@article {10851, title = {Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency.}, journal = {J Allergy Clin Immunol Pract}, volume = {6}, year = {2018}, month = {2018 Nov - Dec}, pages = {2165-2167}, issn = {2213-2201}, doi = {10.1016/j.jaip.2018.02.029}, author = {Valencic, Erica and Grasso, Antonio Giacomo and Conversano, Ester and Lucaf{\`o}, Marianna and Piscianz, Elisa and Gregori, Massimo and Conti, Francesca and Cancrini, Caterina and Tommasini, Alberto} } @article {8035, title = {To Extinguish the Fire from Outside the Cell or to Shutdown the Gas Valve Inside? Novel Trends in Anti-Inflammatory Therapies.}, journal = {Int J Mol Sci}, volume = {16}, year = {2015}, month = {2015}, pages = {21277-93}, abstract = {

Cytokines are the most important soluble mediators of inflammation. Rare pediatric diseases provided exemplar conditions to study the anti-inflammatory efficacy of new generation therapies (biologics/biopharmaceuticals) selectively targeting single cytokines. Monoclonal antibodies and recombinant proteins have revolutionized anti-inflammatory therapies in the last two decades, allowing the specific targeting of single cytokines. They are very effective in extinguishing inflammation from outside the cell, even with the risk of an excessive and prolonged immunosuppression. Small molecules can enter the cell and shutdown the valve of inflammation by directly targeting signal proteins involved in cytokine release or in response to cytokines. They are orally-administrable drugs whose dosage can be easily adjusted to obtain the desired anti-inflammatory effect. This could make these drugs more suitable for a wide range of diseases as stroke, gout, or neurological impairment, where inflammatory activation plays a pivotal role as trigger. Autoinflammatory diseases, which have previously put anti-cytokine proteins in the limelight, can again provide a valuable model to measure the real potential of small inhibitors as anti-inflammatory agents.

}, issn = {1422-0067}, doi = {10.3390/ijms160921277}, author = {Marcuzzi, Annalisa and Piscianz, Elisa and Valencic, Erica and Monasta, Lorenzo and Vecchi Brumatti, Liza and Tommasini, Alberto} } @article {8028, title = {Two-gene mutation in a single patient: Biochemical and functional analysis for a correct interpretation of exome results.}, journal = {Mol Med Rep}, volume = {12}, year = {2015}, month = {2015 Oct}, pages = {6128-32}, abstract = {

Next-generation sequencing (NGS) has generated a large amount of sequence data with the requirement of frequent critical revisions of reported mutations. This innovative tool has proved to be effective in detecting pathogenic mutations; however, it requires a certain degree of experience to identify incidental findings. In the present study, whole exome sequencing analysis was performed for the molecular diagnosis and correct genotype/phenotype correlation between parents and a patient presenting with an atypical phenotype. In addition, mevalonic acid quantification and frequency analysis of detected variants in public databases and X-chromosome inactivation (XCI) studies on the patient{\textquoteright}s mother were performed. V377I as well as the S135L mutations were identified on the mevalonate kinase deficiency gene and the levels of mevalonic acid in the patient were 5,496 {\textmu}g/ml. A D59G variation, reported in ESP6500 in two healthy individuals, was found on the Martin Probst syndrome gene (RAB40AL). Based on XCI studies on the patient{\textquoteright}s mother, it is likely that RAB40AL escapes XCI, while still remaining balanced. In conclusion, the results of the present study indicated that the Martin Probst syndrome is an X-linked condition, which is probably not caused by RAB40AL mutations. Although NGS is a powerful tool to identify pathogenic mutations, the analysis of genetic data requires expert critical revision of all detected variants.

}, issn = {1791-3004}, doi = {10.3892/mmr.2015.4215}, author = {Bianco, Anna Monica and Faletra, Flavio and Vozzi, Diego and Girardelli, Martina and Knowles, Alessandra and Tommasini, Alberto and Zauli, Giorgio and Marcuzzi, Annalisa} } @article {3524, title = {TNF-α SNP rs1800629 and risk of relapse in childhood acute lymphoblastic leukemia: relation to immunophenotype.}, journal = {Pharmacogenomics}, volume = {15}, year = {2014}, month = {2014 Apr}, pages = {619-27}, abstract = {

AIM: In the AIEOP-BFM ALL (Associazione Italiana Ematologia Oncologia Pediatrica-Berlin Frankfurt M{\"u}nster acute lymphoblastic leukemia) 2000 protocol, 70\% of relapsed patients had favorable prognostic features and fell within less intensive polychemotherapeutic regimens, suggesting the need for better assessing lower risk stratification.

MATERIALS \& METHODS: A novel two-phase study design selected 614 children to be genotyped for TNF-α SNP rs1800629 (-308G>A). A weighted Cox model was applied to evaluate the SNP effect on hazard of relapse, adjusting for immunophenotype, risk group, age and gender and including interaction terms.

RESULTS: Significant interaction was found with immunophenotypes (p = 0.0007, with minor allele genotypes being adverse genetic markers in B-cell acute lymphoblastic leukemia and protective ones in T-cell acute lymphoblastic leukemia), and also with risk protocols (p = 0.0041, with minor allele genotypes as prognostic factor of relapse for standard risk patients [only one T-cell acute lymphoblastic leukemia in the subgroup analyzed]).

CONCLUSION: The presence of at least one A allele in TNF-α SNP rs1800629 should suggest a closer monitoring in B-cell acute lymphoblastic leukemia standard risk patients.

}, keywords = {Adolescent, Antineoplastic Agents, Child, Child, Preschool, Drug Resistance, Neoplasm, Female, Genotype, Humans, Infant, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Phenotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Recurrence, Risk Assessment, Steroids, Tumor Necrosis Factor-alpha}, issn = {1744-8042}, doi = {10.2217/pgs.13.249}, author = {Franca, Raffaella and Rebora, Paola and Athanasakis, Emmanouil and Favretto, Diego and Verzegnassi, Federico and Basso, Giuseppe and Tommasini, Alberto and Valsecchi, Maria Grazia and Decorti, Giuliana and Rabusin, Marco} } @article {1654, title = {Targeting farnesyl-transferase as a novel therapeutic strategy for mevalonate kinase deficiency: in vitro and in vivo approaches.}, journal = {Pharmacol Res}, volume = {61}, year = {2010}, month = {2010 Jun}, pages = {506-10}, abstract = {

Mevalonate kinase deficiency (MKD) is a rare inborn auto-inflammatory disease due to the impairment of the pathway for the biosynthesis of cholesterol and non-sterol isoprenoids. The shortage of isoprenoids compounds and in particular of geranylgeranylpyrophosphate (GGPP) was recently associated to the MKD characteristic inflammatory attacks. The aim of this study is to demonstrate that the normalization of the mevalonate pathway intermediates levels and in particular of GGPP, through the specific inhibition of farnesyl-transferase (FT) with Manumycin A could ameliorate the inflammatory phenotype of MKD patients. The effect of Manumycin A was first evaluated in MKD mouse and cellular models, chemically obtained using the aminobisphosphonate alendronate (ALD), and then in monocytes isolated from 2 MKD patients. Our findings were compared to those obtained by using natural exogenous isoprenoids (NEIs). Manumycin A was able to significantly reduce the inflammatory marker serum amyloid A in ALD-treated Balb/c mice, as well as IL-1 beta secretion in ALD-monocytes and in MKD patients. These results clearly showed that, through the inhibition of FT, an increased number of mevalonate pathway intermediates could be redirected towards the synthesis of GGPP diminishing the inflammatory response. The importance in limiting the shortage of GGPP was emphasized by the anti-inflammatory effect of NEIs that, due to their biochemical structure, can enter the MKD pathway. In conclusion, manumycin A, as well as NEIs, showed anti-inflammatory effect in MKD models and especially in MKD-monocytes, suggesting novel approaches in the treatment of MKD, an orphan disease without any efficacious treatment currently available.

}, keywords = {Adult, Animals, Anti-Inflammatory Agents, Cells, Cultured, Child, Preschool, Enzyme Inhibitors, Farnesyltranstransferase, Female, Humans, Male, Mevalonate Kinase Deficiency, Mevalonic Acid, Mice, Mice, Inbred BALB C, Monocytes, Polyenes, Polyisoprenyl Phosphates, Polyunsaturated Alkamides, Young Adult}, issn = {1096-1186}, doi = {10.1016/j.phrs.2010.02.012}, author = {De Leo, Luigina and Marcuzzi, Annalisa and Decorti, Giuliana and Tommasini, Alberto and Crovella, Sergio and Pontillo, Alessandra} } @article {1665, title = {Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease.}, journal = {J Allergy Clin Immunol}, volume = {125}, year = {2010}, month = {2010 Apr}, pages = {943-946.e1}, keywords = {Age of Onset, Anti-Bacterial Agents, Antibodies, Monoclonal, Child, Drug Therapy, Combination, Gene Deletion, Granulomatous Disease, Chronic, Humans, Inflammatory Bowel Diseases, Male, NADPH Oxidase, Steroids, Treatment Outcome, Vidarabine}, issn = {1097-6825}, doi = {10.1016/j.jaci.2010.01.035}, author = {Freudenberg, Folke and Wintergerst, Uwe and Roesen-Wolff, Angela and Albert, Michael H and Prell, Christine and Strahm, Brigitte and Koletzko, Sibylle and Ehl, Stephan and Roos, Dirk and Tommasini, Alberto and Ventura, Alessandro and Belohradsky, Bernd H and Seger, Reinhard and Roesler, Joachim and G{\"u}ng{\"o}r, Tayfun} }