Psoriasis immunometabolism: progress on metabolic biomarkers and targeted therapy.

Psoriasis is a common inflammatory disease that affects mainly the skin. However, the moderate to severe forms have been associated with several comorbidities, such as psoriatic arthritis, Crohn's disease, metabolic syndrome and cardiovascular disease. Keratinocytes and T helper cells are the dominant cell types involved in psoriasis development via a complex crosstalk between epithelial cells, peripheral immune cells and immune cells residing in the skin. Immunometabolism has emerged as a potent mechanism elucidating the aetiopathogenesis of psoriasis, offering novel specific targets to diagnose and treat psoriasis early. The present article discusses the metabolic reprogramming of activated T cells, tissue-resident memory T cells and keratinocytes in psoriatic skin, presenting associated metabolic biomarkers and therapeutic targets. In psoriatic phenotype, keratinocytes and activated T cells are glycolysis dependent and are characterized by disruptions in the TCA cycle, the amino acid metabolism and the fatty acid metabolism. Upregulation of the mammalian target of rapamycin (mTOR) results in hyperproliferation and cytokine secretion by immune cells and keratinocytes. Metabolic reprogramming through the inhibition of affected metabolic pathways and the dietary restoration of metabolic imbalances may thus present a potent therapeutic opportunity to achieve long-term management of psoriasis and improved quality of life with minimum adverse effects.

Topical Delivery of Rapamycin by Means of Microenvironment-Sensitive Core-Multi-Shell Nanocarriers: Assessment of Anti-Inflammatory Activity in an ex vivo Skin/T Cell Co-Culture Model.

INTRODUCTION: Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin. METHODS: In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium. RESULTS: We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release. CONCLUSION: Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs.

Unraveling the roles of vitamin D status and melanin during Covid­19 (Review).

As the coronavirus disease 2019 (COVID­19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID­19 clinical outcomes, reflecting the 'color of disease'. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non­Caucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune­mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID­19 outcomes among diverse population settings. Moreover, apart from the well­known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID­19.

Impact of vitamin D receptor gene polymorphisms on vitiligo susceptibility and clinical features in a Southeastern European Caucasian population.

An association of vitamin D receptor (VDR) polymorphisms and vitiligo has been suggested. However, previous studies have reported contradictory results while including limited data among Caucasians. The aim of this single­center study was to evaluate the effect of three common VDR gene polymorphisms (FokI, TaqI and BsmI) on susceptibility and clinical aspects of vitiligo in a Southeastern European Caucasian population. A total of 110 unrelated vitiligo cases and 509 general population controls were enrolled from October 2018 to November 2019. Genomic DNA was extracted from whole blood after de­identification and anonymization of the samples and genotyped for the selected VDR polymorphisms by the qPCR (melting curve analysis). Subgroup analysis by clinical features among subsets of patients indicated that, compared to subjects with the FokI TT genotype or T allele, carriers of the FokI CC genotype or C allele exhibited significantly decreased risk of developing vitiligo before the age of 30 [TT vs. CC: odds ratio (OR)=0.286, 95% confidence interval (CI): 0.083­0.984, P=0.041; T vs. C: OR=0.545, 95% CI: 0.313­0.948, P=0.031]. Intra­patient analysis also revealed that, compared to T allele, the presence of TaqI C allele was adversely associated with the incidence of concurrent leukotrichia (T vs. C: OR=1.874, 95% CI: 1.018­3.451, P=0.042). Comparisons between the case and control groups showed no evidence to support an association between susceptibility to vitiligo and the VDR BsmI, TaqI, and FokI polymorphisms in this cohort. Thus, the studied VDR polymorphisms might indirectly impact the clinical course and treatment decision­making despite their lack of association with vitiligo per se. Further research with larger sample sizes, especially across Caucasian individuals, should be performed to confirm these findings.

Positron Emission Tomography in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre- and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the "gold standard" of sentinel lymph node biopsy, recent evidence suggests an important role for 18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to 18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC.

Chemical Peels in Skin Cancer: A Review.

Background: Chemexfoliation is widely used to reverse signs of photodamage. Although photodamage can eventually lead to skin cancer, it remains unclear whether chemical peels also affect photocarcinogenesis. Moreover, concerns about the systemic and/or cutaneous toxicity of peeling agents have already arisen. Objective: This review sought primarily to summarize the data available on the effects of chemical peels on ultraviolet-induced skin carcinogenesis, focusing particular attention on actinic keratoses and cutaneous field cancerization. In addition, considerations about the systemic and/or cutaneous toxicity of peeling agents, particularly trichloracetic acid, are briefly discussed. Methods: The PubMed, MEDLINE, and SCOPUS databases were searched using the keywords "chemical peeling," "actinic keratosis," "cutaneous field cancerization," "skin cancer," "skin cancer prevention," and "cutaneous and systemic carcinogenicity," both alone and in combination with one another. Additional relevant references were also isolated from citations in the reviewed literature. Results: A total of 42 articles involving both in-vitro and in-vivo human and animal models were included for analysis. The data were mainly confined to laboratory animals. Conclusion: Apart from efficacy in clearing visible actinic keratoses, the findings point towards the possible clinical use of chemical peeling for the prevention of skin cancer. To date, no evidence on systemic toxicity following dermal exposure of humans to chemical peels has been identified.

Another window into tumor microenvironment: a case of Β-cell rich folliculotropic mycosis fungoides responding to rituximab.

The role of tumor infiltrating immune cells in cancer development and progression is a new, promising field in oncological research. An increasing number of novel anti-cancer agents are focussing on the tumor microenvironment. Various studies have reported on B-cell infiltrates in mycosis fungoides (MF), but despite the substantial volume of interesting findings, solid evidence regarding their specific role in cancer is still vague. We present a case of tumor stage  MF responding to rituximab. We support the hypothesis that lymphoma-infltrating B-cells have a significant impact on cutaneous lymphoma course and seem to be both an important and effective therapeutic target. The reduction of B-cell population led to disease's overall remission, probably by restoring patient's immunologic tumor control.

The different faces of mycosis fungoides: results of a single-center study.

BACKGROUND: Mycosis fungoides (MF) accounts for the majority of cutaneous lymphomas. Apart from the predominant Alibert-Bazin type, several clinicopathological variants of diverse prevalence and biological behavior have been described. Data on clinical and epidemiological aspects of MF clinical subtypes are still weak. AIM: To outline the clinical and epidemiological profile of the different MF types in a large volume of Greek patients. METHODS: Retrospective analysis of 688 MF cases treated in our lymphoma clinic. Epidemiological, clinical, pathological, and immunohistochemical data were retrieved. RESULTS: Six-hundred and thirty-six patients (416 males, 220 females) were included. The mean age at diagnosis was 60.2 years; the mean duration of disease prior to diagnosis was 63.2 months. Early-stage MF (I-IIA) involved 475 cases (74.7%). The prevalent type was classical MF (68.5%), followed by folliculotropic (17%), poikilodermic (5.5%), and psoriasiform (4.7%) MF. Atypical MF lesions as the sole manifestation of folliculotropic mycosis fungoides (FMF) - alopecia areata-like lesions (n = 10), keratosis pilaris-like lesions (n = 9) or acneiform rash (n = 4) - were also observed. Both poikilodermic and folliculotropic subtypes mainly involved younger patients. A significant diagnostic latency concerning poikilodermic and psoriasiform MF cases was recorded. Only 23 (3.3%) cases were of juvenile onset, with classical and poikilodermic MF equally affecting this age group, closely followed by FMF. CONCLUSIONS: Our study presents the whole clinical-epidemiological spectrum of MF in a large Greek cohort. The high prevalence of atypical MF manifestations characterized by early onset and indolent clinical course stood out among our FMF sample.

Management Strategies Of Palmar Hyperhidrosis: Challenges And Solutions.

Palmar hyperhidrosis is a potentially disabling condition for which management remains a therapeutic challenge. Given the significant impact on quality of life, various treatment options are available, ranging from topical agents and medical devices to systemic therapies and surgical interventions. Nonsurgical approaches, i.e. topical antiperspirants, botulinum toxin injections, iontophoresis, and systemic agents, are all supported by the current literature. Patients with mild-to-moderate disease can often benefit from topical therapies only. As disease severity progresses, systemic oral medication, such as anticholinergic drugs, usually becomes necessary. Last-line surgical approaches (sympathetic denervation) should be reserved for severe refractory cases. Recently, therapeutic strategies have been evolving with several new agents emerging as promising alternatives in clinical trials. In practice, however, each modality comes with its own benefits and risks. An individual therapeutic ladder is generally recommended, taking into account disease severity, benefit-to-risk profile, treatment cost, patient preference, and clinician expertise. This review will provide an update on current and emerging concepts of management for excessive hand sweating to help clinicians optimize therapeutic decision-making.

Onychotillomania: A Chameleon-Like Disorder: Case Report and Review of Literature.

Onychotillomania, or nail-picking disorder, is an uncommon and misdiagnosed behavioral pattern focused on the nail apparatus. It is demarcated by the compulsive or irresistible urge in patients to constantly injure their own nails, with the fingers or tools, inflicting noticeable or even irreversible self-destruction of the nail unit. Despite its rarity, this self-injurious coercion often poses a diagnostic and therapeutic challenge. Not only do many patients deny nail manipulation, but also the disorder has long been recognized to present itself with a wide range of clinical features, which hampers early and indisputable diagnosis. Furthermore, onychotillomania constitutes a persistent and hardly manageable problem, mostly because of its psychocutaneous nature as well as its high propensity to coexist with underlying neuropsychiatric illnesses or other behavioral disorders. However, the medical literature concerning obsessive nail picking still remains relatively scarce. Herein, we present an extraordinary, yet very intriguing case of a Caucasian patient with onychotillomania and onychophagia coexistence masquerading a weird inflammation-like lesion.