IDENTIFICAZIONE DI VARIANTI GENETICHE ASSOCIATE A RISCHIO DI LABIO/PALATOSCHISI O PALATOSCHISI NON-SINDROMICHE E DI INTERAZIONI GENE-AMBIENTE IN UNA AMPIA CASISTICA DI TRIADI EUROPEE

Orofacial clefts (OFCs) are common birth defects affecting approximately 1/700 live births worldwide. OFCs may occur in the context of malformation syndromes or, more often, as isolated anomalies (non-syndromic). Epidemiological and embryological data suggest that cleft lip with or without cleft palate (CL/P) and cleft palate only (CP) may represent etiologically distinct condition. Non-syndromic OFCs (nsCL/P and nsCP) have a complex multifactorial etiology, determined by the interaction of multiple genetic factors and specific environmental conditions affecting the intrauterine environment during early pregnancy, such as nutritional deficiency (hyperhomocysteinemia/folate deficiency), alcohol intake, maternal smoking. The molecular pathways and the identification of genetic elements involved in the developmental malformations of OFC are crucial to improve prevention strategies and recurrence genetic risks counseling. Different approaches such as linkage analysis, gene-candidate association studies, cytogenetic analysis and, more recently, genome-wide association studies (GWAS), led to the identification of several susceptibility loci for OFC development. The present study investigates specific genetic variants within susceptibility loci, in order to identify genetic risks factors for nsCP and/or nsCL/P. Family-based association studies were carried out in a large case-parent trios cohort (EUROCRAN and ITALCLEFT). The studies have focused on functional candidate genes and genetic region identified by GWAS. Genetic polymorphism were investigated in CBS gene (homocysteine metabolism), HLA-G gene (maternal-fetal immune tolerance), IRF6 gene (Wan der Woude syndrome, the most common cleft syndrome) and GREM1 gene (antangonist of Bone Morphogenetic Protein). Analyses were performed considering the cleft phenotype and gene-environment interaction (folic acid intake and maternal smoking in early pregnancy period). A new nsOFC risk variant were identified, in close proximity to IRF6 gene; moreover, significant results were obtain underling interactions between HLA-G genotype and pregnancy specific parameters. The study on nsCP etiology, conducted in collaboration with the De Duve Institute, Leuven University (Belgium), was focused on FAF1, SOX9, MTRR, SFSWAP and MMP17 candidate genes. The study has highlighted an association between polymorphic variants of FAF1 and SOX9 genes in nsCP risk indicating a strong relation with maternal smoking during early pregnancy

Acido folico e oltre: potenziali nuove strategie per la prevenzione

Attualmente non esistotono studi che abbiano dimostrato l’esistenza di effetti collaterali in seguito all’ esposizione a Acido Folico non metabolizzato, mentre sono ampiamente assodati i benefici derivanti dall’assunzione di acido folico prima e durante la gravidanza nella prevenzione delle malformazioni congenite. Tuttavia, l’evidenza di un potenziale effetto negativo della supplementazione con Acido Folico dovrebbe essere tenuto in considerazione, specialmente nei casi in cui vengono prescritte dosi estremamente alte di Acido Folico (come 4-5 mg/die) per prevenire la ricorrenza di malformazioni congenite . Ipotizziamo dunque che, in futuro, i limiti dell’acido folico potrebbero essere superati tramite l’uso di un folato naturale, come l’ L-5-methyl-THF, che possa fornire una prevenzione potenzialmente più sicura e efficacie contro le malformazioni congenite

Epidemiology of orofacial clefts in Emilia Romagna and Tuscany Regions

Background and aim Epidemiological information gathered through Birth defects surveillance is an important adjunct to carrying out clinical and etiological research. Methods An Italian epidemiological investigation on Orofacialclefts (OFCs) conducted by the Congenital Malformation Registries of Emilia/Romagna (http://www.registroimer.it/) and Tuscany (http://www.rtdc.it/) in the period 2001–2011 identified 751 of OFC cases among 724.944 with an overall birth prevalence of 1.04/1,000. Birth prevalence of OFC variessignificantly in Europe ranging from 6,2 to 22,9 with a European mean value of1,45, showing a clear difference between the north and south of Europe (http://www.eurocat-network.eu/). The complex model of inheritance and the frequently conflicting results in different populations on the role of genes that constitute risk factors, suggest the presence of real biological differences. Results Recorded cases included 166 (22%) CL, 286 (38%) CLP and 299 (40%) CP. A predominance of males among CL (P) (M/F 1,60) and of females among CP (M/F 0,79) as confirmed. Among 751 of OFC cases, 661 were live births (88.0%), 7 stillbirths (0.9%), while 83 (11.1%) were terminations of pregnancy.522 cases (69%) were isolated, 118 cases (16%) OFC were present in recognised condition, and 111 cases (15%) were associated with other congenital malformations (MCA). The study confirmed that cardiovascular (27%), musculoskeletal (21%) and central nervous system (21%) defects are frequently associated. Conclusions Thus a routine screening for other malformations may need to be considered in infants with OFC and a multidisciplinary approach of these patients to be organised starting from birth

Squalene epoxidase as a promising metabolic target in cancer treatment

Oncogenic alteration of the cholesterol synthesis pathway is a recognized mechanism of metabolic adaptation. In the present review, we focus on squalene epoxidase (SE), one of the two rate-limiting enzymes in cholesterol synthesis, retracing its history since its discovery as an antimycotic target to its description as an emerging metabolic oncogene by amplification with clinical relevance in cancer. We review the published literature assessing the association between SE over-expression and poor prognosis in this disease. We assess the works demonstrating how SE promotes tumor cell proliferation and migration, and displaying evidence of cancer cell demise in presence of human SE inhibitors in in vitro and in vivo models. Taken together, robust scientific evidence has by now accumulated pointing out SE as a promising novel therapeutic target in cancer treatment

Analysis of cytotoxic activity of peripheral blood natural killer cells in women with recurrent miscarriage

Around 50% of recurrent spontaneous abortions (RSA) remain unexplained. Immunological etiology has been proposed, supported by evidence of lower count of natural killer (NK) cells in peripheral blood of RSA women compared to women with normal delivery history. However, studies concerning the cytotoxic activity of NK cells in women with RSA are still controversial. We performed an observational case-control study assaying peripheral blood NK (pNK) cells cytotoxic activity in non-pregnant RSA women compared to non-pregnant women with normal delivery history. Twelve RSA and nine control women were recruited and blood samples were drawn during the luteal phase of ovarian cycle. pNK cells were incubated with target CFSE-labeled K562 cells and cytotoxicity was measured by cytofluorimetry. In non-pregnant RSA women pNK cytotoxic activity was not significantly altered compared to control women. In luteal phase of ovarian cycle the level of cytotoxic activity of pNK cells is not a marker for predicting RSA, and clinicians should not use pNK activity as a systematic recurrent pregnancy loss examination