@article {8350, title = {Evaluation of energy metabolism and calcium homeostasis in cells affected by Shwachman-Diamond syndrome.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016}, pages = {25441}, abstract = {

Isomorphic mutation of the SBDS gene causes Shwachman-Diamond syndrome (SDS). SDS is a rare genetic bone marrow failure and cancer predisposition syndrome. SDS cells have ribosome biogenesis and their protein synthesis altered, which are two high-energy consuming cellular processes. The reported changes in reactive oxygen species production, endoplasmic reticulum stress response and reduced mitochondrial functionality suggest an energy production defect in SDS cells. In our work, we have demonstrated that SDS cells display a Complex IV activity impairment, which causes an oxidative phosphorylation metabolism defect, with a consequent decrease in ATP production. These data were confirmed by an increased glycolytic rate, which compensated for the energetic stress. Moreover, the signalling pathways involved in glycolysis activation also appeared more activated; i.e. we reported AMP-activated protein kinase hyper-phosphorylation. Notably, we also observed an increase in a mammalian target of rapamycin phosphorylation and high intracellular calcium concentration levels ([Ca(2+)]i), which probably represent new biochemical equilibrium modulation in SDS cells. Finally, the SDS cell response to leucine (Leu) was investigated, suggesting its possible use as a therapeutic adjuvant to be tested in clinical trials.

}, issn = {2045-2322}, doi = {10.1038/srep25441}, author = {Ravera, Silvia and Dufour, Carlo and Cesaro, Simone and Bottega, Roberta and Faleschini, Michela and Cuccarolo, Paola and Corsolini, Fabio and Usai, Cesare and Columbaro, Marta and Cipolli, Marco and Savoia, Anna and Degan, Paolo and Cappelli, Enrico} } @article {1687, title = {Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations.}, journal = {Blood}, volume = {116}, year = {2010}, month = {2010 Dec 23}, pages = {5832-7}, abstract = {

Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 {\texttimes} 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 {\texttimes} 10(9)/L stopped therapy, those with 100 to 150 platelets {\texttimes} 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets {\texttimes} 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 {\texttimes} 10(9)/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42).

}, keywords = {Administration, Oral, Adolescent, Adult, Benzoates, Dose-Response Relationship, Drug, Female, Genetic Predisposition to Disease, Humans, Hydrazines, Male, Molecular Motor Proteins, Mutation, Myosin Heavy Chains, Platelet Aggregation, Platelet Count, Pyrazoles, Receptors, Thrombopoietin, Survival Rate, Thrombocytopenia, Treatment Outcome, Young Adult}, issn = {1528-0020}, doi = {10.1182/blood-2010-08-304725}, author = {Pecci, Alessandro and Gresele, Paolo and Klersy, Catherine and Savoia, Anna and Noris, Patrizia and Fierro, Tiziana and Bozzi, Valeria and Mezzasoma, Anna Maria and Melazzini, Federica and Balduini, Carlo L} } @article {1698, title = {Expression and association data strongly support JARID2 involvement in nonsyndromic cleft lip with or without cleft palate.}, journal = {Hum Mutat}, volume = {31}, year = {2010}, month = {2010 Jul}, pages = {794-800}, abstract = {

Nonsyndromic cleft lip with or without cleft palate (CL/P) affects approximately 1 in 1,000 births. Genetic studies have provided evidence for the role of several genes and candidate loci in clefting; however, conflicting results have frequently been obtained and much have to be done to unravel the complex genetics of CL/P. In the present investigation we have focused on the candidate region in 6p23, a region that have been found linked to CL/P in several investigations, in the attempt to find out the susceptibility gene provisionally named OFC1. Gene expression experiments in mice embryo of positional candidate genes revealed that JARID2 was highly and specifically expressed in epithelial cells in merging palatal shelves. A family-based linkage disequilibrium study confirmed the pivotal role of JARID2 in orofacial development and strongly supports a role for this gene in CL/P etiology (multiallelic haplotype test P=6 x 10(-5)). Understanding the molecular role of JARID2 within facial development may offer additional information to further unravel the complex genetics of CL/P.

}, keywords = {Animals, Cleft Lip, Cleft Palate, DNA Mutational Analysis, Family Health, Female, Gene Expression, Gene Expression Regulation, Developmental, Genetic Predisposition to Disease, Haplotypes, Humans, In Situ Hybridization, Linkage Disequilibrium, Male, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins, Palate, Polycomb Repressive Complex 2, Polymorphism, Single Nucleotide, Pregnancy, Reverse Transcriptase Polymerase Chain Reaction}, issn = {1098-1004}, doi = {10.1002/humu.21266}, author = {Scapoli, Luca and Martinelli, Marcella and Pezzetti, Furio and Palmieri, Annalisa and Girardi, Ambra and Savoia, Anna and Bianco, Anna Monica and Carinci, Francesco} }