Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy.

The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world because of two major reasons: firstly, HCC is one of the most lethal form of malignancies with less than 10% survival rate and secondly, a lack of prudent diagnostics makes early detection of HCC nearly impossible. The poor prognosis of HCC accentuates the need to develop new diagnostic markers and therapeutic approaches. In this review we discuss recent advances made in the discovery of molecular biomarkers and their significance in the detection of HCC. We focus on three major classes of biomarkers: serological, tumor, peri-tumoral tissue and cancer stem cell markers. Considerable progress has been made recently in our understanding of HCC at the molecular level increasing the potential of molecular targeted therapy. A number of molecular targets have been identified that have been showing promising results. Of particular interest is Sorafenib, a multi-tyrosine kinase inhibitor that has been approved for the HCC treatment. Inhibitors of other molecular targets such as VEGF, EGFR, mTOR etc. are emerging as plausible therapeutic agents for the treatment of HCC and are discussed in this review.

Fatty acids and sterols from Cymbopogon martinii var. motia roots.

The hexane and methanol extracts of the roots of Cymbopogon martinii var. motia have been investigated to afford mainly fatty acids and common sterols. A new hydroxy unsaturated fatty acid, namely, 16-hydroxypentacos-14(z)-enoic acid, has also been isolated.

Live Salmonella recruits N-ethylmaleimide-sensitive fusion protein on phagosomal membrane and promotes fusion with early endosome.

To understand intracellular trafficking modulations by live Salmonella, we investigated the characteristics of in vitro fusion between endosomes and phagosomes containing live (LSP) or dead Salmonella (DSP). We observed that fusion of both DSP and LSP were time, temperature and cytosol dependent. GTPgammaS and treatment of the phagosomes with Rab-GDI inhibited fusion, indicating involvement of Rab-GTPases. LSP were rich in rab5, alpha-SNAP, and NSF, while DSP mainly contained rab7. Fusion of endosomes with DSP was inhibited by ATP depletion, N-ethylmaleimide (NEM) treatment, and in NEM-sensitive factor (NSF)-depleted cytosol. In contrast, fusion of endosomes with LSP was not inhibited by ATP depletion or NEM treatment, and occurred in NSF-depleted cytosol. However, ATPgammaS inhibited both fusion events. Fusion of NEM-treated LSP with endosomes was abrogated in NSF- depleted cytosol and was restored by adding purified NSF, whereas no fusion occurred with NEM-treated DSP, indicating that NSF recruitment is dependent on continuous signals from live Salmonella. Binding of NSF with LSP required prior presence of rab5 on the phagosome. We have also shown that rab5 specifically binds with Sop E, a protein from Salmonella. Our results indicate that live Salmonella help binding of rab5 on the phagosomes, possibly activate the SNARE which leads to further recruitment of alpha-SNAP for subsequent binding with NSF to promote fusion of the LSP with early endosomes and inhibition of their transport to lysosomes.

Nutrient absorption.

Some key advances occurred last year in understanding mechanisms involved in nutrient absorption. A novel "prechylomicron transport vesicle" was identified; its movement to the Golgi is the rate-limiting step for triacylglycerol absorption. A scavenger receptor (type BI) in the brush border membrane appears to facilitate cholesterol uptake. Several studies define mechanisms for gastrointestinal peptide hormone stimulation of glucose uptake. An oligopeptide transporter, PepT1, is transcriptionally upregulated by certain dietary amino acids and dipeptides. Surprisingly, both insulin and fasting double the maximum velocity for dipeptide uptake (via PepT1), but they act by different mechanisms. Three transporters, SMVT (sodium-dependent multivitamin transporter for biotin and pantothenate), SVCT (for vitamin C), and CaT1 (for Ca uptake from the lumen) have been cloned and are active when expressed in various cells. Additional studies provide insights on Ca absorption and vitamin D action in aging, estrogen deficiency, and adaptation to a low Ca diet. Nramp2, also called DMT1 (divalent metal ion transporter), seems to be a major regulator of transferrin-independent, nonheme iron uptake. Finally, the protein HFE associates with the transferrin receptor and is part of an iron-sensing mechanism that regulates iron absorption. It is defective in hereditary hemochromatosis. HFE and Nramp2 (DMT1) genes are reciprocally regulated.

Dilated cardiomyopathy in children: determinants of outcome.

OBJECTIVE: To determine the outcome of dilated cardiomyopathy presenting in childhood and the features that might be useful for prognostic stratification. SETTING: Supraregional paediatric cardiology unit. DESIGN: Retrospective analysis. BACKGROUND: The natural history of dilated cardiomyopathy in children is not well characterised. Previous studies have shown a variable relation between age at presentation and outcome, and sudden death has been infrequent. METHODS: Retrospective study of 63 consecutive patients with idiopathic dilated cardiomyopathy presenting between 1979 and 1992. Survival curves were constructed by the Kaplan-Meier method. RESULTS: Age at diagnosis ranged from 1 day to 15 years (median 12 months) and follow up ranged from 1 day to 13 years (median 19 months). Actuarial survival from presentation was 79% at one year (95% confidence interval (95% CI) 66%-88%) and 61% (44%-74%) at five years. Univariate analysis showed that mural thrombus, left ventricular end diastolic pressure > 20 mm Hg, and age at presentation > 2 years were predictors of adverse outcome, but on multivariate analysis only age at presentation was significant. Left ventricular echocardiographic indices either did not improve or deteriorated in 36 children (17 of whom died, four suddenly, and three were transplanted), partially improved in 16 (three of whom died, all suddenly), and returned to normal in 11 (all of whom have survived). CONCLUSIONS: Older age at presentation and lack of improvement in systolic function are associated with an adverse outcome, and early transplantation should be considered in these patients. There is a persistent risk of late sudden death in those children in whom echocardiographic dimensions remain abnormal.

Intravenous feeding of young infants with persistent diarrhoea.

42 infants with persistent diarrhoea were fed intravenously using a simplified regime based on Intralipid and an aminoacid, Fructose and ethanol solution. Peripheral veins were used for up to 56 days, and with scalp veins complications were few and minor. The use of arm and leg veins caused more frequent local problems and is not advised. Central venous lines became necessary in 5 infants, and 3 developed septicaemia. The regime was well tolerated with adequate weight gain when intake was adjusted to the infants' needs. Rates of infusion of 1 g Intralipid/kg hourly over 2 hours and up to 1 g fructose/kg hourly over 14 hours did not cause persistent lipaemia (except transiently in 2 infants) nor metabolic acidosis. Infants must be fully rehydrated with correction of acidosis and electrolyte imbalance before starting intravenous feeding, or acidosis and dehydration from osmotic diuresis may occur. Intravenous feeding should be started gradually and cautiously in severely malnourished infants, and should not be used where liver function is abnormal.

Treatment of hypernatraemic dehydration in infancy.

Thirty-eight infants with severe hyperosmolar dehydration and hypernatraemia were treated, using three regimens of intravenous fluids: A. 1/2 normal saline, given fast; B.1/2 normal saline given slowly; C. 1/5 normal saline. 28 of the infants were studied in a treatment trial, and it is concluded tha 0-18% saline in 4-3% dextrose, with the early addition of potassium given at a rate of 100 ml/kg estimated rehydrated weight per 24 hours gives satisfactory rehydration within 48 hours, with little risk of convulsions.