Delayed diagnosis of coeliac disease increases cancer risk

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Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial

Background Results from small randomised trials on tamoxifen in the treatment of hepatocellular carcinoma (HCC) are conflicting, We studied whether the addition of tamoxifen to best supportive care prolongs survival of patients with HCC. Methods Patients with any stage of HCC were eligible, irrespective of locoregional treatment. Randomisation was centralised, with a minimisation procedure accounting for centre, evidence of disease, and time from diagnosis. Patients were randomly allocated best supportive care alone or in addition to tamoxifen, Tamoxifen was given orally, 40 mg per day, from randomisation until death. Results 496 patients from 30 institutions were randomly allocated treatment from January, 1995, to January, 1997. Information was available for 477 patients. By Sept 15, 1997, 119 (50%) of 240 and 130 (55%) of 237 patients had died in the control and tamoxifen arms, respectively. Median survival was 16 months and 15 months (p=0.54), respectively, No differences were found within subgroups defined by prognostic variables. Relative hazard of death for patients receiving tamoxifen was 1.07 (95% CI 0.83-1.39). Interpretation Our findings show that tamoxifen is not effective in prolonging survival of patients with HCC

Effects of time culture and prototypical CYP3A inducers on CYP2B22, CYP2C, CYP3A28 and nuclear receptors mRNAs in cryopreserved pig hepatocytes

Introduction. The constitutive expression of major drug metabolizing enzymes like cytochromes P450 (CYPs) and related nuclear receptors (NRs) is considered of fundamental importance in drug metabolism studies made in whole-cell systems like hepatocyte primary cultures (HPCs). In fresh and cryopreserved pig HPCs, time-dependent variations of CYP gene expression have been investigated by and large at the post-translational level; furthermore, few data have been published about the effect of time and known CYP3A inducers on NRs mRNAs. In the present study, the transcriptional effects of time and prototypical CYP3A inducers upon CYP2B22, 2C, 3A28 and NR1I2, NR1I3, NR2B1 and NR3C1 were investigated by using cryopreserved pig HPCs. Materials and Methods. To measure time-dependent changes in aforementioned target genes, HPCs were stopped 24, 48, 72 and 96 hrs after plating. As regards the HPCs response to known CYP3A inducers, media containing phenobarbital (PB, 2 mM), pregnenolone 16\u3b1-carbonitrile (PCN, 10 \u3bcM), rifampicin (RIF, 10 \u3bcM), dexamethasone (DEX, 10 \u3bcM) and dimethyl sulfoxide (control) were daily added to monolayers from 24 hrs after plating and up to 72 hrs. Additionally, specific reference genes were identified by using geNormPLUS and Normfinder algorithms. Transcriptional effects were measured by using specific qPCR assays. Results. The geometric mean of three reference genes, namely ribosomal protein large P0 (RPLP0), cyclophilin A (PPIA), glyceraldheyde 3-phosphte dehydrogenase and RPLP0, PPIA and \u3b2-actin was used to normalize time-course and induction qPCR data, respectively. CYP gene expression was strongly down-regulated as a function of time culture; at 48 hrs, CYP2B22 and CYP3A accounted (%) for 7.14\ub11.08 and 19.37\ub111.21 of the RQ value measured at 24 hrs. A low and constant constitutive expression of CYP2C, NR1I2 and NR1I3 was noticed during the whole culturing time, while NR2B1 and NR3C1 mRNA levels were increased (p<0.001 for NR2B1at 96 hrs). Hepatocytes were responsive to model CYP3A inducers; PB significantly increased CYP2B22 (p<0.05), 2C (p<0.01) and 3A (p<0.001) gene expression, while DEX induced CYP3A, NR1I2 (p<0.001) and NR1I3 (p<0.05). Finally, RIF up-regulated only CYP3A mRNA (p<0.05). Conclusions. Data obtained agree with previous published comparative results about time-course and induction in fresh and cryopreserved HPCs. Furthermore, present results would confirm the role played by NRs in CYP expression and regulation phenomena as well as the presence of species-differences in CYP3A drug metabolism. Confirmatory immunoblotting investigations are actually running

Induction of adipose differentiation related protein and neutral lipid droplet accumulation in keratinocytes by skin irritants

Keratinocytes play an important role in skin irritation. In an attempt to investigate mechanistic bases of human skin irritation response, we recently identified the upregulation by skin irritants of adipose differentiation related protein (ADRP) in reconstituted human epidermis. ADRP is a lipid-storage-droplet-associated protein, governing deposition and release of lipids from droplets. The purpose of this study was to characterize, in a human keratinocyte cell line (NCTC 2544), sodium-dodecyl-sulfate-induced ADRP expression, to identify the biochemical events that lead to ADRP expression, and to understand its function in sodium dodecyl sulfate cytotoxicity. Sodium dodecyl sulfate induced a concentration- and time-related production of ADRP that was associated with lipid droplet accumulation. Lipid accumulation following sodium dodecyl sulfate treatment was due to intracellular redistribution rather than lipid neosynthesis, as indicated by equivalent (14) C-oleate and (14) C-acetate incorporations. Other skin irritants, namely benzalkonium chloride, tributyltin, and 12-O-tetradecanoylphorbol 13-acetate, also induce lipid droplet accumulation. Sodium-dodecyl-sulfate-induced ADRP expression and lipid droplet accumulation were modulated by the calcium chelator BAPTA, indicating a role of calcium in ADRP induction. Decrease of sodium-dodecyl-sulfate-induced ADRP expression by specific ADRP antisense oligonucleotide resulted in increased cytotoxicity, indicating a protective role of ADRP and lipid accumulation in the process of cell damage induced by skin irritants. ADRP expression was also induced in vivo following treatment with sodium dodecyl sulfate in an experimental model of skin irritation, indicating that the in vitro model represents irritation