The role of chromosome 22 in the progression of head and neck squamous cell carninoma

Head and neck squamous cell carcinoma (HNSCC) is one o f the ten most frequent cancers in the world. Despite advances in surgery, radiotherapy and chemotherapy over the last 30 years, there has been little improvement in the mortality rate from this disease. HNSCC remains a leading cause of cancer death, particularly once it has metastasised to the regional lymph nodes. The presence of metastatic cervical lymphadenopathy at the time of diagnosis reduces the likelihood of 5-year survival by 50%.Preliminary comparative genomic hybridisation (CGH) work in our laboratory, aimed at identifying genetic markers of metastasis, suggested that amplification of chromosome arm 22q may be important in enabling malignant cells to metastasise. Overamplification of 22q was observed in 5/17 (29%) lymph node metastases (LNM) compared with none of their matched primary tumours. In a further group of 12 non-metastasising primary tumours there was no evidence of either gross deletion or amplification of 22q, supporting its unique association with metastasis. However, a literature search revealed two other studies that had identified significant aberration of 22q in primary head and neck cancers, as opposed to metastases.Thus two contrasting bodies o f evidence exist for the role o f a putative oncogene on 22q in HNSCC. Two studies support a role during initial tumorigenesis, whilst another supports a role in the process of lymph node metastasis. The aim of this thesis was to determine which of these two roles for 22q is more likely in HNSCC, and to narrow the search for the putative oncogene in question. For patients with HNSCC, microsatellite markers were used to investigate allele imbalance (Al) along 22q and in doing so to construct a high resolution AI map of this chromosome arm.The 9 microsatellite markers selected covered approximately 25Mb (72%) of 22q, spanning 22q11.23 to 22ql3.31. A series of 28 patients with nodal metastases from laryngeal or hypopharyngeal squamous cell carcinoma were selected. DNA was extracted from normal tissue and primary tumour for each patient, and microsatellite marker analysis performed. The microsatellite loci examined, and rates of AI were as follows: D22S420 (11%), D22S539 (25%), D22S117 (4%), D22S315 (0%), D22S1163 (15%), D22S280 (20%), D22S277 (15%), D22S283 (11%) and D22S1169 (0%). Overall there was no significant AI (mean rate AI = 8.2%), thus confirming our null hypothesis based on our CGH results that there would be no significant AI between the normal and tumour DNA samples. This finding would tend to refute a role for 22q in initial tumorigenesis, and future work will examine the corresponding lymph node metastases for AI. Microsatellite instability was a very infrequent event (1% cases), suggesting that HNSCC does not primarily arise through defects in the mismatch repair system.The role of 22q at the protein level was also examined using immunohistochemistry. Gene databases were searched for potential candidate oncogenes, which may be responsible for the metastatic competence of head and neck tumours with 22q amplification. The matrix metalloproteinase (MMP) Stromelysin III (MMP-11) is encoded by a gene that resides on 22ql 1.2. Evidence from studies of other malignancies supports a role for MMP-11 in the initial invasive stages of the metastatic cascade. The second part of the thesis tested the hypothesis that there would be no difference in MMP-11 expression between normal tissue and primary tumour, but that there would be increased MMP-11 expression in lymph node metastases. This was found to be the case, with a significantly higher level of MMP-11 detected in the lymph node metastases (p=0.01). MMP-11 may therefore be a putative proto-oncogene responsible for allowing head and neck squamous cell carcinoma cells to metastasise.The sequencing results do not support a specific role for aberrations o f chromosome 22q in initial head and neck tumorigenesis. They also exclude defects in the mismatch repair system as a significant mechanism of tumorigenesis in head and neck cancer. The immunostaining results do support a role for MMP-11 overexpression in the progression from primary tumour to metastasis. It remains to be seen whether the observed overexpression of MMP-11 in metastatic carcinoma cells is due to amplification o f chromosome 22q. This work will be continued, with microsatellite analysis o f the matched lymph node metastases. These findings will increase our understanding o f the molecular mechanisms o f metastasis, and hopefully provide novel therapeutic targets

Recruitment and retention of adolescents for an ecological momentary assessment measurement burst mental health study:The MHIM engagement strategy

Introduction: Recruitment and long-term retention of adolescent participants in longitudinal research are challenging and may be especially so in studies involving remote measurement and biosampling components. The ability to effectively recruit and retain participants can be supported by the use of specific evidence-based engagement strategies that are built in from the earliest stages. Methods: Informed by a review of the evidence on effective engagement strategies and consultations with adolescents (via two Young Person Advisory Groups [YPAGs]; ages 11–13 and 14–17), the current protocol describes the planned participant engagement strategy for the Mental Health in the Moment Study: a multimodal measurement burst study of adolescent mental health across ages 11–19. Results: The protocol incorporates engagement strategies in four key domains: consultations/co-design with the target population, incentives, relationship-building and burden/barrier reduction. In addition to describing general engagement strategies in longitudinal studies, we also discuss specific concerns regarding engagement in data collection methods such as biosampling and ecological momentary assessment where a paucity of evidence exists. Conclusion: Engagement strategies for adolescent mental health studies should be based on existing evidence and consultations with adolescents. We present our approach in developing the planned engagement strategies and also discuss limitations and future directions in engaging adolescents in longitudinal research. Patient or Public Contribution: The study design for this project places a strong emphasis on the active engagement of adolescents throughout its development. Specifically, the feedback and suggestions provided by the YPAGs have been instrumental in refining our strategies for maximising the recruitment and retention of participants

MeerKAT view of the dancing ghosts : peculiar galaxy pair PKS 2130-538 in Abell 3785

We present MeerKAT L-band (886–1682 MHz) observations of the extended radio structure of the peculiar galaxy pair PKS 2130−538 known as the ‘Dancing Ghosts’. The complex of bending and possibly interacting jets and lobes originate from two active galactic nuclei hosts in the Abell 3785 galaxy cluster, one of which is the brightest cluster galaxy. The radio properties of the PKS 2130−538 – flux density, spectral index, and polarization – are typical for large, bent-tail galaxies. We also investigate a number of thin extended low surface brightness filaments originating from the lobes. South-east from the Dancing Ghosts, we detect a region of low surface brightness emission that has no clear origin. While it could originate from the Abell 3785 radio halo, we investigate the possibility that it is associated with the two PKS 2130−538 hosts. We find no evidence of interaction between the two PKS 2130−538 hosts

Nature tourism and Irish film

This article provides a historical overview and reading of seminal Irish film from the perspective of nature tourism. Within Irish cultural studies, tourism is frequently equated with an overly romantic image of the island, which has been used to sell the country abroad. However, using notions like the tourist gaze and taking on board influential debates around space/place, one can posit a more progressive environmental vision of nature and landscape in our readings of film

Constraining the Thermal Dust Content of Lyman-Break Galaxies in an Overdense Field at z~5

We have carried out 870 micron observations in the J1040.7-1155 field, known to host an overdensity of Lyman break galaxies at z=5.16 +/- 0.05. We do not detect any individual source at the S(870)=3.0 mJy/beam (2 sigma) level. A stack of nine spectroscopically confirmed z>5 galaxies also yields a non-detection, constraining the submillimeter flux from a typical galaxy at this redshift to S(870)<0.85 mJy, which corresponds to a mass limit M(dust)<1.2x10^8 M_sun (2 sigma). This constrains the mass of thermal dust in distant Lyman break galaxies to less than one tenth of their typical stellar mass. We see no evidence for strong submillimeter galaxies associated with the ultraviolet-selected galaxy overdensity, but cannot rule out the presence of fainter, less massive sources.Comment: 5 pages, 2 figures. MNRAS in pres

Late-acting dominant lethal genetic systems and mosquito control

BACKGROUND: Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality. RESULTS: We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality. CONCLUSION: Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease control

Ichnological evidence for meiofaunal bilaterians from the terminal Ediacaran and earliest Cambrian of Brazil

The evolutionary events during the Ediacaran–Cambrian transition (~541 Myr ago) are unparalleled in Earth history. The fossil record suggests that most extant animal phyla appeared in a geologically brief interval, with the oldest unequivocal bilaterian body fossils found in the Early Cambrian. Molecular clocks and biomarkers provide independent estimates for the timing of animal origins, and both suggest a cryptic Neoproterozoic history for Metazoa that extends considerably beyond the Cambrian fossil record. We report an assemblage of ichnofossils from Ediacaran–Cambrian siltstones in Brazil, alongside U–Pb radioisotopic dates that constrain the age of the oldest specimens to 555–542 Myr. X-ray microtomography reveals three-dimensionally preserved traces ranging from 50 to 600 μm in diameter, indicative of small-bodied, meiofaunal tracemakers. Burrow morphologies suggest they were created by a nematoid-like organism that used undulating locomotion to move through the sediment. This assemblage demonstrates animal–sediment interactions in the latest Ediacaran period, and provides the oldest known fossil evidence for meiofaunal bilaterians. Our discovery highlights meiofaunal ichnofossils as a hitherto unexplored window for tracking animal evolution in deep time, and reveals that both meiofaunal and macrofaunal bilaterians began to explore infaunal niches during the late Ediacaran

A Spatially Resolved Radio Spectral Index Study of the Dwarf Irregular Galaxy NGC\,1569

© The Author(s) 2018. Published by Oxford University Press on behalf of The Royal Astronomical Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.We study the resolved radio continuum spectral energy distribution of the dwarf irregular galaxy, NGC 1569, on a beam-by-beam basis to isolate and study its spatially resolved radio emission characteristics. Utilizing high-quality NRAO Karl G. Jansky Very Large Array observations that densely sample the 1-34 GHz frequency range, we adopt a Bayesian fitting procedure, where we use Hα emission that has not been corrected for extinction as a prior, to produce maps of how the separated thermal emission, non-thermal emission, and non-thermal spectral index vary across NGC1569's main disc. We find a higher thermal fraction at 1 GHz than is found in spiral galaxies (26 -3 +2 per cent) and find an average non-thermal spectral index α =-0.53 ± 0.02, suggesting that a young population of cosmic ray electrons is responsible for the observed non-thermal emission. By comparing our recovered map of the thermal radio emission with literature Hα maps, we estimate the total reddening along the line of sight to NGC1569 to be E(B - V) = 0.49 ± 0.05, which is in good agreement with other literature measurements. Spatial variations in the reddening indicate that a significant portion of the total reddening is due to internal extinction within NGC1569.Peer reviewedFinal Published versio

Ichnological evidence for meiofaunal bilaterians from the terminal Ediacaran and earliest Cambrian of Brazil

The evolutionary events during the Ediacaran–Cambrian transition (~541 Myr ago) are unparalleled in Earth history. The fossil record suggests that most extant animal phyla appeared in a geologically brief interval, with the oldest unequivocal bilaterian body fossils found in the Early Cambrian. Molecular clocks and biomarkers provide independent estimates for the timing of animal origins, and both suggest a cryptic Neoproterozoic history for Metazoa that extends considerably beyond the Cambrian fossil record. We report an assemblage of ichnofossils from Ediacaran–Cambrian siltstones in Brazil, alongside U–Pb radioisotopic dates that constrain the age of the oldest specimens to 555–542 Myr. X-ray microtomography reveals three-dimensionally preserved traces ranging from 50 to 600 μm in diameter, indicative of small-bodied, meiofaunal tracemakers. Burrow morphologies suggest they were created by a nematoid-like organism that used undulating locomotion to move through the sediment. This assemblage demonstrates animal–sediment interactions in the latest Ediacaran period, and provides the oldest known fossil evidence for meiofaunal bilaterians. Our discovery highlights meiofaunal ichnofossils as a hitherto unexplored window for tracking animal evolution in deep time, and reveals that both meiofaunal and macrofaunal bilaterians began to explore infaunal niches during the late Ediacaran