Publications by authors named "Marcella Martinelli"

71 Publications

Non-syndromic Cleft Palate: An Overview on Human Genetic and Environmental Risk Factors.

Front Cell Dev Biol 2020 20;8:592271. Epub 2020 Oct 20.

Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum - University of Bologna, Bologna, Italy.

The epithelial and mesenchymal cells involved in early embryonic facial development are guided by complex regulatory mechanisms. Any factor perturbing the growth, approach and fusion of the frontonasal and maxillary processes could result in orofacial clefts that represent the most common craniofacial malformations in humans. The rarest and, probably for this reason, the least studied form of cleft involves only the secondary palate, which is posterior to the incisive foramen. The etiology of cleft palate only is multifactorial and involves both genetic and environmental risk factors. The intention of this review is to give the reader an overview of the efforts made by researchers to shed light on the underlying causes of this birth defect. Most of the scientific papers suggesting potential environmental and genetic causes of non-syndromic cleft palate are summarized in this review, including genome-wide association and gene-environment interaction studies.
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http://dx.doi.org/10.3389/fcell.2020.592271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606870PMC
October 2020

Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies.

Hum Mol Genet 2020 06;29(9):1489-1497

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder.
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http://dx.doi.org/10.1093/hmg/ddaa073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268788PMC
June 2020

ROCK1 is associated with non-syndromic cleft palate.

J Oral Pathol Med 2020 Feb 24;49(2):164-168. Epub 2019 Nov 24.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Background: Craniofacial morphogenesis is the result of an intricate multistep network of tightly controlled spatial and temporal signalling that involves several molecules and transcription factors organized into highly coordinated pathways. Any alteration in even one step of this delicate process can lead to congenital malformations such as cleft palate. One of the first steps in embryonal orofacial development is the migration of cells from the neural crests to the branchial arches. Next, the cells have to proliferate, differentiate, move and connect to each other in order to correctly form the palate. Cell contraction, promoted by the interaction of non-muscle myosin II and actin A, is a crucial step in morphogenesis and is regulated by ROCK1 protein.

Methods: A family-based association study was carried out in order to verify whether or not genetic variants of ROCK1 were associated with non-syndromic cleft palate (nsCP). Two cohorts from Italy and Iran, a total of 189 nsCP cases and their parents were enrolled.

Results: The rs35996865-G allele was under-transmitted in cases of nsCP [P = .006, odds ratio (OR) = 0.63 (95% CI 0.45-0.88)].

Conclusion: This investigation reveals for the first time data supporting a role for ROCK1 in nsCP aetiology.
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http://dx.doi.org/10.1111/jop.12973DOI Listing
February 2020

Drug-induced gingival hyperplasia: An in vitro study using amlodipine and human gingival fibroblasts.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419827746

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Gingival overgrowth is a serious side effect that accompanies the use of amlodipine. Several conflicting theories have been proposed to explain the fibroblast's function in gingival overgrowth. To determine whether amlodipine alters the inflammatory responses, we investigated its effects on gingival fibroblast gene expression as compared with untreated cells. Fragments of gingival tissue of healthy volunteers (11 years old boy, 68 years old woman, and 20 years old men) were collected during operation. Gene expression of 29 genes was investigated in gingival fibroblast cell culture treated with amlodipine, compared with untreated cells. Among the studied genes, only 15 (, and ) were significantly deregulated. In particular, the most evident overexpressed genes in treated cells were and . These results seem to indicate a possible role of amlodipine in the inflammatory response of treated human gingival fibroblasts.
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http://dx.doi.org/10.1177/2058738419827746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822186PMC
March 2020

Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419858572

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.
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http://dx.doi.org/10.1177/2058738419858572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822179PMC
March 2020

Copy number variation analysis of twin pairs discordant for cleft lip with or without cleft palate.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419855873

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a frequent orofacial malformation. The comparison of concordance rate observed in monozygotic and dizygotic twins supports high level of heritability and a strong genetic component. However, phenotype concordance for orofacial cleft in monozygotic twins is about 50%. The aim of the present investigation was to detect postzygotic events that may account for discordance in monozygotic twins. High-density SNP microarrays hybridization was used to genotype two pairs of monozygotic twins discordant for nsCL/P. Discordant SNP genotypes and copy number variants were analyzed to identify genetic differences responsible of phenotype discrepancy. A number of differences were observed, none involving known nsCL/P candidate genes or genomic regions. Considering the limitation of the study, related to the small sample size and to the large-scale investigation method, the results suggest that the detection of discordant events in other monozygotic twin pairs would be remarkable and warrant further investigations.
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http://dx.doi.org/10.1177/2058738419855873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822181PMC
March 2020

Berberine and exert a potential anticancer effect on colon cancer cells by acting on specific pathways.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419855567

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Berberine (BBR) is a natural active principle with potential antitumor activity. The compound targets multiple cell signaling pathways, including proliferation, differentiation, and epithelial-mesenchymal transition. The aim of this study was to elucidate the mechanisms behind the anticancer activity of BBR by comparing the effects of purified BBR with those of the extract of , a medicinal plant that produces this metabolite. The expression levels of a panel of 44 selected genes in human colon adenocarcinoma (HCA-7) cell line were quantified by real-time polymerase chain reaction (PCR). BBR treatment resulted in a time- and dose-dependent down regulation of 33 genes differently involved in cell cycle, differentiation, and epithelial-mesenchymal transition. The trend was confirmed across the two types of treatment, the two time points, and the different absolute dosage of BBR. These findings suggest that the presence of BBR in extract significantly contributes to its antiproliferative activity.
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http://dx.doi.org/10.1177/2058738419855567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822188PMC
March 2020

A hydrosilver gel for plaque control in adults affected by chronic periodontitis: Effects on the 'red complex' bacterial load. A prospective longitudinal pilot study using polymerase chain reaction analysis.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738418825212

Paediatric Dentistry, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.

In subjects affected by chronic periodontitis, the chemical control of plaque is a strategy aiming primarily at controlling infection and bacterial loading. The aim is to evaluate the bacterial loading of the so-called 'red complex' associated with a short-term use of a hydrosilver gel (HSG) by using an model in adult subjects affected by chronic periodontitis. This prospective short-term clinical trial involved 10 adult volunteers using a 15-day model. After receiving professional prophylaxis at baseline (t0), each volunteer performed daily applications of HSG at home. After 15 days (t1) from the first application, subgingival plaque samples were collected, and the bacterial loading of species belonging to the red complex was evaluated using polymerase chain reaction (PCR) analyses. The bacterial loading of the red complex showed no statistically significant difference between t0 and t1, although it tended to decrease. HSG can be used at home as an adjunct to domestic oral care because it seems a promising tool, but further studies are needed to involve a larger sample and a longer follow-up.
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http://dx.doi.org/10.1177/2058738418825212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822196PMC
March 2020

Association between oral cleft and transcobalamin 2 polymorphism in a sample study from Nassiriya, Iraq.

Int J Immunopathol Pharmacol 2019 Jan-Dec;33:2058738419855571

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Orofacial clefts are common congenital defects whose prevalence differs between geographical regions and ethnic groups. The inheritance is complex, involving the contribution of both genetic and environmental factors. The involvement of genes belonging to the folate pathway is still matter of debate, with strong evidences of association and conflicting results. After demonstrating the contribution, for a sample from the Italian population, of common mutations mapping on three genes of the folate pathway, our group tried to unravel their contribution in independent sample studies with different ethnicity. In the present investigation a set of 34 triads with oral cleft from Nassiriya, Iraq, has been genotyped for rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS polymorphisms. Association analysis evidenced a decreased risk of cleft for children carrying the 667G allele at TCN2 gene ( = 0.02). This evidence further supported the relationship between polymorphisms of folate related genes and oral clefts, and outlined the relevance of studying populations having different ethnicity.
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http://dx.doi.org/10.1177/2058738419855571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822189PMC
March 2020

Possible effect of SNAIL family transcriptional repressor 1 polymorphisms in non-syndromic cleft lip with or without cleft palate.

Clin Oral Investig 2018 Sep 27;22(7):2535-2541. Epub 2018 Jan 27.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Belmeloro, 8, 40126, Bologna, Italy.

Objective: Orofacial development is a complex process subjected to failure impairing. Indeed, the cleft of the lip and/or of the palate is among the most frequent inborn malformations. The JARID2 gene has been suggested to be involved in non-syndromic cleft lip with or without cleft palate (nsCL/P) etiology. JARID2 interacts with the polycomb repressive complex 2 (PRC2) in regulating the expression patterns of developmental genes by modifying the chromatin state.

Materials And Methods: Genes coding for the PRC2 components, as well as other genes active in cell differentiation and embryonic development, were selected for a family-based association study to verify their involvement in nsCL/P. A total of 632 families from Italy and Asia participated to the study.

Results: Evidence of allelic association was found with polymorphisms of SNAI1; in particular, the rs16995010-G allele was undertransmitted to the nsCL/P cases [P = 0.004, odds ratio = 0.69 (95% C.I. 0.54-0.89)]. However, the adjusted significance value corrected for all the performed tests was P = 0.051.

Conclusions: The findings emerging by the present study suggest for the first time an involvement of SNAI1 in the nsCL/P onset.

Clinical Relevance: Interestingly, SNAI1 is known to promote epithelial to mesenchymal transition by repressing E-cadherin expression, but it needs an intact PRC2 to act this function. Alterations of this process could contribute to the complex etiology of nsCL/P.
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http://dx.doi.org/10.1007/s00784-018-2350-0DOI Listing
September 2018

CD99 polymorphisms significantly influence the probability to develop Ewing sarcoma in earlier age and patient disease progression.

Oncotarget 2016 Nov;7(47):77958-77967

CRS Development of Biomolecular Therapies, Oncology Lab, Rizzoli Orthopaedic Institute, Bologna, Italy.

Ewing sarcoma (EWS), the second most common primary bone tumor in pediatric age, is known for its paucity of recurrent somatic abnormalities. Apart from the chimeric oncoprotein that derives from the fusion of EWS and FLI genes, recent genome-wide association studies have identified susceptibility variants near the EGR2 gene that regulate DNA binding of EWS-FLI. However, to induce transformation, EWS-FLI requires the presence of additional molecular events, including the expression of CD99, a cell surface molecule with critical relevance for the pathogenesis of EWS. High expression of CD99 is a common and distinctive feature of EWS cells, and it has largely been used for the differential diagnosis of the disease. The present study first links CD99 germline genetic variants to the susceptibility of EWS development and its progression. In particular, a panel of 25 single nucleotide polymorphisms has been genotyped in a case-control study. The CD99 rs311059 T variant was found to be significantly associated [P value = 0.0029; ORhet = 3.9 (95% CI 1.5-9.8) and ORhom = 5.3 (95% CI 1.2-23.7)] with EWS onset in patients less than 14 years old, while the CD99 rs312257-T was observed to be associated [P value = 0.0265; ORhet = 3.5 (95% CI 1.3-9.9)] with a reduced risk of relapse. Besides confirming the importance of CD99, our findings indicate that polymorphic variations in this gene may affect either development or progression of EWS, leading to further understanding of this cancer and development of better diagnostics/prognostics for children and adolescents with this devastating disease.
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http://dx.doi.org/10.18632/oncotarget.12862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363635PMC
November 2016

Replication analysis of 15 susceptibility loci for nonsyndromic cleft lip with or without cleft palate in an italian population.

Birth Defects Res A Clin Mol Teratol 2016 Feb 9;106(2):81-7. Epub 2015 Dec 9.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population.

Methods: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios.

Results: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT  = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT  = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations.

Conclusion: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment.
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http://dx.doi.org/10.1002/bdra.23454DOI Listing
February 2016

Possible Gender-Related Modulation by the ROCK1 Gene in Colorectal Cancer Susceptibility.

Pathobiology 2015 20;82(6):252-8. Epub 2015 Oct 20.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Aim: In view of accumulating evidence supporting a pivotal role of the Rho/ROCK pathway in cancer, we investigated Rho-kinase polymorphisms as potential susceptibility factors in colorectal cancer (CRC) in a representative sample of the Italian population.

Methods: DNA obtained from the peripheral blood samples of 137 CRC patients and 141 healthy controls was genotyped for four ROCK1 (rs35996865; rs73963110; rs2127958; rs288980) and five ROCK2 (rs12692437; rs7563468; rs35768389; rs17463896; rs16857265) selected single nucleotide polymorphisms.

Results: None of the allelic variants of the nine selected markers was associated with the occurrence of CRC or with the development of regional lymph node metastasis. By contrast, the ROCK1 rs35996865 G variant allele was significantly more frequent in male patients (p = 0.028) than in the control group.

Conclusion: This finding is, at present, the first that points to a possible gender-related modulation by the ROCK1 gene in CRC susceptibility.
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http://dx.doi.org/10.1159/000439405DOI Listing
August 2016

Non-syndromic cleft lip with or without cleft palate in Asian populations: Association analysis on three gene polymorphisms of the folate pathway.

Arch Oral Biol 2016 Jan 27;61:79-82. Epub 2015 Oct 27.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Belmeloro, 8, 40126 Bologna, Italy.

Objective: Orofacial clefts (OFCs) are one of the most common birth defects in humans. They are the subject of a number of investigations aimed at elucidating the bases of their complex mode of inheritance involving both genetic and environmental factors. Genes belonging to the folate pathway have been among the most studied. The aim of the investigation was to replicate previous studies reporting evidence of association between polymorphisms of folate related genes and the occurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P), using three independent samples of different ancestry: from Tibet, Bangladesh and Iran, respectively.

Design: Specifically, the polymorphisms rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were tested.

Results: A decreased risk of NSCL/P was observed in patients presenting the C677T variant at MTHFR gene (relative risk for heterozygotes=0.53; 95% confidence interval [C.I.]=0.32-0.87). The investigated polymorphisms mapping at TCN2 and CBS genes did not provide any evidence of association.

Conclusion: Overall, these results indicate that NSCL/P risk factors differ among populations and confirm the importance of testing putative susceptibility variants in different genetic backgrounds.
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http://dx.doi.org/10.1016/j.archoralbio.2015.10.019DOI Listing
January 2016

Human Multidrug Resistance 1 gene polymorphisms and Idiopathic Pulmonary Fibrosis.

J Res Med Sci 2015 Jan;20(1):93-6

Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, Bologna, Italy ; Centre of Molecular Genetics, CARISBO Foundation, University of Bologna, Bologna, Italy.

Background: For the first time we tested an association between the human multidrug resistance gene 1 (MDR1) polymorphisms (SNPs) and idiopathic pulmonary fibrosis (IPF). Several MDR1 polymorphisms are associated with pathologies in which they modify the drug susceptibility and pharmacokinetics.

Materials And Methods: We genotyped three MDR1 polymorphisms of 48 IPF patients and 100 control subjects with Italian origins.

Results: No evidence of association was detected.

Conclusion: There are 50 known MDR1 SNPs, and their role is explored in terms of the effectiveness of drug therapy. We consider our small-scale preliminary study as a starting point for further research.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354072PMC
January 2015

Colorectal cancer susceptibility: apparent gender-related modulation by ABCB1 gene polymorphisms.

J Biomed Sci 2014 Sep 4;21:89. Epub 2014 Sep 4.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Belmeloro, 8-40126, Bologna, Italy.

Background: The ATP-binding cassette transporter B1 (ABCB1) gene codes for a membrane efflux pump localized in epithelial cells. Together with other Permeability-glycoproteins in the small and large intestine, its product represents a barrier against xenobiotics, bacterial toxins, drugs and other substances introduced with diet, including carcinogens. The aim of this investigation was to verify the possible contribution of ABCB1 single nucleotide polymorphisms (SNPs) to the genetic risk of colorectal cancer (CRC).

Results: DNA obtained from the peripheral blood of 98 CRC patients and 100 healthy controls was genotyped for the three selected SNPs: 1236C > T (rs1128503), 2677G > T/A (rs2032582), and 3435C > T (rs1045642). Molecular data were analyzed to asses allele and haplotype association with CRC. No evidence of an association between ABCB1 alleles and CRC occurrence as a whole was found. However, ABCB1 showed either association with carcinoma of the sigmoid colon, and appeared able to influence the sex ratio among CRC patients. These two effects seemed to act independently based on multivariate analysis. We showed that ABCB1 polymorphisms were able to influence CRC susceptibility related to tumor localization and patient gender.

Conclusions: We suggest that sensitivity to undetermined risk factors could depend on the genetic background of ABCB1 locus, with a mechanism that also depends on patient gender.
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http://dx.doi.org/10.1186/s12929-014-0089-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428509PMC
September 2014

RFC1 and non-syndromic cleft lip with or without cleft palate: an association based study in Italy.

J Craniomaxillofac Surg 2014 Oct 2;42(7):1503-5. Epub 2014 May 2.

Department of Experimental, Diagnostic and Specialty Medicine, University di Bologna, Via Belmeloro 8, 40126 Bologna, Italy.

The molecular basis of orofacial development is largely unknown and needs to be unravelled. Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial malformation, with an incidence of about 1/700 live births, although variable according to ethnicity. Being a multifactorial disease, it arises as a result of an interplay between genetic and environmental factors. Several approaches have been developed to identify susceptibility genes. Genes belonging to the folate/homocysteine pathway are attracting increasing interest because folate supplementation before and during early pregnancy can reduce the risk of NSCL/P. We performed a family based association study in order to assess if a genetic variant of RFC1 could be involved in NSCL/P onset. We genotyped 404 unrelated probands and their relatives for three biallelic polymorphic variants (rs1051266, rs4818789 and rs3788205), that were selected because they produced conflicting results on previous investigations. Evidence of association was found between the investigated polymorphisms and NSCL/P in our sample of the Italian population, albeit with weak significance levels. Results from this investigation provided a support of previous studies suggesting a role of RFC1 in NSCL/P aetiology, reinforcing the concept that genetic predisposition to NSCL/P varies enormously within different ethnic groups.
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http://dx.doi.org/10.1016/j.jcms.2014.04.021DOI Listing
October 2014

Role of the MIR146A polymorphism in the origin and progression of oral squamous cell carcinoma.

Eur J Oral Sci 2014 Jun 10;122(3):198-201. Epub 2014 Mar 10.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Gene expression and cell behavior are regulated by several factors, including small non-coding RNAs. MicroRNAs affecting cell growth, differentiation, and apoptosis are thought to play an important role in tumorigenesis. The levels of miR-146 appear to be associated with cancer development and progression, including that of oral squamous cell carcinoma. The aim of this investigation was to ascertain whether the single nucleotide polymorphism, rs2910164, mapping in the MIR146A gene, has a role in oral squamous cell carcinoma progression. A genetic association study was performed with a sample set of 346 oral squamous cell carcinomas collected in Italy. Our data indicate that the rs2910164 polymorphism is not associated with tumor development. However, a slight increase in the frequency of the variant allele was observed in Stage II tumors. Further investigations are needed to verify a possible role of the variant allele or rs2910164 in oral squamous cell carcinoma progression.
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http://dx.doi.org/10.1111/eos.12121DOI Listing
June 2014

Evidence of the involvement of the DHFR gene in nonsyndromic cleft lip with or without cleft palate.

Eur J Med Genet 2014 Jan 20;57(1):1-4. Epub 2013 Dec 20.

Department of Experimental, Diagnostic and Specialty Medicine, University di Bologna, Via Belmeloro 8, 40126 Bologna, Italy.

Studies aimed at evidencing genetic causes for neural tube defect (NTD) occurrence have often provided the inspiration for orofacial cleft aetiology investigations. The correlation between the two congenital malformations is provided by the similar incidence timing and the involvement of structures localized in the midline of the embryo. This connection is corroborated by the existence of a number of genes involved in both malformations. In this article, we considered the dihydrofolate reductase (DHFR) gene, previously seen implicated in NTDs, as a candidate for cleft lip with or without cleft palate (CL/P) risk. Four SNPs mapping on the DHFR gene were genotyped for 400 Italian CL/P triads, using TaqMan(®) approach. The rs1677693 provided evidence of association, even if at borderline level (P value 0.049). In particular, the variant allele seems to have a protective effect OR = 0.80 (95% C.I. 0.64-0.99). Moreover, the combination of rs1677693(A)-rs1650723(G) alleles showed a significant association OR 0.64 (95% C.I. 0.47-0.86) (P value = 0.006). This represents the first attempt to demonstrate a role for DHFR in CL/P aetiology, howbeit the study of such gene deserves a deepening.
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http://dx.doi.org/10.1016/j.ejmg.2013.12.002DOI Listing
January 2014

Lab-Test(®) 4: Dental caries and bacteriological analysis.

Dent Res J (Isfahan) 2012 Dec;9(Suppl 2):S139-41

Department of Histology, Embryology and Applied Biology, Centre of Molecular Genetics, CARISBO Foundation, University of Bologna, Bologna, Italy.

Dental caries is one of the most common infectious ultifactorial diseases worldwide, characterized by the progressive demineralization of the tooth, following the action of bacterial acid metabolism. The main factors predisposing the onset of the carious process are: 1) the presence of bacterial species able to lower the pH until critical values of 5.5, 2) the absence of adequate oral hygiene, 3) an inefficient immune response anti-caries, 4) the type of alimentary diet and 5) the structure of the teeth. Among the 200 bacterial species isolated from dental plaque the most pathogenic for dental caries are: Streptococcus mutans, Streptococcus sobrinus, Lactobacillus acidophilus, Actinomices viscusus and Bifidobacterium dentium. Our laboratory (LAB(®) s.r.l., Codigoro, Ferrara, Italy) has developed a test for absolute and relative quantification of the most common oral cariogenic bacteria. The test uses specific primers and probes for the amplification of bacteria genome sequences in Polymerase Chain Reaction Real Time. The results provide a profile of patient infection, helpful for improving the diagnosis and planning of preventive treatment to reduce the bacterial load.
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http://dx.doi.org/10.4103/1735-3327.109723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692161PMC
December 2012

Idiopathic pulmonary fibrosis and polymorphisms of the folate pathway genes.

Clin Biochem 2013 Jan 23;46(1-2):85-8. Epub 2012 Oct 23.

Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Via Belmeloro 8, 40126 Bologna, Italy.

Objectives: This study aims to determine the possible association between folate pathway gene polymorphisms and idiopathic pulmonary fibrosis. This represents the first study carried out on folate pathway gene polymorphisms as possible risk factors in this kind of pathology. The premise is that several polymorphisms mapping on genes responsible for folate uptake are associated with the risk of numerous diseases occurring between pregnancy and old age, and that too little is currently known about idiopathic pulmonary fibrosis.

Design And Methods: We genotyped 9 single nucleotide polymorphisms and 1 polymorphic insertion in 7 essential genes belonging to the folate pathway in 32 Italian idiopathic pulmonary fibrosis patients and 81 control subjects. This was done by PCR and restriction analysis.

Results: Allelic and genotypic association tests indicated that for all the analysed polymorphisms there were no significant differences between patients and controls. Nevertheless, the haplotype association analysis revealed a significant association between idiopathic pulmonary fibrosis and transcobalamin II gene polymorphisms: specifically the haplotype 776G (rs1801198)-c.1026-394G (rs7286680)-444C (rs10418) (OR=2.84; 95% C.I. 1.36-5.93, P value=0.004).

Conclusions: This small-scale preliminary study would suggest the importance of further research focusing on the role of folate in the onset of idiopathic pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.10.009DOI Listing
January 2013

A candidate gene study of one-carbon metabolism pathway genes and colorectal cancer risk.

Br J Nutr 2013 Mar 16;109(6):984-9. Epub 2012 Jul 16.

Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Bologna, Italy.

The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case-control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.
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http://dx.doi.org/10.1017/S0007114512002796DOI Listing
March 2013

New evidence for the role of cystathionine beta-synthase in non-syndromic cleft lip with or without cleft palate.

Eur J Oral Sci 2011 Jun 5;119(3):193-7. Epub 2011 May 5.

Department of Histology, Embryology and Applied Biology, Centre of Molecular Genetics, CARISBO Foundation, University of Bologna, Italy.

Orofacial clefts have a multifactorial aetiology encompassing both genetic and environmental components. While there is wide agreement on the importance of both genetic and nutritional factors, genetic influence in particular has not been well defined. As genetic variants in folate and homocysteine metabolism have been reported to influence the risk of orofacial clefts, an Italian cleft lip with or without cleft palate (CL/P) data set was enrolled for an analysis based on family association to test betaine-homocysteine methyltransferase (BHMT and BHMT2) and cystathionine beta-synthase (CBS) variants. No significant level of association was found between BHMT and BHMT2 variants, while evidence of an allelic association with CL/P was found for the single nucleotide polymorphism rs4920037, mapping at the CBS gene. A log-linear approach indicated that the best genetic model takes into account both mother and child genotypes. This suggests that human orofacial development is influenced by CBS genotypes that possibly operate through intergenerational fetal-maternal interaction.
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http://dx.doi.org/10.1111/j.1600-0722.2011.00824.xDOI Listing
June 2011

No evidence of HAND2 involvement in nonsyndromic cleft lip with or without cleft palate.

Clin Oral Investig 2012 Apr 24;16(2):619-23. Epub 2011 Mar 24.

Department of Histology, Embryology and Applied Biology, Centre of Molecular Genetics, University of Bologna, Via Belmeloro 8, 40126 Bologna, Italy.

Craniofacial morphogenesis is determined by multistep processes involving signalling molecules and transcription factors, which are organised into highly coordinated pathways. Derailment from this intricate network can lead to congenital malformations. Cells migrate from neural crests to populate different structures, such as branchial arches, involved in embryonal orofacial development. The EDN1 pathway is involved in branchial arch development. Gene knockout and knockdown experiments on EDN1 or its downstream effector dHAND resulted in mice that were characterised by craniofacial defects and cleft palate. Our aim was to evaluate whether the transcription factor HAND2 could be implicated in non-syndromic cleft lip with or without cleft palate (CL/P) aetiology. A sample study composed of 39 multiplex Italian pedigrees was enrolled to test linkage between two microsatellite flanking HAND2 locus and CL/P. No evidence of linkage between HAND2 and CL/P was obtained. Indeed, formal levels of exclusion were obtained with different inheritance models. Investigation results did not support a role of HAND2 in CL/P aetiology. Nevertheless a minor contribute of the gene in clefting could not be ruled out.
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http://dx.doi.org/10.1007/s00784-011-0539-6DOI Listing
April 2012

No evidence for a role of CRISPLD2 in non-syndromic cleft lip with or without cleft palate in an Italian population.

Eur J Oral Sci 2011 Feb;119(1):102-5

Department of Histology, Embryology and Applied Biology, Centre of Molecular Genetics, CARISBO Foundation, University of Bologna, Bologna, Italy.

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a malformation with variable phenotypes, resulting from a mixture of genetic and environmental factors. Some studies have supported a role for the 16q24 region and its candidate gene, CRISPLD2, in clefting. A replication study is necessary to confirm these findings. The aim of the present study was to test, by genetic linkage and association analyses, whether the candidate gene, CRISPLD2, represents a risk factor for NSCLP. The analysis of 39 multigenerational families provided formal exclusion of a linkage between NSCLP and the CRISPLD2 locus under different genetic models and non-parametric analyses. The family-based study of 239 unrelated probands and their parents revealed no association between any particular allele or haplotype and NSCLP. Therefore, the present investigation did not support the hypothesis of the involvement of CRISPLD2 in NSCLP malformation, at least with regard to the Italian population.
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http://dx.doi.org/10.1111/j.1600-0722.2010.00801.xDOI Listing
February 2011

A role for epidermal growth factor receptor in idiopathic pulmonary fibrosis onset.

Mol Biol Rep 2011 Oct 4;38(7):4613-7. Epub 2010 Dec 4.

Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Via Belmeloro 8, 40126 Bologna, Italy.

In idiopathic pulmonary fibrosis (IPF) patients the presence of missense polymorphisms (SNP) in members of the epidermal growth factor receptor (EGFR) family or their genetic association could influence the binding affinity of natural ligands, modifying the expression and the behavior of the correlated genes. EGFR family members are particularly involved in the epithelial injury and fibrotic process in IPF. Genetic variations in HER family of receptors may alter the possible therapeutic efficacy of EGFR inhibitors. This study aimed to analyze the relationships between IPF and specific EGF receptor family functional polymorphisms. We tested the presence of common EGFR, HER2 and HER3 non-synonymous SNPs in the peripheral blood of 20 Italian IPF patients and their association with the disease. Our data indicated that the HER2 variant allele frequency was significantly lower in patients than in controls, with an odds ratio of 0.31 (95% CI 0.080, 0.98). Our finding suggests that HER2 variant could be a protective factor against IPF onset.
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http://dx.doi.org/10.1007/s11033-010-0594-0DOI Listing
October 2011

New insights in collagen turnover in orofacial cleft patients.

Cleft Palate Craniofac J 2010 Jul;47(4):393-9

Department of Human Morphology and Biomedical Sciences–Città Study, Extracellular Matrix Laboratory, University of Milan, Italy.

Objective: We aimed to characterize the fibroblast phenotype of patients by analyzing gene and protein expression of cleft lip and/or cleft palate fibroblasts in relation to collagen turnover and extracellular matrix remodeling.

Patients: Human palatal fibroblasts were obtained from three healthy subjects without cleft lip and/or cleft palate and from three subjects with nonsyndromic cleft lip and/or cleft palate. Collagen turnover-related gene and protein expression were analyzed by real-time polymerase chain reaction, Western and dot blots, and sodium dodecyl sulfate zymography.

Results: Cleft lip and/or cleft palate fibroblasts, compared with controls, displayed a down-regulation of collagens type I and III messenger RNA (p < .0001 and p < .001, respectively) but an opposite tendency to increase protein levels. Cleft lip and/or cleft palate cells had higher lysyl hydroxylase-2b messenger RNA levels expressed in relation to collagen type I messenger RNA, down-regulated matrix metalloproteinase-1, tissue inhibitor of matrix metalloproteinase-1, and Secreted Protein Acidic and Rich in Cysteine messenger RNA (p < .0001 and p < .01, respectively). Pro-matrix metalloproteinase-1 tended to decrease, and pro-matrix metalloproteinase-2 and -9 were down-regulated (p < .01, p < .05, respectively), as was Secreted Protein Acidic and Rich in Cysteine protein expression (p < .05).

Conclusions: Our results suggest that the cleft lip and/or cleft palate fibroblast phenotype is characterized by a tendency toward interstitial collagen deposition due to posttranslational modifications, such as decreased collagen degradation by matrix metalloproteinases and increased collagen cross-links. These findings may contribute to the knowledge of the cleft lip and/or cleft palate fibroblast phenotype and may be useful to the surgeon when considering the potential wound contraction and subsequent undesired scarring in cleft lip and/or cleft palate ocurring after the surgical closure of a cleft palate.
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http://dx.doi.org/10.1597/07-196.1DOI Listing
July 2010

Expression and association data strongly support JARID2 involvement in nonsyndromic cleft lip with or without cleft palate.

Hum Mutat 2010 Jul;31(7):794-800

Department of Histology, Embryology and Applied Biology, Centre of Molecular Genetics, University of Bologna, Via Belmeloro, 8, 40126 Bologna, Italy.

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.
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http://dx.doi.org/10.1002/humu.21266DOI Listing
July 2010

Anorganic bovine bone (Bio-Oss) regulates miRNA of osteoblast-like cells.

Int J Periodontics Restorative Dent 2010 Feb;30(1):83-7

Institute of Histology, University of Bologna and Center of Molecular Genetics, CARISBO Foundation, Bologna, Italy.

Bio-Oss (Geistlich) is composed of an organic bovine bone and has been widely used in several bone regeneration procedures during oral surgery. However, how this biomaterial enhances osteoblast activity to promote bone formation is not completely understood. MicroRNAs (miRNAs) represent a class of small, functional, noncoding RNAs of 19 to 23 nucleotides that regulate the transcription of messenger RNAs (mRNAs) in proteins. In this study, the miRNA microarray technique was used to investigate translation regulation in an osteoblast-like cell line (MG63) exposed to Bio-Oss. Nine up-regulated miRNAs (mir-423, mir-492, mir-191, mir-23a, mir-377, mir-494, mir-214, mir-193b, mir-320) and 4 down-regulated miRNAs (mir-27a, mir-24, mir-188, let-7c) were identified. Because each miRNA regulates 100 mRNAs, only mRNAs related to bone formation were analyzed. The vast majority of detected mRNAs are down-regulated, including some homeobox genes (genes that regulate the morphogenesis of an entire segment of the body), such as noggin and EN1. An indirect positive effect was demonstrated on bone morphogenetic protein-4. To the authors' knowledge, the data reported here are the first on translation regulation in osteoblasts exposed to Bio-Oss. This study may be relevant in better understanding the molecular mechanism of bone regeneration and used as a potential tool for analyzing the combined use of cytokines.
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February 2010

Bio-Oss®acts on Stem cells derived from Peripheral Blood.

Oman Med J 2010 Jan;25(1):26-31

Objectives: This study aims to study how Bio-Oss® can induce osteoblast differentiation in mesenchymal stem cells, the expression levels of bone related genes and mesenchymal stem cells markers using real time Reverse Transcription-Polymerase Chain Reaction.

Methods: PB-hMSCs stem preparations were obtained for gradient centrifugation from peripheral blood of healthy anonymous volunteers, using the Acuspin System-Histopaque 1077. The samples were then cultured for 7 days for RNA processing, and the expression was quantified using real time PCR.

Results: Bio-Oss® caused an induction of osteoblast transcriptional factor like RUNX2 and of bone related genes; SPP1 and FOSL1. In contrast, the expression of ENG was significantly decreased in stem cells treated with Bio-Oss® with respect to untreated cells, indicating the differentiation effect of this biomaterial on stem cells.

Conclusion: The results obtained can be relevant to enhance the understanding of the molecular mechanism of bone regeneration and can act as a model for comparing other materials with similar clinical effects.
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http://dx.doi.org/10.5001/omj.2010.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215382PMC
January 2010