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Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.

In the present study, we have explored the involvement of Toll-like Receptor 4 (TLR4) in atrial fibrillation (AF), by using a meta-analysis of publicly available human transcriptomic data. The meta-analysis revealed 565 upregulated and 267 downregulated differentially expressed genes associated with AF. Pathway enrichment analysis highlighted a significant overrepresentation in immune-related pathways for the upregulated genes. A significant overlap between AF differentially expressed genes and TLR4-modulated genes was also identified, suggesting the potential role of TLR4 in AF-related transcriptional changes. Additionally, the analysis of other Toll-like receptors (TLRs) revealed a significant association with TLR2 and TLR3 in AF-related gene expression patterns. The examination of MYD88 and TICAM1, genes associated with TLR4 signalling pathways, indicated a significant yet nonspecific enrichment of AF differentially expressed genes. In summary, this study offers novel insights into the molecular aspects of AF, suggesting a pathophysiological role of TLR4 and other TLRs. By targeting these specific receptors, new treatments might be designed to better manage AF, offering hope for improved outcomes in affected patients.

The existing literature supports the anti-inflammatory, antioxidant, and antiviral capacities of the polyphenol extracts derived from Geranium sanguineum L. These extracts exhibit potential in hindering viral replication by inhibiting enzymes like DNA polymerase and reverse transcriptase. The antiviral properties of G. sanguineum L. seem to complement its immunomodulatory effects, contributing to infection resolution. While preclinical studies on G. sanguineum L. suggest its potential effectiveness against COVID-19, there is still a lack of clinical evidence. Therefore, the polyphenols extracted from this herb warrant further investigation as a potential alternative for preventing and treating COVID-19 infections.

Alzheimer's disease (AD) is a neurodegenerative disorder classically characterized by two neuropathological hallmarks: β-amyloid plaques and tau tangles in the brain. However, the cellular and molecular mechanisms involved in AD are still elusive, which dampens the possibility of finding new and more effective therapeutic interventions. Current in vitro models are limited in modelling the complexity of AD pathogenesis. In this study, we aimed to characterize the AD expression signature upon a meta-analysis of multiple human datasets, including different cell populations from various brain regions, and compare cell-specific alterations in AD patients and in vitro models to highlight the appropriateness and the limitations of the currently available models in recapitulating AD pathology. The meta-analysis showed consistent enrichment of the Rho GTPases signaling pathway among different cell populations and in the models. The accuracy of in vitro models was higher for neurons and lowest for astrocytes. Our study underscores the particularly low fidelity in modelling down-regulated genes across all cell populations. The top enriched pathways arising from meta-analysis of human data differ from the enriched pathways arising from the overlap. We hope that our data will prove useful in indicating a starting point in the development of future, more complex, 3D in vitro models.

Pomegranate ( Punica granatum L.) is a rich source of polyphenols, including ellagitannins and ellagic acid. The plant is used in traditional medicine, and its purified components can provide anti-inflammatory and antioxidant activity and support of host defenses during viral infection and recovery from disease. Current data show that pomegranate polyphenol extract and its ellagitannin components and metabolites exert their beneficial effects by controlling immune cell infiltration, regulating the cytokine secretion and reactive oxygen and nitrogen species production, and by modulating the activity of the NFκB pathway. In vitro, pomegranate extracts and ellagitannins interact with and inhibit the infectivity of a range of viruses, including SARS-CoV-2. In silico docking studies show that ellagitannins bind to several SARS-CoV-2 and human proteins, including a number of proteases. This warrants further exploration of polyphenol-viral and polyphenol-host interactions in in vitro and in vivo studies. Pomegranate extracts, ellagitannins and ellagic acid are promising agents to target the SARS-CoV-2 virus and to restrict the host inflammatory response to viral infections, as well as to supplement the depleted host antioxidant levels during the stage of recovery from COVID-19.

Pomegranate ( Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood-brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.

Although the introduction of HAART has completely changed the natural course of HIV infection, the number of chronic forms of HIV-associated neurocognitive disorder (HAND) has risen. It is estimated that up to half of subjects undergoing HAART therapy exhibit mild cognitive impairments. In the current study, we apply the gene co-expression network modular analysis, a well-established system biology approach, to the gene expression profiles of cases from the National NeuroAIDS Tissue Consortium (NNTC). We observed a negative enrichment for genes associated with the control of immune responses and putatively regulated by the transcription factors IRF8 and SPI1 and by both type I and II interferons. Our study provides evidence of altered immune responses, which are likely associated with the occurrence of HAND in the absence of HIV encephalitis (HIVE).

Background: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease which affects more than 50 million patients and represents 60-80% of all cases of dementia. Mutations in the APP gene, mostly affecting the γ-secretase site of cleavage and presenilin mutations, have been identified in inherited forms of AD., Methods: In the present study, we performed a meta-analysis of the transcriptional signatures that characterize two familial AD mutations (APP V7171F and PSEN1 M146V ) in order to characterize the common altered biomolecular pathways affected by these mutations. Next, an anti-signature perturbation analysis was performed using the AD meta-signature and the drug meta-signatures obtained from the L1000 database, using cosine similarity as distance metrics., Results: Overall, the meta-analysis identified 1479 differentially expressed genes (DEGs), 684 downregulated genes, and 795 upregulated genes. Additionally, we found 14 drugs with a significant anti-similarity to the AD signature, with the top five drugs being naftifine, moricizine, ketoconazole, perindopril, and fexofenadine., Conclusions: This study aimed to integrate the transcriptional profiles associated with common familial AD mutations in neurons in order to characterize the pathogenetic mechanisms involved in AD and to find more effective drugs for AD.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-β plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the "neuronal system" (R-HSA-112316) and the "synaptic signaling" (GO:0099536), while the "regulation of protein catabolic process" (GO:00042176) and "transport of small molecules" (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients.

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of β-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 ( Galectin-8 ) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with various clinical features. Autoreactive B cells play a role in disease pathogenesis, through the production of multiple autoantibodies, which form immune complexes and induce the inflammatory response and tissue damage associated with SLE. Recently, tetraspanins, and in particular, TSPAN32, have been recognized to play a central role in immunity, as they are involved in various biological processes, such as the antigen presentation and the activation of lymphocytes. Evidence suggests that tetraspanins could represent in the future a target for therapeutic purposes in patients suffering from autoimmune/immunoinflammatory disorders. In the present study, by performing in silico analyses of high-throughput data, we evaluated the expression levels of TSPAN32 in B cell activation and investigated its modulation in circulating B cells from SLE patients. Our data show that B cell activation is associated with a significant downregulation of TSPAN32. Additionally, significantly lower levels of TSPAN32 were observed in circulating plasmablasts from SLE patients as compared to healthy donor plasmablasts. In addition, type I interferons (IFNs)-related genes were enriched among the genes negatively correlated to TSPAN32, in SLE plasmablasts. Accordingly, IFN-α is able to induce a dose-dependent downregulation of TSPAN32 in B cells. Overall, the data here presented suggest the potential use of TSPAN32 as a diagnostic marker and therapeutic target for the evaluation and management of humoral immune responses in chronic diseases, such as SLE.

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease caused by a lack of dystrophin, leading to membrane instability, cell damage, and inflammatory response. However, gene-editing alone is not enough to restore the healthy phenotype and additional treatments are required. In the present study, we have first conducted a meta-analysis of three microarray datasets, GSE38417, GSE3307, and GSE6011, to identify the differentially expressed genes (DEGs) between healthy donors and DMD patients. We have then integrated this analysis with the knowledge obtained from DisGeNET and DIAMOnD, a well-known algorithm for drug-gene association discoveries in the human interactome. The data obtained allowed us to identify novel possible target genes and were used to predict potential therapeutical options that could reverse the pathological condition.

Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.

Atopic dermatitis (AD) is a pathological skin condition with complex aetiological mechanisms that are difficult to fully understand. Scientific evidence suggests that of all the causes, the impairment of the skin barrier and cutaneous dysbiosis together with immunological dysfunction can be considered as the two main factors involved in this pathological skin condition. The loss of the skin barrier function is often linked to dysbiosis and immunological dysfunction, with an imbalance in the ratio between the pathogen Staphylococcus aureus and/or other microorganisms residing in the skin. The bibliographic research was conducted on PubMed, using the following keywords: 'atopic dermatitis', 'bacterial therapy', 'drug delivery system' and 'alternative therapy'. The main studies concerning microbial therapy, such as the use of bacteria and/or part thereof with microbiota transplantation, and drug delivery systems to recover skin barrier function have been summarized. The studies examined show great potential in the development of effective therapeutic strategies for AD and AD-like symptoms. Despite this promise, however, future investigative efforts should focus both on the replication of some of these studies on a larger scale, with clinical and demographic characteristics that reflect the general AD population, and on the process of standardisation, in order to produce reliable data.

At least since March 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic and the multi-organ coronavirus disease 2019 (COVID-19) are keeping a firm grip on the world. Although most cases are mild, older patients and those with co-morbidities are at increased risk of developing a cytokine storm, characterized by a systemic inflammatory response leading to acute respiratory distress syndrome and organ failure. The present paper focuses on the small molecule MP1032, describes its mode of action, and gives rationale why it is a promising option for the prevention/treatment of the SARS-CoV-2-induced cytokine storm. MP1032 is a phase-pure anhydrous polymorph of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt that exhibits good stability and bioavailability. The physiological action of MP1032 is based on a multi-target mechanism including localized, self-limiting reactive oxygen species (ROS) scavenging activities that were demonstrated in a model of lipopolysaccharide (LPS)-induced joint inflammation. Furthermore, its immune-regulatory and PARP-1-modulating properties, coupled with antiviral effects against SARS-CoV-2, have been demonstrated in various cell models. Preclinical efficacy was elucidated in LPS-induced endotoxemia, a model with heightened innate immune responses that shares many similarities to COVID-19. So far, during oral clinical development with three-month daily administrations, no serious adverse drug reactions occurred, highlighting the outstanding safety profile of MP1032.

Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients' survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.

The role of infections in the pathogenesis of autism spectrum disorder (ASD) is still controversial. In this study, we aimed to evaluate markers of infections and immune activation in ASD by performing a meta-analysis of publicly available whole-genome transcriptomic datasets of brain samples from autistic patients and otherwise normal people. Among the differentially expressed genes, no significant enrichment was observed for infectious diseases previously associated with ASD, including herpes simplex virus-1 (HSV-1), cytomegalovirus and Epstein-Barr virus in brain samples, nor was it found in peripheral blood from ASD patients. Interestingly, a significant number of genes belonging to the "prion diseases" pathway were found to be modulated in our ASD brain meta-analysis. Overall, our data do not support an association between infection and ASD. However, the data do provide support for the involvement of pathways related to other neurodegenerative diseases and give input to uncover novel pathogenetic mechanisms underlying ASD.

Alzheimer's disease (AD) represents the most common neurodegenerative disorder, with 47 million affected people worldwide. Current treatment strategies are aimed at reducing the symptoms and do slow down the progression of the disease, but inevitably fail in the long-term. Induced pluripotent stem cells (iPSCs)-derived neuronal cells from AD patients have proven to be a reliable model for AD pathogenesis. Here, we have conducted an in silico analysis aimed at identifying pathogenic gene-expression profiles and novel drug candidates. The GSE117589 microarray dataset was used for the identification of Differentially Expressed Genes (DEGs) between iPSC-derived neuronal progenitor (NP) cells and neurons from AD patients and healthy donors. The Discriminant Analysis Module (DAM) algorithm was used for the identification of biomarkers of disease. Drugs with anti-signature gene perturbation profiles were identified using the L1000FWD software. DAM analysis was used to identify a list of potential biomarkers among the DEGs, able to discriminate AD patients from healthy people. Finally, anti-signature perturbation analysis identified potential anti-AD drugs. This study set the basis for the investigation of potential novel pharmacological strategies for AD. Furthermore, a subset of genes for the early diagnosis of AD is proposed.

Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.

Tetraspanins are a conserved family of proteins involved in a number of biological processes. We have previously shown that Tetraspanin-32 (TSPAN32) is significantly downregulated upon activation of T helper cells via anti-CD3/CD28 stimulation. On the other hand, TSPAN32 is marginally modulated in activated Treg cells. A role for TSPAN32 in controlling the development of autoimmune responses is consistent with our observation that encephalitogenic T cells from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice exhibit significantly lower levels of TSPAN32 as compared to naïve T cells. In the present study, by making use of ex vivo and in silico analysis, we aimed to better characterize the pathophysiological and diagnostic/prognostic role of TSPAN32 in T cell immunity and in multiple sclerosis (MS). We first show that TSPAN32 is significantly downregulated in memory T cells as compared to naïve T cells, and that it is further diminished upon ex vivo restimulation. Accordingly, following antigenic stimulation, myelin-specific memory T cells from MS patients showed significantly lower expression of TSPAN32 as compared to memory T cells from healthy donors (HD). The expression levels of TSPAN32 was significantly downregulated in peripheral blood mononuclear cells (PBMCs) from drug-naïve MS patients as compared to HD, irrespective of the disease state. Finally, when comparing patients undergoing early relapses in comparison to patients with longer stable disease, moderate but significantly lower levels of TSPAN32 expression were observed in PBMCs from the former group. Our data suggest a role for TSPAN32 in the immune responses underlying the pathophysiology of MS and represent a proof-of-concept for additional studies aiming at dissecting the eventual contribution of TSPAN32 in other autoimmune diseases and its possible use of TSPAN32 as a diagnostic factor and therapeutic target.

Recent preclinical and clinical observations have offered relevant insights on the etiopathogenesis of late onset Alzheimer's disease (AD) and upregulated immunoinflammatory events have been described as underlying mechanisms involved in the development of AD. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by several cells of the innate and adaptive immune system, as well as non-immune cells. In the present review, we highlight experimental, genetic, and clinical studies on MIF in rodent models of AD and AD patients, and we discuss emerging therapeutic opportunities for tailored modulation of the activity of MIF, that may potentially be applied to AD patients. Dismantling the exact role of MIF and its receptors in AD may offer novel diagnostic and therapeutic opportunities in AD., Competing Interests: The authors declare no conflict of interest.

The emerging role of epigenetics in the pathogenesis of autoimmune diseases has recently attracted much interest on the possible use of epigenetic modulators for the prevention and treatment of these diseases. In particular, we and others have shown that drugs that inhibit DNA methylation, such as azacitidine (AZA) and decitabine (DAC), already used for the treatment of acute myeloid leukemia, exert powerful beneficial effects in rodent models of type 1 diabetes, multiple sclerosis, and Guillain Barrè syndrome. Along this line of research, we have presently studied the effects of DAC in a murine model of rheumatoid arthritis induced by type II collagen and have demonstrated that DAC administration was associated with a significant amelioration of the clinical condition, along with in vivo and ex vivo modification of the immunological profile of the so-treated mice, that exhibited a diminished production of Th1 and Th17 pro-inflammatory cytokines and reduction of anti-type II collagen autoantibodies., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease with X-linked recessive inheritance, that leads patients to premature death. The loss of dystrophin determines membrane instability, causing cell damage and inflammatory response. Macrophage migration inhibitory factor (MIF) is a cytokine that exerts pleiotropic properties and is implicated in the pathogenesis of a variety of diseases. Recently, converging data from independent studies have pointed to a possible role of MIF in dystrophic muscle disorders, including DMD. In the present study, we have investigated the modulation of MIF and MIF-related genes in degenerative muscle disorders, by making use of publicly available whole-genome expression datasets. We show here a significant enrichment of MIF and related genes in muscle samples from DMD patients, as well as from patients suffering from Becker's disease and limb-girdle muscular dystrophy type 2B. On the other hand, transcriptomic analysis of in vitro differentiated myotubes from healthy controls and DMD patients revealed no significant alteration in the expression levels of MIF-related genes. Finally, by analyzing DMD samples as a time series, we show that the modulation of the genes belonging to the MIF network is an early event in the DMD muscle and does not change with the increasing age of the patients, Overall, our analysis suggests that MIF may play a role in vivo during muscle degeneration, likely promoting inflammation and local microenvironment reaction.

Neuroblastoma (NB) represents one of the most frequent pediatric solid tumors. Macrophage migration inhibitory factor (MIF) is a cytokine exerting multiple biological functions. More recently, a second member of the MIF family of cytokine has been identified, the D-dopachrome tautomerase (DDT), that exerts several overlapping functions with MIF. Growing evidence suggests a key role for MIF and DDT in the development of cancer. The aim of this study is to characterize the prognostic value of MIF and DDT in NB. We show that higher expression levels of MIF and DDT in Stage 4 NB samples are associated with a poorer prognosis, independently of the presence of MYCN amplification. Moreover, higher levels of MIF are mostly enriched by Th1 cells, while lower levels of MIF are associated with an increased proportion of B cells, Cytotoxic T cells, Dendritic cells and Natural Killer T cells. We also show that treatment with the histone deacetylase (HDAC) inhibitor, vorinostat, of the NB cell line, SH-SY5Y, determines a significant reduction in the expression of both MIF and DDT. Finally, MIF and DDT inhibition by short interfering RNA is able to revert vincristine sensitivity in vitro. Overall, our data suggest that MIF exert pro-tumorigenic properties in NB, likely by dampening antigen presentation and cytotoxic immune responses, and we propose the HDAC inhibitors as a potential therapeutic strategy for NB patients., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background and objectives : Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT) are two pleiotropic and primarily, but not exclusively, proinflammatory cytokines belonging to the MIF family of cytokines that have recently been shown to be implicated in the pathogenesis of progressive forms of human progressive Multiple Sclerosis (MS) and the experimental model counterpart in rodents. Materials and Methods: We have presently evaluated a transcriptomic analysis of the expression of MIF, DDT, their receptors CD74 and CD44, and MIF co-receptors CXCR2, CXCR4, and CXCR7 in peripheral blood of patients with Clinically Isolated Syndrome (CIS), with rapid progression to clinical defined MS. Results: Our analysis reveals that MIF, DDT, and CD44 are overexpressed in CD4 + T cells from patients with CIS, as compared to healthy controls. Accordingly, a significant overlap was observed between the genes overexpressed in CD4 + T cells from patients with CIS and the genes belonging to the MIF regulatory network. This upregulated expression appeared to be unique for CD4 + T cells, as other immune cells including CD8 + T cells, B cells, and monocytes from these patients exhibited expression levels of these molecules that were superimposable to those observed in healthy controls. Conclusions: Overall, our data suggest that the overexpression MIF cytokine family signature may occur in CD4 + T cells from patients with CIS, and that this phenomenon may be implicated in the pathogenesis of the disease, offering the possibility to represent both a diagnostic marker and a therapeutic target., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell-cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.

Immunotherapy is a promising new therapeutic approach for neuroblastoma (NBM): an anti-GD2 vaccine combined with orally administered soluble beta-glucan is undergoing a phase II clinical trial and nivolumab and ipilimumab are being tested in recurrent and refractory tumors. Unfortunately, predictive biomarkers of response to immunotherapy are currently not available for NBM patients. The aim of this study was to create a computational network model simulating the different intracellular pathways involved in NBM, in order to predict how the tumor phenotype may be influenced to increase the sensitivity to anti-programmed cell death-ligand-1 (PD-L1)/programmed cell death-1 (PD-1) immunotherapy. The model runs on COPASI software. In order to determine the influence of intracellular signaling pathways on the expression of PD-L1 in NBM, we first developed an integrated network of protein kinase cascades. Michaelis-Menten kinetics were associated to each reaction in order to tailor the different enzymes kinetics, creating a system of ordinary differential equations (ODEs). The data of this study offers a first tool to be considered in the therapeutic management of the NBM patient undergoing immunotherapeutic treatment., Competing Interests: The authors declare no conflict of interest.

KCNMA1 is a gene located at 10q22 that encodes the pore-forming α-subunit of the large-conductance Ca 2+ -activated K⁺ channel. KCNMA1 is down-regulated in gastric carcinoma tumors, through hypermethylation of its promoter. In the present study, we have evaluated the expression levels of KCNMA1 both in a mouse model of Colorectal Cancer (CRC) and in human CRC samples. Additionally, epigenetic mechanisms of KCNMA1 gene regulation were investigated. We observed a significant down-regulation of KCNMA1 both in a human and mouse model of CRC. No differences in KCNMA1 levels were, however, observed at different TNM stages. We also wanted to determine whether the modulation in KCNMA1 was dependent on epigenetic mechanisms. A statistically significant inverse correlation between KCNMA1 expression and mir-17-5p levels was observed in patients with CRC. Furthermore, in the tumor samples, we found a significant hypermethylation of the promoter, in the loci cg24113782 and cg25655799, compared to healthy tissue. Overall, our data suggest the possible use of KCNMA1 as a therapeutic target in the early stages of CRC., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.