Publications by authors named "Cecilia Anichini"

13 Publications

  • Page 1 of 1

Antioxidant strategies in genetic syndromes with high neoplastic risk in infant age.

Tumori 2014 Nov-Dec;100(6):590-9

Oxidative stress plays a key role in carcinogenesis. Oxidative damage to cell components can lead to the initiation, promotion and progression of cancer. Oxidative stress is also a distinctive sign in several genetic disorders characterized by a cancer predisposition such as ataxia-telangiectasia, Fanconi anemia, Down syndrome, Beckwith-Wiedemann syndrome and Costello syndrome. Taking into account the link between oxidative stress and cancer, the capacity of antioxidant agents to prevent or delay neoplastic development has been tested in various studies, both in vitro and in vivo, with interesting and promising results. In recent years, research has been conducted into the molecular mechanisms linking oxidative stress to the pathogenesis of the genetic syndromes we consider in this review, with the resulting identification of possible new therapeutic targets. The aim of this review is to focus on the oxidative mechanisms intervening in carcinogenesis in cancer-prone genetic disorders and to analyze the current status and future prospects of antioxidants.
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http://dx.doi.org/10.1700/1778.19256DOI Listing
May 2015

Antioxidant effects of potassium ascorbate with ribose in costello syndrome.

Anticancer Res 2013 Feb;33(2):691-5

Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Viale Mario Bracci 36, 53100, Siena, Italy.

Background: Costello syndrome is a rare genetic condition characterized by coarse facies, short stature, loose folds of skin especially on hands and feet, severe feeding difficulties and failure to thrive. Other features include cardiac anomalies, developmental disability and increased risk of neoplasms. Given the link between oxidative stress (OS) and carcinogenesis, we tested the hypothesis that OS occurs in this syndrome, supposing its role both in cancer development and in other clinical features.

Patients And Methods: We describe four cases with Costello syndrome in which we verified the presence of OS by measuring a redox biomarker profile including total hydroperoxides, non-protein-bound iron, advanced oxidation protein products, thyols, carbonyl groups and isoprostanes. Thus, we introduced an antioxidant agent, namely potassium ascorbate with ribose (PAR) into the therapy and monitored the redox profile every three months to verify its efficacy.

Results: A progressive decrease in OS biomarkers occurred, together with an improvement in the clinical features of the patients.

Conclusion: OS was proven in all four cases of Costello syndrome. The antioxidant therapy with PAR demonstrated positive effects. These promising results need further research to confirm the relevance of OS and the efficacy of PAR therapy in Costello syndrome.
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February 2013

The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites.

Hum Mol Genet 2013 Feb 30;22(3):544-57. Epub 2012 Oct 30.

Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.

At chromosome 11p15.5, the imprinting centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4-2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith-Wiedemann syndrome, although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wild-type allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes.
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http://dx.doi.org/10.1093/hmg/dds465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542864PMC
February 2013

Beckwith-Wiedemann syndrome: potassium ascorbate with ribose therapy in a syndrome with high neoplastic risk.

Anticancer Res 2011 Nov;31(11):3973-6

Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Viale Mario Bracci 36, 53100 Siena, Italy.

Background: Beckwith-Wiedemann Syndrome (BWS) is a genomic imprinting disorder characterized by overgrowth and increased risk of malignancy. We studied the oxidative stress (OS) pattern of our patients with BWS and administered, for the first time, potassium ascorbate with ribose (PAR) once a day as long-term therapy in order to correct the effects induced by free radicals.

Patients And Methods: We describe the clinical features of three patients examined every three months in our clinic. OS was ascertained by measuring a panel of OS biomarkers: non-protein-binding iron, total hydroperoxides, advanced oxidation protein products, isoprostanes, carbonyl groups and thiols. After the presence of OS was established, treatment with PAR was started at the dosage of 300 mg of Potassium Bicarbonate and 150 mg of Ascorbic Acid in aqueous solution and changes occurring in OS biomarkers were followed dosing every three months.

Results: Our patients showed higher levels of OS biomarkers than controls at the time of diagnosis. There was a reduction in OS biomarker values for all three patients with treatment. No primary or secondary neoplastic disease was observed in 9 months of follow-up.

Conclusion: This is the first report showing OS occurring in BWS. No drug until this report has been published showing efficacy against OS in any cancer. Given the limited number of patients, care must be taken to mitigate enthusiasm. We are collecting data for a large number of BWS patients to confirm these preliminary results.
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November 2011

Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair.

Nat Genet 2009 Sep 16;41(9):1022-6. Epub 2009 Aug 16.

Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.

N-myristoylation is a common form of co-translational protein fatty acylation resulting from the attachment of myristate to a required N-terminal glycine residue. We show that aberrantly acquired N-myristoylation of SHOC2, a leucine-rich repeat-containing protein that positively modulates RAS-MAPK signal flow, underlies a clinically distinctive condition of the neuro-cardio-facial-cutaneous disorders family. Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2(S2G) in vitro enhanced MAPK activation in a cell type-specific fashion. Induction of SHOC2(S2G) in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype previously associated with aberrant signaling. These results document the first example of an acquired N-terminal lipid modification of a protein causing human disease.
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http://dx.doi.org/10.1038/ng.425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765465PMC
September 2009

18, X, Y aneuploidies and transmission electron microscopy studies in spermatozoa from five carriers of different reciprocal translocations.

Asian J Androl 2009 May 6;11(3):325-32. Epub 2009 Apr 6.

Department of Biomedical Sciences, Applied Biology Section, University of Siena, Siena 53100, Italy.

We analysed ejaculated spermatozoa from five infertile men with different balanced reciprocal translocations to contribute to the study of meiotic segregation of chromosomes 18, X and Y and also to evaluate sperm morphology by transmission electron microscopy (TEM) analysis. Conventional lymphocyte karyotype analyses highlighted different reciprocal balanced translocations: t(12;13), t(4;9), t(X;8), t(8;10) and t(3;16). Semen analysis was performed by light and TEM. Fluorescence in situ hybridization was performed directly on sperm nuclei using centromeric probes for chromosomes 18, X and Y. The carriers of the balanced reciprocal translocations considered in the present study showed a very similar pattern of sperm pathologies: diffused presence of apoptosis and immaturity. All patients showed meiotic segregation derangements, highlighted by the presence of sperm diploidies and sex chromosome disomies particularly related to the failure of the first meiotic division. However, an increased incidence of chromosome 18 aneuploidy was detected in spermatozoa from t(X;8) and t(8;10) carriers. We have also reported values from sex chromosomes such as t(X;8), although the X chromosome was involved in translocation. Since patients with reciprocal translocations and spermatogenetic impairment are candidates for intracytoplasmic sperm injection cycles, the study of sperm parameters, and particularly of the level of aneuploidy rates, would provide better information for couples at risk and would contribute to the data in the literature for a better understanding of the effects of chromosomal rearrangement on the whole meiotic process and, in particular, on chromosomes not involved in translocation.
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http://dx.doi.org/10.1038/aja.2008.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735288PMC
May 2009

Effect of emotional stress on sperm quality.

Indian J Med Res 2008 Sep;128(3):254-61

Department of Surgery, Biology Section, Interdepartmental Centre for Research & Therapy of Male Infertility, University of Siena, Italy.

Background & Objective: Emotional stress plays a detrimental role on fertility. In this study male patients with idiopathic infertility were selected after evaluation of psychological stress to evaluate a positive effect of a stress therapy on their semen quality.

Methods: A total of 20 patients with infertility were enrolled in the study and randomly divided in two groups. Ejaculates were examined by light and transmission electron microscopy (TEM). Meiotic segregation was also investigated by fluorescence in situ hybridization (FISH). Ten patients were treated with Conveyer of Modulating Radiance (CRM) therapy and sperm characteristics and meiotic segregation were evaluated again three months at the end of treatment.

Results: TEM data showed that, among sperm pathologies, necrosis and apoptosis were higher and the number of "healthy" sperm was significantly reduced in both groups of stressed men compared to reference values. The number of "healthy" sperm was significantly higher in the treated group after therapy, indicating a recovery of sperm quality, although no significant decrease in sperm pathologies was observed. FISH analysis showed that the mean frequencies of sex chromosomes disomies and diploidies significantly decreased after stress therapy.

Interpretation & Conclusion: The effects induced by stress also seem to include meiotic and structural alterations in sperm cells. The spermatogenic process was improved after a cycle of CRM therapy indicating that stress is an additional risk factor for idiopathic infertility.
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September 2008

Pregnancy in a gerodermia osteodysplastica patient: a case report.

Am J Obstet Gynecol 2008 Jan;198(1):e17-9

Department of Gynaecology and Obstetrics, and Pathophysiology of Human Reproduction, University of Naples Federico II, Naples, Italy.

Gerodermia osteodysplastica is a rare autosomal recessive connective tissue disorder included in the cutis laxa syndromes. We report the first case of pregnancy in a 26-year-old patient with gerodermia osteodysplastica, which terminated in successful cesarean delivery at term. The course, management, and potential concerns of such an extraordinary pregnancy are described.
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http://dx.doi.org/10.1016/j.ajog.2007.09.037DOI Listing
January 2008

Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms' tumour.

Hum Mol Genet 2007 Feb 11;16(3):254-64. Epub 2006 Dec 11.

Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy.

The imprinted expression of the IGF2 and H19 genes is controlled by the Imprinting Centre 1 (IC1) at chromosome 11p15.5. This is a methylation-sensitive chromatin insulator that works by binding the zinc-finger protein CTCF in a parent-specific manner. Microdeletions abolishing some of the CTCF target sites (CTSs) of IC1 have been associated with the Beckwith-Wiedemann syndrome (BWS). However, the link between these mutations and the molecular and clinical phenotypes was debated. We have identified two novel families with IC1 deletions, in which individuals with the clinical features of the BWS are present in multiple generations. By analysing the methylation pattern at the IGF2-H19 locus together with the clinical phenotypes in the individuals with maternal and those with paternal transmission of five different deletions, we demonstrate that maternal transmission of 1.4-1.8 kb deletions in the IC1 region co-segregates with the hypermethylation of the residual CTSs and BWS phenotype with complete penetrance, whereas normal phenotype is observed upon paternal transmission. Although gene expression could not be assayed in all cases, the methylation detected at the IGF2 DMR2 and H19 promoter suggests that IC1 hypermethylation is consistently associated with biallelic activation of IGF2 and biallelic silencing of H19. Comparison of these deletions with a 2.2 kb one previously reported by another group indicates that the spacing of the CTSs on the deleted allele is critical for the gain of the abnormal methylation and penetrance of the clinical phenotype. Furthermore, we observe that the hypermethylation resulting from the deletions is always mosaic, suggesting that the epigenetic defect at the IGF2-H19 locus is established post-zygotically and may cause body asymmetry and heterogeneity of the clinical phenotype. Finally, the IC1 microdeletions are associated with a high incidence of Wilms' tumour, making their molecular diagnosis particularly important for genetic counselling and tumour surveillance at follow-up.
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http://dx.doi.org/10.1093/hmg/ddl448DOI Listing
February 2007

Photoparoxysmal responses in children with chromosomal aberrations.

Epilepsy Res 2006 Dec 20;72(2-3):164-70. Epub 2006 Sep 20.

Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Viale M. Bracci, 53100 Siena, Italy.

Electroencephalographic (EEG) anomalies and epilepsy are commonly observed in the clinical picture of patients with chromosomal aberrations. However, no investigations have been performed on the relationship between chromosomal disorders and photoparoxysmal response (PPR). In this study, we evaluate the characteristics of PPRs elicited with intermittent photic stimulation during a routine electroencephalogram in children affected by chromosomal anomalies and correlated this with the clinical profile of the child. A review of the literature has also been performed. PPRs occurred in 14% (4/28) of patients. PPRs were brief (
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http://dx.doi.org/10.1016/j.eplepsyres.2006.07.016DOI Listing
December 2006

Epilepsy and electroencephalographic findings in pericentric inversion of chromosome 12.

J Child Neurol 2004 Aug;19(8):604-8

Department of Pediatrics, University of Siena, Siena, Italy.

Epilepsy, together with mental retardation, represents a common manifestation of chromosomal aberrations. Specific electroencephalographic (EEG) and epileptic patterns have been described in several chromosomal disorders, such as Angelman's syndrome, Miller-Dieker syndrome, Wolf-Hirschhorn syndrome, and ring 20 syndrome. A peculiar electroclinical pattern has also been identified in trisomy 12p syndrome. We report three patients with a pericentric inversion of chromosome 12, with breakpoints localized to p11-q13 and affected by epilepsy or EEG anomalies. Two suffered from epilepsy, which, in the clinical course, was mainly characterized by complex partial seizures with a semiology related to the temporal lobe. In one patient, myoclonic absences, head drop, and massive jerky attacks were also present. In both patients, generalized 3 Hz bursts were registered, together with multifocal and focal paroxysmal activity, which were most prominent in the temporoparietal and temporal areas, respectively. In the other patient, who had no epilepsy, EEG showed bioccipital paroxysmal activity. In all patients, the clinical picture was characterized by the presence of moderate mental retardation and behavioral disorders. The incidence of epilepsy or EEG anomalies among patients with a pericentric inversion of chromosome 12 remains to be ascertained. However, the present study confirms that chromosome 12 anomalies can be associated with epilepsy. Although myoclonic absence-like episodes can occasionally be part of the epileptic phenotype, the electroclinical pattern in pericentric inversion of chromosome 12 seems to be more polymorphic when compared with that observed in trisomy 12p syndrome.
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http://dx.doi.org/10.1177/088307380401900807DOI Listing
August 2004

Electroencephalographic and epileptic patterns in X chromosome anomalies.

J Clin Neurophysiol 2004 Jul-Aug;21(4):249-53

Department of Pediatrics, University of Siena, Siena, Italy.

Although epilepsy and mental retardation are commonly observed in individuals with chromosomal aberrations, the identification of EEG/epileptic profiles in those with specific chromosome anomalies remains difficult. A few syndromes seem to show peculiar clinical and EEG associations. The authors report an electroclinical investigation on a group of patients carrying X chromosome anomalies: 16 patients with Turner's syndrome, 17 with Klinefelter's syndrome, 1 with an X-autosomal rearrangement, 2 with Xq isochromosome [Xq(i)], and 7 with triple X syndrome. Epilepsy and/or EEG anomalies were found in three of the patients with Klinefelter's syndrome, in one patient with an X-autosomal rearrangement, and in five of those with triple X syndrome. No epilepsy or EEG anomalies were detected in the other patients. Epilepsy may be associated with Klinefelter's syndrome. In addition, the authors found that an electroclinical pattern, represented by paroxysmal activity in the posterior regions (temporo-parieto-occipital areas) with complex partial seizures and easily controlled by antiepileptic drugs, may be present in patients with triple X syndrome. In contrast, gross X-autosomal rearrangements are associated with polymorphic EEG/epileptic findings. Although further studies are needed to validate these observations, they clearly confirm the strict relationship between X chromosome anomalies and epilepsy.
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http://dx.doi.org/10.1097/00004691-200407000-00003DOI Listing
December 2004