Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel

Background

TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.

Experimental Design

Each patient was randomly assigned to treatment with epirubicin 90 mg/m² (n = 109) or paclitaxel 200 mg/m² (n = 114) every 3rd week as monotherapy for 4–6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy.

Principal Findings

While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p>0.5).

Conclusion

TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy.     

Liver concentrations of copper, cobalt, and selenium in wild Norwegian red deer (Cervus elaphus)

Liver samples from 245 wild red deer (Cervus elaphus) collected during the licensed hunting season in 2001 from five different locations in western Norway were analyzed for copper (Cu), cobalt (Co), and selenium (Se). The associations between these trace elements and geographical location, age group, and sex were studied. The median (and range of) liver concentrations (microg/g wet weight) for all the examined deer were: Cu 20 (1.7-103), Co 0.08 (<0.01-0.18), and Se 0.09 (0.04-1.0). The results indicate a generally low status of Cu and Se. In total, 15 (6%) red deer had deficient Cu levels (< 4 (microg/g). For all three elements, the liver concentrations showed a significant geographic variation. The geographic difference was most distinct for Cu. The lowest median Cu concentration was found in deer from the island Hitra, where 13% of the animals had deficient Cu levels. Significant differences between age groups were found for all elements, and generally, the adults (> or =2.5 yr) had the highest levels. No significant sex differences within the various age groups were found, with three exceptions: female calves and adults had significantly higher Co levels than male deer, and adult males had significantly higher Se levels than adult females. The Cu and Se status of wild red deer in parts of Norway is low; however, the significance of this needs to be explored further.     

Malignant catarrhal fever in free-ranging cervids associated with OvHV-2 and CpHV-2 DNA

Pathologic lesions were summarized in 18 free-ranging cervids (15 moose [Alces alces], two roe deer [Capreolus capreolus], and one red deer [Cervus elaphus]) diagnosed with malignant catarrhal fever (MCF) after examination at the National Veterinary Institute, Oslo 1982-2005. Eye lesions (conjunctivitis, corneal opacity, fibrin clots in the anterior eye chamber) were the most frequent gross finding. Erosive-ulcerative mucosal lesions in the nose and mouth were also commonly found. Histopathology revealed a nonpurulent vasculitis and perivasculitis in the central nervous system (CNS) typical of MCF in 16 of the cases. The diagnosis in the remaining two animals was based upon histologic eye lesions consistent with MCF (CNS not available for examination). Polymerase chain reaction was run on samples from 15 individuals for evidence of MCF-virus DNA, and ovine herpesvirus-2 (OvHV-2) DNA was detected in five moose, one roe deer, and one red deer, and caprine herpesvirus-2 (CpHV-2) DNA was detected in two moose and one roe deer. Sera from 1,000 free-ranging cervids were tested for specific antibodies to MCF-associated viruses (MCFV) by competitive inhibition enzyme-linked immunosorbent assay. The seroprevalences were: red deer 5%, reindeer (Rangifer tarandus) 4%, roe deer 2%, and moose 0.4% (n = 250 for all four species). The results indicate that sheep and goat MCFV may cause serious disease in wild moose, roe deer, and red deer. The seropositive cervids most likely represent individuals infected with either OvHV-2 or CpHV-2, but may also reflect infections with other related MCFV.     

Obesity-Susceptibility Loci and Their Influence on Adiposity-Related Traits in Transition from Adolescence to Adulthood - The HUNT Study

Introduction

Obesity-susceptibility loci have been related to adiposity traits in adults and may affect body fat estimates in adolescence. There are indications that different sets of obesity-susceptibility loci influence level of and change in obesity-related traits from adolescence to adulthood.

Objectives

To investigate whether previously reported obesity-susceptible loci in adults influence adiposity traits in adolescence and change in BMI and waist circumference (WC) from adolescence into young adulthood. We also examined whether physical activity modifies the effects of these genetic loci on adiposity-related traits.

Methods

Nine obesity-susceptibility variants were genotyped in 1 643 adolescents (13–19 years old) from the HUNT study, Norway, who were followed-up into young adulthood. Lifestyle was assessed using questionnaires and anthropometric measurements were taken. The effects of genetic variants individually and combined in a genetic predisposition score (GPS) on obesity-related traits were studied cross-sectionally and longitudinally. A modifying effect of physical activity was tested.

Results

The GPS was significantly associated to BMI (B: 0.046 SD/allele [0.020, 0.073], p = 0.001) in adolescence and in young adulthood (B: 0.041 SD/allele [0.015, 0.067], p = 0.002) as it was to waist circumference (WC). The GPS was not associated to change in BMI (p = 0.762) or WC (p = 0.726). We found no significant interaction effect between the GPS and physical activity.

Conclusions

Our observations suggest that obesity-susceptibility loci established in adults affect BMI and WC already in adolescence. However, an association with change in adiposity-related traits from adolescence to adulthood could not be verified for these loci. Neither could an attenuating effect of physical activity on the association between the obesity-susceptibility genes and body fat estimates be revealed.     

DHA induces ER stress and growth arrest in human colon cancer cells: associations with cholesterol and calcium homeostasis

Polyunsaturated fatty acids (PUFAs) are normal constituents of the diet, but have properties different from other fatty acids (e.g., through generation of signaling molecules). N-3 PUFAs reduce cancer cell growth, but no unified mechanism has been identified. We show that docosahexaenoic acid (DHA; 22:6 n-3) causes extensive changes in gene expression patterns at mRNA level in the colon cancer cell line SW620. Early changes include unfolded protein response (UPR) and increased levels of phosphorylated eIF2alpha as verified at protein level. The latter is considered a hallmark of endoplasmic reticulum (ER) stress and is abundantly present already after 3 h. It may coordinate many of the downstream changes observed, including signaling pathways for cell cycle arrest/apoptosis, calcium homeostasis, cholesterol metabolism, ubiquitination, and proteasomal degradation. Also, eicosapentaenoic acid (EPA), but not oleic acid (OA), induced key mediators of ER stress and UPR at protein level. Accumulation of esterified cholesterol was not compensated for by increased total levels of cholesterol, and mRNAs for cholesterol biosynthesis as well as de novo synthesis of cholesterol were reduced. These results suggest that cytotoxic effects of DHA are associated with signaling pathways involving lipid metabolism and ER stress.     

The gastrointestinal tract of Adélie penguins – morphology and function

The aim of this study was to provide data on the morphology of the gastrointestinal tract of Adélie penguins (Pygoscelis adeliae). It was found to consist of a long oesophagus, a two-chambered stomach, a small intestine measuring only 5.22body length, two rudimentary caeca and a short colon, typical of carnivorous birds. The stomach comprised a glandular proventriculus and a muscular gizzard that frequently contained grit. An acidic pH was recorded in both chambers. Ultrastructural studies of the small intestinal mucosal membrane revealed epithelial cells with elongated, irregular microvilli and high affinity for toluidine blue, absorptive intestinal epithelial cells and goblet cells. Numerous large lymphocyte-like cells were observed close to the brush border of the epithelium, and empty spaces on the epithelial surface reflected normal cell loss in the small intestine. The rudimentary caeca and colon provide relatively little volume and time for symbiotic bacteria to aid the digestion of crustacean chitin.     

An Integrated Understanding of the Rapid Metabolic Benefits of a Carbohydrate-Restricted Diet on Hepatic Steatosis in Humans

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Conversion efficiency of bank vole prion protein in vitro is determined by residues 155 and 170, but does not correlate with the high susceptibility of bank voles to sheep scrapie in vivo

The misfolded infectious isoform of the prion protein (PrP(Sc)) is thought to replicate in an autocatalytic manner by converting the cellular form (PrP(C)) into its pathogenic folding variant. The similarity in the amino acid sequence of PrP(C) and PrP(Sc) influences the conversion efficiency and is considered as the major determinant for the species barrier. We performed in vitro conversion reactions on wild-type and mutated PrP(C) to determine the role of the primary sequence for the high susceptibility of bank voles to scrapie. Different conversion efficiencies obtained with bank vole and mouse PrP(C) in reactions with several prion strains were due to differences at amino acid residues 155 and 170. However, the conversion efficiencies obtained with mouse and vole PrP(C) in reactions with sheep scrapie did not correlate with the susceptibility of the respective species to this prion strain. This discrepancy between in vitro and in vivo data may indicate that at least in the case of scrapie transmission to bank voles additional host factors can strongly modulate the species barrier. Furthermore, in vitro conversion reactions with different prion strains revealed that the degree of alteration of the conversion efficiency induced by amino acid exchanges was varying according to the prion strain. These results support the assumption that the repertoire of conformations adopted by a certain PrP(C) primary sequence is decisive for its convertibility to the strain-specific PrP(Sc) conformation.