TY - JOUR T1 - Low-dose sirolimus in two cousins with autoimmune lymphoproliferative syndrome-associated infection. JF - Pediatr Int Y1 - 2018 A1 - Nocerino, Agostino A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Pelos, Giorgio A1 - Tommasini, Alberto KW - Anti-Bacterial Agents KW - Autoimmune Lymphoproliferative Syndrome KW - Child KW - Child, Preschool KW - Dose-Response Relationship, Drug KW - Female KW - Humans KW - Immunosuppressive Agents KW - Infant KW - Male KW - Otitis Media KW - Pneumonia, Bacterial KW - Sirolimus VL - 60 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29480551?dopt=Abstract ER - TY - JOUR T1 - Neuronal Dysfunction Associated with Cholesterol Deregulation. JF - Int J Mol Sci Y1 - 2018 A1 - Marcuzzi, Annalisa A1 - Loganes, Claudia A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Monasta, Lorenzo A1 - Bilel, Sabrine A1 - Bortul, Roberta A1 - Celeghini, Claudio A1 - Zweyer, Marina A1 - Tommasini, Alberto KW - Anticholesteremic Agents KW - Cell Line, Tumor KW - Cholesterol KW - Electron Transport KW - Humans KW - Lovastatin KW - Mitochondria KW - Neurons KW - Neuroprotective Agents KW - Organophosphorus Compounds KW - Ubiquinone AB -

Cholesterol metabolism is crucial for cells and, in particular, its biosynthesis in the central nervous system occurs in situ, and its deregulation involves morphological changes that cause functional variations and trigger programmed cell death. The pathogenesis of rare diseases, such as Mevalonate Kinase Deficiency or Smith⁻Lemli⁻Opitz Syndrome, arises due to enzymatic defects in the cholesterol metabolic pathways, resulting in a shortage of downstream products. The most severe clinical manifestations of these diseases appear as neurological defects. Expanding the knowledge of this biological mechanism will be useful for identifying potential targets and preventing neuronal damage. Several studies have demonstrated that deregulation of the cholesterol pathway induces mitochondrial dysfunction as the result of respiratory chain damage. We set out to determine whether mitochondrial damage may be prevented by using protective mitochondria-targeted compounds, such as MitoQ, in a neuronal cell line treated with a statin to induce a biochemical block of the cholesterol pathway. Evidence from the literature suggests that mitochondria play a crucial role in the apoptotic mechanism secondary to blocking the cholesterol pathway. Our study shows that MitoQ, administered as a preventive agent, could counteract the cell damage induced by statins in the early stages, but its protective role fades over time.

VL - 19 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29783748?dopt=Abstract ER - TY - JOUR T1 - Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice. JF - Curr Med Chem Y1 - 2018 A1 - Marcuzzi, Annalisa A1 - Loganes, Claudia A1 - Celeghini, Claudio A1 - Kleiner, Giulio KW - Acyl Coenzyme A KW - Cholesterol KW - Drug Repositioning KW - Farnesyl-Diphosphate Farnesyltransferase KW - Humans KW - Hypercholesterolemia KW - Mevalonate Kinase Deficiency KW - Oxazepines KW - Phosphotransferases (Alcohol Group Acceptor) KW - Piperidines AB -

BACKGROUND: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.

OBJECTIVE: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints' conditions and their quality of life.

METHODS: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.

RESULTS: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.

CONCLUSIONS: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.

VL - 25 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28901277?dopt=Abstract ER - TY - JOUR T1 - Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage. JF - Nutrients Y1 - 2017 A1 - Loganes, Claudia A1 - Lega, Sara A1 - Bramuzzo, Matteo A1 - Vecchi Brumatti, Liza A1 - Piscianz, Elisa A1 - Valencic, Erica A1 - Tommasini, Alberto A1 - Marcuzzi, Annalisa KW - Anti-Inflammatory Agents, Non-Steroidal KW - Apoptosis KW - Cell Survival KW - Curcuma KW - Curcumin KW - Cytokines KW - Epithelial Cells KW - HT29 Cells KW - Humans KW - Inflammation KW - Interferon-gamma KW - Interleukin-7 KW - Intestinal Mucosa KW - NF-kappa B KW - Phosphorylation KW - Signal Transduction AB -

The purpose of this study is to determine if a preventive treatment with curcumin can protect intestinal epithelial cells from inflammatory damage induced by IFNγ. To achieve this goal we have used a human intestinal epithelial cell line (HT29) treated with IFNγ to undergo apoptotic changes that can reproduce the damage of intestinal epithelia exposed to inflammatory cytokines. In this model, we measured the effect of curcumin (curcuminoid from ) added as a pre-treatment at different time intervals before stimulation with IFNγ. Curcumin administration to HT29 culture before the inflammatory stimulus IFNγ reduced the cell apoptosis rate. This effect gradually declined with the reduction of the curcumin pre-incubation time. This anti-apoptotic action by curcumin pre-treatment was paralleled by a reduction of secreted IL7 in the HT29 culture media, while there was no relevant change in the other cytokine levels. Even though curcumin pre-administration did not impact the activation of the NF-κB pathway, a slight effect on the phosphorylation of proteins in this inflammatory signaling pathway was observed. In conclusion, curcumin pre-treatment can protect intestinal cells from inflammatory damage. These results can be the basis for studying the preventive role of curcumin in inflammatory bowel diseases.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28587282?dopt=Abstract ER - TY - JOUR T1 - Action of methotrexate and tofacitinib on directly stimulated and bystander-activated lymphocytes. JF - Mol Med Rep Y1 - 2016 A1 - Piscianz, Elisa A1 - Candilera, Vanessa A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Paron, Greta A1 - De Iudicibus, Sara A1 - Decorti, Giuliana A1 - Tommasini, Alberto AB -

Chronic inflammation associated with autoimmune activation is characteristic of rheumatic diseases from childhood to adulthood. In recent decades, significant improvements in the treatment of these types of disease have been achieved using disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) and, more recently, using biologic inhibitors. The recent introduction of kinase inhibitors (for example, tofacitinib; Tofa) further increases the available ARDs. However, there are patients that do not respond to any treatment strategies, for whom combination therapies are proposed. The data regarding the combined action of different drugs is lacking and the knowledge of the mechanisms of ARDs and their actions upon pathogenic lymphocytes, which are hypothesized to sustain disease, is poor. An in vitro model of inflammation was developed in the current study, in which stimulated and unstimulated lymphocytes were cultured together, but tracked separately, to investigate the action of MTX and Tofa on the two populations. By analysing lymphocyte proliferation and activation, and cytokine secretion in the culture supernatants, it was established that, due to the presence of activated cells, unstimulated cells underwent a bystander activation that was modulated by the ARDs. Additionally, varying administration schedules were demonstrated to affect lymphocytes differently in vitro, either directly or via bystander activation. Furthermore, MTX and Tofa exerted different effects; while MTX showed an antiproliferative effect, Tofa marginally effected activation, although only a slight antiproliferative action, which could be potentiated by sequential treatment with MTX. Thus, it was hypothesized that these differences may be exploited in sequential therapeutic strategies, to maximize the anti‑rheumatic effect. These findings are notable and must be accounted for, as bystander‑activated cells in vivo could contribute to the spread of autoimmune activation and disease progression.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27175898?dopt=Abstract ER - TY - JOUR T1 - Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology. JF - Int J Mol Sci Y1 - 2016 A1 - Marcuzzi, Annalisa A1 - Piscianz, Elisa A1 - Zweyer, Marina A1 - Bortul, Roberta A1 - Loganes, Claudia A1 - Girardelli, Martina A1 - Baj, Gabriele A1 - Monasta, Lorenzo A1 - Celeghini, Claudio AB -

Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria-related.

VL - 17 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26978350?dopt=Abstract ER - TY - JOUR T1 - Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. JF - Clin Immunol Y1 - 2015 A1 - Lougaris, Vassilios A1 - Faletra, Flavio A1 - Lanzi, Gaetana A1 - Vozzi, Diego A1 - Marcuzzi, Annalisa A1 - Valencic, Erica A1 - Piscianz, Elisa A1 - Bianco, AnnaMonica A1 - Girardelli, Martina A1 - Baronio, Manuela A1 - Loganes, Claudia A1 - Fasth, Anders A1 - Salvini, Filippo A1 - Trizzino, Antonino A1 - Moratto, Daniele A1 - Facchetti, Fabio A1 - Giliani, Silvia A1 - Plebani, Alessandro A1 - Tommasini, Alberto KW - B-Lymphocytes KW - Child, Preschool KW - Female KW - Germinal Center KW - Humans KW - Hyper-IgM Immunodeficiency Syndrome KW - Infant KW - Male KW - Mutation KW - Phenotype KW - Phosphatidylinositol 3-Kinases KW - RNA Splice Sites KW - Sequence Analysis, DNA VL - 159 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25939554?dopt=Abstract ER - TY - JOUR T1 - The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency. JF - BMC Pediatr Y1 - 2015 A1 - Girardelli, Martina A1 - Arrigo, Serena A1 - Barabino, Arrigo A1 - Loganes, Claudia A1 - Morreale, Giuseppe A1 - Crovella, Sergio A1 - Tommasini, Alberto A1 - Bianco, Anna Monica AB -

BACKGROUND: Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

CASE PRESENTATION: We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

CONCLUSION: Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26671016?dopt=Abstract ER - TY - JOUR T1 - Inhibition of mesenchymal stromal cells by pre-activated lymphocytes and their culture media. JF - Stem Cell Res Ther Y1 - 2014 A1 - Valencic, Erica A1 - Loganes, Claudia A1 - Cesana, Stefania A1 - Piscianz, Elisa A1 - Gaipa, Giuseppe A1 - Biagi, Ettore A1 - Tommasini, Alberto KW - CD4-Positive T-Lymphocytes KW - CD8-Positive T-Lymphocytes KW - Cell Proliferation KW - Cell Survival KW - Cells, Cultured KW - Coculture Techniques KW - Culture Media, Conditioned KW - Cytokines KW - Humans KW - Killer Cells, Natural KW - Lymphocyte Activation KW - Mesenchymal Stromal Cells AB -

INTRODUCTION: Despite having a proven immunosuppressive potential in vitro, human mesenchymal stromal cells (MSCs) are reported to display variable efficacy in vivo and, in fact, their proven benefit in the clinical practice is still limited and controversial.

METHODS: The interplay between clinical grade MSCs and pre-activated donor lymphocytes or selected lymphocyte subsets was studied in vitro. The kinetics of MSC growth and viability was evaluated by adhesion-dependent changes of culture plate impedance and biochemically by a colorimetric assay. Activation of natural killer (NK) cells was assessed as well, using a flow cytometry assay.

RESULTS: A strong inhibition of MSC growth was rapidly induced by the addition of pre-activated lymphocytes but not of resting lymphocytes. Inhibition seems not to be attributable to a single cell population, as similar results can be obtained by depleting NK cells or by using either selected CD4+ or CD8+ lymphocytes. In addition, conditioned medium (CM) from activated lymphocytes was able to inhibit MSC growth in a dose-dependent manner. Furthermore, licensing with IFN-γ partially protected MSCs from pre-activated lymphocytes but not from their CM. These results suggest an inhibitory role of lymphocyte-activation-derived substances. However, the identification of a single molecule responsible for MSC inhibition remained elusive, even if preliminary experiments showed that ATP and, to a lesser extent, TNF-α might play a role.

CONCLUSIONS: These results suggest that survival of MSCs can be affected by soluble mediators released by activated lymphocytes. Thus it can be hypothesized that MSC immunosuppressive action in vivo could be impaired by ongoing immune activation through the release of inflammatory mediators.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24405828?dopt=Abstract ER - TY - JOUR T1 - Piccolipiù, a multicenter birth cohort in Italy: protocol of the study. JF - BMC Pediatr Y1 - 2014 A1 - Farchi, Sara A1 - Forastiere, Francesco A1 - Vecchi Brumatti, Liza A1 - Alviti, Sabrina A1 - Arnofi, Antonio A1 - Bernardini, Tommaso A1 - Bin, Maura A1 - Brescianini, Sonia A1 - Colelli, Valentina A1 - Cotichini, Rodolfo A1 - Culasso, Martina A1 - De Bartolo, Paolo A1 - Felice, Laura A1 - Fiano, Valentina A1 - Fioritto, Alessandra A1 - Frizzi, Alfio A1 - Gagliardi, Luigi A1 - Giorgi, Giulia A1 - Grasso, Chiara A1 - La Rosa, Francesca A1 - Loganes, Claudia A1 - Lorusso, Paola A1 - Martini, Valentina A1 - Merletti, Franco A1 - Medda, Emanuela A1 - Montelatici, Veronica A1 - Mugelli, Isabella A1 - Narduzzi, Silvia A1 - Nisticò, Lorenza A1 - Penna, Luana A1 - Piscianz, Elisa A1 - Piscicelli, Carlo A1 - Poggesi, Giulia A1 - Porta, Daniela A1 - Ranieli, Antonella A1 - Rapisardi, Gherardo A1 - Rasulo, Assunta A1 - Richiardi, Lorenzo A1 - Rusconi, Franca A1 - Serino, Laura A1 - Stazi, Maria Antonietta A1 - Toccaceli, Virgilia A1 - Todros, Tullia A1 - Tognin, Veronica A1 - Trevisan, Morena A1 - Valencic, Erica A1 - Volpi, Patrizia A1 - Ziroli, Valentina A1 - Ronfani, Luca A1 - Di Lallo, Domenico KW - Adolescent KW - Child KW - Child Development KW - Child Welfare KW - Child, Preschool KW - Cohort Studies KW - Environmental Exposure KW - Humans KW - Infant KW - Infant, Newborn KW - Italy KW - Prospective Studies KW - Socioeconomic Factors AB -

BACKGROUND: The fetal and infant life are periods of rapid development, characterized by high susceptibility to exposures. Birth cohorts provide unique opportunities to study early-life exposures in association with child development and health, as well as, with longer follow-up, the early life origin of adult diseases. Piccolipiù is an Italian birth cohort recently set up to investigate the effects of environmental exposures, parental conditions and social factors acting during pre-natal and early post-natal life on infant and child health and development. We describe here its main characteristics.

METHODS/DESIGN: Piccolipiù is a prospective cohort of expected 3000 newborns, who will be recruiting in six maternity units of five Italian cities (Florence, Rome, Trieste, Turin and Viareggio) since October 2011. Mothers are contacted during pregnancy or at delivery and are offered to participate in the study. Upon acceptance, their newborns are recruited at birth and followed up until at least 18 years of age. At recruitment, the mothers donate a blood sample and complete a baseline questionnaire. Umbilical cord blood, pieces of umbilical cord and heel blood spots are also collected. Postnatal follow-up currently occurs at 6, 12, and 24 months of age using on-line or postal self administered questionnaire; further questionnaires and medical examinations are envisaged. Questionnaires collect information on several factors, including mother's and/or child's environmental exposures, anthropometric measures, reproductive factors, diet, supplements, medical history, cognitive development, mental health and socioeconomic factors. Health promotion materials are also offered to parents.

DISCUSSION: Piccolipiù will broaden our understanding of the contribution of early-life factors to infant and child health and development. Several hypotheses on the developmental origins of health can be tested or piloted using the data collected from the Piccolipiù cohort. By pooling these data with those collected by other existing birth cohorts it will be possible to validate previous findings and to study rare exposures and outcomes.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24506846?dopt=Abstract ER - TY - JOUR T1 - Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling. JF - J Crohns Colitis Y1 - 2014 A1 - Naviglio, Samuele A1 - Arrigo, Serena A1 - Martelossi, Stefano A1 - Villanacci, Vincenzo A1 - Tommasini, Alberto A1 - Loganes, Claudia A1 - Fabretto, Antonella A1 - Vignola, Silvia A1 - Lonardi, Silvia A1 - Ventura, Alessandro KW - Child, Preschool KW - Colon KW - Colonoscopy KW - Female KW - Humans KW - Infant KW - Inflammatory Bowel Diseases KW - Loeys-Dietz Syndrome KW - Male KW - Signal Transduction KW - Transforming Growth Factor beta AB -

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys-Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases.

VL - 8 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24486179?dopt=Abstract ER -