A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya)

The 1950s excavations by Charles McBurney in the Haua Fteah, a large karstic cave on the coast of northeast Libya, revealed a deep sequence of human occupation. Most subsequent research on North African prehistory refers to his discoveries and interpretations, but the chronology of its archaeological and geological sequences has been based on very early age determinations. This paper reports on the initial results of a comprehensive multi-method dating program undertaken as part of new work at the site, involving radiocarbon dating of charcoal, land snails and marine shell, cryptotephra investigations, optically stimulated luminescence (OSL) dating of sediments, and electron spin resonance (ESR) dating of tooth enamel. The dating samples were collected from the newly exposed and cleaned faces of the upper 7.5m of the ~14.0m-deep McBurney trench, which contain six of the seven major cultural phases that he identified. Despite problems of sediment transport and reworking, using a Bayesian statistical model the new dating program establishes a robust framework for the five major lithostratigraphic units identified in the stratigraphic succession, and for the major cultural units. The age of two anatomically modern human mandibles found by McBurney in Layer XXXIII near the base of his Levalloiso-Mousterian phase can now be estimated to between 73 and 65ka (thousands of years ago) at the 95.4% confidence level, within Marine Isotope Stage (MIS) 4. McBurney's Layer XXV, associated with Upper Palaeolithic Dabban blade industries, has a clear stratigraphic relationship with Campanian Ignimbrite tephra. Microlithic Oranian technologies developed following the climax of the Last Glacial Maximum and the more microlithic Capsian in the Younger Dryas. Neolithic pottery and perhaps domestic livestock were used in the cave from the mid Holocene but there is no certain evidence for plant cultivation until the Graeco-Roman period. © 2013 Elsevier Ltd.

An Update of the Rules for Pyranoside Sulfonate Displacement

The original 1967 Richardson–Hough rules for predicting SN2 displacement viability in carbohydrate sulfonate derivatives with external nucleophiles have now been updated. Not only do the original rules still hold, but the newly updated rules rationalize why O-triflates (trifluoromethanesulfonate esters) frequently allow many seemingly “disallowed” pyranosidic nucleophilic substitutions to proceed. The new guidelines, which are based on three decades of experimental evidence, allow the feasibility of many pyranosidic O-triflate SN2 displacements to be gauged beforehand.

Connectivity and Physical Activity: Using Footpath Networks to Measure the Walkability of Built Environments

There is now a strong body of research that suggests that the form of the built environment can influence levels of physical activity, leading to an increasing interest in incorporating health objectives into spatial planning and regeneration policies and projects. There have been a number of strands to this research, one of which has sought to develop “objective” measurements of the built environment using Geographic Information Science (GIS) involving measures of connectivity and proximity to compare the relative “walkability” of different neighbourhoods. The development of the “walkability index” (e.g. Leslie et al 2007, Frank et al 2010) has become a popular indicator of spatial distribution of those features of the built environment that are considered to have the greatest positive influence on levels of physical activity. The success of this measure is built on its ability to succinctly capture built environment correlates of physical activity using routinely available spatial data, which includes using road centre lines as a basis of a proxy for connectivity.

This paper discusses two key aspects of the walkability index. First, it follows the suggestion of Chin et al (2008) that the use of a footpath network (where available), rather than road centre lines, may be far more effective in evaluating walkability. This may be particularly important for assessing changes in walkability arising from pedestrian-focused infrastructure projects, such as greenways. Second, the paper explores the implication of this for how connectivity can be measured. The paper takes six different measures of connectivity and first analyses the relationships between them and then tests their correlation with actual levels of physical activity of local residents in Belfast, Northern Ireland. The analysis finds that the best measurements appear to be intersection density and metric reach and uses this finding to discuss the implications of this for developing tools that may better support decision-making in spatial planning.

Supervised walking in comparison with fitness training for chronic back pain in physiotherapy: results of the SWIFT single-blinded randomized controlled trial (ISRCTN17592092)

Effectiveness of brief/minimal contact self-activation interventions that encourage participation in physical activity (PA) for chronic low back pain (CLBP >12 weeks) is unproven. The primary objective of this assessor-blinded randomized controlled trial was to investigate the difference between an individualized walking programme (WP), group exercise class (EC), and usual physiotherapy (UP, control) in mean change in functional disability at 6 months. A sample of 246 participants with CLBP aged 18 to 65 years (79 men and 167 women; mean age ± SD: 45.4 ± 11.4 years) were recruited from 5 outpatient physiotherapy departments in Dublin, Ireland. Consenting participants completed self-report measures of functional disability, pain, quality of life, psychosocial beliefs, and PA were randomly allocated to the WP (n = 82), EC (n = 83), or UP (n = 81) and followed up at 3 (81%; n = 200), 6 (80.1%; n = 197), and 12 months (76.4%; n = 188). Cost diaries were completed at all follow-ups. An intention-to-treat analysis using a mixed between-within repeated-measures analysis of covariance found significant improvements over time on the Oswestry Disability Index (Primary Outcome), the Numerical Rating Scale, Fear Avoidance-PA scale, and the EuroQol EQ-5D-3L Weighted Health Index (P < 0.05), but no significant between-group differences and small between-group effect sizes (WP: mean difference at 6 months, 6.89 Oswestry Disability Index points, 95% confidence interval [CI] -3.64 to -10.15; EC: -5.91, CI: -2.68 to -9.15; UP: -5.09, CI: -1.93 to -8.24). The WP had the lowest mean costs and the highest level of adherence. Supervised walking provides an effective alternative to current forms of CLBP management.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.

METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.

RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)).

CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Rules and Stereoelectronic Guidelines for the Anionic Nucleophilic Displacement of Furanoside and Furanose O-sulfonates

Rules for predicting anionic S_N2 displacement viability in furanose and furanoside sulfonates are presented

Age-specific risk factor profiles of adenocarcinomas of the esophagus: a pooled analysis from the international BEACON consortium

Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people, however the etiology of these cancers is poorly understood. We therefore investigated associations of body- mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux, and use of non-steroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients, and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50–59, 60–69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR=8.06, 95%CI: 4.52, 14.37; Peffect modification=0.01) and BMI (ORBMI ≥30 vs. <25=4.19, 95%CI: 2.23, 7.87; Peffect modification=0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.

Recent Developments in the Analysis of the Black Mat Layer and Cosmic Impact at 12.8ka

Recent analyses of sediment samples from "black mat" sites in South America and Europe support previous interpretations of an ET impact event that reversed the Late Glacial demise of LGM ice during the Bølling Allerød warming, resulting in a resurgence of ice termed the Younger Dryas (YD) cooling episode. The breakup or impact of a cosmic vehicle at the YD boundary coincides with the onset of a 1-kyr long interval of glacial resurgence, one of the most studied events of the Late Pleistocene. New analytical databases reveal a corpus of data indicating that the cosmic impact was a real event, most possibly a cosmic airburst from Earth's encounter with the Taurid Complex comet or unknown asteroid, an event that led to cosmic fragments exploding interhemispherically over widely dispersed areas, including the northern Andes of Venezuela and the Alps on the Italian/French frontier. While the databases in the two areas differ somewhat, the overall interpretation is that microtextural evidence in weathering rinds and in sands of associated paleosols and glaciofluvial deposits carry undeniable attributes of melted glassy carbon and Fe spherules, planar deformation features, shock-melted and contorted quartz, occasional transition and platinum metals, and brecciated and impacted minerals of diverse lithologies. In concert with other black mat localities in the Western USA, the Netherlands, coastal France, Syria, Central Asia, Peru, Argentina and Mexico, it appears that a widespread cosmic impact by an asteroid or comet is responsible for deposition of the black mat at the onset of the YD glacial event. Whether or not the impact caused a 1-kyr interval of glacial climate depends upon whether or not the Earth had multiple centuries-long episodic encounters with the Taurid Complex or asteroid remnants; impact-related changes in microclimates sustained climatic forcing sufficient to maintain positive mass balances in the reformed ice; and/or inertia in the Atlantic thermohaline circulation system persisted for 1kyr. 

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. 

Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. 

Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. 

Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. 

Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus.

Polybius’ ‘previous landslide’: Proof that Hannibal’s invasion route crossed the col de la traversette

Both Polybius and Livy described a landslide/landslip that blocked the Punic Army’s exfiltration from a high col on the water divide in the Western Alps. The landslide, more aptly termed rockfall, has been a source of contention amongst classicists for centuries despite the fact that only two cols—Clapier and Traversette—exhibit rockfall debris on the lee side of the Alps. While the Clapier rockfall is too small and too young to have provided blockage, the Traversette debris is nearly as Polybius described it when he retraced the invasion route some 60 years after the event. His ‘two-tier’ description of the deposit, a doublet of younger and older rock rubble, including measurements of width and volume are close to modern measurements and prove that he knew, in advance, the route Hannibal had followed. It would take a practiced eye to correctly identify the stratigraphic complexity inherent in the Traversette Rockfall. Here we present weathering ratios, soil stratigraphic, mineral, chemical and microbiological evidence in support of Polybius’ observations as a considerable background database for future geoarchaeological exploration.

Limited range coverage problems

Tal como o título indica, esta tese estuda problemas de cobertura com alcance limitado. Dado um conjunto de antenas (ou qualquer outro dispositivo sem fios capaz de receber ou transmitir sinais), o objectivo deste trabalho é calcular o alcance mínimo das antenas de modo a que estas cubram completamente um caminho entre dois pontos numa região. Um caminho que apresente estas características é um itinerário seguro. A definição de cobertura é variável e depende da aplicação a que se destina. No caso de situações críticas como o controlo de fogos ou cenários militares, a definição de cobertura recorre à utilização de mais do que uma antena para aumentar a eficácia deste tipo de vigilância. No entanto, o alcance das antenas deverá ser minimizado de modo a manter a vigilância activa o maior tempo possível. Consequentemente, esta tese está centrada na resolução deste problema de optimização e na obtenção de uma solução particular para cada caso. Embora este problema de optimização tenha sido investigado como um problema de cobertura, é possível estabelecer um paralelismo entre problemas de cobertura e problemas de iluminação e vigilância, que são habitualmente designados como problemas da Galeria de Arte. Para converter um problema de cobertura num de iluminação basta considerar um conjunto de luzes em vez de um conjunto de antenas e submetê-lo a restrições idênticas. O principal tema do conjunto de problemas da Galeria de Arte abordado nesta tese é a 1-boa iluminação. Diz-se que um objecto está 1-bem iluminado por um conjunto de luzes se o invólucro convexo destas contém o objecto, tornando assim este conceito num tipo de iluminação de qualidade. O objectivo desta parte do trabalho é então minimizar o alcance das luzes de modo a manter uma iluminação de qualidade. São também apresentadas duas variantes da 1-boa iluminação: a iluminação ortogonal e a boa !-iluminação. Esta última tem aplicações em problemas de profundidade e visualização de dados, temas que são frequentemente abordados em estatística. A resolução destes problemas usando o diagrama de Voronoi Envolvente (uma variante do diagrama de Voronoi adaptada a problemas de boa iluminação) é também proposta nesta tese.

Geometric optimization on visibility problems: metaheuristic and exact solutions

Os problemas de visibilidade têm diversas aplicações a situações reais. Entre os mais conhecidos, e exaustivamente estudados, estão os que envolvem os conceitos de vigilância e ocultação em estruturas geométricas (problemas de vigilância e ocultação). Neste trabalho são estudados problemas de visibilidade em estruturas geométricas conhecidas como polígonos, uma vez que estes podem representar, de forma apropriada, muitos dos objectos reais e são de fácil manipulação computacional. O objectivo dos problemas de vigilância é a determinação do número mínimo de posições para a colocação de dispositivos num dado polígono, de modo a que estes dispositivos consigam “ver” a totalidade do polígono. Por outro lado, o objectivo dos problemas de ocultação é a determinação do número máximo de posições num dado polígono, de modo a que quaisquer duas posições não se consigam “ver”. Infelizmente, a maior parte dos problemas de visibilidade em polígonos são NP-difíceis, o que dá origem a duas linhas de investigação: o desenvolvimento de algoritmos que estabelecem soluções aproximadas e a determinação de soluções exactas para classes especiais de polígonos. Atendendo a estas duas linhas de investigação, o trabalho é dividido em duas partes. Na primeira parte são propostos algoritmos aproximados, baseados essencialmente em metaheurísticas e metaheurísticas híbridas, para resolver alguns problemas de visibilidade, tanto em polígonos arbitrários como ortogonais. Os problemas estudados são os seguintes: “Maximum Hidden Vertex Set problem”, “Minimum Vertex Guard Set problem”, “Minimum Vertex Floodlight Set problem” e “Minimum Vertex k-Modem Set problem”. São também desenvolvidos métodos que permitem determinar a razão de aproximação dos algoritmos propostos. Para cada problema são implementados os algoritmos apresentados e é realizado um estudo estatístico para estabelecer qual o algoritmo que obtém as melhores soluções num tempo razoável. Este estudo permite concluir que as metaheurísticas híbridas são, em geral, as melhores estratégias para resolver os problemas de visibilidade estudados. Na segunda parte desta dissertação são abordados os problemas “Minimum Vertex Guard Set”, “Maximum Hidden Set” e “Maximum Hidden Vertex Set”, onde são identificadas e estudadas algumas classes de polígonos para as quais são determinadas soluções exactas e/ou limites combinatórios.