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Biomedical subjects

M Morganti

Publications and source records attributed to M Morganti.

At least 19 recordsLinked to original sources
PubMed2002

Atherosclerosis and cancer: common pathways on the vascular endothelium.

This article reviews experimental and clinical data on atherosclerosis and cancer showing common pathogenic mechanisms. It is suggested that common pathways follow dysfunction of the vascular endothelium. The activation of the haemostatic system and the overexpression of cytokines and adhesion molecules by the endothelial cells represent important features of this dysfunction. These mechanisms can be responsible for progression of both diseases and explain the higher incidence of thromboembolic events in cancer patients, the occurrence of similar laboratory findings and the effect of many drugs on the course of the two diseases. Our article confirms that atherosclerosis and cancer share common mechanisms, and we hope it will stimulate further clinical trials on the use of drugs active on the haemostatic system in cancer patients.

Animals↗
PubMed2000

Von Willebrand's factor mediates the adherence of human tumoral cells to human endothelial cells and ticlopidine interferes with this effect.

The aim of this study was to explore whether von Willebrand's factor (vWF) plays a role in the adhesion of human colon tumor cells to human endothelial cells in our coculture system. Cell colony density was evaluated basally (endothelial plus colon tumor cells) and following the addition of: purified vWF, vWF plus vWF-blocking antibodies, antibodies against various integrins and adhesion molecules (alpha2 b integrin, beta1 integrin, beta3 integrin, intercellular adhesion molecule-I, intercellular adhesion molecule-II, vitronectin receptor CD61 CD51, laminin alpha6/beta4 receptor), and various drugs inhibiting the hemostatic system (ticlopidine, heparin, acetyl salicylic acid [ASA], defibrotide, indobuphen, dipyridamole, sulfinpyrazone). Furthermore, vWF concentration was measured in the supernatant fluid of the coculture system basally and following the addition of the above-listed drugs. Cell colony density (as measured by light absorption) increased by 33% following the addition of vWF and returned to a value similar to the basal level with antibodies against vWF, while it did not change significantly following the addition of antibodies against the other integrins or adhesion molecules tested. The same parameter was reduced by 35% following the addition of ticlopidine, while it showed a smaller or no change with the other drugs tested. Similarly, vWF concentration in the cell coculture supernatant showed the greatest reduction (from 0.22 to 0.11 mg/mL) following the addition of ticlopidine. These data suggest that vWF mediates the adherence of human tumor cells to human endothelial cells and that ticlopidine interferes with this effect.

Cell Adhesion↗
PubMed2000

Modulation of dihydrofolate reductase gene expression in methotrexate-resistant human leukemia CCRF-CEM/E cells by antisense oligonucleotides.

An increase in the cellular levels of dihydrofolate reductase (DHFR) is one of the most common mechanisms of tumor resistance to methotrexate (MTX), an antimetabolite that is widely used in the treatment of a variety of human malignancies. The MTX-resistant phenotype generally occurs as a consequence of DHFR gene amplification which in turn is responsible for DHFR gene overexpression. We have designed antisense oligodeoxynucleotides (aODNs) against the DHFR mRNA and tested their in vitro effect on human leukemia CCRF-CEM/E cells, overexpressing the DHFR gene about 20-fold in comparison with the CCRF-CEM/S parental cell line. An aODN complementary to a region encompassing the AUG translation start (DHFR1) of DHFR mRNA and a mixture of two aODNs complementary to the 5' untranslated region (DHFR2+DHFR3) have been used. A DHFR1 scrambled-sequence ODN and a fully degenerated ODN were the controls. All ODNs had a phosphodiester backbone. DHFR1 and the relevant scrambled ODN were also capped with two phosphorothioate derivatives at both the 5' and 3' ends in order to increase ODN stability against serum nucleases. ODNs were vehiculated with a cationic lipid, N-[1-(dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate (DOTAP), known to enhance ODN cell uptake and biological activity. The effects of ODNs on DHFR gene expression were studied after a 4 day treatment by measuring both DHFR mRNA levels, using a semi-quantitative reverse transcription polymerase chain reaction method, and DHFR protein levels by flow cytometry. A marked reduction in DHFR mRNA levels (79.7 and 74.2%, respectively) was observed with both DHFR1 and DHFR2+DHFR3 aODNs, associated with a lower decrease in DHFR enzyme (44.8 and 61%, respectively). aODN effects on MTX cytotoxicity in CCRF-CEM/E cells were also assessed. No marked enhancement of in vitro MTX cytotoxicity was observed following co-exposure of cells with aODNs and the tested concentrations of the antifol (0.05 and 0.5 microM), indicating that no substantial reversal of the MTX-resistant phenotype was induced by the study aODNs.

DNA Primers↗
PubMed1999

Marked variation of thymidylate synthase and folylpolyglutamate synthetase gene expression in human colorectal tumors.

Patients with advanced colorectal cancer are currently being treated with 5-fluorouracil (5-FU)-based chemotherapy. A growing number of patients with resectable disease receive adjuvant therapy with 5-FU/levamisole (LEV) or 5-FU/folinic acid (LV). However, many patients still fail on these treatments, due to occurrence of natural or acquired tumor resistance. Among clinically relevant mechanisms of resistance to fluoropyrimidines, increased expression of thymidylate synthase (TS) has been emphasized. Another potentially relevant mechanism involves a decrease in folylpolyglutamate synthetase (FPGS) expression. To establish the value of these genes as prognostic factors and predictors of the outcome of 5-FU-based chemotherapy in colorectal cancer, we measured their expression in colorectal tumors from patients undergoing surgery and postoperative chemotherapy and compared it with that in normal colonic mucosa. This was done by a semi quantitative, nonradioisotopic polymerase chain reaction (PCR) method using beta-actin as an internal standard and expressed as a TS/beta-actin or a FPGS/beta-actin mRNA ratio. In tumor samples from 21 colorectal cancer patients, TS gene expression varied 118-fold. The median TS/beta-actin ratio was, in fact, 41.36 x 10(-3) (range 2.49 x 10(-3) to 294.54 x 10(-3)). Little variation in TS gene expression was observed in corresponding normal colic mucosa; the TS/beta-actin gene ratio was lower (median 26.16 x 10(-3); range 8.49 x 10(-3) to 69.49 x 10(-3)). Among tumor explants from 20 patients, FPGS expression varied over 161-fold. A similar marked variation was also observed in normal colonic mucosal samples (over 185-fold). Overall and disease-free survival data suggest an inverse association between the level of tumor TS and FPGS expression and clinical prognosis. The availability of this sensitive and accurate assay for gene expression should now make it possible to extend these laboratory/clinical correlations to larger populations.

Adult↗
PubMed1998

Uremic medium increases cytokine-induced PAI-1 secretion by cultured endothelial cells.

The overall fibrinolytic activity is depressed in patients with chronic renal failure where a prothrombotic state is described, thereby enhancing the risk of vascular occlusive events. The mechanism responsible for fibrinolysis derangement has not yet been elucidated. To evaluate the effect of the uremic environment on the fibrinolytic activity of endothelial cells, we studied plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) production by human umbilical vein endothelial cells (HUVEC) in culture, exposed either to uremic or normal sera, before and after cytokine stimulation. Twenty uremics were studied: 11 were on conservative dietary treatment and nine were on maintenance hemodialysis. Eight healthy subjects served as controls. Before cytokine stimulation, no difference in the HUVEC supernatant concentration of t-PA and PAI-1 was found among the groups studied. After stimulation with interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, the HUVEC supernatant levels of PAI-1 in the uremics were higher than in the controls, whereas the supernatant levels of t-PA did not differ. Our data provide evidence that uremic serum, in concert with IL-1 or TNF-alpha, can enhance PAI-1 secretion by endothelial cells, thereby depressing the fibrinolytic system. This impaired endothelial fibrinolytic response to hypercoagulation could favor vascular events, which are the major cause of morbidity and mortality in patients with chronic uremia.

Adult↗
PubMed1997

Piggy-back versus conventional technique in liver transplantation: report of a randomized trial.

Liver transplantation with preservation of the recipient vena cava (the "piggy-back" technique) has been proposed as an alternative to the traditional method. We performed a randomized study on 39 cirrhotic patients, 20 who underwent the piggy-back technique (group 1) and 19 the traditional method using venovenous bypass (group 2) to evaluate the feasibility and true advantages of the piggy-back technique compared to the traditional method. Two patients were switched to the conventional technique due to the presence of a caudate lobe embracing the vena cava in one patient and a caval lesion in the other. Statistically significant differences between the two groups were only found for the warm ischemia time (48.5 +/- 13 min for piggy-back vs 60 +/- 12 min for the conventional method) and for renal failure (zero cases in group 1 vs four cases in group 2). We therefore believe that liver transplantation with the piggy-back technique can easily be performed in almost all cases, and that only a few, specific situations, such as a very enlarged caudate lobe, do not justify its routine use.

Adult↗
PubMed1997

p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study.

Chemotherapeutic management of ovarian cancers is a difficult task as these neoplasms show significant differences in chemosensitivity, even if they share identical clinicopathological features. The present study was undertaken to investigate the prognostic and predictive role of p53 alterations in ovarian cancer. To this end, using different technical approaches, i.e. genetic and immunohistochemical analyses, we analysed a series of 68 ovarian neoplasms including 15 low malignant potential (LMP) tumours and 53 invasive carcinomas. We never observed p53 abnormalities in LMP tumours. p53 alterations were present only in invasive ovarian carcinomas, and they were detected much more frequently in tumours characterized by high histological grade (P = 0.01) and advanced-stage disease (P = 0.006 and P = 0.05 for gene mutations and protein expression respectively). For 33 patients with invasive ovarian cancer, information was available concerning response to cisplatin-based chemotherapy. A strong correlation (P = 0.001) has emerged between p53 alterations and response to chemotherapy; only one (14%) of seven patients who had a pathological complete response to antiblastic drugs showed p53 aberrations, whereas 18 (82%) of 22 cases with partial response and all of the four non-responsive patients scored positive for p53 abnormalities. We also observed that patients with p53 mutations had a significantly shorter progression-free survival than patients with p53-negative tumours (P = 0.05). Taken together, our results strongly suggest that in epithelial ovarian malignancies tumours showing p53 aberrations are significantly less sensitive to chemotherapy and more aggressive than those with functional p53. Thus, a routine analysis of this gene could have profound implications for the treatment of ovarian cancer.

Antineoplastic Agents↗
PubMed1996

Plasmatic parameters of coagulation activation in thrombotic microangiopathy.

Coagulation activation and fibrinolysis parameters were studied in eleven cases of thrombotic microangiopathy concerning eight adult patients. In addition to routine coagulation tests, antithrombin III, von Willebrand factor (vWF), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), D-dimer (DD), and plasminogen activator inhibitor type 1 (PAI-1) were measured in the plasma at the time of diagnosis and as soon as remission was achieved after therapy with plasma exchange and Iloprost. In the acute phase all patients showed normal aPTT, normal or slightly prolonged prothrombin time, normal or enhanced plasma levels of fibrinogen and antithrombin III, at variance with results in patients affected by disseminated intravascular coagulation. Mean F1+2, TAT, DD, vWF and PAI-1 were elevated in the acute phase, but decreased significantly in the early phase of remission. Our data provide evidence of increased thrombin generation rate which takes place in the acute phase of the disease and does not result in consumption coagulopathy, due to appropriate inhibition by antithrombin III; blood coagulation activation promptly decreased as soon as remission was achieved. Cross-linked fibrin deposition together with PAI-1 may consolidate the platelet plug, eventually resulting in microvascular occlusion and ischemia.

Adolescent↗
PubMed1996

Detection of minimal but significant amount of von Willebrand factor in human omentum mesothelial cell cultures.

The presence of von Willebrand factor (vWF) in human mesothelial cells is a controversial issue. The aim of this paper was to investigate the presence of vWF in human mesothelial cell cultures by means of multiple specific techniques and to compare the amount of vWF to that in endothelial cell cultures. Morphological evidence that vWF is present in the cell cytoplasm in human omentum mesothelial cells (HOMC) has been obtained by vWF staining by means of anti-vWF antibodies and immunofluorescence. The vWF concentration value (measured by ELISA) was 0.02 ng/mL in the supernatant of HOMC (160,000 ng/mL cells/mL after 12-48 hours) and between 0.08-0.12 ng/mL in the supernatant of endothelial cell cultures (160,000 cells/mL). Ethidium-bromide staining of PCR products recorded the typical vWF signal both in the endothelial and in the mesothelial cell cultures, although it was noticeably more intense in the endothelial cell culture. These data show that minimal but significant amounts of vWF are present in human mesothelial cell cultures.

Cell Culture Techniques↗
PubMed1996

Expression of tissue-type plasminogen activator, plasminogen activator inhibitor and von Willebrand factor in the supernatant of endothelial cell cultures in response to the seeding of adenocarcinoma cell line HRT-18.

Plasminogen activator inhibitor (PAI-1), tissue type plasminogen activator (tPA) and von Willebrand factor (vWF) concentrations were measured by ELISA in the supernatant of the following cultures: endothelial cells from human umbilical vein (HUVEC); human colon cancer cells (HRT-18); and co-culture cells of HUVEC + HRT-18. No measurable amount of the three substances was found in the supernatant of HRT-18 cell culture. Compared to the value in the HUVEC supernatant, in the UVEC/HRT-18 co-cultures, tPA concentration was significantly lower (P = 0.0047), PAI-1 significantly higher (P = 0.026) and vWF also significantly higher (P = 0.0048). These data indicate that HRT-18 tumor cells do not produce tPA, PAI-1 and vWF; however, these tumor cells induce endothelial cells to change the production of these substances. As a consequence, the interaction between tumor and endothelial cells in vivo may lead to depression of fibrinolysis and enhancement of platelet adhesion.

Adenocarcinoma↗
PubMed1995

Liver resection without blood transfusion.

A retrospective study was carried out of 522 elective liver resections to determine the impact of blood transfusion on the immediate postoperative outcome and on long-term survival. The number of liver resections without transfusion has increased in recent years, as a result of improvement in surgical technique with less blood loss during operation and more careful choice of the timing of transfusion. In resections carried out in the past 5 years, the indication for intraoperative transfusion was restricted and the decision was made jointly by the surgeon and anaesthetist, and in any case only if the haematocrit was below 25 per cent. Of resections carried out in the past 2 years, 59 per cent did not require intraoperative transfusion. Postoperative deaths and complications were related to blood transfusion, particularly in patients with cirrhosis, in whom stepwise logistic regression analysis showed that transfusion was the only factor that correlated significantly with complications. Transfusion also affected the long-term survival of patients operated on for hepatocellular carcinoma and colorectal carcinoma metastases in univariate analysis and was the only factor shown by multivariate analysis to correlate with survival for hepatocellular carcinoma in patients with cirrhosis.

Adolescent↗
PubMed1995

[Incidence of dilatation of residual cystic duct in liver transplantation. Our experience with 152 cases].

In our series of patients, we studied the incidence of residual cystic duct mucocele, which is still considered a rare complication in orthotopic liver transplantation (OLT). 152 OLTs were performed in 138 patients in the II Surgery Dept. of Bologna University, May 1986 to June 1994; a termino-terminal choledocho-choledochal anastomosis was performed in 145 of them. A choledocho-jejunal anastomosis was performed in other 7 patients. In 3 patients we observed an anechoic ovoidal structure localized just before the portal vein, near the main bile duct (MBD). Then, we monitored the evolution of this finding by ultrasonography (US), Doppler US, CT and CT-cholangiography. Integrated imaging, clinical and surgical data, led to the diagnosis of non-obstructive mucocele of residual cystic duct in OLT. To date, this complication has not led, on our series, to the necessity of new surgical procedures for cholestasis by MBD compression, which is in disagreement with literature data. In our series, the incidence of residual cystic duct mucocele is 2%, which is a higher value than those reported in the literature, suggesting that this condition be investigated carefully as a non-rare complication in OLT.

Adult↗
PubMed1994

Inhibition of MDR1 gene expression by antimessenger oligonucleotides lowers multiple drug resistance.

The multiple drug resistance of neoplastic cells is mediated by overexpression of the human MDR1 gene, which encodes the transmembrane efflux pump P-glycoprotein. In both cell lines and human tumors the MDR phenotype closely correlates with MDR1 mRNA and P-glycoprotein levels. Reversion of the MDR phenotype was attempted in human colorectal adenocarcinoma doxorubicin (Dx)-resistant cells (Lo Vo/Dx) by long-term administration of an equimolecular mixture of three unmodified ODNs (18mer) targeted to adjacent binding sites of the MDR1 mRNA and carried by a synthetic cationic lipid (DOTAP). Three different experimental parameters were used to evaluate the antimessenger agent's effectiveness in comparison with a random sequence ODN: the level of cell resistance to Dx; the level of P-glycoprotein (determined by flow cytometry); the level of MDR1 mRNA (determined by quantitative RT-PCR). Experimental data indicate that the level of both the MDR1 mRNA and the P-glycoprotein is reduced by approximately 50% by treatment of Lo Vo/Dx cells with a 10 microM total concentration of the aODN mixture every 24 h for 15 days. In agreement with these findings, sensitivity to Dx of the antimessenger agent-treated Lo Vo/Dx cells was almost doubled in comparison with random sequence ODN-treated controls.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Bisegmentectomy 5-8 for the removal of tumors of the 8th hepatic segment--a technical note.

Isolated resection of the 8th segment is a technical challenge. The deep location of the afferent portal pedicle mandates the performance of a wedge resection that leaves a deep and narrow wound in which hemostasis is difficult to achieve. Furthermore the relationships with the middle and right hepatic veins jeopardize the transparenchymal approach. For the removal of tumors located in the 8th segment, we propose a combined resection of the 8th and 5th segments, whose pedicles arise from the anterior right pedicle of the portal vein. The technique permits a safe liver resection and ensures a satisfactory surgical margin.

Aged↗
PubMed1993

Surgical experience with 168 primary liver cell carcinomas treated with hepatic resection.

Liver resections were performed in 168 patients with hepatocellular carcinoma (HCC) over the past 10 years; 116 were cirrhotics. Operative mortality was 7.7% (8.6% in the cirrhotic group and 5.8% in non-cirrhotics). In the years 1987-1992 the operative mortality decreased from 15.6% to 4.9% (P < .05). A statistical analysis of survival was made with the data of 155 patients with a follow-up of more than 1 month after curative resection: 56 (36.1%) died, while 99 (63.8%) are currently alive, with a follow-up varying from 2 to 76 months. The actuarial survival rate is 56.7% after 3 years and 36.3% after 5 years (59% and 35.2% for cirrhotics; 52.2% and 37.7% for non-cirrhotics, respectively). Satisfactory results can be obtained after liver resections in HCC, even in the presence of cirrhosis. Further efforts are needed in the early diagnosis of HCC, to prevent the formation of satellite nodules and the intrahepatic tumoral spread, which represent the major cause of exclusion from surgical therapy.

Adolescent↗