids as antitumoral drugs is explored in relation to the inflammatory component of skin cancer. In vivo and in vitro studies that employed either phyto-, endo-, or synthetic cannabinoids were considered in this paper. Cannabinoids are regarded with growing interest as eligible drugs in the treatment of skin inflammatory conditions, with potential anticancer effects, and the readiness in monitoring of effects and the facility of topical application may contribute to the growing support of the use of these substances. Despite the promising early results, further controlled human studies are required to establish the definitive role of these products in the pathophysiology of skin inflammation and their usefulness in the clinical setting.

Non-melanoma skin cancer (NMSC) is the most common form of cancer worldwide, comprising 95% of all cutaneous malignancies and approximately 40% of all cancers. In spite of intensive efforts aimed towards awareness campaigns and sun-protective measures, epidemiological data indicate an increase in the incidence of NMSC. This category of skin cancers has many common environmental triggers. Arising primarily on sun-exposed skin, it has been shown that ultraviolet radiation is, in the majority of cases, the main trigger involved in the pathogenesis of NMSC. Aside from the well-known etiopathogenic factors, studies have indicated that several neuroactive factors are involved in the carcinogenesis of two of the most common types of NMSC, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), with the exception of penile SCC, for which a paucity of specific data on their pathogenic role exists. The complex interaction between the peripheral nervous system and target cells in the skin appears to be mediated by locally released neuroendocrine factors, such as catecholamines, substance P, calcitonin gene-related peptide and somatostatin, as well as neurohormones, such as proopiomelanocortin and its derived peptides, α-melanocyte-stimulating hormone and adrenocorticotropin. All these factors have been, at least at some point, a subject of debate regarding their precise role in the pathogenesis of NMSC. There is also a significant body of evidence indicating that psychological stress is a crucial impact factor influencing the course of skin cancers, including SCC and BCC. Numerous studies have suggested that neuroendocrine factor dysregulation, as observed in stress reactions, may be involved in tumorigenesis, accelerating the development and progression, and suppressing the regression of NMSC. Further studies are required in order to elucidate the exact mechanisms through which neuroactive molecules promote or inhibit cutaneous carcinogenesis, as this could lead to the development of more sophisticated and tailored treatment protocols, as well as open new perspectives in skin cancer research.

Squamous cells carcinoma (SCC) is the second most frequent of the keratinocyte-derived malignancies after basal cell carcinoma and is associated with a significant psychosocial and economic burden for both the patient himself and society. Reported risk factors for the malignant transformation of keratinocytes and development of SCC include ultraviolet light exposure, followed by chronic scarring and inflammation, exposure to chemical compounds (arsenic, insecticides, and pesticides), and immune-suppression. Despite various available treatment methods and recent advances in noninvasive or minimal invasive diagnostic techniques, the risk recurrence and metastasis are far from being negligible, even in patients with negative histological margins and lymph nodes. Analyzing normal, dysplastic, and malignant keratinocyte proteome holds special promise for novel biomarker discovery in SCC that could be used in the future for early detection, risk assessment, tumor monitoring, and development of targeted therapeutic strategies.

Mast cells play a key role in modulation of stress-induced cutaneous inflammation. In this study we investigate the impact of repeated exposure to stress on mast cell degranulation, in both hairy and glabrous skin. Adult male Wistar rats were randomly divided into four groups: Stress 1 day(n=8), Stress 10 days(n=7), Stress 21 days(n=6), and Control(n=8). Rats in the stress groups were subjected to 2 h/day restraint stress. Subsequently, glabrous and hairy skin samples from animals of all groups were collected to assess mast cell degranulation by histochemistry and transmission electron microscopy. The impact of stress on mast cell degranulation was different depending on the type of skin and duration of stress exposure. Short-term stress exposure induced an amplification of mast cell degranulation in hairy skin that was maintained after prolonged exposure to stress. In glabrous skin, even though acute stress exposure had a profound stimulating effect on mast cell degranulation, it diminished progressively with long-term exposure to stress. The results of our study reinforce the view that mast cells are active players in modulating skin responses to stress and contribute to further understanding of pathophysiological mechanisms involved in stress-induced initiation or exacerbation of cutaneous inflammatory processes.