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Abstract: Psoriasis is a immune-mediated, chronic, inflammatory skin dis-ease. In HIV positive (HIV+) patients we usually observe more serious clinical features and recalcitrant course. Furthermore, therapeutic man-agement of HIV+ patient is complex and requires collaboration with the infectious disease specialist. We report the case of a patient affected by severe psoriasis who contracted HIV infection during biological therapy and, subsequently, succesfully treated with ixekizumab.

Abstract: Blue nevi are a heterogeneous group of lesions that can display a variety of different clinicopathological characteristics. Although attempts are made to classify each lesion into defined subtypes, there can be overlap between the subtypes. The clinical , dermoscopic and histolopathologic features of a case of proliferative nodule arising within blue nevus is discussed. Running title: Blue nevi are an heterogeneous group of melanocytic lesions blue tinctorial properties. Proliferative nodules are rare benign lesions often present at birth as a component of a large congenital melanocytic nevi, congenital or acquired nevi. We first report a case of proliferative nodule arising within blue nevus.

Natural yeast with superior fermentative traits can serve as a platform for the development of recombinant strains that can be used to improve the sustainability of bioethanol production from starch. This process will benefit from a consolidated bioprocessing (CBP) approach where an engineered strain producing amylases directly converts starch into ethanol. The yeast Saccharomyces cerevisiae L20, previously selected as outperforming the benchmark yeast Ethanol Red, was here subjected to a comparative genomic investigation using a dataset of industrial S. cerevisiae strains. Along with Ethanol Red, strain L20 was then engineered for the expression of α-amylase amyA and glucoamylase glaA genes from Aspergillus tubingensis by employing two different approaches (delta integration and CRISPR/Cas9). A correlation between the number of integrated copies and the hydrolytic abilities of the recombinants was investigated. L20 demonstrated important traits for the construction of a proficient CBP yeast. Despite showing a close relatedness to commercial wine yeast and the benchmark Ethanol Red, a unique profile of gene copy number variations (CNVs) was found in L20, mainly encoding membrane transporters and secretion pathway proteins but also the fermentative metabolism. Moreover, the genome annotation disclosed seven open reading frames (ORFs) in L20 that are absent in the reference S288C genome. Genome engineering was successfully implemented for amylase production. However, with equal amylase gene copies, L20 proved its proficiency as a good enzyme secretor by exhibiting a markedly higher amylolytic activity than Ethanol Red, in compliance to the findings of the genomic exploration. The recombinant L20 dT8 exhibited the highest amylolytic activity and produced more than 4 g/L of ethanol from 2% starch in a CBP setting without the addition of supplementary enzymes. Based on the performance of this strain, an amylase/glucoamylase ratio of 1:2.5 was suggested as baseline for further improvement of the CBP ability. Overall, L20 showed important traits for the future construction of a proficient CBP yeast. As such, this work shows that natural S. cerevisiae strains can be used for the expression of foreign secreted enzymes, paving the way to strain improvement for the starch-to-bioethanol route., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gronchi, De Bernardini, Cripwell, Treu, Campanaro, Basaglia, Foulquié-Moreno, Thevelein, Van Zyl, Favaro and Casella.)

Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents the most effective drug in the treatment of AD. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Here, we assessed the impact of donepezil on the vascular phenotype of an established model of accelerated senescence that develops spontaneously AD, the SAMP8 mouse. Three groups of animals were included: SAMR1 (control strain), SAMP8, and SAMP8 treated with donepezil. Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests by Morris Water Maze, animals were euthanized, and their mesenteric arteries were processed for functional experiments. Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated cognitive dysfunction. SAMP8 exhibited a higher media-to-lumen ratio than SAMR1 and donepezil-treated animals. Endothelial function was impaired in SAMP8 animals compared to SAMR1. The addition of vitamin C improved the vasodilatory response to acetylcholine in SAMP8. Treatment with donepezil improved endothelial function in SAMP8 animals and reduced the additional vasodilation induced by vitamin C. In conclusion, in the SAMP8 AD model, cognitive impairment is associated with endothelial dysfunction and vascular remodeling which could contribute to cardiovascular events in AD since the prodromal phases of the disease. Treatment with donepezil alleviates vascular dysfunction associated with AD through an increase in NO availability likely by counteracting inflammation and oxidative stress., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson's disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and pre-clinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.

This retrospective single-center study analyzes the efficacy and safety of isotretinoin for the treatment of moderate to severe acne in real-life clinical practice, particularly with regard to acne severity, isotretinoin cumulative dosage, and patients' gender. The results suggest the opportunity of an early isotretinoin systemic treatment in patients affected by moderate acne and emphasize the importance of an appropriate dose adjustment in order to minimize adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Skroza, Tolino, Balduzzi, Bernardini, Mambrin, Marchesiello, Marraffa, Rossi, Volpe, Proietti and Potenza.)

Erythrodermic psoriasis (EP) is a very rare but extremely severe subtype of chronic plaque psoriasis. Its pathogenesis still remains unknown, and current therapeutic strategies frequently end in failure. Erythrodermic psoriasis often requires hospitalization in order to control any kind of possible serious complications. Treatment of EP is a challenge for clinicians because international guidelines are lacking. Nevertheless, Th17 has been shown to be the second-most predominant T-cell type after Th2 in EP lesions. There is a growing body of evidence supporting the safety and efficacy of biologics in rapidly achieving near-total clearance of EP, particularly within the IL-17 class. Herein we report a series of 5 cases of EP successfully treated with anti-interleukines 17: Ixekizumab and Secukinumab.

Background and Purpose: Enteric neurogenic/inflammation contributes to bowel dysmotility in obesity. We examined the role of NLRP3 in colonic neuromuscular dysfunctions in mice with high-fat diet (HFD)-induced obesity., Experimental Approach: Wild-type C57BL/6J and NLRP3-KO (Nlrp3 -/- ) mice were fed with HFD or standard diet for 8 weeks. The activation of inflammasome pathways in colonic tissues from obese mice was assessed. The role of NLRP3 in in vivo colonic transit and in vitro tachykininergic contractions and substance P distribution was evaluated. The effect of substance P on NLRP3 signalling was tested in cultured cells., Key Results: HFD mice displayed increased body and epididymal fat weight, cholesterol levels, plasma resistin levels and plasma and colonic IL-1β levels, colonic inflammasome adaptor protein apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) and caspase-1 mRNA expression and ASC immunopositivity in macrophages. Colonic tachykininergic contractions were enhanced in HFD mice. HFD NLRP3 -/- mice developed lower increase in body and epididymal fat weight, cholesterol levels, systemic and bowel inflammation. In HFD Nlrp3 -/- mice, the functional alterations of tachykinergic pathways and faecal output were normalized. In THP-1 cells, substance P promoted IL-1β release. This effect was inhibited upon incubation with caspase-1 inhibitor or NK 1 antagonist and not observed in ASC -/- cells., Conclusion and Implications: In obesity, NLRP3 regulates an interplay between the shaping of enteric immune/inflammatory responses and the activation of substance P/NK 1 pathways underlying the onset of colonic dysmotility. Identifying NLRP3 as a therapeutic target for the treatment of bowel symptoms related to obesity., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Efficacy of anti-TNF-a agents seems inferior to IL-17 and IL-23 inhibitors. Nevertheless, after biosimilars approval, anti TNF-a agents are recommended as first-line for psoriatic patients, for economic reasons., Methods: Predictive factors of response or non-response to adalimumab in bionaive patients who started adalimumab (originator or biosimilar) over 12 years in 9 dermatologic centers in Italy. Effectiveness was assessed with Psoriasis Area and Severity Index (PASI75 and PASI90) at weeks 12, 24 and 48. Multiple logistic regressions were used for variables predicting clinical response; Kaplan-Meier survival curves and Cox regression for drug survival., Results: The drug survival analysis showed reduced hazard ratio of overall discontinuation with male gender and scalp localization. In contrast, baseline PASI and genital psoriasis were significantly associated with increased risk of overall discontinuation. Predictive factors of non-response seemed elevated in patients with baseline PASI, older age groups, previously treated patients with phototherapy, females or patients with palmo-plantar while scalp psoriasis, previous cyclosporine and acitretin appeared as a positive predictive factor., Conclusions: This real-life analysis might be useful for clinicians in case of bio-naive patients with moderate-to-severe psoriasis and various comorbidities.

Saccharomyces cerevisiae has long been part of human activities related to the production of food and wine. The industrial demand for fermented beverages with well-defined and stable characteristics boosted the isolation and selection of strains conferring a distinctive aroma profile to the final product. To uncover variants characterizing oenological strains, the sequencing of 65 new S. cerevisiae isolates, and the comparison with other 503 publicly available genomes were performed. A hybrid approach based on short Illumina and long Oxford Nanopore reads allowed the in-depth investigation of eleven genomes and the identification of putative laterally transferred regions and structural variants. A comparative analysis between clusters of strains belonging to different datasets allowed the identification of novel relevant genetic features including single nucleotide polymorphisms, insertions and structural variants. Detection of oenological single nucleotide variants shed light on the existence of different levels of modulation for the mevalonate pathway relevant for the biosynthesis of aromatic compounds., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Since all clinical trials conducted during the development of anti-COVID-19 vaccines have adopted among the exclusion criteria the presence of immunodepression or immunomodulating therapy, to date, the effects of vaccination against the new coronavirus 2 in people under such conditions have yet to be clearly defined. The primary objective of the study is to assess the safety of treatment with biotechnological drugs in patients suffering from moderate-severe psoriasis and subjected to the prophylactic vaccination against SARS-Cov-2. Additionally, the secondary objective of the research is to investigate the existence of a possible impact of anti-COVID-19 vaccination on the natural chronic-relapsing course and the severity of the psoriatic disease. The study included 436 patients with moderate-severe psoriasis, both male and female, in treatment with biologics. The data were collected using the direct interview method. A reduction of 74.13% of average Psoriasis Area Severity Index (PASI )compared to baseline (T0) was found in all subjects; this does not differ significantly from the group that underwent vaccination (73.4%). Moreover; at the end of the study, neither mild nor severe adverse events (ADR) were observed among them. In conclusion, biotechnological drugs used in the management of patients with moderate-severe psoriasis demonstrate a high safety profile also in subjects immunized against SARS-Cov-2.

Background: Erythroplasia of Queyrat (EQ) is a rare squamous cell carcinoma in situ, usually occurring on the glans penis, the prepuce, or the urethral meatus. Therapy is mandatory because it can progress to invasive carcinoma in up to 30% of cases. Treatment options include 5-fluorouracil, curettage, cryotherapy, radiotherapy, laser, partial or total penectomy, and microsurgery, as also with imiquimod and photodynamic therapies., Methods: Between 2015 to 2018 we treated five patients, with histologically confirmed EQ, with ingenol mebutate (IM) 0.015% gel applied for 3 days consecutively., Results: Three patients showed complete response at one year follow up. Two patients showed partial response after two months, so they received a second course of therapy with IM. At one-year follow-up, one of them showed complete response, the other partial response., Conclusions: Our experience demonstrated that IM may be considered as an effective and safe treatment option in EQ. IM offers various advantages such as easy and fast application, rapid complete remission, better compliance, few side effects and excellent cosmetical results. The authors call for further exploitation in bigger trials.

BACKGROUND: Acne is a chronic multifactorial skin disease with a high prevalence among adolescents. The therapeutic approach for mild to moderate papulopustular acne includes the use of systemic tetracycline. Increased risk of antibiotic resistance necessitates research into alternative therapeutic approaches, such as zinc sulphate. Efficacy of zinc sulphate in acne treatment is widely reported in the literature, but drug comparison studies are lacking. OBJECTIVE: We sought to compare the efficacy and safety of zinc sulphate to lymecycline for the treatment of mild to moderate papulopustular acne. METHODS: One hundred patients were equally randomized to receive either zinc sulphate or lymecycline. Acne severity was evaluated using the subjective Global Acne Grading System (GAGS) and the Acne-specific Quality of Life (AQoL) questionnaire at baseline and after four and 12 weeks. RESULTS: Both zinc sulphate and lymecycline induced a statistically significant reduction in GAGS scores at four and 12 weeks of treatment. The improvements in AQoL scores in patients treated with zinc sulphate were significantly higher than those in the lymecycline group. CONCLUSIONS: Our study suggests that zinc sulphate is a valid alternative therapeutic approach in the treatment of mild to moderate papulopustular acne relative to lymecycline in terms of clinical efficacy, tolerability, and the occurrence of side effects., Competing Interests: FUNDING:No funding was provided for this article. DISCLOSURES:The authors report no conflicts of interest relevant to the content of this article., (Copyright © 2021. Matrix Medical Communications. All rights reserved.)

Background : The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods : Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. Results : A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort 26 patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. Conclusion : The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen 'cytokine storm' of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.

Over recent years, several investigations have suggested that Parkinson's disease (PD) can be regarded as the consequence of a bowel disorder. Indeed, gastrointestinal symptoms can occur at all stages of this neurodegenerative disease and in up to a third of cases, their onset can precede the involvement of the central nervous system. Recent data suggest that enteric glial cells (EGCs) may play a major role in PD-related gastrointestinal disturbances, as well as in the development and progression of the central disease. In addition to their trophic and structural functions, EGCs are crucial for the homeostatic control of a wide range of gastrointestinal activities. The main purpose of this review was to provide a detailed overview of the role of EGCs in intestinal PD-associated alterations, with particular regard for their participation in digestive and central inflammation as well as the dynamic interactions between glial cells and intestinal epithelial barrier. Accumulating evidence suggests that several pathological intestinal conditions, associated with an impairment of barrier permeability, may trigger dysfunctions of EGCs and their shift towards a proinflammatory phenotype. The reactive gliosis is likely responsible for PD-related neuroinflammation and the associated pathological changes in the ENS. Thus, ameliorating the efficiency of mucosal barrier, as well as avoiding IEB disruption and the related reactive gliosis, might theoretically prevent the onset of PD or, at least, counteract its progression., Competing Interests: The authors declare no conflict of interest.

Objective: To assess the role of CD3 + CD20 + CD4 - CD8 - double-negative (DN) or CD3 + CD20 + CD4/CD8 + T cells and the related pro-inflammatory cytokines in the humor aqueous, in mediating retinal microvascular changes in patients with chronic plaque-type moderate to severe psoriasis., Design: A total of 76 patients (57.6 ± 11.7 years) with chronic plaque-type psoriasis were initially evaluated. Nineteen patients (19 eyes) and 19 healthy volunteers (19 eyes) were subjected to dermatological evaluation with Psoriasis Area Severity Index (PASI) and the Dermatology life quality index (DLQI). Retinal images were processed using an automatized software. On the same day, a venous sample was collected and analyzed using multiparametric flow cytometry. Three out of 6 patients who presented cataract, consented to perform surgery with humor aqueous collection. The samples were analyzed using a Multi-Analyte ELISA kit for the simultaneous quantification of IL1α, IL1β, IL2, IL4, IL6, IL8, IL10, IL12, IL17A, IFNγ, TNF-α, GMCSF., Results: The CD3 + CD4 + /CD8 + CD20 + CD56 - T cells expression was greater in the psoriatic patients (+73.9%, P < 0.001) compared to controls, but not the DN T cells (-8.2%, P = 0.30). Ocular complications were diagnosed in 61.1% of patients, microvascular parameters including artero-venous ratio (P = 0.04), subfoveal choriocapillaris/Sattler's layer, and choroidal thickness (CT, both P < 0.001) were significantly altered in psoriasis subgroup. The increased circulating levels of the CD3 + CD4 + /CD8 + CD20 + CD56 - T cells were associated with thinning of subfoveal CT (P = 0.03) and Haller's layer (P = 0.01). Instead, the DN T cells presented an inverse relationship with disease duration (P = 0.02), DLQI score (P = 0.02), and the use of biological therapy (P = 0.05). The related cytokine patterns possibly modified in this cellular context have been investigated. No significant differences were observed in cytokines levels between psoriasis and controls, the most significant difference was detected on IL-6, without reaching statistical significance (fold change of 1.4, P = 0.13)., Conclusion: Our findings demonstrated that CD20 + T cell subpopulation is highly represented in psoriasis regardless of the use of immunomodulatory therapies, and the diffuse microvascular alterations suggested possible endothelial damage as mainstream for the genesis of psoriatic-mediated complications as further supported by the comparable concentrations of cytokines, at least as humor aqueous content, with respect to healthy eyes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aims: Literature highlights the role of risk factors like age, body mass index (BMI), tobacco smoking, alcohol intake and diet in the pathogenesis of several cancer types but little is known for non-melanoma skin cancers (NMSC). The aim of this epidemiological study was to evaluate the correlation between modifiable risk factors (BMI, metabolic panel, diet, lifestyle, medical history) and not modifiable risk factors (gender, age) and NMSC development., Methods: From February 2018 to September 2019, 162 patients affected by NMSC were compared to a group of 167 controls. A univariate and multivariate analysis was conducted to elaborate the data collected through face-to-face interviews., Results: While our evidence did not always reach statistical significance, NMSC study group patients exhibited high rates of analyzed risk factors (male gender aging over 55 years, high BMI, reduced physical activity) compared to the control group., Conclusions: Our study indicates that practicing more than 30 min of physical activity daily could be a protective factor against the NMSC onset. Other risk factors were not correlated with NMSC, but more evidence is needed to establish a possible link.

Acne is a chronic inflammatory relapsing disease that affect predominantly adolescents, with scarring as a frequent sequele. Early and appropriate therapy allows better management of the disease, longer remission, scars risk reduction, and improvement of quality of life. According to therapeutic algorithm, systemic isotretinoin can be used in severe acne and also in moderate forms resistant to other systemic treatments. The aims of this real-life observational study were to determine and compare the effectiveness of isotretinoin evaluated by Global Acne Grading System and Acne Quality of Life in moderate and in severe acne, correlation between efficacy and cumulative dose of isotretinoin, tolerability, and recurrence rate. Moreover, the differences in efficacy and tolerability between male and female patients were compared. The treatment with systemic isotretinoin led to an improvement in acne severity and quality of life in all observed subjects., (© 2020 Wiley Periodicals LLC.)

This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of 'escape routes', so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

Actinic keratosis (AK) is a common skin disease related to ultraviolet chronic exposure, that is now considered a squamous cell carcinoma in situ. Primary skin cancer prevention strategies should be recommended for high risk patients. There is a wide spectrum of treatment options available for AKs, and several variables should be taken into account regarding the best therapeutic choice for each patient. The purpose of this article is to review the current treatment strategies for AKs localized on the face and scalp, with a focus on the practical point of view that could be useful for choosing the best therapeutic option. The two main therapeutic approaches will be distinguished first: lesion-directed and field-directed. Afterwards, the treatment based on clinical type and patient comorbidity will be discussed.

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa , transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.

The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma.

An early identification of non-responders in oncology is of crucial importance to rapidly switch treatment regimens. Here we report a positron emission tomography, (PET)-guided switch from immunotherapy to targeted therapy in a patient affected by metastatic melanoma. We describe the case of a 78-years-old male patient diagnosed with nodular melanoma, submitted to baseline PET/CT with 18fluorodeoxyglucose (18F-FDG) that showed cutaneous and skeletal metastases (stage IV). The patients started immunotherapy with pembrolizumab. A PET/CT performed 3 months after the start of immunotherapy demonstrated progressive metabolic disease both at skeletal and cutaneous level, confirmed also by the biopsy. As patients resulted positive for BRAF V600k mutation, treatment regimen was rapidly switched to combined anti-BRAF/MEK targeted therapy. The PET/CT performed 3 months later, showed almost complete metabolic response. Ten months after the beginning of targeted therapy, the patient continues to present a durable metabolic response. PET/CT with 18F-FDG may help in monitoring the response to treatment in metastatic melanoma thus defining personalized therapeutic pathways.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with elevated prevalence of comorbidities, especially metabolic and cardiovascular diseases. We used a tool called Heart Rate Variability (HRV) in order to assess the correlation between HS and alterations of the sympathetic-vagal equilibrium in the autonomic cardiovascular regulation system. We found increased sympathetic activity, associated with a higher risk of cardiovascular disease. HS, according to our results, is an independent cardiovascular risk factor., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Nevena Skroza et al.)

Introduction: This Italian multicenter retrospective study evaluated safety and efficacy of the anti-TNF drug, adalimumab, in a cohort of patients affected by tuberculosis (TB), hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). Psoriasis is an autoimmune disease affecting around 3% of the Italian population and associated with several comorbidities, including arthritis, cardio-metabolic diseases and depression. In its moderate-to-severe form, psoriasis profoundly impairs quality of life of patients., Aim: Therefore, these patients deserve systemic treatments including conventional DMARDS (disease modifying anti-rheumatic drugs) and biologics. Management of moderate and severe psoriasis patients affected by relevant infections such as TB, HBV, HCV and HIV may be difficult because of the toxicity of the conventional systemic treatment., Material and Methods: The CONNECTING study analysed 28 moderate to severe psoriasis patients infected by TB, HBV, HCV and HIV who were treated with adalimumab for up to 96 weeks together with respective prophylactic treatment., Results: We observed a rapid decrease in PASI (psoriasis area severity index) reaching a 75% improvement in 91% of patients. Some of these patients ( n = 9) were also affected by arthritic comorbidity. The patients experienced a rapid decrease in pain, measured by pain VAS (visual analogic scale) that reached 0 in all of them. Monitoring of the respective infection did not show any worsening or reactivation of infection or any severe adverse events during the entire observation period., Conclusions: Adalimumab is effective and safe in patients affected by these important infections., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2020 Termedia Sp. z o. o.)

Background and Aim: Patients with Parkinson's disease (PD) are often characterized by functional gastrointestinal disorders. Such disturbances can occur at all stages of PD and precede the typical motor symptoms of the disease by many years. However, the morphological alterations associated with intestinal disturbances in PD are undetermined. This study examined the remodelling of colonic wall in 6-hydroxydopamine (6-OHDA)-induced PD rats., Methods: 8 weeks after 6-OHDA injection animals were sacrificed. Inflammatory infiltrates, collagen deposition and remodelling of intestinal epithelial barrier and tunica muscularis in the colonic wall were assessed by histochemistry, immunohistochemistry, immunofluorescence and western blot analysis., Results: 6-OHDA rats displayed significant alterations of colonic tissues as compared with controls. Signs of mild inflammation (eosinophil infiltration) and a transmural deposition of collagen fibres were observed. Superficial colonic layers were characterized by severe morphological alterations. In particular, lining epithelial cells displayed a reduced claudin-1 and transmembrane 16A/Anoctamin 1 (TMEM16A/ANO1) expression; goblet cells increased their mucin expression; colonic crypts were characterized by an increase in proliferating epithelial cells; the density of S100-positive glial cells and vimentin-positive fibroblast-like cells was increased as well. Several changes were found in the tunica muscularis: downregulation of α-smooth muscle actin/desmin expression and increased proliferation of smooth muscle cells; increased vimentin expression and proliferative phenotype in myenteric ganglia; reduction of interstitial cells of Cajal (ICCs) density., Conclusions: A pathological remodelling occurs in the colon of 6-OHDA rats. The main changes include: enhanced fibrotic deposition; alterations of the epithelial barrier; activation of mucosal defense; reduction of ICCs. These results indicate that central nigrostriatal denervation is associated with histological changes in the large bowel at mucosal, submucosal and muscular level. These alterations might represent morphological correlates of digestive symptoms in PD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC -/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD., Competing Interests: The authors declare no conflict of interest.

A number of digestive and extra-digestive disorders, including inflammatory bowel diseases, irritable bowel syndrome, intestinal infections, metabolic syndrome and neuropsychiatric disorders, share a set of clinical features at gastrointestinal level, such as infrequent bowel movements, abdominal distension, constipation and secretory dysfunctions. Several lines of evidence indicate that morphological and molecular changes in intestinal epithelial barrier and enteric neuromuscular compartment contribute to alterations of both bowel motor and secretory functions in digestive and extra-digestive diseases. The present review has been conceived to provide a comprehensive and critical overview of the available knowledge on the morphological and molecular changes occurring in intestinal epithelial barrier and enteric neuromuscular compartment in both digestive and extra-digestive diseases. In addition, our intent was to highlight whether these morphological and molecular alterations could represent a common path (or share some common features) driving the pathophysiology of bowel motor dysfunctions and related symptoms associated with digestive and extra-digestive disorders. This assessment might help to identify novel targets of potential usefulness to develop original pharmacological approaches for the therapeutic management of such disturbances., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Recent data support the theory of the involvement of IL-17 in the pathogenesis of several chronic inflammatory skin diseases (psoriasis, atopic dermatitis, acne, hidradenitis suppurativa) and autoimmune skin diseases (alopecia areata, vitiligo, bullous diseases). Even if the role of IL-17 in inflammatory and autoimmune diseases has been reported extensively, its role in tumor is still controversial. Some reports show that Th17 cells eradicate tumors, while others reveal that they promote the initiation and early growth of tumors. Herein, we review the role of IL-17 in the involvement of some common dermatologic diseases: psoriasis, atopic dermatitis, hidradenitis suppurativa, acne, vitiligo, melanoma, and nonmelanoma skin cancers., (© 2020 The Authors. International Journal of Dermatology published by Wiley Periodicals, Inc. on behalf of International Society of Dermatology.)

Background: Inadequate treatment and delayed access to care represent critical issues regarding psoriasis. In Italy, patients treated with biologics are scanty and patients' misinformation could interfere with both biologics prescription and access to care. Literature provide data on disease awareness and perception about biologics in already-treated patients, but there is a lack of information concerning patients never treated with such drugs., Methods: We conducted a national survey including three academic-based psoriasis care centers at Bologna, Rome and Catania. A questionnaire named Psoriatic Patients's Awareness on Biologics (PPAB) was administered to patients naïve for biologics and accessing for the fist-time to a psoriasis care center., Results: Patients from Northern Italy referred to more reliable sources of information and awareness on biologics decreased from North to South. The increase of the Psoriasis Area Severity Index was associated to unawareness about biologics and impaired self-evaluation on the eligibility to treatment. Patients under systemic conventional /multiple therapy were more likely to be unaware about biologics., Conclusions: Our survey demonstrates that psoriatic patients' awareness is still an unmet need. For more, patients potentially eligible for biologics (severe or treated with systemic conventional/multiple therapy) were less informed. We believe that patients' misinformation could have delayed the access to a psoriasis care center, so that when patients sought help their condition was more severe and required systemic conventional/multiple therapy. Our results reiterate the importance of physicians in the information process and urge the need of a common network among office dermatologists, general practitioners and psoriasis care centers.

Erythroplasia of Queyrat (EQ) is a rare disease involving the mucosal and transitional surfaces of the penis. Effective treatment is necessary to minimize progression to squamous cell carcinoma. The standard therapy for EQ, partial or radical penectomy, is invasive; photodynamic therapy (PDT) may be an effective, non-surgical tissue-sparing option. We report the case of a 67-year-old patient with long-standing EQ who was suc-cessfully treated with methyl aminolevulinate-PDT (MAL-PDT). A complete clinical response, confirmedby incisional biopsy, was achieved af-ter fivesessions of every-other-week treatment. The patient experienced moderate edema, erythema and pain within 5-7 days after the treatment, without urination problems. Our experience and a review of the published literature suggest that MAL-PDT may represent a valuable treatment option for selected cases of histopathologically-confirmed EQ.

Psoriasis is a chronic inflammatory systemic disease caused by deregulation of the interleukin-23/-17 axis that allows the activation of Th17 lymphocytes and the reprogramming of keratinocytes proliferative response, thereby inducing the secretion of cyto-/chemokines and antimicrobial peptides. Beside cell-to-cell contacts and release of cytokines, hormones and second messengers, cells communicate each other through the release of extracellular vesicles containing DNA, RNA, microRNAs and proteins. It has been reported the alteration of extracellular vesicles trafficking in several diseases, but there is scarce evidence of the involvement of extracellular vesicles trafficking in the pathogenesis of psoriasis. The main goal of the study was to characterize the release, the cargo content and the capacity to transfer bioactive molecules of extracellular vesicles produced by keratinocytes following recombinant IL-17A treatment if compared to untreated keratinocytes. A combined approach of standard ultracentrifugation, RNA isolation and real-time RT-PCR techniques was used to characterize extracellular vesicles cargo. Flow cytometry was used to quantitatively and qualitatively analyse extracellular vesicles and to evaluate cell-to-cell extracellular vesicles transfer. We report that the treatment of human keratinocytes with IL-17A significantly modifies the extracellular vesicles cargo and release. Vesicles from IL-17A-treated cells display a specific pattern of mRNA which is undid by IL-17A neutralization. Extracellular vesicles are taken up by acceptor cells irrespective of their content but only those derived from IL-17A-treated cells enable recipient cells to express psoriasis-associated mRNA. The results imply a role of extracellular vesicles in amplifying the pro-inflammatory cascade induced in keratinocyte by pro-psoriatic cytokines., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: There are no conflicts of interest.

Background: Consensus among dermatologists and rheumatologists in the diagnosis and assessment of musculoskeletal diseases in psoriasis (PsO) patients is needed. This study assesses characteristics of musculoskeletal pain in patients with PsO for the presence of psoriatic arthritis (PsA) and evaluation of a novel 16-item visual instrument (PsA-Disk)., Methods: Data were collected from eight dermatological/rheumatological centres across Italy. Patients with PsO completed PEST (Psoriasis Epidemiology Screening Tool) and PsA-Disk questionnaires during the first visit. A rheumatological visit was performed to confirm the presence of PsA. Both validity and reliability of PsA-Disk were assessed., Results: A total of 573 patients with PsO were examined at the first visit, and 120 (21%) were diagnosed with PsA. Patients with PsA compared with patients with PsO ( n = 119) presented statistically significant differences for: nail involvement, PEST score ⩾3, higher erythrocyte sedimentation rate (ESR), Nail Psoriasis Severity Index (NAPSI)-feet, NAPSI-(hands + feet) and PsA-Disk scores (73.9 ± 32.1 versus 58.1 ± 39.8, p  < 0.001). Patients with PsA with knee arthritis had higher PsA-Disk scores (98.4 ± 26 versus 71.5 ± 31.9, p  = 0.006) that were also correlated with number of swollen ( r  = 0.2, p < 0.05) and tender joints ( r = 0.24, p = 0.021), patient ( r = 0.4, p < 0.001) and physician-pain-visual analogue scale (VAS; r = 0.33, p < 0.001), patient global assessment (PGA)-VAS ( r = 0.23, p = 0.025), physician-health assessment questionnaire (HAQ; r = 0.38, p = 0.011), Disease Activity Score (DAS)-44 ( r = 0.25, p = 0.023) and Disease Activity in Psoriatic Arthritis (DAPSA; r = 0.31, p = 0.005). The instrument had excellent reliability in terms of internal consistency (Cronbach's alpha = 0.90) and stability (intraclass correlation = 0.98). Moderate agreement between PsA-Disk and PEST (Cohen's kappa = 0.46) was observed, while construct validity appeared appropriate [PsA + patients: PsA-Disk score (interquartile range; IQR) =71 (50-96); PsA-patients: PsA-Disk score (IQR)=50 (20-90); p < 0.001]., Conclusion: PsA-Disk may be considered a valid novel instrument aiding both dermatologists and rheumatologists in the rapid detection and assessment of musculoskeletal disease characteristics., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.