Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

Infection with high-risk types of human papilloma virus (HPV) is currently the best-established prognostic marker for head and neck squamous cell carcinoma (HNSCC), one of the most common and lethal human malignancies worldwide. Clinical trials have been launched to address the concept of treatment de-escalation for HPV-positive HNSCC with the final aim to reduce treatment related toxicity and debilitating long-term impacts on the quality of life. However, HPV-related tumors are mainly restricted to oropharyngeal SCC (OPSCC) and there is an urgent need to establish reliable biomarkers for all patients at high risk for treatment failure. A patient cohort (n = 295) with mainly non-OPSCC (72.9%) and a low prevalence of HPV16-related tumors (8.8%) was analyzed by MassARRAY to determine a previously established prognostic methylation score (MS). Kaplan-Meier revealed a highly significant correlation between a high MS and a favorable survival for OPSCC (P = 0.0004) and for non-OPSCC (P<0.0001), which was confirmed for all HNSCC by multivariate Cox regression models (HR: 9.67, 95% CI [4.61–20.30], P<0.0001). Next, we established a minimal methylation signature score (MMSS), which consists of ten most informative of the originally 62 CpG units used for the MS. The prognostic value of the MMSS was confirmed by Kaplan-Meier analysis for all HNSCC (P<0.0001) and non-OPSCC (P = 0.0002), and was supported by multivariate Cox regression models for all HNSCC (HR: 2.15, 95% CI [1.36–3.41], P = 0.001). In summary, the MS and the MMSS exhibit an excellent performance as prognosticators for survival, which is not limited by the anatomical site, and both could be implemented in future clinical trials.     

Regional differences in prediction models of lung function in Germany

Background

Little is known about the influencing potential of specific characteristics on lung function in different populations. The aim of this analysis was to determine whether lung function determinants differ between subpopulations within Germany and whether prediction equations developed for one subpopulation are also adequate for another subpopulation.

Methods

Within three studies (KORA C, SHIP-I, ECRHS-I) in different areas of Germany 4059 adults performed lung function tests. The available data consisted of forced expiratory volume in one second, forced vital capacity and peak expiratory flow rate. For each study multivariate regression models were developed to predict lung function and Bland-Altman plots were established to evaluate the agreement between predicted and measured values.

Results

The final regression equations for FEV₁ and FVC showed adjusted r-square values between 0.65 and 0.75, and for PEF they were between 0.46 and 0.61. In all studies gender, age, height and pack-years were significant determinants, each with a similar effect size. Regarding other predictors there were some, although not statistically significant, differences between the studies. Bland-Altman plots indicated that the regression models for each individual study adequately predict medium (i.e. normal) but not extremely high or low lung function values in the whole study population.

Conclusions

Simple models with gender, age and height explain a substantial part of lung function variance whereas further determinants add less than 5% to the total explained r-squared, at least for FEV1 and FVC. Thus, for different adult subpopulations of Germany one simple model for each lung function measures is still sufficient.     

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06×10⁻⁶, OR = 0.67 [95% CI 0.57–0.79] for the minor allele T). Three more SNPs showed p < 2.21×10⁻⁵. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n = 564, n = 981 controls, p = 2.07×10⁻³, OR = 0.79 [95% CI 0.67–0.92]), France 1 (n = 433 cases, n = 395 controls, p = 3.73×10⁻³, OR = 0.74 [95% CI 0.60–0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26×10⁻⁴, OR = 0.63 [95% CI 0.50–0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28×10⁻¹³, OR = 0.72 [95% CI 0.65–0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.     

Association between Ambient Temperature and Acute Myocardial Infarction Hospitalisations in Gothenburg,Sweden: 1985–2010

Cardiovascular disease (CVD) is the number one cause of death globally and evidence is steadily increasing on the role of non-traditional risk factors such as meteorology and air pollution. Nevertheless, many research gaps remain, such as the association between these non-traditional risk factors and subtypes of CVD, such as acute myocardial infarction (AMI). The objective of this study was to investigate the association between daily ambient temperature and AMI hospitalisations using a case-crossover design in Gothenburg, Sweden (1985–2010). A secondary analysis was also performed for out-of-hospital ischemic heart disease (IHD) deaths. Susceptible groups by age and sex were explored. The entire year as well as the warm (April−September) and cold periods (October–March) were considered. In total 28 215 AMI hospitalisations (of 22 475 people) and 21 082 out-of-hospital IHD deaths occurred during the 26-year study period. A linear exposure-response corresponding to a 3% and 7% decrease in AMI hospitalisations was observed for an inter-quartile range (IQR) increase in the 2-day cumulative average of temperature during the entire year (11°C) and the warm period (6°C), respectively, with and without adjustment for PM₁₀, NO₂, NO_x or O₃. No heat waves occurred during the warm period. No evidence of an association in the cold period nor any association between temperature and IHD deaths in the entire year, warm or cold periods - with and without adjusting for PM₁₀, NO₂, NO_x or O₃ was found. No susceptible groups, based on age or sex, were identified either. The inverse association between temperature and AMI hospitalisations (entire year and warm period) in Gothenburg is in accordance with the majority of the few other studies that investigated this subtype of CVD.     

Posttraumatic Stress Disorder and Not Depression Is Associated with Shorter Leukocyte Telomere Length: Findings from 3,000 Participants in the Population-Based KORA F4 Study

Background

A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD.

Methods

Data are derived from the population-based KORA F4 study (2006–2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed.

Results

The multiple model revealed a significant association between partial PTSD and TL (beta = −0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = −0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations.

Conclusions

Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging.     

Human-Mediated Dispersal of Seeds by the Airflow of Vehicles

Human-mediated dispersal is known as an important driver of long-distance dispersal for plants but underlying mechanisms have rarely been assessed. Road corridors function as routes of secondary dispersal for many plant species but the extent to which vehicles support this process remains unclear. In this paper we quantify dispersal distances and seed deposition of plant species moved over the ground by the slipstream of passing cars. We exposed marked seeds of four species on a section of road and drove a car along the road at a speed of 48 km/h. By tracking seeds we quantified movement parallel as well as lateral to the road, resulting dispersal kernels, and the effect of repeated vehicle passes. Median distances travelled by seeds along the road were about eight meters for species with wind dispersal morphologies and one meter for species without such adaptations. Airflow created by the car lifted seeds and resulted in longitudinal dispersal. Single seeds reached our maximum measuring distance of 45 m and for some species exceeded distances under primary dispersal. Mathematical models were fit to dispersal kernels. The incremental effect of passing vehicles on longitudinal dispersal decreased with increasing number of passes as seeds accumulated at road verges. We conclude that dispersal by vehicle airflow facilitates seed movement along roads and accumulation of seeds in roadside habitats. Dispersal by vehicle airflow can aid the spread of plant species and thus has wide implications for roadside ecology, invasion biology and nature conservation.     

The Bruchpilot cytomatrix determines the size of the readily releasable pool of synaptic vesicles

Synaptic vesicles (SVs) fuse at a specialized membrane domain called the active zone (AZ), covered by a conserved cytomatrix. How exactly cytomatrix components intersect with SV release remains insufficiently understood. We showed previously that loss of the Drosophila melanogaster ELKS family protein Bruchpilot (BRP) eliminates the cytomatrix (T bar) and declusters Ca²⁺ channels. In this paper, we explored additional functions of the cytomatrix, starting with the biochemical identification of two BRP isoforms. Both isoforms alternated in a circular array and were important for proper T-bar formation. Basal transmission was decreased in isoform-specific mutants, which we attributed to a reduction in the size of the readily releasable pool (RRP) of SVs. We also found a corresponding reduction in the number of SVs docked close to the remaining cytomatrix. We propose that the macromolecular architecture created by the alternating pattern of the BRP isoforms determines the number of Ca²⁺ channel-coupled SV release slots available per AZ and thereby sets the size of the RRP.