The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (P_{HLA-A-aa-site-62} = 7.4×10⁻²⁹; P _{HLA-B-aa-site-116} = 6.5×10⁻¹⁹; P _{HLA-C-aa-site-156} = 6.8×10⁻⁸ respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.     

Influence of different CLA isomers on insulin resistance and adipocytokines in pre-diabetic, middle-aged men with PPARγ2 Pro12Ala polymorphism

Conjugated linoleic acids (CLAs) are natural PPARγ ligands, which showed conflicting effects on metabolism in humans. We examined metabolic effects of different isomers of CLA in subjects with PPARγ2 Pro12Ala polymorphisms. A total of 35 men underwent four intervention periods in a crossover study design: subjects with either genotypes received c9, t11 CLA or t10, c12 CLA, a commercially available 1:1 mix of both isomers or reference oil (linoleic acid (LA)). Adipocytokines, insulin, glucose and triglycerides were assessed in the fasting state and after a standardized mixed meal. Across all genotypes, there was a significant (p = 0.025) CLA treatment effect upon postprandial (pp) HOMA-IR values, with c9, t11 CLA and CLA isomer mix improving, but t10, c12 CLA isomer worsening. In Ala12Ala subjects, the t10, c12 isomer caused weight gain (p = 0.03) and tended to increase postprandial insulin levels (p = 0.05). In Pro12Pro subjects, t10, c12 resulted in reduction in waist circumference (p = 0.03). The comparison of the different genotype groups revealed statistically different changes in fasting and postprandial insulin, HOMA-IR and leptin after intervention. c9, t11 CLA and the commercial CLA mix showed beneficial effects on insulin sensitivity compared with LA, while t10, c12 CLA adversely affects body weight and insulin sensitivity in different PPAR genotypes. CLA isomers have different effects on metabolism in Ala and Pro carriers.     

Extreme Telomere Length Dimorphism in the Tasmanian Devil and Related Marsupials Suggests Parental Control of Telomere Length

Telomeres, specialised structures that protect chromosome ends, play a critical role in preserving chromosome integrity. Telomere dynamics in the Tasmanian devil (Sarcophilus harrisii) are of particular interest in light of the emergence of devil facial tumour disease (DFTD), a transmissible malignancy that causes rapid mortality and threatens the species with extinction. We used fluorescent in situ hybridisation to investigate telomere length in DFTD cells, in healthy Tasmanian devils and in four closely related marsupial species. Here we report that animals in the Order Dasyuromorphia have chromosomes characterised by striking telomere length dimorphism between homologues. Findings in sex chromosomes suggest that telomere length dimorphism may be regulated by events in the parental germlines. Long telomeres on the Y chromosome imply that telomere lengthening occurs during spermatogenesis, whereas telomere diminution occurs during oogenesis. Although found in several somatic cell tissue types, telomere length dimorphism was not found in DFTD cancer cells, which are characterised by uniformly short telomeres. This is, to our knowledge, the first report of naturally occurring telomere length dimorphism in any species and suggests a novel strategy of telomere length control. Comparative studies in five distantly related marsupials and a monotreme indicate that telomere dimorphism evolved at least 50 million years ago.     

Parental Acceptance of HPV Vaccine in Peru: A Decision Framework

Objective and Method

Cervical cancer is the third most common cancer affecting women worldwide and it is an important cause of death, especially in developing countries. Cervical cancer is caused by human papillomavirus (HPV) and can be prevented by HPV vaccine. The challenge is to expand vaccine availability to countries where it is most needed. In 2008 Peru’s Ministry of Health implemented a demonstration project involving 5^th grade girls in primary schools in the Piura region. We designed and conducted a qualitative study of the decision-making process among parents of girls, and developed a conceptual model describing the process of HPV vaccine acceptance.

Results

We found a nonlinear HPV decision-making process that evolved over time. Initially, the vaccine’s newness, the requirement of written consent, and provision of information were important. If information was sufficient and provided by credible sources, many parents accepted the vaccine. Later, after obtaining additional information from teachers, health personnel, and other trusted sources, more parents accepted vaccination. An understanding of the issues surrounding the vaccine developed, parents overcome fears and rumors, and engaged in family negotiations–including hearing the girl’s voice in the decision-making process. The concept of prevention (cancer as danger, future health, and trust in vaccines) combined with pragmatic factors (no cost, available at school) and the credibility of the offer (information in the media, recommendation of respected authority figure) were central to motivations that led parents to decide to vaccinate their daughters. A lack of confidence in the health system was the primary inhibitor of vaccine acceptance.

Conclusions

Health personnel and teachers are credible sources of information and can provide important support to HPV vaccination campaigns.     

Clock gene variation in Tachycineta swallows

Many animals use photoperiod cues to synchronize reproduction with environmental conditions and thereby improve their reproductive success. The circadian clock, which creates endogenous behavioral and physiological rhythms typically entrained to photoperiod, is well characterized at the molecular level. Recent work provided evidence for an association between Clock poly-Q length polymorphism and latitude and, within a population, an association with the date of laying and the length of the incubation period. Despite relatively high overall breeding synchrony, the timing of clutch initiation has a large impact on the fitness of swallows in the genus Tachycineta. We compared length polymorphism in the Clock poly-Q region among five populations from five different Tachycineta species that breed across a hemisphere-wide latitudinal gradient (Fig. 1). Clock poly-Q variation was not associated with latitude; however, there was an association between Clock poly-Q allele diversity and the degree of clutch size decline within breeding seasons. We did not find evidence for an association between Clock poly-Q variation and date of clutch initiation in for any of the five Tachycineta species, nor did we found a relationship between incubation duration and Clock genotype. Thus, there is no general association between latitude, breeding phenology, and Clock polymorphism in this clade of closely related birds.Figure 1Photos of Tachycineta swallows that were used in this study: A) T. bicolor from Ithaca, New York, B) T. leucorrhoa from Chascomús, Argentina, C) T. albilinea from Hill Bank, Belize, D) T. meyeni from Puerto Varas, Chile, and E) T. thalassina from Mono Lake, California, Photographers: B: Valentina Ferretti; A, C-E: David Winkler.     

Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance

MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.     

Multivariate statistical analysis of distribution of deep-water gorgonian corals in relation to seabed topography on the norwegian margin

Investigating the relationship between deep-water coral distribution and seabed topography is important for understanding the terrain habitat selection of these species and for the development of predictive habitat models. In this study, the distribution of the deep-water gorgonians, Paragorgia arborea and Primnoa resedaeformis, in relation to terrain variables at multiple scales of 30 m, 90 m and 170 m were investigated at Røst Reef, Traena Reef and Sotbakken Reef on the Norwegian margin, with Ecological Niche Factor Analysis applied. To date, there have been few published studies investigating this aspect of gorgonian distribution. A similar correlation between the distribution of P. arborea and P. resedaeformis and each particular terrain variable was found at each study site, but the strength of the correlation between each variable and distribution differed by reef. The terrain variables of bathymetric position index (BPI) and curvature at analysis scales of 90 m or 170 m were most strongly linked to the distribution of both species at the three geographically distinct study sites. Both gorgonian species tended to inhabit local topographic highs across all three sites, particularly at Sotbakken Reef and Traena Reef, with both species observed almost exclusively on such topographic highs. The tendency for observed P. arborea to inhabit ridge crests at Røst Reef was much greater than was indicated for P. resedaeformis. This investigation identifies the terrain variables which most closely correlate with distribution of these two gorgonian species, and analyzes their terrain habitat selection; further development of predictive habitat models may be considered essential for effective management of these species.     

Individual exposure to NO2 in relation to spatial and temporal exposure indices in Stockholm, Sweden: the INDEX study

Epidemiology studies of health effects from air pollution, as well as impact assessments, typically rely on ambient monitoring data or modelled residential levels. The relationship between these and personal exposure is not clear. To investigate personal exposure to NO(2) and its relationship with other exposure metrics and time-activity patterns in a randomly selected sample of healthy working adults (20-59 years) living and working in Stockholm. Personal exposure to NO(2) was measured with diffusive samplers in sample of 247 individuals. The 7-day average personal exposure was 14.3 μg/m(3) and 12.5 μg/m(3) for the study population and the inhabitants of Stockholm County, respectively. The personal exposure was significantly lower than the urban background level (20.3 μg/m(3)). In the univariate analyses the most influential determinants of individual exposure were long-term high-resolution dispersion-modelled levels of NO(2) outdoors at home and work, and concurrent NO(2) levels measured at a rural location, difference between those measured at an urban background and rural location and difference between those measured in busy street and at an urban background location, explaining 20, 16, 1, 2 and 4% (R(2)) of the 7-day personal NO(2) variation, respectively. A regression model including these variables explained 38% of the variation in personal NO(2) exposure. We found a small improvement by adding time-activity variables to the latter model (R(2)?=?0.44). The results adds credibility primarily to long-term epidemiology studies that utilise long-term indices of NO(2) exposure at home or work, but also indicates that such studies may still suffer from exposure misclassification and dilution of any true effects. In contrast, urban background levels of NO(2) are poorly related to individual exposure.     

The impact of acute psychosocial stress on magnetoencephalographic correlates of emotional attention and exogenous visual attention

Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST-like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short-lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite.