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Biomedical subjects

Gianluigi Giannelli

Publications and source records attributed to Gianluigi Giannelli.

At least 19 recordsLinked to original sources
PubMed2006

Antifibrogenic effect of IFN-alpha2b on hepatic stellate cell activation by human hepatocytes.

Liver fibrosis commonly occurs in patients with hepatitis C virus (HCV) infection as a consequence of the chronic liver damage, thus leading to the development of liver cirrhosis. When hepatic stellate cells (HSCs) become active, they play an essential role in liver fibrogenesis. In this study, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), commonly elevated in chronic C hepatitis, stimulate the production of matrix metalloprotease-9 (MMP-9) by human hepatocytes at a transcriptional and translational level, but the addition of recombinant interferon-alpha2b (rIFN-alpha2b) hampers this effect. Furthermore, a human HSC line is activated in vitro by incubation with human MMP-9 in the presence of collagen I, and this effect is blocked by the MMP inhibitor BB94. A similar activation was observed when incubating HSCs with conditioned medium of hepatocytes previously stimulated with IL-1beta and TNF-alpha but not when using conditioned medium of hepatocytes costimulated with IL-1beta or TNF-alpha together with rIFN-alpha2b. In conclusion, our results show that hepatocytes stimulated by inflammatory cytokines participate in the activation of HSCs via MMP-9 production and that antiviral therapy modulates such activation.

Actins↗
PubMed2006

Novel concepts in hepatocellular carcinoma: from molecular research to clinical practice.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, burdened by a constantly increasing frequency. Therapy is currently restricted to invasive techniques but prognosis and survival are still unsatisfactory, mainly because of HCC recurrence and metastasis diffusion. This review will focus on the problem of tumor recurrence and/or metastasis, pointing out the role of the tissue microenvironment in affecting HCC behavior; new experimental findings will also be discussed in the light of their implications in medical care. Finally, new therapeutic approaches will be considered, paying particular attention to the tissue microenvironment as a potential target. In conclusion, this review will attempt to stimulate debate on translational research into HCC biology, in the field of clinical applications.

Antineoplastic Agents↗
PubMed2006

[Extrapulmonary sarcoidosis with prevalent liver involvement: a new case and review of the literature].

A few cases of sarcoidosis are associated with progressive liver disease. We report a case of sarcoidosis with prevalent hepatic location. This case emphasizes the possibility of an organ-specific extrapulmonary presentation of sarcoidosis and in this context, outlines the fact that hepatic involvement, independent of any pulmonary and/or mediastinal lymph nodes involvement, may be more frequent than has been reported up to now.

Adult↗
PubMed2005

ZD6474 inhibits proliferation and invasion of human hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is characterized by hypervascularization, neoangiogenesis formation and blood vessel invasion. Recently, it has been demonstrated that an inhibitor of the vascular endothelial growth factor (VEGF) receptor, ZD6474, may directly inhibit the growth of tumor cells. ZD6474 effectiveness was investigated on cell growth, apoptosis, adhesion, migration and invasion and related to the drug-dependent modulation of main molecular targets on HCC cells. ZD6474 inhibited HCC cell proliferation, however, such effect was reverted by Laminin-5 (Ln-5) but not by other extracellular matrix proteins (ECM). ZD6474 also inhibited HCC cell adhesion, migration and invasion, whereas the simultaneous treatment with the drug and Ln-5 strongly recovered those effects. Under the same experimental conditions, ZD6474 inhibited the expression of phosphorylated EGFR in all cell lines while the effect on p-Erk1/2 was dependent on cellular invasive characteristics. Nonetheless, co-incubation with Ln-5 completely recovered this effect. Our results support the hypothesis that ZD6474 could represent an interesting therapeutic opportunity for patients with HCC scarcely expressing the ECM protein, Ln-5.

Apoptosis↗
PubMed2005

SCCA antigen combined with alpha-fetoprotein as serologic markers of HCC.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Because of its increased incidence in the last decade and the estimated further increase in the next 2 decades, HCC is arousing great interest. In Europe and North America, it commonly develops on cirrhotic livers, and surveillance programs have therefore been suggested to identify early HCC, at a stage when it remains suitable for surgical therapy and has a better clinical outcome. The only serologic marker used in clinical practice is alpha-fetoprotein (alpha-FP), but its sensitivity is poor. In our study, 120 patients with HCC and 90 patients with liver cirrhosis were investigated. We report for the first time to our knowledge that as a marker of HCC, the squamous cell carcinoma (SCCA) antigen has high sensitivity (84.2%) but low specificity (48.9%). However, the combination of alpha-FP and SCCA yielded a correct serologic diagnosis in 90.83% of the HCC patients. A small percentage of patients remain undetected, likely because of the low specificity of SCCA. In conclusion, the combined use of alpha-FP and SCCA antigen represents a more powerful tool for the serologic detection of HCC.

Adult↗
PubMed2005

Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and a common occurrence in patients with liver cirrhosis in western and North American countries. Ultrasound screening is a powerful technique for HCC diagnosis, whereas the only available serologic test, alpha-fetoprotein, has poor reliability. It has been reported that the squamous cell carcinoma antigen (SCCA) is overexpressed in HCC tissue. In our study, the expression of SCCA was investigated in tumoral and peritumoral tissues and in the serum of 52 HCC patients, as well as in the serum of 48 cirrhotic patients. The results show that SCCA expression is much stronger in the tumoral than in the peritumoral tissue of HCC. Moreover, it is also evident in metastatic nodules present in the peritumoral tissue. SCCA serum levels were significantly higher in HCC samples than in cirrhotic samples. However, no correlation was found between SCCA expression and the HCC histologic degree, nor did SCCA expression correlate with tumor size, presence of metastasis or clinical outcome. In conclusion, in HCC patients, the SCCA antigen could represent a useful marker for the detection of micro-metastasis in the tissues and for large-scale screening of serum in patients at risk.

Adult↗
PubMed2005

Treatment of community-acquired pneumonia: a descriptive study in an Apulian department of internal medicine.

BACKGROUND: Infections of the lower airways pose a serious problem for the health service, both because of the burden of the disease and because of the large number of resources that need to be devoted to treating it. MATERIAL/METHODS: The present study describes the use of antibiotics to treat acute bronchopneumonia in the Internal Medicine Department "Cesare Frugoni" of a university hospital in southern Italy. A total of 493 patients were studied during a 4.5-year period. RESULTS: In 98.2% of cases an empirical approach to treatment was adopted, and only in 57 patients was targeted treatment administered. Mean duration of the antibiotic therapy was 11.3 days, with a wide range. Assessment of prognosis in the different groups showed that this did not seem to depend on the type of treatment approach or on the type and/or number of antibiotics used. Instead, targeted therapy was correlated with a shorter duration of treatment. Blood culture was very rarely carried out. The almost invariably empirical approach to treatment of bronchopneumonia infections resulted in longer hospital stay and a greater consumption of antibiotics, often of latest generation. CONCLUSIONS: Therefore, more studies would be useful to investigate the real adherence to the guidelines in the clinical practice. Finally, blood culture should be performed routinely in these patients, although the time required for the test could be a limiting factor.

Adult↗
PubMed2005

Clinical role of serum and tissue matrix metalloprotease-9 expression in chronic HCV patients treated with pegylated IFN-alpha2b and ribavirin.

In chronic hepatitis C, the main goal of antiviral therapies is to block viral replication and to slow down the development of fibrosis. In this study, a decrease in matrix metalloprotease-9 (MMP-9) but not of MMP-2 and the tissue inhibitors of MMP (TIMP-1 and TMP-2) was observed in the plasma of chronic hepatitis C patients at the end of the follow-up period after ribavirin plus interferon-alpha2b (PEG-IFN-alpha2b) treatment in sustained virologic responders but not in nonresponders. Consistently, similar results are observed by immunofluorescence and real-time PCR in tissue specimens collected before and after therapy from the same patients in whom both Kupffer cells and hepatocytes express MMP-9. In conclusion, our results show that MMP-9 decreases in responder patients both in the serum and in the liver after therapy. Further studies are needed to investigate this new possible therapeutic activity of PEG-IFN-alpha2b.

Adult↗
PubMed2005

The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease that can potentially involve all tissues and organs of the human body. Based on the extent of the disease and organ involvement, different subsets of patients and organ involvement, different subsets of patients have been identified and several classifications proposed have been identified and several classifications proposed aiming to better stratify affected patients. The occurrence aiming to better stratify affected patients. The occurrence of pulmonary arterial hypertension (PAH), characterized of pulmonary arterial hypertension (PAH), characterized by altered tissue remodelling of the entire vessel wall, is the most severe complication that influences prognosis and survival. The molecular basis underlying the vascular damage is not yet known, but a family of enzymes named matrix metalloproteinases (MMPs), with a proteolytic activity towards several extra-cellular matrix (ECM) components, is likely to be involved. Recently, a dual inhibitor of endothelin-1, bosentan, has been successfully evaluated in clinical trials in PAH patients. RESEARCH DESIGN AND METHOD: The aim of this study is to investigate the expression of MMP-2 and MMP-9 in the serum of different subsets of SSc patients, and in patients treated with bosentan. Thirty-five Caucasian patients with SSc were enrolled in the study, 12 of whom were found to have isolated PAH assessed by Doppler echocardiography. Eight patients fully met the inclusion criteria and were eligible for therapy with bosentan given at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for 50 weeks(15). The remaining patients (4/12) initiated bosentan therapy for a few weeks and, therefore, were considered at the baseline level only. Serum samples were analysed by gelatine zymography. RESULTS: The results suggest that MMP-9 but not MMP-2 is differently expressed according to the degree of organ involvement. In particular, MMP-9 serum levels are significantly decreased in PAH with respect to other subsets of SSc patients. Moreover, in bosentan-treated patients, after 12 months of therapy MMP-9 significantly (p < 0.05) increased and correlated with an improved clinical outcome, as measured by the '6-minutes walking' test. CONCLUSIONS: This is the first time that MMP-9 serum levels are reported to be down-regulated in PAH patients and up-regulated following bosentan treatment. Whether MMP-9 has a pathogenetic role in the vascular damage observed in PAH patients or it is a marker of bosentan effectiveness is not yet known. However, MMP-9 may be an important molecule that needs further investigation in SSc patients to better define its role.

Adult↗
PubMed2005

Predictive value of early virological response to treatment with different interferon-based regimens plus ribavirin in patients with chronic hepatitis C.

Early virological response (EVR) to different interferon-based regimens plus ribavirin and its ability to predict the outcome of therapy in patients with chronic hepatitis C were investigated. The study design was as follows: 64 naive patients were considered, 32/64 received pegylated interferon alpha-2b (Peg-IFN-alpha2b) plus ribavirin and the remaining 32 received leucocyte interferon alpha (IFN-alpha) plus ribavirin. At week 4 of treatment, EVR was present in 68.7% and 37.5% of patients treated with Peg-IFN-alpha2b plus ribavirin, and with leucocyte interferon alpha (IFN-alpha) plus ribavirin, respectively (p = 0.024). At week 12, the cumulative EVR rates did not differ between the two groups (71.9% vs 56.2%, p >0.05) because a higher proportion of patients achieved EVR for the first time after more than 4 weeks of therapy in the standard IFN-alpha group. Sustained virological response (SVR) rates, however, resulted significantly higher in the Peg-IFN-alpha2b group (65.6% vs 37.5%; p = 0.045) since a higher proportion of patients who received standard IFN-alpha relapsed during the follow-up. In the standard IFN-alpha group, HCV genotype 1 (p = 0.035), high baseline viral load (p = 0.035) and the presence of bridging fibrosis/cirrhosis (p = 0.011) were closely associated with significantly lower SVR rates. In the Peg-IFN-alpha2b group, only bridging fibrosis/cirrhosis (p = 0.02) negatively influenced the outcome of treatment. Overall, 33/41 (80.5%) patients with EVR at week 12 were sustained responders, yielding a positive predictive value (PPV) of 0.80. However, when SVR was related to the time taken to reach EVR, 32/34 (94.1%) patients with EVR at week 4 of therapy (PPV = 0.94) versus 1/7 (14.3%) patients who had EVR after more than 4 weeks of therapy (PPV = 0.14) resulted sustained responders (p = 0.000057). In conclusion, EVR at week 4 of treatment is strongly associated with the likelihood of achieving SVR, regardless of the therapeutic regimen. However, when compared with standard IFN-alpha plus ribavirin, treatment with Peg-IFN-alpha2b plus ribavirin significantly increases the probability of viral clearance within the first 4 weeks of treatment. Finally, patients who do not clear the virus within the first 12 weeks of treatment have no chance of achieving SVR, justifying discontinuation of therapy in these patients.

Adult↗
PubMed2005

[Syndrome of overlap: Chronic hepatitis C/autoimmune hepatitis: fact or fancy?].

Non-organ specific autoantibodies are common in patients with chronic hepatitis C, making differential diagnosis difficult between viral, autoimmune forms and hepatitis C/autoimmune hepatitis overlap syndrome. The lack of additional criteria of autoimmunity in most patients leads to the definition of a "false" hepatitis C-autoimmune hepatitis overlap syndrome, while the "true" overlap syndrome occurs in a very few number of subjects. In patients with "false" overlap syndrome the first choice therapy is based on the administration of interferon plus ribavirin. On the contrary, first-line therapy with corticosteroids should be restricted to the "true" hepatitis overlap syndrome with the new therapeutic option of interferon/corticosteroid association.

Adrenal Cortex Hormones↗
PubMed2005

[Clarkson syndrome: a rare clinical condition characterized by generalized edema associated to monoclonal gammopathy].

Generalized edema is commonly due to cardiac failure, renal changes, hepatic and metabolic disturbances, or it can be idiopathic, i.e. primitive lymphedema. Here we describe a patient with several episodes of fluid extravasation characterized by hypotension, hemoconcentration and functional renal insufficiency. These findings, associated to a monoclonal gammopathy, lead to the diagnosis of systemic capillary leak syndrome or Clarkson Syndrome. This rare and perplexing disorder, characterized by a typical three-phase clinical feature, is due to an endothelium permeability alteration, rather responsible of these paroxysmal manifestations. Interleukin-2-pathway is considered as one of the underlying mechanisms. During acute phase the patient underwent therapy with plasma-expanders and glucocorticoids, although in quiescent phase we administered aminophylline, salbutamol and prednisone. After three months, the patient is asymptomatic.

Adrenergic beta-Agonists↗
PubMed2004

Proteolytic imbalance is reversed after therapeutic surgery in breast cancer patients.

The occurrence of metastasis severely affects prognosis and survival of breast cancer patients. In order to metastasize, breast cancer cells need to cross the basement membrane (BM) tissue boundaries. Matrix metalloproteases (MMPs) are enzymes with proteolytic activity towards extracellular matrix components (ECM) of the BM, that are blocked by physiological tissue inhibitors (TIMPs). Cancer metastasis occurs as a result of an imbalance between MMPs, in particular MMP-2 and MMP-9, and TIMPs, in particular TIMP-2 and TIMP-1. This is the first study to report that pro-MMP-9 and TIMP-1 serum concentrations are inversely correlated in breast cancer patients. In the same patients, we determined the pro-MMP-9, the TIMP-1, the pro-MMP-2 and TIMP-2 before and after surgical eradication of the breast cancer. Our results show that after surgery, when the breast cancer tissue was removed, pro-MMP-9 concentrations dramatically decreased and TIMP-1 concentrations strongly increased, with statistically significant differences, so that a new balance was established. No statistically significant differences were observed regarding pro-MMP-2 and TIMP-2. Also, no correlation was found between pro-MMP-2, pro-MMP-9, TIMP-1 and TIMP-2 and a number of clinical and pathological parameters. In conclusion, our study suggests that pro-MMP-9 and TIMP-1 could be used as markers of disease during the follow-up of breast cancer patients and possibly as prognostic markers, although more studies are needed to address this issue.

Adult↗
PubMed2004

MxA and PKR expression in chronic hepatitis C.

The effectiveness of therapy for chronic hepatitis C (CHC) patients has greatly improved in the last few years, and the gold standard is currently held to be pegylated interferon (IFN) in combination with ribavirin. Overall, however, the percentage of patients achieving a sustained virologic response (SVR) is only around 50%,and it is not possible to predict those patients who will benefit from therapy. The molecular mechanisms underlying lack of therapeutic response remain unknown. In this study, we investigated the tissue expression of MxA and RNA-dependent protein kinase (PKR), two antiviral proteins modulated by IFN, in biopsy samples from hepatitis C patients before the beginning of therapy. Our results show that expression of MxA, but not of PKR, is significantly lower in responders compared with nonresponders. No differences were observed regarding the hepatitis C virus (HCV) genotype and the viral load. These results suggest that expression of the MxA protein could play a role among the mechanisms underlying responsiveness to therapy.

Antiviral Agents↗
PubMed2003

Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma.

PURPOSE: The purpose of this work was to study the expression of the extracellular matrix protein laminin-5 (Ln-5) in hepatocellular carcinoma (HCC), which is the fifth most frequent cancer and the third most common cause of tumor-related death in the world. The occurrence of metastasis is the main problem in HCC patients. Ln-5 is an extracellular matrix component that promotes adhesion and migration; it is present at the basement membrane and has recently been associated with cancer metastasis. Although Ln-5 has been shown to promote motility and scatter of rat liver cells, it has never been found in the liver. EXPERIMENTAL DESIGN: We studied the expression and localization of the alpha3, beta3, and gamma2 chains of Ln-5 in 40 HCC patients. We analyzed tissue samples collected from the HCC primary nodule and from peritumoral and metastatic tissues. The presence of Ln-5 was investigated by immunohistochemistry, reverse transcription-PCR, and Northern blot analysis. The clinical outcome of the patients was evaluated over a 4-year follow-up period. RESULTS: This study provides the first report that Ln-5 is present in the HCC primary nodule, but not in normal or peritumoral cirrhotic tissues. In particular, the gamma2 chain is strongly associated with the occurrence of metastasis (96%; P < 0.001) and with worse prognosis. In peritumoral tissues, Ln-5 has been detected along the advancing edge of the metastatic nodule. CONCLUSIONS: Ln-5 is associated with a more metastatic phenotype of HCC, and its detection could be an important finding both as an unfavorable prognostic factor and as a diagnostic marker for detecting micrometastasis in peritumoral tissues.

Biomarkers, Tumor↗
PubMed2003

Case of multiple myeloma mimicking an infectious disease with fever, intrahepatic cholestasis, renal failure, and pulmonary insufficiency.

We describe a case of multiple myeloma (MM) presenting with high fever, inflammatory chemistry abnormalities, simultaneous acute renal failure, cholestatic hepatitis, and acute lung failure. The extremely aggressive course and pulmonary involvement in the form of pulmonary alveolar proteinosis (PAP) are discussed, stressing the unusual nature of the findings and the variable picture of MM.

Acute Kidney Injury↗
PubMed2002

Localization and possible role of two different alpha v beta 3 integrin conformations in resting and resorbing osteoclasts.

Integrins are membrane receptors that mediate interactions between cells and the extracellular matrix. We recently showed that the osteoclast integrin alpha(v)beta(3) exists in two different conformations, so-called 'basal' and 'activated', with each exhibiting a distinct function. In this study we demonstrate that, in non-resorbing osteoclasts, the 'activated' form of alpha(v)beta(3) accumulates in the motile areas of the plasma membrane. During bone resorption this conformation is prevalent in the ruffled membrane, whereas the 'basal' form of alpha(v)beta(3) is also present in the sealing zone. Moreover, hepatocyte growth factor (HGF) and macrophage colony stimulating factor (M-CSF), two molecules involved in osteoclastogenesis and osteoclast survival, modulate alpha(v)beta(3) conformation in vitro. Preincubation with HGF or M-CSF induces a shift of conformation of alpha(v)beta(3) in primary human osteoclasts (OCs) and in the osteoclast-like cell line (GCT 23). Activated integrin promotes osteoclast migration to the alpha(v)beta(3) ligand osteopontin and enhances bone resorption. Thus, HGF and M-CSF modulate the alpha(v)beta(3) conformational states required for osteoclast polarization and resorption. The capacity of growth factors to alter the affinity of alpha(v)beta(3) toward its ligands offers a potential explanation for the diverse responses of osteoclasts to the same ligand.

Antibodies, Monoclonal↗