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Biomedical subjects

F Mosca

Publications and source records attributed to F Mosca.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells.

Proteins belonging to the ras superfamily are involved in cell proliferation of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeranyl-transferase. Enzyme inhibition by drugs may thus represent a promising approach to the treatment of cancer. Therefore, the combined effect of BAL9611, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-transferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependently inhibited SW620 cell growth with 50% inhibitory concentration (IC(50)) of 0.47 +/- 0.03 and 5.24 +/- 1.41 microM (mean +/- SE), respectively. The isobologram analysis performed at the IC(50)level revealed that the combined treatment was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21rhoA and farnesylation of p21ras; both drugs inhibited p42ERK2/MAPK phosphorylation, but their combination was more effective than either drug alone. Moreover, the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted with SW620 tumours. Finally, both drugs were able to induce cell death by apoptosis in vitro and in vivo, as demonstrated by perinuclear chromatin condensation, cytoplasm budding and nuclear fragmentation, and interoligonucleosomal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational isoprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activation is associated with post-translational geranylgeranylation and farnesylation of p21rhoA and p21ras.

Alkyl and Aryl Transferases↗
PubMed2001

Bcl-2 expression in pancreas development and pancreatic cancer progression.

Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression.

Adenocarcinoma↗
PubMed2001

Modulation of beta2 integrin phenotype, adhesion, chemotaxis, and oxidative burst of neutrophils by cyclosporine.

Cyclosporine (CsA) is an immunosuppressive drug widely used to prevent allograft rejection, but its action on neutrophil function is not well known. Neutrophils play an important role in tissue damage during allograft rejection; chemotactic recruitment, adhesion to endothelial cells and oxidative burst of neutrophils are early events during allograft rejection. The aim of this work was to evaluate the effect of CsA on beta2 integrins' surface expression, adhesion to human umbilical endothelial cells (HUVECs), chemotaxis and oxidative burst by neutrophils. For any neutrophil function studied, data obtained from activated neutrophils exposed to CsA were compared with those derived from untreated controls. Results show that CsA does not block neutrophil chemotaxis and does not reduce surface expression of CD11 complex and HUVECs' adhesion at all concentrations tested (15, 100 and 500 ng/mL) and at incubation times of 1, 2 and 4 h as compared to controls. On the other hand, the drug affects significantly the CD18 phenotype after two hours of treatment at the maximum concentration (500 ng/mL) (P < 0.05; ANOVA) and the oxidative burst after four hours (P < 0.01; ANOVA). This study provides evidence that in addition to the well-known CsA effects on lymphocyte functions, the drug affects some neutrophil functions with dose- and time-dependent modalities.

Antibodies, Monoclonal↗
PubMed2001

Very early tracheal extubation without predetermined criteria in a liver transplant recipient population.

This study of all patients undergoing orthotopic liver transplantation (OLT) at our center between January 1997 and December 1999 evaluated the feasibility and safety of very early tracheal extubation without previous selection. Anesthetic management was the same in all cases, and tracheal extubation was performed on the basis of standardized criteria routinely adopted in operating rooms throughout the world, i.e., no residual curarization or anesthetic action, ability to swallow efficiently, and stable hemodynamics. One hundred sixty-nine patients underwent 181 OLTs during the study period. Tracheal extubation was performed within 3 hours of surgery in 115 cases, 8 hours in 19 cases, and 8 to 24 hours in 10 cases. In 36 cases, artificial ventilation was required for more than 24 hours or weaning was not possible. One patient died of primary graft nonfunction within 24 hours and was excluded from the analysis. The feasibility of early extubation was influenced by the amount of intraoperative transfused blood; efficacy of kidney, cardiac, and pulmonary function; and presence of encephalopathy (P <.001). No correlation was found with age or pre-OLT severity of hepatic disease, and the postoperative period was not compromised by early weaning. Very early extubation was feasible and safe in a large number of unselected transplant recipients, thus suggesting that the definition of early tracheal extubation should be changed from 8 to 3 hours after surgery.

Adult↗
PubMed2001

Human adult and foetal liver sulphotransferases: inhibition by mefenamic acid and salicylic acid.

1. The aim was to see whether mefenamic acid and salicylic acid had different inhibition profiles for SULT1A1 (substrate: 4-nitrophenol) and SULT1A3 (dopamine) activities and on (-)-salbutamol and minoxidil sulphation rates in the human adult and mid-gestational foetal livers. 2. The activity (pmolmin(-1) mg(-1) of SULT1A1 was 662 +/- 78 (adult) and 246 +/- 159 (foetus; p = 0.003) and that of SULT1A3 was 24 +/- 4 (adult) and 121 +/- 90 (foetus; p = 0.030). The rate (pmol min(-1) mg(-1)) of (-)-salbutamol sulphation was 109 +/- 27 (adult) and 117 +/- 34 (foetus; p = (0.144) and that of minoxidil sulphation was 202 +/- 38 (adult) and 108 +/- 44 (foetus; p = 0.001). 3. With mefenamic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 0.2 +/- 0.004 (adult) and 0.01 +/- 0.002 (foetus; p = 0.001); for SULT1A3 it was 76 +/- 6 (adult) and 77 +/- 13 (foetus; p = 0.889); for the rate of ( )-salbutamol sulphation it was 0.07 +/- 0.005 (adult) and not determinable (foetus) and for minoxidil sulphation it was 1.6 +/- 0.7 (adult) and 0.15 +/- 0.04 (foetus; p = 0.076). 4. With salicylic acid as an inhibitor, the IC50 (microM) for SULT1A1 was 30 +/- 2 (adult) and 25 +/- 1 (foetus; p = 0.011); for SULT1A3 it was 690 +/- 36 (adult) and 570 +/- 16 (foetus; p = 0.229); for the rate of ( )-salbutamol sulphation it was 93 +/- 11 (adult) and 344 +/- 42 (foetus; p = 0.010); with minoxidil as substrate, the IC50 was not determinable. 5. In summary, SULT1A1, SULT1A3 and the sulphotransferases towards (-)-salbutamol and minoxidil had measurable activities in the mid-gestational human foetal liver. Mefenamic acid was a more potent inhibitor than salicylic acid of both human adult and foetal liver SULT1A1 and SULT1A3 activities. Foetal liver SULT1A1 was more susceptible than adult liver SULT1A1 to inhibition by mefenamic acid and salicylic acid. These results are consistent with the view that sulphotransferases develop early in the human foetal liver and drugs may inhibit their activities.

Adult↗
PubMed2001

Apoptosis and adaptive responses to oxidative stress in human endothelial cells exposed to cyclosporin A correlate with BCL-2 expression levels.

Treatment of transplanted patients with cyclosporin A (CSA) may cause adverse effects such as nephrotoxicity and hypertension. As CSA is known to induce oxidative stress in several tissues, it may cause vascular problems by triggering oxidative stress in endothelial cells (EC). However, oxidative stress has been reported for acute exposure to CSA concentrations exceeding its clinical range, whereas immunosuppression requires life-long treatment with therapeutic concentrations. We therefore compared the effects of 21 h pharmacological (200 microM) vs. 8 days clinical (0.5-2.5 microM) doses of CSA on cultured human EC. Pharmacological doses of CSA cause a decrease in cell density via apoptosis and a down-regulation of the antiapoptotic protein Bcl-2. However, these effects are independent of CSA-induced oxidative stress. In contrast, therapeutic concentrations of CSA cause Bcl-2 up-regulation and modification of EC morphology, both effects blocked by antioxidants. Therefore, a low level of oxidants may act in EC as second messengers that up-regulate Bcl-2, thus promoting survival of impaired EC. Our data suggest that the oxidative stress induced by clinical concentrations of CSA may be involved in the adverse effects of the drug on the vascular system of transplanted patients via an adaptive response involving Bcl-2 up-regulation rather than an apoptotic process

Apoptosis↗
PubMed2001

[Pancreatic pseudocysts. Our experience with 21 cases treated surgically].

Twenty-one consecutive patients with pancreatic pseudocyst have been reviewed. Nine cases have been treated with internal drainage, 9 with external drainage, while 3 patients have undergone distal pancreatectomy. No mortality was associated to the surgical treatment, while morbidity was of 9.5% due to pancreatic fistulas. Based on their own experience and literature review the Authors describe clinical, diagnostic and therapeutic features of the disease and point out the good results of cistojejunostomy with Roux-en-Y loop.

Adult↗
PubMed2001

Benign paroxysmal positional vertigo, incidence and treatment.

Benign paroxysmal positional vertigo is characterized by acute vertigo that is accentuated by movements of the head. It can be identified by the presence of nystagmus triggered by certain head positions. Over a 1-year period, among 1,902 cases of different types of equilibrium disorders, there were 98 cases of BPPV including 63 BPPV ofthe posterior canal, 21 of the lateral canal, 13 combined (HC + PC) and one case affecting the anterior canal. Most of the cases were idiopathic. Treatment was based on the Semont maneuver for BPPV-PC. BPPV-HC was treated with the Vannucchi maneuver and a personal method. The one case of BPPV-AC was treated with a modified Semont maneuver. Satisfactory therapeutic results were noted in all cases. Cases with a long-term follow-up showed a high percentage of elimination of relapse after 24 months.

Adult↗
PubMed2001

[Blood coagulation monitoring during liver transplantation: Sonoclot analysis and laboratory tests].

BACKGROUND: Aim of this paper is to validate blood coagulation data obtained using the Sonoclot thromboelastographic analyser (Sienco Inc., Morrison, USA) by means of standard laboratory tests during orthotopic liver transplantation (OLT). METHODS DESIGN: comparative study between laboratory data and Sonoclot analysis on simultaneously collected blood samples. SETTING: National Health System Liver Transplantation Center. PATIENTS: fifty-one patients, both males and females, affected by terminal hepatic disease submitted to OLT were enrolled in the study. DATA COLLECTION: simultaneous blood samples were collected during the pre-anhepatic, anhepatic and post-reperfusion phases of OLT; coagulation status was assessed by means of either standard Laboratory tests (INR, aPTT, Fibrinogen, PLT, D-Dimer) and Sonoclot analyser data (SonACT, Rate, Time to Peak, Downward Deflection); a statistical analysis was performed (Pearson s chi(2) test). RESULTS: A statistically significative correlation between the analysed data was found. The Sonoclot analyser was useful in identifying platelets dysfunction and was more sensitive to detect fibrinolysis. CONCLUSIONS: The Sonoclot thromboelastographic analyser is a reliable device for monitoring coagulation during OLT.

Adult↗
PubMed2001

Combined percutaneous and surgical approach to a postnephrectomy arteriovenous fistula.

The case of a patient with long-standing severe heart failure that was ultimately found to be secondary to a large communication between the right renal artery stump and the inferior vena cava is reported. The occurrence of an arteriovenous fistula should be suspected in patients who underwent previous nephrectomy since early diagnosis would avoid relevant cardiac complications and the demise of a patient suffering from a disease that may be corrected surgically or percutaneously. We describe a combined approach that allowed the percutaneous decompression of the inferior vena cava and relief of the volume overload to the heart prior to the surgical ligation of the arteriovenous fistula. This approach should be considered a valuable option for treating long-standing high output postnephrectomy arteriovenous fistulas.

Aged↗
PubMed2001

Laparoscopic and hand-assisted laparoscopic live donor nephrectomy.

Renal grafts from living donors represent an important source of organs, particularly for young patients with chronic renal failure. Laparoscopic donor nephrectomy is a relatively new technique, which has the potential to increase the pool of available kidney grafts by removing some disincentives to live donation. The technique used for left kidney donation at our center, the first to introduce laparoscopic live donor nephrectomy in Italy, is described in this report. To further reduce warm ischemia time, the kidney is preloaded inside the extraction bag and 2 staplers are used to transect the renal artery and vein. The spread of the new technique in our country and in the rest of Europe is likely to raise the issue of training in laparoscopic surgery for transplant surgeons.

Creatinine↗
PubMed2001

[Prevention of mycotic infections in liver transplant recipients: comparison of two chemoprophylactic protocols].

BACKGROUND: The aim of the study was to compare and evaluate the efficacy of two chemoprophylactic protocols against mycotic infections in a liver transplant recipients population. DESIGN: single-blind, randomized. SETTING: Liver transplant Center of a National Health System teaching hospital. METHODS: Eighty-eight consecutive patients submitted to liver transplantation were enrolled in the study. Immediately before surgery they were randomized to receive sequential treatment with intravenous liposomal amphotericine B + oral itraconazole or intravenous fluconazole + oral itraconazole. Intravenous drugs were administered in the first postoperative week, and oral treatments for the following three weeks. In addition to analyzing the frequency and incidence of colonization, local and disseminated infection of mycotic origin, the causes of death and the possible risk factors for mycotic disease have been examined. RESULTS: Eighty-five patients completed the study. No significative difference was evident in the two groups as regards to single organ and systemic fungal infection rate. Two out of a total of 5 deaths were related to mycotic disease. Pre-transplant fungal colonization, more severe liver disease indicating the transplant procedure and the rejection of the graft were all risk factors for the development of mycotic infection. CONCLUSIONS: The two protocols used in the study showed and equal efficacy in preventing fungal infections in liver transplant recipients.

Adult↗