African cratonic lithosphere carved by mantle plumes.

How cratons, the ancient cores of continents, evolved since their formation over 2.5 Ga ago is debated. Seismic tomography can map the thick lithosphere of cratons, but its resolution is low in sparsely sampled continents.

Water-soluble platinum phthalocyanines as potential antitumor agents.

Breast cancer represents the second cause of death in the European female population. The lack of specific therapies together with its high invasive potential are the major problems associated to such a tumor. In the last three decades platinum-based drugs have been considered essential constituents of many therapeutic strategies, even though with side effects and frequent generation of drug resistance.

Selective activation of nuclear bile acid receptor FXR in the intestine protects mice against cholestasis.

Background & Aims: Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs.

Down-regulation of the LXR transcriptome provides the requisite cholesterol levels to proliferating hepatocytes.

Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism.

CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice.

Dysfunction of the NF1 gene coding a RAS GAP is the major cause of neurofibromatosis type 1 (NF1), whereas neurofibromatosis type 2 (NF2) is caused primarily by dysfunction of the NF2 gene product called merlin that inhibits directly PAK1, an oncogenic Rac/CDC42-dependent Ser/Thr kinase. It was demonstrated previously that PAK1 is essential for the growth of both NF1 and NF2 tumors. Thus, several anti-PAK1 drugs, including FK228 and CEP-1347, are being developed for the treatment of NF tumors.

In vitro and in vivo stability of caffeic acid phenethyl ester, a bioactive compound of propolis.

The in vitro biochemical stability of caffeic acid phenethyl ester in rat and human plasma was investigated and compared with the stability of other caffeic acid esters (chlorogenic acid and rosmarinic acid). The incubation of the compounds in rat plasma for up to 6 h showed that caffeic acid phenethyl ester, but not the other compounds, was hydrolyzed, whereas human plasma did not affect the stability of all the assayed compounds. The products in rat plasma were caffeic acid and an unknown compound, which was identified by mass spectrometry as caffeic acid ethyl ester, produced by transesterification in the presence of ethanol used as vehicle for standard compounds.

Characterization of liver lesions by real-time contrast-enhanced ultrasonography.

Objective: The aim of this study was to identify the most common patterns of various common liver lesions at real-time contrast-enhanced ultrasonography with second-generation contrast agents and their role in the differentiation of malignant from benign lesions.

Patients And Methods: The enhancement pattern in the arterial phase and its modifications in subsequent portal and sinusoidal phases were separately evaluated in (i) 171 liver lesions detected at conventional ultrasonography in 125 noncirrhotic patients (87 metastases, six cholangiocellular carcinoma, 38 focal nodular hyperplasia, 30 hemangiomas, seven focal fatty sparing/changes, two hepatocellular adenomas and one hepatocellular carcinoma) and (ii) 75 lesions detected in 67 cirrhotic patients (66 hepatocellular carcinoma and nine dysplastic nodules). The final diagnosis was made by contrast-enhanced helical computed tomography and/or magnetic resonance imaging or by ultrasonography-guided biopsy when the diagnosis was equivocal at conventional imaging techniques (45 lesions).

Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression.

Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (1) increased expression of membrane-associated P-glycoprotein, (2) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis (ET-743).

Echo-enhanced ultrasonography: is it the future gold standard of imaging in acute pancreatitis?

We report the imaging of a patient in whom the diagnosis of acute pancreatitis and the assessment of disease severity was carried out using echo-enhanced ultrasonography. Contrast-enhanced computed tomography confirmed the echo-enhanced ultrasonography picture. Echo-enhanced ultrasonography may become the imaging technique of choice in assessing the severity of acute pancreatitis since it is easy to perform, safe and lends itself to emergency situations.

Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma.

In a prospective study, we examined the impact of arterial hypervascularity, as established by the European Association for the Study of the Liver (EASL) recommendations, as a criterion for characterizing small (1-3 cm) nodules in cirrhosis. A total of 72 nodules (1-2 cm, n = 41; 2.1-3 cm, n = 31) detected by ultrasonography in 59 patients with cirrhosis were included in the study.

Development and validation of a liquid chromatographic-tandem mass spectrometric method for the determination of caffeic acid phenethyl ester in rat plasma and urine.

Caffeic acid phenethyl ester (CAPE) is one of the most bioactive compounds of propolis, a resinous substance collected and elaborated by honeybees. A new liquid chromatography-electrospray ionisation tandem mass spectrometric method was developed and validated for its determination in rat plasma and urine, using taxifolin as internal standard. After sample preparation by liquid/liquid extraction with ethyl acetate, chromatographic separations were carried out with an ODS-RP column using a binary mobile phase gradient of acetonitrile in water.

Usefulness of contrast-enhanced perfusional sonography in the assessment of hepatocellular carcinoma hypervascular at spiral computed tomography.

Background/aims: Diagnosis of hepatocellular carcinoma (HCC) relies strongly on the detection of hypervascularity in the arterial phase and, in this setting, spiral computed tomography (CT) is the most widely used method. This prospective study aimed to investigate the usefulness of low mechanical index harmonic ultrasound (US), using a second generation contrast-enhanced technique, in the assessment of vascular pattern of HCC shown to be hypervascular at spiral CT.

Methods: A total of 79 cirrhotic patients with 103 nodules (mean+/-SD 28+/-13 mm) with arterial hypervascularity at spiral CT were studied.

Determination of aplidin, a marine-derived anticancer drug, in human plasma, whole blood and urine by liquid chromatography with electrospray ionisation tandem mass spectrometric detection.

A sensitive and highly specific liquid chromatographic method with electrospray ionisation tandem mass spectrometric detection (LC-ESI-MS/MS) is reported for the determination in human plasma, whole blood and urine of Aplidin (APL), a novel depsipeptide derived from the tunicate Aplidium albicans with a potent cytotoxic activity under investigation in clinical studies. Didemnin B was used as internal standard and, after protein precipitation with acetonitrile and liquid-liquid extraction with chloroform, APL was separated by liquid chromatography using a reversed-phase C18 column and a linear gradient of acetonitrile in water (both containing 0.5% formic acid).

Liver metastases from rectal carcinoma: disease progression during chemotherapy despite loss of arterial-phase hypervascularity on real-time contrast-enhanced harmonic sonography at low acoustic energy.

We used a new sonographic technique, real-time contrast-enhanced harmonic sonography at low acoustic energy, to evaluate liver perfusion and liver metastases from colorectal cancer in a 73-year-old woman after chemotherapy. After 6 weeks of chemotherapy, liver metastases that had been clearly visible on conventional sonography before chemotherapy were no longer detectable on conventional sonography but were still evident on contrast-enhanced sonography. At about 6 months after initiation of chemotherapy, the lesions were all visible again on conventional sonography and had become significantly larger, although some no longer showed contrast enhancement during the arterial phase.

Effect of Aplidin in acute lymphoblastic leukaemia cells.

The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent.

Review article: percutaneous treatment of hepatocellular carcinoma.

In early stage hepatocellular carcinoma (HCC), liver transplantation, surgical resection and percutaneous techniques are classified as radical treatments, and may be offered to about 25% of all patients with HCC evaluated in referral centres. The restricted inclusion criteria for surgical resection and the shortage of liver donors for transplantation have stimulated an increasing demand for minimally invasive treatments able to achieve effective and reproducible percutaneous tumour ablation, with less associated morbidity and lower cost than other interventions. Among percutaneous techniques, ethanol injection has proven to be highly effective in single HCC up to 3 cm, with a rate of complete response of 80%, being well tolerated and with a limited risk of minor complication.

Effect of Levovist on splanchnic hemodynamics in cirrhotic patients.

This study was aimed to assess the effect of Levovist on Doppler parameters of splanchnic hemodynamics. A total of 12 patients with cirrhosis and 12 healthy subjects underwent Doppler ultrasound (US) examination of the portal vein and of the hepatic, splenic and superior mesenteric arteries before, 5 to 8 and 12 to 15 min after the start of an 8-min long IV infusion of 2.5 g of Levovist.

Liquid chromatography-electrospray mass spectrometry study of cysteine-10 S-glutathiolation in recombinant glutathione S-transferase of Ochrobactrum anthropi.

Glutathione S-transferase of Ochrobactrum anthropi (OaGST), a bacterium isolated from soils contaminated by xenobiotic pollutants, was recently purified, cloned and characterised in our laboratories. The recombinant OaGST (rOaGST), highly expressed in Escherichia coli, when purified by glutathione-affinity chromatography and then analysed by electrospray ionisation mass spectrometry (ESI-MS), has evidenced a disulphide bond with glutathione (S-glutathiolation), which was removable by reduction with 2-mercaptoethanol. Enzymatic digestion of rOaGST with endoproteinase Glu-C, followed by liquid chromatography (LC)-ESI-MS analyses of the peptide mixtures under both reducing and not reducing conditions, have shown that glutathione was covalently bound to the Cys10 residue of rOaGST.

Liquid chromatography-tandem mass spectrometry analysis of oleuropein and its metabolite hydroxytyrosol in rat plasma and urine after oral administration.

We describe a liquid chromatography-electrospray ionisation tandem mass spectrometry method for the qualitative and quantitative determination of the secoiridoid oleuropein and its bioactive metabolite hydroxytyrosol in rat plasma and urine. Samples were prepared by liquid-liquid extraction using ethyl acetate with a recovery for both compounds of about 100% in plasma and about 60% in urine. The chromatographic separation was performed with a RP-ODS column using a water-acetonitrile linear gradient.

Influence of the spleen on portal haemodynamics: a non-invasive study with Doppler ultrasound in chronic liver disease and haematological disorders.

Background: Splanchnic haemodynamic parameters for the differential diagnosis of splenomegalies of different origins are still suboptimal and the role of spleen enlargement in cirrhosis remains controversial. In an attempt to elucidate these questions, we assessed splanchnic haemodynamics in chronic liver diseases and various other disorders with splenomegaly.

Methods: Study groups comprised: (i) patients with chronic liver disease (89 with cirrhosis, 35 with chronic hepatitis), (ii) patients with splenomegaly without relevant portal hypertension (14 with haematological splenomegaly and 25 liver transplant recipients without complications), (iii) 15 patients with arterial hypertension, (iv) 22 healthy controls.

Amino acid sequence of the major form of toad liver glutathione transferase.

To investigate structural relationship between amphibian and mammalian GSTs the complete amino acid sequence of the major form of glutathione transferase present in toad liver (Bufo bufo) was determined. The enzyme subunit is composed of 210 amino acid residues corresponding to a molecular mass of 24,178 Da. In comparison with the primary structure of amphibian bbGSTP1-1, toad liver GST showed 54% sequence identity.

Influence of liver fibrosis on hepatic artery Doppler resistance index in chronic hepatitis of viral origin.

Background: Hepatic arterial Doppler sonography is increasingly being used in liver diagnostics. The determinants of the elevation of hepatic artery impedance indexes in chronic liver disease, however, have still not been fully clarified. The aim of the present study was to investigate the relationship between histological alterations and liver circulation in chronic hepatitis.

Neutrophil proteases can inactivate human PAR3 and abolish the co-receptor function of PAR3 on murine platelets.

Three members of the protease-activated receptor family, PAR1, PAR3 and PAR4, are activated when thrombin cleaves the receptor N-terminus, exposing a tethered ligand. Proteases other than thrombin can also cleave PAR family members and, depending upon whether this exposes or removes the tethered ligand, either activate or disable the receptor. For example, on human platelets PAR1 is disabled by cathepsin G, although aggregation still occurs because cathepsin G can activate PAR4.