Disentangling the complexity of psoriasis in the post-genome-wide association era.

In recent years, genome-wide association studies (GWAS) have been instrumental in unraveling the genetic architecture of complex diseases, including psoriasis. The application of large-scale GWA studies in psoriasis has illustrated several associated loci that participate in the cutaneous inflammation, however explaining a fraction of the disease heritability. With the advent of high-throughput sequencing technologies and functional genomics approaches, the post-GWAS era aims to unravel the functional mechanisms underlying the inter-individual variability in psoriasis patients. In this review, we present the key advances of psoriasis GWAS in under-represented populations, rare, non-coding and structural variants and epistatic phenomena that orchestrate the interplay between different cell types. We further review the gene-gene and gene-environment interactions contributing to the disease predisposition and development of comorbidities through Mendelian randomization studies and pleiotropic effects of psoriasis-associated loci. We finally examine the holistic approaches conducted in psoriasis through system genetics and state-of-the-art transcriptomic analyses, discussing their potential implication in the expanding field of precision medicine and characterization of comorbidities.

Protein network and pathway analysis in a pharmacogenetic study of cyclosporine treatment response in Greek patients with psoriasis.

Although cyclosporine comprises a well-established systemic therapy for psoriasis, patients show important heterogeneity in their treatment response. The aim of our study was the pharmacogenetic analysis of 200 Greek patients with psoriasis based on the cyclosporine pathway related protein-protein interaction (PPI) network, reconstructed through the PICKLE meta-database. We genotyped 27 single nucleotide polymorphisms, mapped to 22 key protein nodes of the cyclosporine pathway, via the utilization of the iPLEX®GOLD panel of the MassARRAY® System. Single-SNP analyses showed statistically significant associations between CALM1 rs12885713 (P = 0.0108) and MALT1 rs2874116 (P = 0.0006) polymorphisms with positive response to cyclosporine therapy after correction for multiple comparisons, with the haplotype analyses further enhancing the predictive value of rs12885713 as a pharmacogenetic biomarker for cyclosporine therapy (P = 0.0173). Our findings have the potential to improve our prediction of cyclosporine efficacy and safety in psoriasis patients, as well as provide the framework for the pharmacogenetics of biological therapies in complex diseases.

Revisiting miRNA Association with Melanoma Recurrence and Metastasis from a Machine Learning Point of View.

The diagnostic and prognostic value of miRNAs in cutaneous melanoma (CM) has been broadly studied and supported by advanced bioinformatics tools. From early studies using miRNA arrays with several limitations, to the recent NGS-derived miRNA expression profiles, an accurate diagnostic panel of a comprehensive pre-specified set of miRNAs that could aid timely identification of specific cancer stages is still elusive, mainly because of the heterogeneity of the approaches and the samples. Herein, we summarize the existing studies that report several miRNAs as important diagnostic and prognostic biomarkers in CM. Using publicly available NGS data, we analyzed the correlation of specific miRNA expression profiles with the expression signatures of known gene targets. Combining network analytics with machine learning, we developed specific non-linear classification models that could successfully predict CM recurrence and metastasis, based on two newly identified miRNA signatures. Subsequent unbiased analyses and independent test sets (i.e., a dataset not used for training, as a validation cohort) using our prediction models resulted in 73.85% and 82.09% accuracy in predicting CM recurrence and metastasis, respectively. Overall, our approach combines detailed analysis of miRNA profiles with heuristic optimization and machine learning, which facilitates dimensionality reduction and optimization of the prediction models. Our approach provides an improved prediction strategy that could serve as an auxiliary tool towards precision treatment.

Pharmacoepigenomics circuits induced by a novel retinoid-polyamine conjugate in human immortalized keratinocytes.

Retinoids are widely used in diseases spanning from dermatological lesions to cancer, but exhibit severe adverse effects. A novel all-trans-Retinoic Acid (atRA)-spermine conjugate (termed RASP) has shown previously optimal in vitro and in vivo anti-inflammatory and anticancer efficacy, with undetectable teratogenic and toxic side-effects. To get insights, we treated HaCaT cells which resemble human epidermis with IC50 concentration of RASP and analyzed their miRNA expression profile. Gene ontology analysis of their predicted targets indicated dynamic networks involved in cell proliferation, signal transduction and apoptosis. Furthermore, DNA microarrays analysis verified that RASP affects the expression of the same categories of genes. A protein-protein interaction map produced using the most significant common genes, revealed hub genes of nodal functions. We conclude that RASP is a synthetic retinoid derivative with improved properties, which possess the beneficial effects of retinoids without exhibiting side-effects and with potential beneficial effects against skin diseases including skin cancer.

KRASG12C Can Either Promote or Impair Cap-Dependent Translation in Two Different Lung Adenocarcinoma Cell Lines.

KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFRWT CL1-5 and A549 cells for integration of a Tet-inducible KRASG12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRASG12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRASG12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRASG12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.

Mammalian PNLDC1 is a novel poly(A) specific exonuclease with discrete expression during early development.

PNLDC1 is a homologue of poly(A) specific ribonuclease (PARN), a known deadenylase with additional role in processing of non-coding RNAs. Both enzymes were reported recently to participate in piRNA biogenesis in silkworm and C. elegans, respectively. To get insights on the role of mammalian PNLDC1, we characterized the human and mouse enzymes. PNLDC1 shows limited conservation compared to PARN and represents an evolutionary related but distinct group of enzymes. It is expressed specifically in mouse embryonic stem cells, human and mouse testes and during early mouse embryo development, while it fades during differentiation. Its expression in differentiated cells, is suppressed through methylation of its promoter by the de novo methyltransferase DNMT3B. Both enzymes are localized mainly in the ER and exhibit in vitro specificity restricted solely to 3' RNA or DNA polyadenylates. Knockdown of Pnldc1 in mESCs and subsequent NGS analysis showed that although the expression of the remaining deadenylases remains unaffected, it affects genes involved mainly in reprogramming, cell cycle and translational regulation. Mammalian PNLDC1 is a novel deadenylase expressed specifically in cell types which share regulatory mechanisms required for multipotency maintenance. Moreover, it could be involved both in posttranscriptional regulation through deadenylation and genome surveillance during early development.

Expanding the repertoire of deadenylases.

Deadenylases belong to an expanding family of exoribonucleases involved mainly in mRNA stability and turnover, with the exception of PARN which has additional roles in the biogenesis of several important non-coding RNAs, including miRNAs and piRNAs. Recently, PARN in C. elegans and its homolog PNLDC1 in B. mori were reported as the elusive trimmers mediating piRNA biogenesis. In addition, characterization of mammalian PNLDC1 in comparison to PARN, showed that is specifically expressed in embryonic stem and germ cells, as well as during early embryo development. Moreover, its expression is correlated with epigenetic events mediated by the de novo DNMT3b methyltransferase and knockdown in stem cells upregulates important genes that regulate multipotency. The recent data suggest that at least some new deadenylases may have expanded roles in cell metabolism as regulators of gene expression, through mRNA deadenylation, ncRNAs biogenesis and ncRNA-mediated mRNA targeting, linking essential mechanisms that regulate epigenetic control and transition events during differentiation. The possible roles of mammalian PNLDC1 along those dynamic networks are discussed in the light of new extremely important findings.

Investigation on Toxicity and Teratogenicity in Rats of a Retinoid-Polyamine Conjugate with Potent Anti-Inflammatory Properties.

Previous studies have shown that N(1),N(12)-bis(all-trans-retinoyl)spermine (RASP), a retinoid analog, inhibits RNase P activity and angiogenesis in the chicken embryo chorioallantoic membrane, demonstrates anti-tumor activity on prostate cancer cells, and acts as anti-inflammatory agent, being more effective and less toxic than all-trans retinoic acid. In an attempt to further characterize the biological profile of RASP, we tested its effects on organ toxicity and teratogenicity by daily oral gavage of RASP at a level of 50 mg/Kg of body weight in two generations of rats. We found that this compound does not induce changes to the body growth, the appearance of physical features, and the animal's reflexes. Additionally, no substantial histopathological lesions were found in brain, heart, lung, thymus, liver, thyroid gland, adrenal gland, pituitary gland, kidneys, spleen, skin, femora, prostate, testis, epididymis, vagina, uterus, and ovaries of RASP-treated animals. These results suggest RASP, as a promising lead compound for the treatment of several dermatological disorders and certain cancer types, has apparently minimal toxic side-effects as revealed in this two-generation reproduction study in rats.

Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids.

Selective alkylation of the antipsoriatic drug dithranol (DTR) at C-10 with tert-butyl bromoacetate, followed by acid-mediated deprotection, produced the corresponding carboxylic acid 4 which was coupled with selectively protected polyamines (PAs), such as putrescine (PUT), spermidine (SPD) and spermine (SPM), dopamine and aliphatic amines and substituted benzylamines producing a series of DTR-PA hybrids, after acid-mediated deprotection, as well as simple amides. The compounds were tested as antioxidants and inhibitors of lipoxygenase (LOX). The amides 4,4'-dimethoxybenzhydrylamide 13 (86% and 95%), 2,4-dimethoxybenzylamide 12 (87% and 81%) and dodecylamide 9 (98% and 74%), and the hybrid DTR-SPM (7) (93% and 87%), showed the highest antioxidant activity in the DPPH and AAPH assays, whereas the most potent inhibitors of LOX were amide 13 (IC50=7 µM), the benzylamide 10 (IC50=7.9 µM) and the butylamide 8 (IC50=10 µM). Molecular binding studies showed that binding of these derivatives into the hydrophobic domain blocks approach of substrate to the active site, inhibiting soybean LOX. Amide 13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester 3 (IC50=0.357 µM) and the amides 9 (IC50=0.022 µM) and 13 (IC50=0.56 µM) exhibited higher antiproliferative activity than DTR (IC50=0.945 µM) on HaCaT keratinocytes whereas amide 13 generally presented better cytocompatibility. Amide 13 is a very promising lead compound for further development as an anti-inflammatory and antiproliferative agent.

Neuroticism and inflammatory skin diseases: a bidirectional Mendelian randomization study.

Previous observational studies have linked inflammatory skin diseases with mental health issues and neuroticism. However, the specific impact of neuroticism and its subclusters (i.e. worry, depressed affect, and sensitivity to environmental stress and adversity) on these conditions remains underexplored. In this work, we explored causal associations between common inflammatory skin diseases and neuroticism. We conducted a two-sample, bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies in psoriasis, atopic dermatitis, neuroticism and relevant genetic subclusters conducted on participants of European ancestry. Corrections for sample overlap were applied where necessary. We found that psoriasis was causally associated with increased levels of worry (odds ratio, 95% confidence intervals: 1.011, 1.006-1.016, P = 3.84 × 10-6) while none of the neuroticism subclusters showed significant association with psoriasis. Sensitivity analyses revealed considerable evidence of directional pleiotropy between psoriasis and neuroticism traits. Conversely, genetic liability to atopic dermatitis did not exhibit any significant association with neuroticism traits. Notably, genetically predicted worry was linked to an elevated risk of atopic dermatitis (odds ratio, 95% confidence intervals: 1.227, 1.067-1.41, P = 3.97 × 10-3). Correction for overlapping samples confirmed the robustness of these results. These findings suggest potential avenues for future interventions aimed at reducing stress and worry among patients with inflammatory skin conditions.

Expression profiles of MMP-9 and EMMPRIN in chronic rhinosinusitis with nasal polyps.

Objective: Metalloproteinases (MMPs) are implicated in tissue remodeling in chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the expression profiles of MMP-9 and the extracellular matrix metalloproteinase inducer (EMMPRIN) in nasal polyps compared to healthy mucosa. Methods: Tissue samples from 37 CRSwNP patients undergoing functional endoscopic sinus surgery and mucosal specimens from 12 healthy controls were obtained intra-operatively. MMP-9 and EMMPRIN mRNA levels were assessed by reverse transcription-polymerase chain reaction and their protein expression by Western blot analysis. Results: MMP-9 mRNA expression levels were significantly elevated in CRSwNP compared to controls (p < 0.05). MMP-9 protein levels presented an increasing trend but with no statistical significance (p > 0.05). No statistically significant difference in EMMPRIN mRNA and protein levels was identified. Conclusions: Upregulation of MMP-9 in nasal polyps is evident and highlights its role in the pathogenesis of CRSwNP. The lack of concordance between MMP-9 mRNA and protein levels may be attributed to post-translational gene expression regulation. Although EMMPRIN expression was not significantly different between the two groups, its role remains to be elucidated. MMP-9 may be a valuable biomarker and treatment target in CRSwNP.

Intrinsic Effects of Exposome in Atopic Dermatitis: Genomics, Epigenomics and Regulatory Layers.

Atopic dermatitis (AD) or atopic eczema is an increasingly manifested inflammatory skin disorder of complex etiology which is modulated by both extrinsic and intrinsic factors. The exposome includes a person's lifetime exposures and their effects. We recently reviewed the extrinsic exposome's environmental risk factors that contribute to AD. The periods of pregnancy, infancy, and teenage years are recognized as crucial stages in the formation of AD, where the exposome leads to enduring impacts on the immune system. However, research is now focusing on the interactions between intrinsic pathways that are modulated by the extrinsic exposome, including genetic variation, epigenetic modifications, and signals, such as diet, stress, and microbiome interactions. As a result, immune dysregulation, barrier dysfunction, hormonal fluctuations, and skin microbiome dysbiosis are important factors contributing to AD development, and their in-depth understanding is crucial not only for AD treatment but also for similar inflammatory disorders.

The Imprint of Exposome on the Development of Atopic Dermatitis across the Lifespan: A Narrative Review.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects more than 200 million people worldwide, including up to 20% of children and 10% of the adult population. Although AD appears frequently in childhood and often continues into adulthood, about 1 in 4 adults develop the adult-onset disease. The prenatal period, early childhood, and adolescence are considered critical timepoints for the development of AD when the exposome results in long-lasting effects on the immune system. The exposome can be defined as the measure of all the exposures of an individual during their lifetime and how these exposures relate to well-being. While genetic factors could partially explain AD onset, multiple external environmental exposures (external exposome) in early life are implicated and are equally important for understanding AD manifestation. In this review, we describe the conceptual framework of the exposome and its relevance to AD from conception and across the lifespan. Through a spatiotemporal lens that focuses on the multi-level phenotyping of the environment, we highlight a framework that embraces the dynamic complex nature of exposome and recognizes the influence of additive and interactive environmental exposures. Moreover, we highlight the need to understand the developmental origins of AD from an age-related perspective when studying the effects of the exposome on AD, shifting the research paradigm away from the per se categorized exposome factors and beyond clinical contexts to explore the trajectory of age-related exposome risks and hence future preventive interventions.

Noncoding RNA circuitry in melanoma onset, plasticity, and therapeutic response.

Melanoma, the cancer of the melanocyte, is the deadliest form of skin cancer with an aggressive nature, propensity to metastasize and tendency to resist therapeutic intervention. Studies have identified that the re-emergence of developmental pathways in melanoma contributes to melanoma onset, plasticity, and therapeutic response. Notably, it is well known that noncoding RNAs play a critical role in the development and stress response of tissues. In this review, we focus on the noncoding RNAs, including microRNAs, long non-coding RNAs, circular RNAs, and other small RNAs, for their functions in developmental mechanisms and plasticity, which drive onset, progression, therapeutic response and resistance in melanoma. Going forward, elucidation of noncoding RNA-mediated mechanisms may provide insights that accelerate development of novel melanoma therapies.

Pharmacogenetic Analysis of the MIR146A rs2910164 and MIR155 rs767649 Polymorphisms and Response to Anti-TNF Treatment in Patients with Crohn's Disease and Psoriasis.

The clinical heterogeneity regarding the response profile of the antitumor necrosis factor (anti-TNF) in patients with Crohn's disease (CD) and psoriasis (PsO) is attributed, amongst others, to genetic factors that influence the regulatory mechanisms which orchestrate the inflammatory response. Here, we investigated the possible associations between the MIR146A rs2910164 and MIR155 rs767649 variants and the response to anti-TNF therapy in a Greek cohort of 103 CD and 100 PsO patients. We genotyped 103 CD patients and 100 PsO patients via the PCR-RFLP method, utilizing the de novo formation of a restriction site for the SacI enzyme considering the MIR146A rs2910164, while Tsp45I was employed for the MIR155 rs767649 variant. Additionally, we investigated the potential functional role of the rs767649 variant, exploring in silico the alteration of transcription factor binding sites (TFBSs) mapped on its genomic location. Our single-SNP analysis displayed a significant association between the rare rs767649 A allele and response to therapy (Bonferroni-corrected p value = 0.012) in patients with PsO, a result further enhanced by the alteration in the IRF2 TFBS caused by the above allele. Our results highlight the protective role of the rare rs767649 A allele in the clinical remission of PsO, implying its utilization as a pharmacogenetic biomarker.

Tongue graft-versus-host disease: remission with ruxolitinib.

Graft-versus-host disease (GvHD) is a potentially life-threatening and commonly encountered event of allogeneic haematopoietic stem cell transplantation. Here, we present a young adult male with primary refractory Hodgkin's lymphoma who received a transplant and developed cutaneous GvHD after donor lymphocyte infusion, which was managed with cyclosporine and steroids. However, while the patient was under immunosuppressive treatment, diffuse confluent whitish patches on the patient's tongue were observed. A biopsy of the tongue lesions revealed lichenoid, hyperkeratotic tissue changes and intraepithelial T-cell infiltration consistent with chronic GvHD. He was treated with mycophenolate mofetil for 6 months with minimal improvement. Janus-associated kinase inhibitor (ruxolitinib) treatment was commenced, with complete resolution of the tongue lesions and treatment discontinuation 5 months later. Currently, 5 years after allogeneic transplantation, he is in remission and does not need immunosuppressive therapy.

Making a mouse out of a molehill: how precision modeling repurposes drugs for congenital giant nevi.

Patients with congenital giant nevi (CGN), which can compromise quality of life and progress to melanoma, have limited treatment options. Choi et al. have demonstrated that topical application of a proinflammatory hapten for alopecia treatment [squaric acid dibutylester (SADBE)] caused nevus regression and prevented melanoma in an Nras mouse CGN model. Their results demonstrate the promise of repurposing drugs through precision modeling.

Contribution of the Environment, Epigenetic Mechanisms and Non-Coding RNAs in Psoriasis.

Despite the increasing research and clinical interest in the predisposition of psoriasis, a chronic inflammatory skin disease, the multitude of genetic and environmental factors involved in its pathogenesis remain unclear. This complexity is further exacerbated by the several cell types that are implicated in Psoriasis's progression, including keratinocytes, melanocytes and various immune cell types. The observed interactions between the genetic substrate and the environment lead to epigenetic alterations that directly or indirectly affect gene expression. Changes in DNA methylation and histone modifications that alter DNA-binding site accessibility, as well as non-coding RNAs implicated in the post-transcriptional regulation, are mechanisms of gene transcriptional activity modification and therefore affect the pathways involved in the pathogenesis of Psoriasis. In this review, we summarize the research conducted on the environmental factors contributing to the disease onset, epigenetic modifications and non-coding RNAs exhibiting deregulation in Psoriasis, and we further categorize them based on the under-study cell types. We also assess the recent literature considering therapeutic applications targeting molecules that compromise the epigenome, as a way to suppress the inflammatory cutaneous cascade.