Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children

Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-"boosted" lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines

Hidradenitis Suppurativa: A Perspective on Genetic Factors Involved in the Disease.

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease of the pilosebaceous unit, clinically consisting of painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin areas. HS can be defined as a complex skin disease with multifactorial etiologies, including-among others-genetic, immunologic, epigenetic, and environmental factors. Based on genetic heterogeneity and complexity, three different forms can be recognized and considered separately as sporadic, familial, and syndromic. To date, several genetic variants associated to disease susceptibility, disease-onset, and/or treatment response have been reported; some of these reside in genes encoding the gamma-secretase subunits whereas others involve autoinflammatory and/or keratinization genes. The aim of this perspective work is to provide an overview of the contribution of several genetic studies encompassing family linkage analyses, target candidate gene studies, and -omic studies in this field. In our viewpoint, we discuss the role of genetics in Hidradenitis suppurativa considering findings based on Sanger sequencing as well as the more recent Next Generation Sequencing (i.e., exome sequencing or RNA Sequencing) with the aim of better understanding the etio-pathogenesis of the disease as well as identifying novel therapeutic strategies.ThisworkwassupportedbyaBiomolecularAnalysesforTailoredMedicineinAcneiNversa (BATMAN)project, funded by ERA PerMed (JTC_2018) to A.V.M and S.C. and by a Starting Grant (SG-2019-12369421) funded by the Italian Ministry of Health to P.M.T

Clinical and molecular characterization of hidradenitis suppurativa: a practical framework for novel therapeutic targets.

Background: The pathophysiological picture underlying hidradenitis suppurativa (HS) and its syndromic forms is still patchy, thus presenting a great challenge for dermatologists and researchers since just by better understanding the pathogenesis of disease we could identify novel therapeutic targets. Methods: We propose a practical framework to improve subcategorization of HS patients and support the genotype-phenotype correlation, useful for endotype-directed therapies development. Results: This framework includes (i) clinical work-up that involves the collection of demographic, lifestyle, and clinical data as well as the collection of different biological samples; (ii) genetic-molecular work-up, based on multi-omics analysis in combination with bioinformatics pipelines to unravel the complex etiology of HS and its syndromic forms; (iii) functional studies, – represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D) and organoids –, of candidate biomarkers and genetic findings necessary to validate novel potential molecular mechanisms possibly involved and druggable in HS; (iv) genotype-phenotype correlation and clinical translation in tailored targeted therapies. Conclusion: Omic findings should be merged and integrated with clinical data; moreover, the skin-omic profiles from each HS patient should be matched and integrated with the ones already reported in public repositories, supporting the efforts of the researchers and clinicians to discover novel biomarkers and molecular pathways with the ultimate goal of providing faster development of novel patient-tailored therapeutic approaches.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERAPerMed, by Starting Grant (SG-2019-12369421) funded by the Italian Ministry of Health, by Grant (RC16/2018) from the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” funded by the Italian Ministry of Health, and by a grant from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan (protocol No. 487_2020). This work was also partially supported by Italian Ministry of Health (Ricerca Corrente 2023)/Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Italy

Multiomics integration in skin diseases with alterations in notch signaling pathway: PlatOMICs phase 1 deployment

The high volume of information produced in the age of omics was and still is an important step to understanding several pathological processes, providing the enlightenment of complex molecular networks and the identification of molecular targets associated with many diseases. Despite these remarkable scientific advances, the majority of the results are disconnected and divergent, making their use limited. Skin diseases with alterations in the Notch signaling pathway were extensively studied during the omics era. In the GWAS Catalog, considering only studies on genomics association (GWAS), several works were deposited, some of which with divergent results. In addition, there are thousands of scientific articles available about these skin diseases. In our study, we focused our attention on skin diseases characterized by the impairment of Notch signaling, this pathway being of pivotal importance in the context of epithelial disorders. We considered the pathologies of five human skin diseases, Hidradenitis Suppurativa, Dowling Degos Disease, Adams-Oliver Syndrome, Psoriasis, and Atopic Dermatitis, in which the molecular alterations in the Notch signaling pathway have been reported. To this end, we started developing a new multiomics platform, PlatOMICs, to integrate and re-analyze omics information, searching for the molecular interactions involved in the pathogenesis of skin diseases with alterations in the Notch signaling pathway.This work was supported by a grant from the Institute for Maternal and Child Health IRCCS “Burlo Garofolo/Italian Ministry of Health” (BioHub 03/20), by the grant Interreg Italia-Slovenia, ISE-EMH 07/2019 and by CNPq (311415/2020-2)

Aquaporins Are One of the Critical Factors in the Disruption of the Skin Barrier in Inflammatory Skin Diseases

The skin is the largest organ of the human body, serving as an effective mechanical barrier between the internal milieu and the external environment. The skin is widely considered the first-line defence of the body, with an essential function in rejecting pathogens and preventing mechanical, chemical, and physical damages. Keratinocytes are the predominant cells of the outer skin layer, the epidermis, which acts as a mechanical and water-permeability barrier. The epidermis is a permanently renewed tissue where undifferentiated keratinocytes located at the basal layer proliferate and migrate to the overlying layers. During this migration process, keratinocytes undertake a differentiation program known as keratinization process. Dysregulation of this differentiation process can result in a series of skin disorders. In this context, aquaporins (AQPs), a family of membrane channel proteins allowing the movement of water and small neutral solutes, are emerging as important players in skin physiology and skin diseases. Here, we review the role of AQPs in skin keratinization, hydration, keratinocytes proliferation, water retention, barrier repair, wound healing, and immune response activation. We also discuss the dysregulated involvement of AQPs in some common inflammatory dermatological diseases characterised by skin barrier disruption.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed (JTC_2018) to S.C.; by a Starting Grant (SG- 2019-12369421) funded by Italian Ministry of Health to P.M.T.; by two grants, from the Italian Ministry of University and Research (MUR) “Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale 2017” (PRIN2017 # 2017J92TM5) and “Fondo Integrativo Speciale per la Ricerca 2020” (FISR 2020 CoVAPin # FISR2020IP_04051), to Giuseppe Calamita; and a grant from the University of Bari “Horizon Europe Seeds 2022-2023” (Uniba Euroseeds #S10) to Giuseppe Calamita

Pleiotropic role of notch signaling in human skin diseases

Notch signaling orchestrates the regulation of cell proliferation, differentiation, migration and apoptosis of epidermal cells by strictly interacting with other cellular pathways. Any disruption of Notch signaling, either due to direct mutations or to an aberrant regulation of genes involved in the signaling route, might lead to both hyper-or hypo-activation of Notch signaling molecules and of target genes, ultimately inducing the onset of skin diseases. The mechanisms through which Notch contributes to the pathogenesis of skin diseases are multiple and still not fully understood. So far, Notch signaling alterations have been reported for five human skin diseases, suggesting the involvement of Notch in their pathogenesis: Hidradenitis Suppurativa, Dowling Degos Disease, Adams–Oliver Syndrome, Psoriasis and Atopic Dermatitis. In this review, we aim at describing the role of Notch signaling in the skin, particularly focusing on the principal consequences associated with its alterations in these five human skin diseases, in order to reorganize the current knowledge and to identify potential cellular mechanisms in common between these pathologies.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed and by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health’ (RC16/2018

Holistic health record for Hidradenitis suppurativa patients.

Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease with a complex etiopathogenesis whose treatment poses a challenge in the clinical practice. Here, we present a novel integrated pipeline produced by the European consortium BATMAN (Biomolecular Analysis for Tailored Medicine in Acne iNversa) aimed at investigating the molecular pathways involved in HS by developing new diagnosis algorithms and building cellular models to pave the way for personalized treatments. The objectives of our european Consortium are the following: (1) identify genetic variants and alterations in biological pathways associated with HS susceptibility, severity and response to treatment; (2) design in vitro two-dimensional epithelial cell and tri-dimensional skin models to unravel the HS molecular mechanisms; and (3) produce holistic health records HHR to complement medical observations by developing a smartphone application to monitor patients remotely. Dermatologists, geneticists, immunologists, molecular cell biologists, and computer science experts constitute the BATMAN consortium. Using a highly integrated approach, the BATMAN international team will identify novel biomarkers for HS diagnosis and generate new biological and technological tools to be used by the clinical community to assess HS severity, choose the most suitable therapy and follow the outcome.This work was supported by a Biomolecular Analyses for Tailored Medicine in AcneiNversa (BATMAN) project, funded by ERA PerMed (JTC_2018) through the Italian Ministry of Health, the “Fondazione Regionale per la Ricerca Biomedica” (FRRB), the Slovenian Ministry of Education, Science, and Sport (MIZŠ), the Austrian Science fund (I 4229), the Federal Ministry of Education and Research Germany (BMBF), and ANR automate (ANR-20-CE15-0018-01). This work was also supported by and by a grant from the Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo/Italian Ministry of Health (RC16/2018) and by a Starting Grant (SG-2019-12369421) founded by the Italian Ministry of Health. Figures were created with BioRender.com

Transcriptome Meta-Analysis Confirms the Hidradenitis Suppurativa Pathogenic Triad: Upregulated Inflammation, Altered Epithelial Organization, and Dysregulated Metabolic Signaling

Hidradenitis suppurativa (HS) is an inflammatory skin condition clinically characterized by recurrent painful deep-seated nodules, abscesses, and sinus tracks in areas bearing apocrine glands, such as axillae, breasts, groins, and buttocks. Despite many recent advances, the pathophysiological landscape of HS still demands further clarification. To elucidate HS pathogenesis, we performed a meta-analysis, set analysis, and a variant calling on selected RNA-Sequencing (RNA-Seq) studies on HS skin. Our findings corroborate the HS triad composed of upregulated inflammation, altered epithelial differentiation, and dysregulated metabolism signaling. Upregulation of specific genes, such as KRT6, KRT16, serpin-family genes, and SPRR3 confirms the early involvement of hair follicles and the impairment of barrier function in HS lesioned skin. In addition, our results suggest that adipokines could be regarded as biomarkers of HS and metabolic-related disorders. Finally, the RNA-Seq variant calling identified several mutations in HS patients, suggesting potential new HS-related genes associated with the sporadic form of this disease. Overall, this study provides insights into the molecular pathways involved in HS and identifies potential HS-related biomarkers.This work was supported by “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)”—Finance Code 001, Fondation René Touraine, “Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)” (311415/2020-2 and 430353/2018-9), and EraPerMed 2018-17 European Community funds. L.A.C.B. is supported by CNPq (311415/2020-2). This work was also supported by the Italian Ministry of Health, through the contribution given to the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy for the Starting Grant (SG-2019-12369421) and for RC03/2020

A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach