Host-Microbiome Crosstalk in Chronic Wound Healing.

The pathogenesis of chronic wounds (CW) involves a multifaceted interplay of biochemical, immunological, hematological, and microbiological interactions. Biofilm development is a significant virulence trait which enhances microbial survival and pathogenicity and has various implications on the development and management of CW. Biofilms induce a prolonged suboptimal inflammation in the wound microenvironment, associated with delayed healing. The composition of wound fluid (WF) adds more complexity to the subject, with proven pro-inflammatory properties and an intricate crosstalk among cytokines, chemokines, microRNAs, proteases, growth factors, and ECM components. One approach to achieve information on the mechanisms of disease progression and therapeutic response is the use of multiple high-throughput 'OMIC' modalities (genomic, proteomic, lipidomic, metabolomic assays), facilitating the discovery of potential biomarkers for wound healing, which may represent a breakthrough in this field and a major help in addressing delayed wound healing. In this review article, we aim to summarize the current progress achieved in host-microbiome crosstalk in the spectrum of CW healing and highlight future innovative strategies to boost the host immune response against infections, focusing on the interaction between pathogens and their hosts (for instance, by harnessing microorganisms like probiotics), which may serve as the prospective advancement of vaccines and treatments against infections.

Perspectives on Psoriasiform Adverse Events from Immune Checkpoint Inhibitors: Lessons Learned from Our Practice.

Background: New oncologic therapies, including immune checkpoint inhibitors (ICIs), have revolutionized the survival and prognosis of cancer patients. However, these therapies are often complicated by immune-related adverse effects (irAEs) that may impact quality of life and potentially limit their use. Among these adverse events are psoriasis and psoriatic arthritis that may develop de novo or flare under treatment with ICIs. Given the exceptional immune status of patients receiving ICIs, managing these conditions without interfering with the effect of the oncologic treatment may prove very challenging. Aim: To review the literature data on ICI-induced psoriasis exacerbation or development, to present our own experience, and to discuss the pathogenic mechanisms underlying this association and the optimal therapeutic approach for these patients. Case Reports: We report three cases of ICI-induced de novo psoriasis and two cases of ICI-induced psoriasis exacerbation that required systemic treatment. Oral acitretin treatment successfully controlled psoriasis lesions in three cases and allowed for the continuation of immunotherapy. Literature Review: We performed a medical literature search across several databases (PubMed, Medline, Google Scholar) using the search terms "immune checkpoint inhibitor-induced psoriasis/psoriasiform dermatitis/psoriasis arthritis". We identified and revised 80 relevant publications that reported 1102 patients with psoriasis and/or psoriasis arthritis induced or exacerbated by ICIs. We assessed the type of cancer, the therapeutic agent involved, the clinical form of psoriasis, the presence or absence of psoriatic arthritis, the personal and family history of psoriasis, the age, the gender, the time until onset or exacerbation of skin lesions, the specific treatment recommended, the need for ICI discontinuation, and the patient's outcome. Conclusions: As ICIs represent a fairly novel therapy, the association with several adverse effects is only now unraveling. Psoriasis exacerbation or onset following the initiation of immunotherapy is one such example, as more and more reports and case series are being published. Awareness of the relationship between psoriasis and treatment with ICIs, prompt recognition, and initiation of adequate skin-directed therapies are essential for the avoidance of skin lesions worsening, the need for systemic treatments that may interfere with ICIs' effects, or the discontinuation of the latter. In the absence of generally accepted guidelines, it is advisable to treat patients with severe, widespread psoriasis with drugs that do not impair the effects of immunotherapy and thus do not alter the patient's prognosis.

Single nucleotide polymorphism rs13079080 is associated with differential regulation of the succinate receptor 1 (SUCNR1) gene by miRNA-4470.

Oxidative stress is a feature of many common diseases. It leads to excessive formation and subsequent release of the mitochondrial metabolite succinate, which acts as a signalling molecule through binding the succinate receptor (SUCNR1). Recently, a potential role for SUCNR1 was proposed in age-related macular degeneration (AMD), a common cause of vision loss in the elderly associated with increased oxidative stress. Here, we evaluated the potential effect of genetic variants in SUCNR1 on its expression through differential micro-RNA (miRNA) binding to target mRNA, and investigated the relevance of altered SUCNR1 expression in AMD pathogenesis. We analysed common SUCNR1 SNPs for potential miRNA binding sites and identified rs13079080, located in the 3'-UTR and binding site for miRNA-4470. Both miRNA-4470 and SUCNR1 were found to be expressed in human retina. Moreover, using a luciferase reporter assay, a 60% decrease in activity was observed when miRNA-4470 was co-expressed with the C allele compared to the T allele of rs13079080. Finally, genotyping rs13079080 in an AMD case-control cohort revealed a protective effect of the TT genotype on AMD compared to the CC genotype (p = 0.007, odds ratio = 0.66). However, the association was not confirmed in the case-control study of the International AMD Genomics Consortium. Our study demonstrates that the T allele of rs13079080 in SUCNR1 disrupts a binding site for miRNA-4470, potentially increasing SUCNR1 expression and consequently increasing the capacity of sensing and dealing with oxidative stress. Therefore, it would be worthwhile assessing the relevance of rs13079080 in other oxidative stress-associated diseases in future studies.

A Peculiar Presentation of a Debilitating Condition: Calciphylaxis.

Calciphylaxis is a debilitating condition associated with significant morbidity and mortality, often associated with patients with end-stage renal disease, in which the calcification of cutaneous arterioles and small arteries occurs, leading to subsequent ischemia and cutaneous infarction. Herein, we report the case of a diabetic patient with end-stage kidney disease on dialysis, presenting multiple intensely painful necrotic plaques on the lower extremities. The suspicion of calciphylaxis was raised based on the patient's medical history and clinical presentation, subsequently confirmed by radiological examination, which revealed calcifications along vascular pathways. Diagnosis can be established based on clinical and paraclinical grounds alone, and some clinicians may forego skin biopsy and initiate treatment presumptively. The management of calciphylaxis remains a challenge and requires a multidisciplinary approach since most patients experience intense pain that is often unresponsive to conventional analgesics, leading to a reduced quality of life.

A Current Diagnostic and Therapeutic Challenge: Tinea Capitis.

Tinea capitis is a dermatophyte scalp infection with a marked prevalence among the pediatric population. However, in the last few years, its epidemiology has changed due to increasing population migration worldwide. Host-specific and environmental factors contribute to the pathogenesis of tinea capitis. Clinically, tinea capitis may present as a subtle hair loss accompanied by scalp scaling, alopecia with scaly patches, or alopecia with black dots. A more severe form of tinea capitis is represented by kerion celsi, which clinically presents as a tender plaque covered by pustules and crusts. If left untreated, this dermatophytic infection may resolve with permanent scarring and alopecia. The pathological changes found in tinea capitis are reflected by a spectrum of clinical changes. Zoophilic infections typically prompt an extensive inflammatory reaction, while anthropophilic dermatophytoses often lack inflammation and result in more persistent lesions. Tinea capitis typically requires systemic antifungal therapy. Griseofulvin, terbinafine, itraconazole, and fluconazole are the main antifungal agents used. Currently, the duration of antifungal therapy varies based on the clinical presentation and type of dermatophyte involved. Through the reported cases and literature review, we aim to emphasize the importance of the early recognition of atypical variants of tinea capitis in immunocompetent children for the prompt initiation of systemic antifungal therapy, minimizing the need for prolonged treatment. Additionally, we emphasize the importance of regular laboratory testing during systemic antifungal therapy, particularly liver enzyme tests, to prevent adverse events, especially in cases requiring long-term treatment.

Cutaneous Adverse Reactions Associated with Tattoos and Permanent Makeup Pigments.

Tattooing is the procedure of implanting permanent pigment granules and additives into the dermal layer of the skin, serving various purposes such as decoration, medical identification, or accidental markings. There has been a significant rise in the popularity of decorative tattooing as a form of body art among both teenagers and young adults. Thus, the incidence of tattoos is increasing, with expanding applications such as permanent makeup, scar camouflage, nipple-areola, lips, and eyebrows tattooing, and utilization in oncological radiotherapy such as colon marking. However, there have been reported a broad range of adverse reactions linked to tattooing, encompassing allergic reactions, superficial and deep cutaneous infections, autoimmune disorders induced by the Koebner phenomenon, cutaneous tumors, and others. These reactions exhibit different onset times for symptoms, ranging from immediate manifestations after tattoo application to symptoms emerging several years later. Given the limited information on a tattoo's side effects, this review aims to elucidate the clinical spectrum of cutaneous complications of tattoos in different patients. The analysis will investigate both allergic and nonallergic clinical presentations of tattoo-related side effects, microscopic findings from skin biopsies, and therapeutic outcomes. This exploration is essential to improve our understanding of tattoo-related cutaneous complications and associated differential diagnoses and highlight the significance of patient awareness regarding potential risks before getting a tattoo.

Cutaneous Melanoma and Glioblastoma Multiforme Association-Case Presentation and Literature Review.

The occurrence of both melanoma and glioma was first suggested by the observation of a familial association between these conditions, which was later confirmed by the description of the melanoma-astrocytoma syndrome, an extremely rare, inherited affliction in which people have an increased risk of developing melanoma and nervous system tumors. Taking into consideration the common embryologic precursor, the neuroectoderm, it was hypothesized that this syndrome is associated with a genetic disorder. While some families with germline CDKN2A mutations are prone to develop just melanomas, others develop both melanomas and astrocytomas or even other nervous-system neoplasms. Herein, we report the case of a 63-year-old male patient with no personal or family history of malignancy who had primary melanoma followed by glioblastoma. Our case report suggests that the occurrence of both melanoma and glioblastoma is most likely not coincidental but instead linked to genetic mutations of common embryologic precursors or signaling pathways.

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients.

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2-3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 17, interleukin 23, interleukin 22, and interleukin 1ß. An in-depth understanding of the pathophysiology of psoriasis led to significant advances in the development of safe and efficient novel therapeutic options, with four classes of biologic therapy being approved for the management of moderate to severe psoriasis: tumor necrosis factor alpha inhibitors, interleukin 23 inhibitors, anti-interleukin 12/23 agents, anti-interleukin 17 agents, as well as small-molecule inhibitors, such as apremilast. Psoriasis is associated with comorbid conditions, namely psoriatic arthritis, cardiovascular disease, metabolic syndrome, psychiatric disorders, malignancy, as well as inflammatory bowel disease. For patients affected by both psoriasis and inflammatory bowel disease, there is a strong recommendation to avoid IL-17 inhibitors since they may play a part in the exacerbation of the gastrointestinal disease. Our aim was to perform a thorough literature review regarding the development of inflammatory bowel disease lesions in psoriasis patients treated with IL-17 inhibitors, along with a case presentation to emphasize the need for close follow-up of these patients.

Risks of Biologic Therapy and the Importance of Multidisciplinary Approach for an Accurate Management of Patients with Moderate-Severe Psoriasis and Concomitant Diseases.

Psoriasis is a chronic multisystem inflammatory disease associated with a plethora of comorbidities including metabolic syndrome, cardiovascular disease, hypertension, diabetes, hyperlipidemia, obesity, anxiety, depression, chronic kidney disease, and malignancy. Advancement in unveiling new key elements in the pathophysiology of psoriasis led to significant progress in the development of biologic agents which target different signaling pathways and cytokines involved in the inflammatory cascade responsible for the clinical manifestations found in psoriasis. Currently available novel therapeutic options for moderate-severe psoriasis include tumor necrosis factor alpha inhibitors, inhibitors of the interleukin 17, and inhibitors of the interleukin 23. Nevertheless, concerns have been raised with respect to the possible risks associated with the use of biologic therapy requiring close collaboration between dermatologists and physicians of different specialties. Our aim was to perform an in-depth literature review and discuss the potential risks associated with biologic therapy in patients with psoriasis and concurrent diseases with a focus on the influence of novel therapeutic agents on liver function in the context of hepatopathies, particularly viral hepatitis. A multidisciplinary teamwork and periodic evaluation of psoriasis patients under biologic therapy is highly encouraged to obtain an accurate management for each case.

Immunohistochemical expression of p53, Ki67, α-SMA, CD44 and CD31 in different histological subtypes of basal cell carcinoma.

Basal cell carcinoma (BCC) is a common, locally invasive tumor that arises within sun-damaged skin and rarely develops on the palms and soles or mucous membranes. Men generally have higher rates of BCC than women. Incidence also increases with age and the median age of diagnosis is 68 years old. Mortality from BCC is rare and cases of aggressive, local destructive, metastatic BCCs are more likely from tumors with aggressive histopathological (HP) patterns. The aim of this study was to investigate and correlate the immunohistochemical expression of p53, Ki67, alpha-smooth muscle actin (α-SMA), cluster of differentiation (CD)44 and CD31 with both aggressive and nonaggressive types of BCCs. In our study, we observed a varied staining pattern for p53, with the highest reactivity noticed in the peripheral palisading zone. The staining pattern for Ki67 was similar to p53, with a more pronounced reaction in the periphery of the tumor. We found different Ki67 and p53 expression among the various subtypes of BCC. The CD31 reactivity, mostly seen in the stroma, was positive in all BCCs and varied significantly between its different HP subtypes. Regarding stromal expression of α-SMA, the adenoid and basosquamous types had the most intense reaction in our study. The CD44 tumor expression was correlated in our study to the aggressive pattern of BCCs.

The Impact of Long-Term Antibiotic Therapy of Cutaneous Adverse Reactions to EGFR Inhibitors in Colorectal Cancer Patients.

Colorectal cancer (CRC) is an important public health issue, in terms of incidence and mortality, with approximately 1.8 million new cases reported worldwide in 2018. Advancements in understanding pathophysiological key steps in CRC tumorigenesis have led to the development of new targeted therapies such as those based on epidermal growth factor receptor inhibitors (EGFR inhibitors). The cutaneous adverse reactions induced by EGFR inhibitors, particularly papulopustular rash, often require long-term antibiotic treatment with tetracycline agents (mostly minocycline and doxycycline). However, this raises several issues of concern: possible occurrence of gut dysbiosis in already vulnerable CRC patients, selection of highly antibiotic resistant and/or virulent clones, development of adverse reactions related to tetracyclines, interference of antibiotics with the response to oncologic therapy, with a negative impact on disease prognosis etc. In the context of scarce information regarding these issues and controversial opinions regarding the role of tetracyclines in patients under EGFR inhibitors, our aim was to perform a thorough literature review and discuss the main challenges raised by long-term use of tetracyclines in advanced CRC patients receiving this targeted therapy.

Ubiquitin-Dependent Degradation of Mitochondrial Proteins Regulates Energy Metabolism.

The ubiquitin proteasome system (UPS) regulates many cellular functions by degrading key proteins. Notably, the role of UPS in regulating mitochondrial metabolic functions is unclear. Here, we show that ubiquitination occurs in different mitochondrial compartments, including the inner mitochondrial membrane, and that turnover of several metabolic proteins is UPS dependent. We specifically detailed mitochondrial ubiquitination and subsequent UPS-dependent degradation of succinate dehydrogenase subunit A (SDHA), which occurred when SDHA was minimally involved in mitochondrial energy metabolism. We demonstrate that SDHA ubiquitination occurs inside the organelle. In addition, we show that the specific inhibition of SDHA degradation by UPS promotes SDHA-dependent oxygen consumption and increases ATP, malate, and citrate levels. These findings suggest that the mitochondrial metabolic machinery is also regulated by the UPS.