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S Giunta

Publications and source records attributed to S Giunta.

At least 19 recordsLinked to original sources
PubMed2005

Transthyretin inhibition of amyloid beta aggregation and toxicity.

OBJECTIVES: The aim of this study was to investigate transthyretin (prealbumin) effects on Abeta25-35-induced cytotoxicity. DESIGN AND METHODS: In view of the well-recognized literature data demonstrating that Abeta25-35 fibrillar aggregates cause in vitro cytotoxicity to human red blood cells and apoptotic changes to SK-N-BE neuroblastoma cells in cultures (ultrastructural evidence), we tested transthyretin effects on these two experimental models. RESULTS: Incubation of Abeta25-35 with transthyretin (at transthyretin concentrations equal to CSF physiological levels) demonstrated both inhibition of red blood cells lysis and neutralization of SK-N-BE neuroblastoma cells ultrastructural apoptotic changes. Moreover, transthyretin was shown to be able to inhibit the formation of fibrillar macroaggregates of Abeta25-35. CONCLUSIONS: The findings imply that experimental systems investigating Abeta-induced cytotoxicity consider the protective interaction of transthyretin with Abeta; an interaction to be considered also in vivo in view of the fact that transthyretin immunoreactivity has been previously demonstrated in amyloid plaques of brains from Alzheimer's disease patients.

Amino Acid Sequence↗
PubMed2003

Coenzyme Q10, antioxidant status and ApoE isoforms.

The aim of this study was to inquire the antioxidant status in plasma and lipoproteins isolated from normal subjects possessing different ApoE genotypes. For this purpose we investigated blood samples from 106 healthy blood donors: the distribution of ApoE alleles (E2/E2 = 0.9%, E2/E3 = 10.4%, E2/E4 = 2.8%, E3/E3 = 71.7%, E3/E4 = 12.3% and E4/E4 1.9% with 1, 11, 3, 76, 13, and 2 subjects respectively for each genotype) was in agreement with previous data. Almost no differences were found in the concentrations of both coenzyme Q10 (CoQ10) and vitamin E for the different genotypes. Concentration of CoQ10 in isolated lipoproteins was also similar, in the different genotypes, when referred to cholesterol; CoQ10 in LDL was higher for the E3/E3 subjects when referred to protein. Neither CoQ10 nor vitamin E correlated with paraoxonase (PON) activity or cholesteryl-ester hydroperoxides (CHP). Furthermore, there was no correlation between the same lipophilic antioxidants and CHP levels. The only E2 homozygous subject found had high levels of PON and low levels of CHP; the two E4/E4 subjects had low PON activity together with low levels of CHP.

Alleles↗
PubMed2002

Helicobacter pylori masks differences in homocysteine plasma levels between controls and type 2 diabetic patients.

BACKGROUND: Data in the literature have not clarified whether type 2 diabetes mellitus affects homocysteine plasma levels. Different variables able to influence homocysteine could be the cause of these controversial findings. An important but neglected confounding factor is Helicobacter pylori, which has been demonstrated to be a cause of elevated levels of homocysteine and which is prevalent in the Caucasian population, ranging from 30 to 40% incidence. Starting from these findings we wanted to verify whether differences in homocysteine levels exist between a type 2 diabetic population and a control group, taking into account the presence/absence of Helicobacter pylori. DESIGN: The study was carried out on a group of uncomplicated and normotensive type 2 diabetic patients (n = 30, 55.7 +/- 9.7 years) and on a control group (n = 43, 51.2 +/- 11.3 years). On these subjects we evaluated: main parameters of glyco- and lipo-metabolic balance, presence of Helicobacter pylori by 13C Urea Breath Test, plasma homocysteine, vitamin B12, folate and genetic polymorphism of methylenetetrahydrofolate reductase. RESULTS: Evaluating the two groups as a whole, significant differences in homocysteine were found when considering Helicobacter pylori presence/absence (14.0 +/- 6.5 vs. 10.6 +/- 4.7 micromol L-1, respectively, P < 0.01) without differences of vitamins and the genetic polymorphism of methylenetetrahydrofolate reductase. The positive interaction found among Helicobacter pylori, diabetes and homocysteine (P = 0.03) taking into account all the other evaluated confounding factors, demonstrates that a significant difference in homocysteine plasma levels exists between diabetics and controls (Helicobacter pylori-negative: diabetics 12.5 +/- 5.6 micromol L-1, controls 9.4 +/- 3.8 micromol L-1; Helicobacter pylori-positive: diabetics 13.6 +/- 5.8 micromol L-1, controls 14.3 +/- 7.0 micromol L-1). CONCLUSIONS: Type 2 diabetes seems to induce per se higher levels of homocysteine, which appears to be one of the factors responsible for the increased risk of vascular damage.

Adult↗
PubMed2000

Proteases with plasminogen activator activity in hamster oviduct.

At present the physiological role of most oviductal proteins remains unknown. In this work, we present evidence that the oviductal secretion as well as the crude oviductal tissue-extract show proteolytic-like esterase and amidase activity. The proteolytic activity of the oviductal enzymes was higher in the oviducts of superovulated hamster females than in those of normal ones, indicating that gonadotrophic hormones would stimulate the synthesis and secretion of these enzymes. Some of their properties were analyzed in the 15,600-g supernatant of both oviductal tissue extracts (OE) and oviductal fluid (OF). The enzymatic activity toward the synthetic substrates p-tosyl-l-arginine methyl ester-HCl (TAME) and alpha-N-benzoyl-dl-arginine-p-nitroanilide HCl (BAPNA) was activated by calcium ions, reached a maximum at pH 7.5, and was inhibited by soybean trypsin inhibitor (SBTI), N-alpha-p-tosyl-l-lysine chloromethyl ketone HCl (TLCK), phenyl methyl sulfonyl fluoride (PMSF), and benzamidine. The OE glycoprotein fraction recognized by WGA-Sepharose affinity columns (37% total proteins) showed proteolytic activity with properties similar to the OE and OF enzymes. The protease activity could be ascribed to a plasminogen activator (PA) detected in the Triton X-100 treated tissue crude membrane fraction (Triton-CMF) and in the oviductal secretion of the superovulated females. In the Triton-CMF fraction, 100% of the proteolytic activity was plasminogen-dependent. The use of amiloride, a selective urokinase-type plasminogen activator (uPA) inhibitor, shows that 90% of this activity was due to a tissue-type plasminogen activator (tPA) and 10% to uPA whereas in the uterus 100% of the activity was tPA. Only a small percentage of the OF proteolytic activity was plasminogen-dependent, probably due to the presence of PA inhibitors in this medium.

Amidohydrolases↗
PubMed2000

Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE).

Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.

Aged↗
PubMed2000

Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis.

AIMS: Some low-grade malignant tumours arising in the abdomen tend to remain loco-regionally confined to peritoneal surfaces, without systemic dissemination. In these cases complete surgical tumour cytoreduction followed by intra- or post-operative regional chemotherapy has curative potential. The aim of this study was to evaluate the outcome for patients treated in this way. METHODS: Peritonectomy was performed, involving the complete removal of all the visceral and parietal peritoneum involved by disease. After peritonectomy, hyperthermic antiblastic perfusion was carried out throughout the abdominopelvic cavity for 90 min, at a temperature of 41.5-42.5 degrees C, with mitomycin C (3.3 mg/m2/l) and cisplatin (25 mg/m2/l) (for appendicular or colorectal primaries), or cisplatin alone (for ovarian primaries). Alternatively, the immediate post-operative regional chemotherapy was performed with 5-fluorouracil (13.5 mg/kg) and Lederfolin (125 mg/m2) (for colonic or appendicular tumours) or cisplatin (25 mg/m2) (for ovarian tumours), each day for 5 days. RESULTS: Thirty-five patients affected by extensive peritoneal carcinomatosis were submitted to peritonectomy, with no residual macroscopic disease in all cases except three. Twenty-six patients were able to undergo the combined treatment involving loco-regional chemotherapy. Complications were observed in 54% of the patients and led to death in four of them. At a mean follow-up of 17 months overall 2-year survival was 55.2%, with a median survival of 26 months. CONCLUSIONS: After a learning curve of 18 months the feasibility of the integrated treatment increased to more than 90%, while mortality decreased dramatically. The curative potential of the combined therapeutic approach seems high in selected patients with peritoneal carcinomatosis not responding to systemic chemotherapy. Careful selection of patients can minimize the surgical risk, but the treatment should currently be reserved for clinical trials.

Adult↗
PubMed2000

Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients.

The addition of oxaliplatin (L-OHP) to a 5-fluorouracil (5-FU)/ leucovorin (FA) regimen was retrospectively evaluated in 35 consecutive advanced colorectal cancer patients after progression of disease. L-OHP, 25 mg/m2/day, was infused from 10.00-22.00 with a peak flow at 16.00 while 5-FU, 700 mg/m2/day and FA, 150 mg/m2/day of the I-form or 300 mg/m2/day of the racemic form, from 22.00 to 10.00 with a nocturnal peak at 4.00, for 5 days every 3 weeks in 24 patients and for 4 days every 2 weeks in the other 11. Diarrhea and sensitive neuropathy were the most relevant types of toxicity (17% of patients). An objective response was achieved in 8/35 patients (23%) [95% CL 9-37], stabilization in 15 patients (43%) which included five minor responses, and progression in 12. There was no relevant difference in quality of life assessed with the EORTC QLQ C30+3 questionnaire before and after treatment. Median duration of response and median progression-free survival were 6 months; median overall survival was 11 months. This retrospective study showed that it is possible to reverse resistance to chronomodulated 5-FU by adding chronomodulated L-OHP to the previous regimen; comparison with different schedules of this combination should be performed in order to identify the best tolerated and active regimen as second-line treatment of advanced colorectal cancer.

Adult↗
PubMed2000

Transformation of beta-amyloid (A beta) (1-42) tyrosine to L-dopa as the result of in vitro hydroxyl radical attack.

A form of beta-amyloid peptide A beta ending at amino acid 42 (A beta42) is the major component of senile amyloid plaques in Alzheimer's Disease (AD). The A beta-peptide earliest modifications are extremely important since they constitute the key events in the progression towards further changes finally leading to fibril formation and to A beta deposits which constitute the core pathological change in AD. Chemical and conformational early modifications of the beta-amyloid peptide are critical steps in AD pathogenesis and have been widely investigated. We now show that a Fenton-type OH-generating system is capable of generating L-Dopa (3,4-dihydroxyphenylalanine) in the tyrosine residue of A beta-peptide via aromatic ring hydroxylation, as the result of hydroxyl radical attack on proteins. Since L-Dopa is not a constituent of mammalian proteins and peptides, the formation of L-Dopa in A beta in vitro constitutes a possible important modification caused by hydroxyl radical attack. These results lay the groundwork for further studies on modification and damage associated with the degenerative disorder in AD where oxidative stress and inflammation are known to occur.

Alzheimer Disease↗
PubMed1999

Regulation of the human stress response gene GADD153 expression: role of ETS1 and FLI-1 gene products.

We have previously shown that ETS transcription factors, regulate cell growth and differentiation, and ETS1 and ETS2 are able to transcriptionally regulate wt p53 gene expression. In the present study we show that the ETS transcription factors also play a role in regulating expression of GADD153, a wt p53 inducible gene, which induces growth arrest and apoptosis in response to stress signals or DNA damage. We report the presence of a single EBS in the human GADD153 promoter, and that the GADD45 gene promoter lacks EBSs. The GADD153 promoter EBS shows a very high affinity for ETS1 and FLI-1 gene products. In addition, our data show that both ETS1 and FLI-1 strongly activate transcription of the GADD153 EBS linked to the CAT reporter gene. Our results also demonstrate how ETS1 and FLI-1 specifically regulate GADD153 expression. In addition, ectopic ETS2 protein expression resulted in only a weak induction of the same CAT reporter construct. The ETS1 and FLI-1 proteins provide a novel mechanism of activation for GADD153, allowing these two ETS genes to control its expression during cell growth and differentiation, rather than in response to oxidative stress.

Animals↗
PubMed1999

99Tcm-MIBI scintimammography in 300 consecutive patients: factors that may affect accuracy.

We evaluated the diagnostic yield of 99Tcm-MIBI scintimammography in a relatively large series of consecutive patients referred for breast surgery on the basis of physical examination or mammogram. 99Tcm-MIBI uptake was correlated to tumour size, receptor status, neovascularity, proliferating activity, P-170 glycoprotein expression and the patient's gonadal state. Three hundred consecutive patients referred to our institution, with either a positive mammogram or a palpable mass, were entered into the study. All patients underwent 99Tcm-MIBI scintimammography. Pathological status was obtained after surgery in all patients. Breast cancer was diagnosed in 218 (73%) patients. The MIBI scan was positive in 89% (194/218) cancer patients and in 17% (14/82) of patients with benign masses (false-positives); the scan was negative in 24 (11%) cancer patients (false-negatives). The sensitivity of MIBI scintigraphy was higher for tumours > 1 cm (95 vs 48% in lesions < or = 1 cm) and in pre-menopausal women (95 vs 85%). Conversely, the specificity was better for lesions < 1 cm (100%) and in post-menopausal women (89%). The positive predictive value of MIBI scan was good both in small (< 1 cm) and large tumours (100% and 93%, respectively) and slightly modified by gonadal state (89% and 96% in pre- and post-menopausal state). The negative predictive value was unsatisfactory, especially in small tumours and in older patients. The diagnostic performance increased stratifying data for tumour size, indicating that lesion size is a major determinant in the diagnostic accuracy of MIBI scintimammography. We conclude that 99Tcm-MIBI scintimammography is useful in the diagnostic evaluation of young patients, because it can select patients for further invasive diagnostic procedures. In older patients, a positive 99Tcm-MIBI scan is highly suggestive of malignancy and might be an indication for surgery. In the case of a negative scan, biopsy is advisable given the poor negative predictive value. Small tumour size and a well-differentiated histotype characterize false-negative cases.

Adult↗
PubMed1999

In vitro peroxidase oxidation induces stable dimers of beta-amyloid (1-42) through dityrosine bridge formation.

beta-amyloid (A beta) is a normal soluble peptide found in the cerebrospinal fluid (CSF) and other biological fluids. A beta fibrils are associated with Alzheimer's disease (AD) senile plaques. We have used purified soluble A beta (1-42) and A beta (12-28) peptides in order to determine the oxidative modification induced in these peptides by exposure to peroxidase and hydrogen peroxide. We have demonstrated that under these in vitro conditions, dimeric forms of A beta (1-42) can be detected by high-resolution polyacrylamide SDS-PAGE electrophoresis. Further experiments performed by reverse-phase high performance liquid chromatography (RP-HPLC), and monitored by fluorescence detection, showed that the dimeric A beta (1-42) forms induced by the peroxidase reaction are the outcomes of dityrosine bridge formation. This cross-link results from the enzyme catalyzed oxidation. During this reaction, phenolic coupling of tyrosine residues of two A beta (1-42) peptides occurs. No detectable peroxidative modifications were observed with the A beta (12-28) peptide which lacks a tyrosine residue. Since oxidative stress is thought to be associated with AD, the experimental model described here can help in understanding the early events leading to chemical, structural and conformational modifications before the conversion of sA beta to amyloid fibrils and eventually the formation of senile plaques in AD.

Amino Acid Sequence↗
PubMed1999

The integrated treatment of peritoneal carcinomatosis. A preliminary experience.

Some low-grade malignant tumors arising in the abdomen, lack of infiltrative attitude and "redistribute" on the peritoneum with no extraregional spreading. In this cases the complete tumor cytoreduction followed by intra- or postoperative regional chemotherapy has curative intent. Peritonectomy is the complete removal of all the parietal peritoneum and the visceral peritoneum involved by disease. After peritonectomy hyperthermic antiblastic perfusion is carried out throughout the abdomino-pelvic cavity for 60 minutes, at a temperature of 41.5 degrees C, with mitomycin C (3.3 mg/m2/Lt of perfusate) and cisplatin (25 mg/m2/Lt) (appendicular or colorectal primary), or cisplatin alone is (ovarian primary). Alternatively the immediate postoperative regional chemotherapy is performed with 5-fluorouracil (13.5 mg/Kg) and Lederfolin (125 mg/m2) (colic or appendicular tumor) or cisplatin (25 ng/m2) (ovarian tumor), each day for 5 days. Twenty patients affected by extensive peritoneal carcinomatosis (12 ovarian, 5 colonic, 1 appendicular, 1 mesothelial and 1 gastric primary) were submitted to peritonectomy with no residual macroscopic disease in all cases except three. Six patients were treated with intraoperative intra-abdominal hyperthermic antiblastic perfusion, while immediate postoperative intra-abdominal chemotherapy was given in 4 patients and systemic chemotherapy in other 5. Hospital mortality was 20%. At a mean follow-up of 11 months 14 patients are alive, 11 without disease and the median overall survival is 10.2 months. The curative potential of the combined therapeutic approach seems high in patients with peritoneal carcinomatosis from ovarian or colorectal primary not responding to systemic chemotherapy. Selection criteria of patients can strictly affect the surgical risk and the treatment has to be reserved for controlled clinical trials.

Abdominal Neoplasms↗
PubMed1999

99mTc-MIBI scintimammography using a dedicated nuclear mammograph.

UNLABELLED: This study reports on a prototype single-photon emission mammograph (SPEM) dedicated to 99mTc-hexakis-2-methoxyisobutile isonitrile (MIBI) scintimammography. Main technical features are reported together with physical performance. Preliminary patient data are also reported. METHODS: The SPEM detector head is composed of a CsI(T1) scintillating array coupled to a Hamamatsu R3292 position-sensitive photomultiplier tube with crossed-wire anode. The high-resolution collimator is 35-mm thick with a 1.7-mm hole diameter and a 0.2-mm septal thickness. The electronic acquisition system is composed of five integrated cards with computation based on high-speed programmable microprocessors. The readout electronics include correction maps for on-line energy correction and spatial uniformity. The small size of the detector head allows the use of mechanical breast compression to minimize detection distance and tissue scatter. After physical SPEM performance evaluation in vivo scintimammography was performed in 29 patients and was compared with a state-of-the-art Anger camera. RESULTS: The SPEM showed an intrinsic spatial resolution of 2 mm, an energy resolution of 23% FWHM at 122 keV and spatial uniformities of 18% (integral) and 13.5% (differential). The SPEM imaged one 0.4-cm carcinoma missed by the Anger camera and resolved as separate lumps an irregular focal uptake on the Anger camera image. The remaining cases yielded concordant results. CONCLUSION: The SPEM prototype presented in this study shows adequate physical characteristics for 99mTc-MIBI scintimammography.

Adult↗
PubMed1998

Involvement of blood serum in amphibian fertilization.

A proteolytic enzyme secreted by the first portion of amphibian oviduct, pars recta, called oviductin in Xenopus laevis, causes ultrastructural alterations on the extracellular matrix of coelomic eggs, turning them susceptible to fertilization. Although great advances have been made in the field of reproduction, the molecular mechanisms responsible for the fusion between the egg and the sperm are yet to be understood. We have recently demonstrated the presence of proteins from pars recta fluid in blood serum and extracellular matrix of coelomic eggs in Bufo arenarum. Here we show, using immunofluorescence procedures, that blood serum components are present in the extracellular matrix of coelomic and pars recta fluid-conditioned eggs in Bufo arenarum. Furthermore, by assessing the neutralizing effect on the conditioning activity of pars recta fluid on coelomic eggs we found that antibodies against pars recta secretions and blood serum inhibited the effect of sperm-lysin on the vitelline envelope of conditioned oocytes and impaired fertilization by sperm. Thus, serum proteins appear to be implicated in the molecular events that lead to amphibian fertilization.

Animals↗
PubMed1997

A phase I trial of 5-day chronomodulated infusion of 5-fluorouracil and 1-folinic acid in patients with metastatic colorectal cancer.

The aim of this phase I study was to establish the maximum tolerated dose (MTD) of 5-fluorouracil (5-FU), administered as a 5-day chronomodulated infusion in combination with 1-folinic acid (FA) to ambulatory metastatic colorectal cancer patients. Consecutive cohorts of 6 patients were given 5-FU and FA infusions from 10.00 p.m. to 10.00 a.m. with peak delivery at 4.00 a.m. by means of a multichannel programmable pump. The FA dose was always the same (150 mg/m2/d). For the first cohort, the 5-FU dose level was 600 mg/m2/d at the first course, escalated by 100 mg/m2 for each subsequent cohort. Intrapatient dose was also escalated by 100 mg/m2 if toxicity was less than grade 2. The courses were repeated every 3 weeks. Thirty-four patients (17 previously treated) received a total of 154 courses. Dose-limiting toxicity consisted of stomatitis and diarrhoea. No significant haematological, cutaneous or cardiac toxicity was encountered. The MTD of 5-FU was reached at the fourth level (first course at 900 mg/m2/d equal to 4500 mg/m2/course) with 5-FU increased to 1100 mg/m2/d (5500 mg/m2/course) in 4 patients. The received 5-FU dose intensity (DI) over the first 3 courses at this level was 1318 mg/m2/week. Thirty-three patients were assessed for response. An objective response was achieved in 1 out of the 13 previously-treated and in 8 out of the 20 previously-untreated patients. The chronomodulated infusion of 5-FU at a dose of 900 mg/m2/d, together with FA at 150 mg/m2/d for 5 days, was safely delivered to out-patients with metastatic colorectal cancer. The low toxic profile and activity of this regimen in previously untreated patients deserves further exploration for the treatment of 5-FU-sensitive tumours.

Adenocarcinoma↗
PubMed1997

[Cancer in the elderly. Clinico-epidemiologic considerations].

The elderly population is rapidly increasing in Western countries. Old age indirectly represents one of the most important risk factors for the development of neoplasias. In Italy in 1991 a total of 14,572 deaths from tumours were recorded, equivalent to 27% of all deaths; of these over 66% affected individuals aged over 65 years old. In the 65-74 age bracket mortality caused by tumour is the prime cause of death in Italy and is undergoing an exponential increase over time. The most frequently found tumours and above all the cause of the greatest number of deaths in the elderly population are lung cancer, prostate cancer, breast cancer, colorectal cancer, stomach cancer. To date the only weapon that has proved efficacious in some tumours (breast, colon-rectal, prostate, melanoma) is early diagnosis through screening and adequate treatment. The elderly are an extremely heterogeneous population and it is therefore not easy to provide guidelines that are applicable to the entire population. Firstly, it is important to provide more information in order to permit effective and targeted prevention. In order to fulfil this objective, structures offering the necessary equipment and skills will have to be create; training must be provided for personnel in this type of preventive medicine; lastly, the awareness of doctors towards this type of medicine must be increased by providing the correct information.

Aged↗