Human papillomavirus (HPV) related Oropharynx Cancer in the United Kingdom – An evolution in the understanding of disease aetiology

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3-54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99-1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9-2.2); 2011: 4.1 (95% CI, 4.0-4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV- cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented.</p

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The continent-ocean transition at the Deep Galicia Margin: insights from wide-angle seismic data

Magma-poor rift margins provide the ideal environment in which to study the processes responsible for continental breakup and the transition to seafloor spreading. The Iberia-Newfoundland rifted margin in the North Atlantic Ocean has long been an archetype of such rifted margins, with previous studies of this margin having shaped the current understanding of how rifted margins evolve. The Deep Galicia margin is situated on the Iberia margin and is characterised by continental hyperextension, observed as a complex pattern of faulting, thin continental fault blocks, and the serpentinisation, with local exhumation of mantle peridotites along an interpreted detachment surface known as the S reflector. West of these features, the enigmatic Peridotite Ridge has previously been inferred to delimit the western extent of this continent-ocean transition. This thesis presents a variety of analyses applied to new wide-angle seismic data collected at the Deep Galicia margin in 2013. Travel-time tomography modelling of a 160-km-long wide-angle seismic profile provides new insights into the transition from continental thinning to the onset of oceanic crust. West of the Peridotite Ridge, mantle exhumation is seen to continue over a short distance (&lt; 25 km), before shallow and sparse Moho reflections indicate the earliest formation (&lt; 122 Ma) of an anomalously thin (0.5 – 1.5 km) oceanic crustal layer. This thin oceanic crust is inferred to be underlain by serpentinised mantle peridotite, indicated by low velocity gradients and a smooth transition to mantle velocities. East of the Peridotite Ridge, a combination of travel-time tomography and time-domain full-waveform inversion were used to produce a high resolution P-wave velocity model of the hyperextended continental crust and the underlying mantle, separated by the S reflector. This model is used to interpret previously unidentified faults and crustal blocks in seismic reflection imaging, giving an increased understanding of the fine-scale patterns of deformation. Velocities below the S reflector are shown to vary between 5.5 and 8.0 km s-1, corresponding to peridotite serpentinisation of 70% to 0% (unaltered), respectively. Lower seismic velocities and higher degrees of serpentinisation are coincident with the terminus of normal faulting, and is interpreted to be the result of preferential mantle hydration along such faults. Additionally, analysis of ambient noise recorded during this seismic experiment has been used to determine the phase velocity dispersion of fundamental Rayleigh waves, which were inverted to give estimates of the shear velocity within the hyperextended domain. Shear wave velocities are seen to be 0.94 ± 0.12 km s-1 in the sediments, 2.21 ± 0.36 km s-1 in the upper crust, 3.48 ± 0.36 km s-1 in the lower crust, and 4.25 ± 0.35 km s-1 in the uppermost mantle

Paleo-Fluid Expulsion Influencing Contouritic Drift Formation on the Chatham Rise, New Zealand

The Chatham Rise is located offshore of New Zealand's South Island. Vast areas of the Chatham Rise are covered in circular to elliptical seafloor depressions that appear to be forming through a bathymetrically controlled mechanism, as seafloor depressions 2-5 km in diameter are found in water depths of 800-1100 m. High resolution P-Cable 3D seismic data were acquired in 2013 across one of these depressions. The seafloor depression is interpreted as a mounded contourite. Our data reveal several smaller buried depressions (<20-650 m diameter) beneath the mounded contourite that we interpret as paleo-pockmarks. These pockmarks are underlain by a complex polygonal fault system that deforms strata and an unusual conical feature. We interpret the conical feature as a sediment remobilization structure based on the presence of stratified reflections within the feature, RMS amplitude values and lack of velocity anomaly that would indicate a non-sedimentary origin. The sediment remobilization structure, polygonal faults and paleo-depressions are indicators of past subsurface fluid flow. We hypothesize that the pockmarks provided the necessary topographic roughness for formation of the mounded contourites thus linking fluid expulsion and deposition of contouritic drifts

Resolving the fine-scale velocity structure of continental hyperextension at the Deep Galicia Margin using full-waveform inversion

Continental hyperextension during magma-poor rifting at the Deep Galicia Margin is characterised by a complex pattern of faulting, thin continental fault blocks, and the serpentinisation, with local exhumation, of mantle peridotites along the S-reflector, interpreted as a detachment surface. In order to understand fully the evolution of these features, it is important to image seismically the structure and to model the velocity structure to the greatest resolution possible. Travel-time tomography models have revealed the long-wavelength velocity structure of this hyperextended domain, but are often insufficient to match accurately the short-wavelength structure observed in reflection seismic imaging. Here we demonstrate the application of two-dimensional (2D) time-domain acoustic full-waveform inversion to deep water seismic data collected at the Deep Galicia Margin, in order to attain a high resolution velocity model of continental hyperextension. We have used several quality assurance procedures to assess the velocity model, including comparison of the observed and modelled waveforms, checkerboard tests, testing of parameter and inversion strategy, and comparison with the migrated reflection image. Our final model exhibits an increase in the resolution of subsurface velocities, with particular improvement observed in the westernmost continental fault blocks, with a clear rotation of the velocity field to match steeply dipping reflectors. Across the S-reflector there is a sharpening in the velocity contrast, with lower velocities beneath S indicative of preferential mantle serpentinisation. This study supports the hypothesis that normal faulting acts to hydrate the upper mantle peridotite, observed as a systematic decrease in seismic velocities, consistent with increased serpentinisation. Our results confirm the feasibility of applying the full-waveform inversion method to sparse, deep water crustal datasets

A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51

Fanconi anaemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. A total of 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM-002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, 'FA-Rffrt ', which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and paediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders, our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility

A novel Fanconi anemia subtype associated with a dominant-negative mutation in RAD51

Fanconi anemia (FA) is a hereditary disease featuring hypersensitivity to DNA cross-linker-induced chromosomal instability in association with developmental abnormalities, bone marrow failure and a strong predisposition to cancer. 17 FA disease genes have been reported, all of which act in a recessive mode of inheritance. Here we report on a de novo g.41022153G>A; p.Ala293Thr (NM_002875) missense mutation in one allele of the homologous recombination DNA repair gene RAD51 in an FA-like patient. This heterozygous mutation causes a novel FA subtype, “FA-R”, which appears to be the first subtype of FA caused by a dominant-negative mutation. The patient, who features microcephaly and mental retardation, has reached adulthood without the typical bone marrow failure and pediatric cancers. Together with the recent reports on RAD51-associated congenital mirror movement disorders our results point to an important role for RAD51-mediated homologous recombination in neurodevelopment, in addition to DNA repair and cancer susceptibility