Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Background: There is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.

Methods: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.

Results: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.

Conclusions: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.

Physical Activity, Gender, Weight Status, and Wellbeing in 9- to 11-Year-Old Children: A Cross-Sectional Survey

Background: The aim of this study was to examine the relationship between physical activity and wellbeing in children, and to further explore the extent to which this may vary by gender and weight status. Method: A representative sample of 1424 9- to 11-year-olds completed a self-report measure of physical activity, the Child Health and Illness Profile, KIDSCREEN, and a self-esteem scale. Body Mass Index (BMI) measurements were also obtained. Results: 24% of children achieved the recommended level of 60 minutes of moderate-tovigorous intensity physical activity (MVPA) per day, with more boys than girls achieving this level. Children achieving the recommended level of MVPA scored significantly higher on measures of the Child Health and Illness Profile (F(5, 1354) = 5.03; P < .001), KIDSCREEN (F(3, 1298) = 4.68; P = .003), and self-esteem (F(1,1271) = 18.73; P = .003) than less active children although the effect sizes were small (ηp2 ≈ .01). Substantial gender differences in wellbeing were found reflecting gender specific behaviors and socialization. Weight status had negligible influence on wellbeing. Conclusions: Children who meet the recommended guidelines of MVPA were more likely to have better wellbeing. When attempting to raise children’s physical activity levels consideration should be given to the specific relationships between wellbeing and physical activity.

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

Climate change response in Europe: What's the reality? Analysis of adaptation and mitigation plans from 200 urban areas in 11 countries

Urban areas are pivotal to global adaptation and mitigation efforts. But how do cities actually perform in terms of climate change response? This study sheds light on the state of urban climate change adaptation and mitigation planning across Europe. Europe is an excellent test case given its advanced environmental policies and high urbanization. We performed a detailed analysis of 200 large and medium-sized cities across 11 European countries and analysed the cities' climate change adaptation and mitigation plans. We investigate the regional distribution of plans, adaptation and mitigation foci and the extent to which planned greenhouse gas (GHG) reductions contribute to national and international climate objectives. To our knowledge, it is the first study of its kind as it does not rely on self-assessment (questionnaires or social surveys). Our results show that 35 % of European cities studied have no dedicated mitigation plan and 72 % have no adaptation plan. No city has an adaptation plan without a mitigation plan. One quarter of the cities have both an adaptation and a mitigation plan and set quantitative GHG reduction targets, but those vary extensively in scope and ambition. Furthermore, we show that if the planned actions within cities are nationally representative the 11 countries investigated would achieve a 37 % reduction in GHG emissions by 2050, translating into a 27 % reduction in GHG emissions for the EU as a whole. However, the actions would often be insufficient to reach national targets and fall short of the 80 % reduction in GHG emissions recommended to avoid global mean temperature rising by 2 °C above pre-industrial levels. © 2013 Springer Science+Business Media Dordrecht.

Tephrochronology and the extended intimate (integration of ice‐core, marine and terrestrial records) event stratigraphy 8-128kab2k

The comparison of palaeoclimate records on their own independent timescales is central to the work of the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) network. For the North Atlantic region, an event stratigraphy has been established from the high-precision Greenland ice-core records and the integrated GICC05 chronology. This stratotype provides a palaeoclimate signal to which the timing and nature of palaeoenvironmental change recorded in marine and terrestrial archives can be compared. To facilitate this wider comparison, without assuming synchroneity of climatic change/proxy response, INTIMATE has also focussed on the development of tools to achieve this. In particular the use of time-parallel marker horizons e.g. tephra layers (volcanic ash). Coupled with the recent temporal extension of the Greenland stratotype, as part of this special issue, we present an updated INTIMATE event stratigraphy highlighting key tephra horizons used for correlation across Europe and the North Atlantic. We discuss the advantages of such an approach, and the key challenges for the further integration of terrestrial palaeoenvironmental records with those from ice cores and the marine realm.

Child Poverty in Northern Ireland: Results from the Poverty and Social Exclusion Study

- There is general agreement that the measurement of child poverty is based on both low income and deprivation.

- Adjusting incomes for different household types, measuring before or after housing costs, and the selection of deprivation items all have an impact on poverty rates.

- The consensual poverty method, which takes account of what the population considers to be basic necessities, is described. The study found a high level of agreement on the basic necessities for children.

- The study found that only a few children lacked very basic necessities such as three meals a day and adequate clothing, but a third of all children (150,000) were deprived of an annual holiday and 75,000 children are growing up in cold and damp homes.

- Overall, the study found that 24% or 106,000 children are living in low income households and are deprived of four or more items.

- The study found those who had a ‘high experience’ of the conflict were significantly more deprived than those with no conflict experience and that a fifth of all children are living with an adult/s who have ‘high experience’.

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs () across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of  from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of  from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of  despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

S21 Culture Independent Identification Of Bacterial Communities In The Respiratory Tract Of Patients With Copd, Healthy Non-smokers And Healthy Smokers

Introduction and aims: The role bacteria play in the development and progression of Chronic Obstructive Pulmonary Disease (COPD) is unclear. We used culture-independent methods to describe differences and/or similarities in microbial communities in the lower airways of patients with COPD, healthy non-smokers and smokers.

Methods: Bronchial wash samples were collected from patients with COPD (GOLD 1–3; n = 18), healthy non-smokers (HV; n = 11) and healthy smokers (HS; n = 8). Samples were processed using the Illumina MiSeq platform. The Shannon-Wiener Index (SW) of diversity, lung obstruction (FEV1/FVC ratio) and ordination by Non-Metric Multidimensional Scaling (NMDS) on Bray-Curtis dissimilarity indices were analysed to evaluate how samples were related. Principal component analysis (PCA) was performed to assess the effect specific taxa had within each cohort. Characteristics of each cohort are shown in Table 1.

Results: There was no difference in taxa richness between cohorts (range: 69–71; p = 0.954). Diversity (SW Index) was significantly lower in COPD samples compared to samples from HV and HS (p = 0.009 and p = 0.033, respectively). There was no significant difference between HV and HS (p = 0.186). The FEV1/FVC ratio was significantly lower for COPD compared to HV (p = 9*10–8) and HS (p = 2*10–6), respectively. NMDS analysis showed that communities belonging to either of the healthy groups were more similar to each other than they were to samples belonging to the COPD group. PCA analysis showed that members of Streptococcus sp. and Haemophilus sp. had the largest effect on the variance explained in COPD. In HS, Haemophilus sp., Fusobaterium sp., Actinomyces sp., Prevotella sp. and Veillonella sp. had the largest effect on the variance explained, while in HV Neisseria sp., Porphyromonas sp., Actinomyces sp., Atopobium sp., Prevotella and Veillonella sp. had the largest effect on the variance explained.

Conclusions: The study demonstrates that microbial communities in the lower airways of patients with COPD are significantly different from that seen in healthy comparison groups. Patients with COPD had lower microbial diversity than either of the healthy comparison groups, higher relative abundance of members of Streptococcus sp. and lower relative abundance of a number of key anaerobes.Characteristics

Periodontal Manifestations of Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE) Syndrome in an 11 Year Old Patient

Introduction: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) is an auto inflammatory syndrome caused by an autosomal recessive gene mutation. This very rare syndrome has been reported in only 14 patients worldwide. A number of clinical signs have been reported including joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced childhood lipodystrophy. Further symptoms include recurrent fevers, purpuric skin lesions, periorbital erythema and failure to thrive. This is the first reported case of periodontal manifestations associated with CANDLE syndrome. 
Case Presentation: An 11 year old boy was referred to Cork University Dental School and Hospital with evidence of severe periodontal destruction. The patient’s medical condition was managed in Great Ormond Street Children’s Hospital, London. The patient’s dental management included initial treatment to remove teeth of hopeless prognosis followed by prosthodontic rehabilitation using removable partial dentures. This was followed by further non-surgical periodontal treatment and maintenance. In the long term, the potential definitive restorative options, including dental implants, will be evaluated in discussion with the patient’s medical team.
Conclusion: Periodontitis as a manifestation of systemic disease is one of seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system. A number of systemic diseases have been associated with advanced periodontal destruction including Diabetes Mellitus, Leukaemia and Papillon-Lefevre Syndrome. In the case described, treatment necessitated a multidisciplinary approach with input from medical and dental specialities for a young patient with severe periodontal destruction associated with CANDLE syndrome.