Guglielmina Ranzani - Academia.edu (original) (raw)

Papers by Guglielmina Ranzani

Gastroenterology, 2000

en-Y reconstruction of each reflux models and a sham operation. To detect and~uantitate duodeno-e... more en-Y reconstruction of each reflux models and a sham operation. To detect and~uantitate duodeno-esophageal reflux, the rats were examined bile flow by 9 mTc-PMT and intraesophageal pH monitor. The duodeno-esophageal reflux according to 99mTc_PMT and intraesophageal pH monitor, in the DFR group was significantly lower than that in the DER group e 9m Tc_ PMT, 6.2% in the DFR group and 16.2% in the DER group, pH monitor, 26.5% in the DFR group and 75.5% in the DER group, as the median, respectively, p <0.05). The animals were fed a standard maintenance diet without carcinogens and were examined 50 weeks after surgery. Results: While no carcinoma was found among the 3 control group animals, 5 of the 28 animals with DFR (18%) and 17 of the 22 animals with DER (77%) developed esophageal carcinoma. The incidence rates of esophageal carcinoma in the DFR group were significantly lower than in the DER group (p<O.OOI). Five animals with DER group had esophageal double carcinomas. Of the 5 esophageal carcinomas in the DFR group, all cases were SCC. Of the 22 esophageal carcinomas in the DER group, 9 were SCC, 12 ADC, and I adenosquamous cell carcinoma (ASC). The rates of developing of esophageal SCC in the DFR group was higher than that in the DER group (p < 0.00 I). On the other hand, the rate of developing of esophageal ADC in the DFR group was lower than that in the DER group (p<O.OOI). Associated lesions of the esophageal carcinoma, including basal cell hyperplasia, erosion, squamous dysplasia and Barrett's epithelium were found in the DER group higher than in the DFR group. ADC developed from the columnar-lined epithelium near the anastomosis, while SCC arose from the squamous esophagitis. Conclusions: These observation suggested that histologic type of esophageal carcinoma induced by duodeno-esophageal reflux is determined by gradation of duodeno-esophageal reflux in rats.

Human Heredity, 1977

About 280 unrelated individuals living in the province of Bologna (Northern Italy) have been stud... more About 280 unrelated individuals living in the province of Bologna (Northern Italy) have been studied for the following red cell enzymatic markers: phosphoglucomutase (PGM), adenylate kinase (AK), adenosine deaminase (ADA) and phosphohexose isomerase (PHI). 116 subjects from the same sample have also been analysed for red cell acid phosphatase (ACP). The observed gene frequencies are PGM21 = 0.280; AK2 = 0.030; ADA2 = 0.091; ACPa = 0.297; ACPb = 0.647; ACPc = 0.056. In the PHI system two individuals with the variant PHI 3-1 phenotype have been found.

European journal of biochemistry, Nov 1, 1976

We have fractionated from human aneuploid cell cultures three different enzyme fractions degradin... more We have fractionated from human aneuploid cell cultures three different enzyme fractions degrading single-stranded DNA. We have purified and characterized one of these DNases; this is an endonuclease working at alkaline pH (around 9.5) and requiring M$+ for its activity. The enzyme degrades denatured DNA over 100 times more efficiently than native DNA in optimal conditions. The termini produced by the enzyme have 5'P and 3'OH ends. The enzyme can attack, though at reduced rate, the supertwisted circular molecule of Simian virus 40 DNA, whereas it is inactive on the nicked circular molecule. The ultraviolet irradiation of DNA, whether native or denatured, does not affect its efficiency as substrate of the DNase. The properties of this endonuclease distinguish it from those of the other DNases described previously in mammalian cells; the denomination DNase VI is therefore proposed. Its properties are similar to those of DNases described in Ustilago maydis and Bacillus subtilis, for which an essential role in recombination seems likely.

Genes, Chromosomes and Cancer, Sep 4, 2017

Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutatio... more Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6,858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions vs. point mutations in the APC-5' regulatory region.

Virchows Archiv, May 1, 1994

Zeitschrift für Rechtsmedizin, 1982

A sample of the population of Naples has been examined for several red cell enzyme markers. About... more A sample of the population of Naples has been examined for several red cell enzyme markers. About 2,000 newborn have been analyzed for ACP, GLO I, and UMPK; 1,000 of them were also analyzed for PepA and PepB, and 500 for PGM1 and PGMz. In addition about 400 school children have been typed for the P G D and PGP polymorphisms. The observed gene frequencies for the polymorphic systems are: ACpA=0.293, ACP B= 0.667 and ACP c = 0.040; G L O I = 0.372; G P T ~ =0.462; UMPK~ = 0.029; PGM~ =0.279; P G D c = 0.037; pGpl=0.953, pGp2=0.038 and pGp3=0.009. Moreover during the screening of PepA, PepB and G P T markers, some rare alleles have been encountered, one of which, at the GPT locus, has never been reported before. We propose for it the name GPT 1°.

Cancer Genetics and Cytogenetics, 1996

To determine whether a correlation exists between aneuploidy and ~53 status in astrocytic tumors ... more To determine whether a correlation exists between aneuploidy and ~53 status in astrocytic tumors we anal_vzed 48 astrocytomas with different grades of malignancy for the presence of p53 mutations and aneuploidy of chromosomes 1 o and I 7 (Chl 0, Chl7), known to be particularly involved with this type of tumor. We used polymerase chain reaction (PCR)-based denaturing gradient gel electrophoresis [DGGE) analysis on exons 5-8 of the ~53 gene, and fluorescence in situ hybridization (FISH) analysis on interphase nuclei using chromosome specific pericentromeric probes, respectively. Our results showed that ChlWChl7 aneuploidy is a common early event in astrocytomas (90% of low grade tumors are aneuploid). ~53 mutations and Chl7 aneuploidy are early events, but their incidence is not de,pendent on tumor grade. Loss of ChlO is the only alteration that significantly correlates with tumor progression. No significant correlation between the presence of ChlWChl7 aneuploidy and ~53 mutations was found. However, the coexistence of p.53 mutations and aneuploidy, was observed in a subset of cases. The presence of p53 mutations appeared to be a significant predictor of a poor prognosis. In conclusion, genomic instability may or may not be associated with ~53 mutations in astrocytomas, thus suggesting that other cellular determinants can also be responsible for the aneuploidy observed.

Genes, Chromosomes and Cancer, 2014

Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric... more Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligationdependent probe amplification, single-nucleotide primer extension, bisulfite sequencing, reverse-transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells.

Therapeutic Drug Monitoring, 2014

Background: Pain is one of the most prevalent and distressing symptoms in patients with cancer. T... more Background: Pain is one of the most prevalent and distressing symptoms in patients with cancer. There is evidence from observational studies that many patients do not get adequate relief. Although data in the literature confirm the effectiveness of most opioid drugs for the treatment of chronic pain, there is limited information about opioid titration. Methods: The aim of this study was to evaluate the clinical pharmacokinetics of morphine (M) and their correlation with pharmacodynamic results (effective daily dose of M and side effects) during the M titration phase, in the management of chronic cancer pain. Fifty-two consecutive patients were administered Oramorph (Molteni Farmaceutici, Scandicci, Florence, Italy; beginning with 5 mg every 6 hours), to maintain pain intensity at low levels (visual analog scale ,4). M, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) plasma concentrations were determined by a mass spectrometric assay. Results: Expected pharmacokinetic parameters were based on a pharmacokinetic profile extrapolated from 39 patients: M total clearance varied between 1.5 and 6.42 L$h 21 $kg 21 ; the median apparent volume of M distribution was 25.0 L/kg, and the elimination half-life was 4.4 hours. Over the entire period of treatment, a weak correlation between M and M3G or M6G concentrations was found, but the metabolite ratio (M3G/M6G) remained quite stable for each patient and at different sampling times. At the end of titration, the M6G/M ratio was significantly higher in the patients whose effective M concentration was below the median (5.2 ng/mL), than in patients in whom the concentration was above the median (M6G/M: 13.0 and 9.0, respectively). Conclusions: This article presents the pharmacokinetic profiles of M and its metabolites: their concentration ratio could help clinicians to optimize individual therapies and tailor the dose to individual needs. Our results indicate that the relationship between M6G and M could represent a potentially useful parameter to personalize M dosing.

Modern Pathology, 2013

MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondria... more MUTYH is a DNA-base-excision-repair gene implicated in the activation of nuclear and mitochondrial cell-death pathways. MUTYH germline mutations cause an inherited polyposis, MUTYH-associated-polyposis, characterized by multiple adenomas and increased susceptibility to colorectal cancer. Since this carcinogenesis remains partially unknown, we searched for nuclear and mitochondrial gene alterations that may drive the tumorigenic process. Ninety-six adenomas and 7 carcinomas from 12 MUTYH-associated-polyposis and 13 classical/ attenuated adenomatous polyposis patients were investigated by sequencing and pyrosequencing for the presence of mutations in KRAS, BRAF, MT-CO1/MT-CO2 and MT-TD genes. KRAS mutations were identified in 24% MUTYH-associated-polyposis vs 15% classical/attenuated familial polyposis adenomas; mutated MUTYHassociated-polyposis adenomas exhibited only c.34G4T transversions in codon 12, an alteration typically associated with oxidative DNA damage, or mutations in codon 13; neither of these mutations was found in classical/attenuated familial polyposis adenomas (Po0.001). Mutated MUTYH-associated-polyposis carcinomas showed KRAS c.34G4T transversions, prevalently occurring with BRAFV600E; none of the classical/ attenuated familial polyposis carcinomas displayed these alterations. Comparing mitochondrial DNA from lymphocytes and adenomas of the same individuals, we detected variants in 82% MUTYH-associated-polyposis vs 38% classical/attenuated familial polyposis patients (P ¼ 0.040). MT-CO1/MT-CO2 missense mutations, which cause aminoacid changes, were only found in MUTYH-associated-polyposis lesions and were significantly associated with KRAS mutations (P ¼ 0.0085). We provide evidence that MUTYH-associated-polyposis carcinogenesis is characterized by the occurrence of specific mutations in both KRAS and phylogenetically conserved genes of mitochondrial DNA which are involved in controlling oxidative phosphorylation; this implies the existence of a colorectal tumorigenesis in which changes in mitochondrial functions cooperate with RAS-induced malignant transformation.

Laboratory Investigation, 2003

Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the deve... more Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of hundreds to thousands of colorectal adenomatous polyps. In addition to the classic form, there is also attenuated polyposis (attenuated adenomatous polyposis coli; AAPC), which is characterized by a milder phenotype. FAP/AAPC is caused by germline mutations in the adenomatous polyposis coli (APC) gene. Very recently, germline mutations in the base-excision repair gene MYH have been associated with recessive inheritance of multiple colorectal adenomas in a subset of patients. APC pathogenic alterations are mostly (Ͼ95%) represented by frameshift or nonsense mutations leading to the synthesis of a truncated protein. We identified 20 APC truncating mutation carriers out of 30 FAP/AAPC patients from different Italian kindreds. In the remaining 10 patients, we searched for alterations other than truncating mutations by enzymatic mutation detection, real-time quantitative RT-PCR, and genotyping of polymorphic markers encompassing the APC locus. Moreover, to assess whether mutations of genes interacting with APC can substitute or act in association with APC alterations, we sequenced both CTNNB1 (␤-catenin) and CDH1 (E-cadherin) genes. No CTNNB1 or CDH1 mutations were found. On the contrary, four patients showed a reduced APC gene expression compared with healthy subjects. In three of the four cases, genotyping results were compatible with a constitutive allelic deletion. In one case this conclusion was confirmed by haplotype segregation analysis. Our results support the notion that FAP/AAPC can result from APC constitutive haploinsufficiency, with gene deletion being a possible cause of reduced gene expression.

Journal of Molecular Medicine, 2006

Familial adenomatous polyposis is an inherited condition associated with hundreds to thousands of... more Familial adenomatous polyposis is an inherited condition associated with hundreds to thousands of colorectal adenomas conferring a very high risk of cancer at a young age. In addition to "classical" form, there is also an attenuated polyposis, with fewer than 100 polyps and a delayed age of cancer onset. Both classical and attenuated polyposis are characterized by a relevant phenotypic heterogeneity. The disease has been linked to constitutive mutations of either APC tumor suppressor gene, or less frequently, MYH base-excision repair gene. However, the genetic cause remains undetected in up to 70-80% of patients with the attenuated form. This analysis was performed on 26 polyposis patients with the attenuated phenotype. All patients had formerly proven to be negative for APC truncating mutations that typically represent the majority of APC gene alterations. We evaluated the APC mRNA constitutional level by real-time quantitative reverse transcription polymerase chain reaction (PCR). Eleven patients (42%) showed an anomalous APC transcription level. One patient with reduced mRNA was a carrier of a whole APC gene deletion. In seven out of the ten remaining

European Journal of Pain Supplements, 2010

A correct long-term opioid therapy implies the selection of the appropriate opioid and dose for e... more A correct long-term opioid therapy implies the selection of the appropriate opioid and dose for each patient, but it is well demonstrated that the “clinical” approach alone is not sufficient. To this purpose, the literature is stressing that physicians have to focalize even more their attention both on the pharmacokinetic and pharmacodynamic properties of the opioids and on the differences

European Journal of Pain Supplements, 2009

... Guglielmina Nadia Ranzani 1 ,; Simona De Gregori 2 ,; Manuela De Gregori 1,3 ,; Mario Regazzi... more ... Guglielmina Nadia Ranzani 1 ,; Simona De Gregori 2 ,; Manuela De Gregori 1,3 ,; Mario Regazzi 2,* ,; Stefano Govoni 4. ... why patients with CRF have an increase in bioavailability of different drugs, including as an example dihydrocodeine (Naud et al., 2008; Matzke and Frye, 1997 ...

Metabolic brain disease, 2012

The chemical structures of morphine and its metabolites are closely related to the clinical effec... more The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

Diseases of the Colon & Rectum, 2007

Knowledge about hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome clearly evolved ... more Knowledge about hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome clearly evolved during the last 10 to 15 years much more rapidly than in the past century. Consequently, long-established concepts and attitudes that held for many years should now be changed or updated. With regard to classification, we suggest maintaining the eponym BLynch syndrome^for families that have a welldocumented deficiency of the DNA mismatch repair system, whereas Bclinical hereditary nonpolyposis colorectal can

European Journal of Clinical Pharmacology, 2013

To investigate interindividual variability in response to pain treatment, we characterized postop... more To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms. A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry. An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration. By considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy.

Medicine

In a year of surprises and extraordinary challenges, regardless of where we live or work, we have... more In a year of surprises and extraordinary challenges, regardless of where we live or work, we have been facing an extremely small entity and fighting against it, although we do not have the tools and the natural defences sufficiently developed yet. Bearing inmindthat the“dreamisaconstant in life”andthatSPGH has a past full of widely recognized scientific events, the SPGH board of Directors together with its Scientific Commission, facing the pandemic that has deeply disturbed us, reacted with determination and persistence keeping in 2020 the main activity of the Portuguese Society of Human Genetics, its annual scientific meeting. Aiming at providing SPGH members and all Portuguese researchers working in Human Genetics the opportunity to present their research and at offering them relevant talks in updated scientific topics, internationally recognized researchers were invited to the 24th Annual Meeting of SPGH. We deeply thank Prof. Kym Boycott and Prof. Jean-Laurent Casanova, for having accepted our invitation to give a lecture on the topics in which they are experts, “Rare Genetic Diseases” and “Inborn errors of immunity to Sars-CoV-2”, respectively. SPGH members and other researchers, from different Portuguese institutions, contributed with high quality abstracts, encompassing fundamental research, diagnosis, and genetic counselling. SPGH is proud to provide to all those who submitted their work to the 24th AnnualMeeting of our Society (www.spgh.net), the publication of the abstracts in the journal Medicine, thus contributing to a wide dissemination of the research in Human Genetics performed in Portugal. João Gonçalves SPGH President