Concordance between Thioacetamide-Induced Liver Injury in Rat and Human In Vitro Gene Expression Data

The immense resources required and the ethical concerns for animal-based toxicological studies have driven the development of in vitro and in silico approaches. Recently, we validated our approach in which the expression of a set of genes is uniquely associated with an organ-injury phenotype (injury module), by using thioacetamide, a known liver toxicant. Here, we sought to explore whether RNA-seq data obtained from human cells (in vitro) treated with thioacetamide-S-oxide (a toxic intermediate metabolite) would correlate across species with the injury responses found in rat cells (in vitro) after exposure to this metabolite as well as in rats exposed to thioacetamide (in vivo). We treated two human cell types with thioacetamide-S-oxide (primary hepatocytes with 0 (vehicle), 0.125 (low dose), or 0.25 (high dose) mM, and renal tubular epithelial cells with 0 (vehicle), 0.25 (low dose), or 1.00 (high dose) mM) and collected RNA-seq data 9 or 24 h after treatment. We found that the liver-injury modules significantly altered in human hepatocytes 24 h after high-dose treatment involved cellular infiltration and bile duct proliferation, which are linked to fibrosis. For high-dose treatments, our modular approach predicted the rat in vivo and in vitro results from human in vitro RNA-seq data with Pearson correlation coefficients of 0.60 and 0.63, respectively, which was not observed for individual genes or KEGG pathways

Risk of colorectal cancer following CT-verified acute diverticulitis -a nationwide population-based cohort study

AIM: Routine colonoscopy to exclude colorectal cancer (CRC) after CT-verified acute diverticulitis is controversial. This study aimed to compare the incidence of CRC in acute diverticulitis patients with that in the general population. METHOD: Patients with an emergency admission for diverticular disease, to any Norwegian hospital, between January 1st , 2008 and December 31st , 2010 were included through identification in the Norwegian Patient Registry using International Classification of Diseases (ICD-10) codes K57.1-9. To estimate the age-specific distribution of CT-verified acute uncomplicated diverticulitis (AUD) and acute complicated diverticulitis (ACD) in this nationwide study population, numbers from the largest Norwegian emergency hospital were used. Patients diagnosed with CRC within one year following the admission for acute diverticulitis were detected through cross-matching with the Cancer Registry of Norway. Based on both Norwegian age-specific incidence of CRC and estimated age-specific distribution of CT-verified diverticulitis, standard morbidity ratios (SMR) were calculated.RESULTS: A total of 7473 patients with emergency admissions for diverticular disease were identified (estimated CT-verified AUD n=3523, ACD n=1206), and of these 155 patients were diagnosed with CRC within one year. Eighty had a CT-verified diverticulitis at index admission (41 AUD; 51.3% and 39 ACD; 49.7%). Compared to the general population SMR was 6.6 following CT-verified AUD and 16.3 following ACD respectively.CONCLUSION: The risk of CRC is higher than in the general population, the first year after CT-verified acute diverticulitis, especially after ACD. This likely represents misdiagnosis of CRC as acute diverticulitis. Follow-up colonoscopy should be recommended to all patients admitted with acute diverticulitis

Low-energy electron-induced DNA damage: effect of base sequence in oligonucleotide trimers

DNA damage induced by low-energy electrons (LEEs) has attracted considerable attention in recent years because LEEs represent a large percentage of the total energy deposited by ionizing radiation and because LEEs have been shown to damage DNA components. In this article, we have studied the effect of base sequences in a series of oligonucleotide trimers by the analysis of damage remaining within the nonvolatile condensed phase after LEE irradiation. The model compounds include TXT, where X represents one of the four normal bases of DNA (thymine (T), cytosine (C), adenine (A), and guanine (G)). Using HPLC-UV analysis, several known fragments were quantified from the release of nonmodified nucleobases (T and X) as well as from phosphodiester C-O bond cleavage (pT, pXT, Tp, and TXp). The total damage was estimated by the disappearance of the parent peaks in the chromatogram of nonirradiated and irradiated samples. When trimers were irradiated with LEE (10 eV), the total damage decreased 2-fold in the following order: TTT > TCT > TAT > TGT. The release of nonmodified nuclobases (giving from 17 to 24% of the total products) mainly occurred from the terminal sites of trimers (i.e., T) whereas the release of central nucleobases was minor (C) or not at all detected (A and G). In comparison, the formation of products arising from phosphodiester bond cleavage accounted for 9 to 20% of the total damage and it partitioned to the four possible sites of cleavage present in trimers. This study indicates that the initial LEE capture and subsequent bond breaking within the intermediate anion depend on the sequence and electron affinity of the bases, with the most damage attributed to the most electronegative base, T