Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

Triclocarban (3,4,4′-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car−/− mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human health effects from exposure to TCC

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Excitons, biexcitons, and phonons in ultrathin CdSe/ZnSe quantum structures

The optical properties of CdSe nanostructures grown by migration-enhanced epitaxy of CdSe on ZnSe are studied by time-, energy-, and temperature-dependent photoluminescence and excitation spectroscopy, as well as by polarization-dependent four-wave mixing and two-photon absorption experiments. The nanostructures consist of a coherently strained Zn1−xCdxSe/ZnSe quantum well with embedded islands of higher Cd content with sizes of a few nanometer due to strain-induced CdSe accumulation. The local increase in CdSe concentration results in a strong localization of the excitonic wave function, in an increase in radiative lifetime, and a decrease of the dephasing rate. Local LO-phonon modes caused by the strong modulation of the Cd concentration profile are found in phonon-assisted relaxation processes. Confined biexcitons with large binding energies between 20 and 24 meV are observed, indicating the important role of biexcitons even at room temperature

Global trends in biodiversity and ecosystem services from 1900 to 2050

Despite the scientific consensus on the extinction crisis and its anthropogenic origin, the quantification of historical trends and of future scenarios of biodiversity and ecosystem services has been limited, due to the lack of inter-model comparisons and harmonized scenarios. Here, we present a multi-model analysis to assess the impacts of land-use and climate change from 1900 to 2050. During the 20th century provisioning services increased, but biodiversity and regulating services decreased. Similar trade-offs are projected for the coming decades, but they may be attenuated in a sustainability scenario. Future biodiversity loss from land-use change is projected to keep up with historical rates or reduce slightly, whereas losses due to climate change are projected to increase greatly. Renewed efforts are needed by governments to meet the 2050 vision of the Convention on Biological Diversity

Transcriptomic and Epigenetic Regulation of Disuse Atrophy and the Return to Activity in Skeletal Muscle

Physical inactivity and disuse are major contributors to age-related muscle loss. Denervation of skeletal muscle has been previously used as a model with which to investigate muscle atrophy following disuse. Although gene regulatory networks that control skeletal muscle atrophy after denervation have been established, the transcriptome in response to the recovery of muscle after disuse and the associated epigenetic mechanisms that may function to modulate gene expression during skeletal muscle atrophy or recovery have yet to be investigated. We report that silencing the tibialis anterior muscle in rats with tetrodotoxin (TTX)—administered to the common peroneal nerve—resulted in reductions in muscle mass of 7, 29, and 51% with corresponding reductions in muscle fiber cross-sectional area of 18, 42, and 69% after 3, 7, and 14 d of TTX, respectively. Of importance, 7 d of recovery, during which rodents resumed habitual physical activity, restored muscle mass from a reduction of 51% after 14 d TTX to a reduction of only 24% compared with sham control. Returning muscle mass to levels observed at 7 d TTX administration (29% reduction). Transcriptome-wide analysis demonstrated that 3714 genes were differentially expressed across all conditions at a significance of P ≤ 0.001 after disuse-induced atrophy. Of interest, after 7 d of recovery, the expression of genes that were most changed during TTX had returned to that of the sham control. The 20 most differentially expressed genes after microarray analysis were identified across all conditions and were cross-referenced with the most frequently occurring differentially expressed genes between conditions. This gene subset included myogenin (MyoG), Hdac4, Ampd3, Trim63 (MuRF1), and acetylcholine receptor subunit α1 (Chrna1). Transcript expression of these genes and Fboxo32 (MAFbx), because of its previously identified role in disuse atrophy together with Trim63 (MuRF1), were confirmed by real-time quantitative RT-PCR, and DNA methylation of their promoter regions was analyzed by PCR and pyrosequencing. MyoG, Trim63 (MuRF1), Fbxo32 (MAFbx), and Chrna1 demonstrated significantly decreased DNA methylation at key time points after disuse-induced atrophy that corresponded with significantly increased gene expression. Of importance, after TTX cessation and 7 d of recovery, there was a marked increase in the DNA methylation profiles of Trim63 (MuRF1) and Chrna1 back to control levels. This also corresponded with the return of gene expression in the recovery group back to baseline expression observed in sham-operated controls. To our knowledge, this is the first study to demonstrate that skeletal muscle atrophy in response to disuse is accompanied by dynamic epigenetic modifications that are associated with alterations in gene expression, and that these epigenetic modifications and gene expression profiles are reversible after skeletal muscle returns to normal activity

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

10.1371/journal.pone.0054522PLoS ONE81

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

BACKGROUND: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcome of patients with liver cirrhosis. METHODS: In this retrospective international multicentric study, computed tomography (CT) scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. 1-year survival was primary and acute decompensation (oHE, variceal bleeding, ascites) secondary endpoint. RESULTS: 301 patients (169 male) were included in the training cohort. 30% of all patients presented >1 SPSS. TSA cut-off of 83 mm2 was determined to classify patients with small or large TSA (S-/L-TSA). L-TSA patients presented higher MELD (11 vs. 14) and more commonly history of oHE (12% vs. 21%, p83mm2 increases the risk for oHE and mortality in liver cirrhosis. Our results may have impact on clinical use of TSA/SPSS for risk stratification and clinical decision-making considering management of SPSS

Magnetic resonance imaging (MRI) in rectal cancer: a comprehensive review

Magnetic resonance imaging (MRI) has established itself as the primary method for local staging in patients with rectal cancer. This is due to several factors, most importantly because of the ability to assess the status of circumferential resection margin. There are several newer developments being introduced continuously, such as diffusion-weighted imaging and imaging with 3 T. Assessment of loco-regional lymph nodes has also been investigated extensively using different approaches, but more work needs to be done. Finally, evaluation of tumours during or after preoperative treatment is becoming an everyday reality. All these new aspects prompt a review of the most recent advances and opinions. In this review, a comprehensive overview of the current status of MRI in the loco-regional assessment and management of rectal cancer is presented. The findings on MRI and their accuracy are reviewed based on the most up-to-date evidence. Optimisation of MRI acquisition and relevant regional anatomy are also presented, based on published literature and our own experience

A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities

Digital Quantification of Human Eye Color Highlights Genetic Association of Three New Loci

Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits