Aquatic surveys: Glyn Rhonwy Quarries Q1 and Q6

The Glyn Rhonwy Pumped Storage scheme is a proposed hydroelectric facility within Glyn Rhonwy Quarry, a disused slate quarry north-west of Llanberis, Gwynedd. The scheme requires the creation of two large water reservoirs utilising the existing quarries Q1 (SH5595060552) and Q6 (SH5665060855) which will be sealed and dammed to enable increase retention capacity. Water for the scheme will be abstracted from the adjacent Llyn Padarn, a Site of Special Scientific Interest (SSSI hereafter) to fill the upper reservoir. Both Q1 and Q6 currently hold permanent water and it is understood this may require release to Llyn Padarn during the construction phase and once operational, Llyn Padarn could also receive water from the scheme during periods of overflow

AKT1 Loss Correlates with Episomal HPV16 in Vulval Intraepithelial Neoplasia

Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma–HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers. Mucosal HPV types can increase AKT phosphorylation and activity whereas cutaneous HPV types down-regulate AKT1 expression, probably to weaken the cornified envelope to promote viral release. We assessed the presence of mucosal and cutaneous HPV in vulval malignancy and its relationship to AKT1 expression in order to establish the corresponding HPV and AKT1 profile of normal vulval skin, vulval intraepithelial neoplasia (VIN) and vulval squamous cell carcinoma (vSCC). We show that HPV16 is the principle HPV type present in VIN, there were few detectable beta types present and AKT1 loss was not associated with the presence of these cutaneous HPV. We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis. AKT1 loss in our VIN cohort correlated with presence of high copy number, episomal HPV16. Maintained AKT1 expression correlated with low copy number, an increased frequency of integration and increased HPV16E7 expression, a finding we replicated in another untyped cohort of vSCC. Since expression of E7 reflects tumour progression, these findings suggest that AKT1 loss associated with episomal HPV16 may have positive prognostic implications in vulval malignancy

Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18

Ultraviolet (UV) irradiation is a major mutagenic environmental agent, causing the appearance of DNA adducts that, if unrepaired, may give rise to mutations. Ultraviolet radiation has been indicated as a major risk factor in the development of nonmelanoma skin cancers; however, recent reports have suggested that infections with human papillomaviruses, a widespread family of epitheliotropic DNA viruses, may also contribute to the tumorigeneic process. Here, we investigated whether expression of the E6 protein from different HPV types interfere with the repair of thymine dimers caused by UV-B radiation. Results show that unrepaired DNA damage can be observed in UV-B-irradiated cells expressing the E6 protein of HPV types found in cervical and epithelial cancers. Moreover, such cells have the ability to overcome the G(1) cell cycle checkpoint induced as a result of unrepaired DNA. (C) 2004 Cancer Research UK

Simultaneous in-field boost for patients with 1 to 4 brain metastasis/es treated with volumetric modulated arc therapy: a prospective study on quality-of-life

<p>Abstract</p> <p>Purpose</p> <p>To assess treatment toxicity and patients' survival/quality of life (QoL) after volumetric modulated arc therapy (VMAT) with simultaneous in-field boost (SIB) for cancer patients with 1 - 4 brain metastases (BM) treated with or without surgery.</p> <p>Methods and Materials</p> <p>Between March and December 2010, 29 BM patients (total volume BM, < 40 cm³) aged < 80 years, KPS ≥ 70, RPA < III were included in this prospective trial. Whole brain VMAT (30 Gy) and a SIB to the BM (40 Gy) was delivered in 10 fraction. Mean age was 62.1 ± 8.5 years. Fifteen (51.7%) underwent surgery. KPS and MMSE were prospectively assessed. A self-assessed questionnaire was used to assess the QoL (EORTC QLQ-C30 with -BN20 module).</p> <p>Results</p> <p>As of April 2011 and after a mean FU of 5.4 ± 2.8 months, 14 (48.3%) patients died. The 6-month overall survival was 55.1%. Alopecia was only observed in 9 (31%) patients. In 3-month survivors, KPS was significantly (<it>p </it>= 0.01) decreased. MMSE score remained however stable (<it>p </it>= 0.33). Overall, QoL did decrease after VMAT. The mean QLQ-C30 global health status (<it>p </it>= 0.72) and emotional functional (<it>p </it>= 0.91) scores were decreased (low QoL). Physical (<it>p </it>= 0.05) and role functioning score (<it>p </it>= 0.01) were significantly worse and rapidly decreased during treatment. The majority of BN20 domains and single items worsened 3 months after VMAT except headaches (<it>p </it>= 0.046) and bladder control (<it>p </it>= 0.26) which improved.</p> <p>Conclusions</p> <p>The delivery of 40 Gy in 10 fractions to 1 - 4 BM using VMAT was achieved with no significant toxicity. QoL, performance status, but not MMSE, was however compromised 3 months after treatment in this selected cohort of BM patients.</p

The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets

Agrobacterium-mediated transformation systems of Primula vulgaris

Background: Genetic transformation is a valuable tool and an important procedure in plant functional genomics contributing to gene discovery, allowing powerful insights into gene function and genetically controlled characteristics. Primulaceae species provide one of the best-known examples of heteromorphic flower development, a breeding system which has attracted considerable attention, including that of Charles Darwin. Molecular approaches, including plant transformation give the best opportunity to define and understand the role of genes involved in floral heteromorphy in the common primrose, Primula vulgaris, along with other Primula species. Results: Two transformation systems have been developed in P. vulgaris. The first system, Agrobacterium-mediated vacuum infiltration of seedlings, enables the rapid testing of transgenes, transiently in planta. GUS expression was observed in the cotyledons, true leaves, and roots of Primula seedlings. The second system is based on Agrobacterium tumefaciens infection of pedicel explants with an average transformation efficiency of 4.6%. This transformation system, based on regeneration and selection of transformants within in vitro culture, demonstrates stable transgene integration and transmission to the next generation. Conclusion: The two transformation systems reported here will aid fundamental research into important traits in Primula. Although, stable integration of transgenes is the ultimate goal for such analyses, transient gene expression via Agrobacterium-mediated DNA transfer, offers a simple and fast method to analyse transgene functions. The second system describes, for the first time, stable Agrobacterium-mediated transformation of Primula vulgaris, which will be key to characterising the genes responsible for the control of floral heteromorphy

A large West Antarctic Ice Sheet explains early Neogene sea-level amplitude

Early to Middle Miocene sea-level oscillations of approximately 40-60 m estimated from far-field records1-3 are interpreted to reflect the loss of virtually all East Antarctic ice during peak warmth2. This contrasts with ice-sheet model experiments suggesting most terrestrial ice in East Antarctica was retained even during the warmest intervals of the Middle Miocene4,5. Data and model outputs can be reconciled if a large West Antarctic Ice Sheet (WAIS) existed and expanded across most of the outer continental shelf during the Early Miocene, accounting for maximum ice-sheet volumes. Here we provide the earliest geological evidence proving large WAIS expansions occurred during the Early Miocene (~17.72-17.40 Ma). Geochemical and petrographic data show glacimarine sediments recovered at International Ocean Discovery Program (IODP) Site U1521 in the central Ross Sea derive from West Antarctica, requiring the presence of a WAIS covering most of the Ross Sea continental shelf. Seismic, lithological and palynological data reveal the intermittent proximity of grounded ice to Site U1521. The erosion rate calculated from this sediment package greatly exceeds the long-term mean, implying rapid erosion of West Antarctica. This interval therefore captures a key step in the genesis of a marine-based WAIS and a tipping point in Antarctic ice-sheet evolution

Characterization of a Novel Cutaneous Human Papillomavirus Genotype HPV-125

The DNA genome of a novel HPV genotype, HPV-125, isolated from a hand wart of an immuno-competent 19-year old male was fully cloned, sequenced and characterized. The full genome of HPV-125 is 7,809-bp in length with a GC content of 46.4%. By comparing the nucleotide sequence of the complete L1 gene, HPV-125 is phylogenetically placed within cutaneotrophic species 2 of Alphapapillomaviruses, and is most closely related to HPV-3 and HPV-28. HPV-125 has a typical genomic organization of Alphapapillomaviruses and contains genes coding for five early proteins, E6, E7, E1, E2 and E4 and two late capsid proteins, L1 and L2. The genome contains two non-coding regions: the first located between the L1 and E6 genes (nucleotide positions 7,137–7,809, length 673-bp) and the second between genes E2 and L2 (nucleotide positions 3,757–4,216, length 460-bp). The E6 protein of HPV-125 contains two regular zinc-binding domains at amino acid positions 29 and 102, whereas the E7 protein exhibits one such domain at position 50. HPV-125 lacks the regular pRb-binding core sequence within its E7 protein. In order to assess the tissue predilection and clinical significance of HPV-125, a quantitative type-specific real-time PCR was developed. The 95% limit-of-detection of the assay was 2.5 copies per reaction (range 1.7–5.7) and the intra- and inter-assay coefficients of variation were 0.47 and 2.00 for 100 copies per reaction, and 1.15 and 2.15 for 10 copies per reaction, respectively. Testing of a representative collection of HPV-associated mucosal and cutaneous benign and malignant neoplasms and hair follicles (a total of 601 samples) showed that HPV-125 is a relatively rare HPV genotype, with cutaneous tropism etiologically linked with sporadic cases of common warts

Clinical practice guideline on the optimal radiotherapeutic management of brain metastases

BACKGROUND: An evidence-based clinical practice guideline on the optimal radiotherapeutic management of single and multiple brain metastases was developed. METHODS: A systematic review and meta-analysis was performed. The Supportive Care Guidelines Group formulated clinical recommendations based on their interpretation of the evidence. External review of the report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from Cancer Care Ontario's Practice Guidelines Coordinating Committee (PGCC). RESULTS: One hundred and nine Ontario practitioners responded to the survey (return rate 44%). Ninety-six percent of respondents agreed with the interpretation of the evidence, and 92% agreed that the report should be approved. Minor revisions were made based on feedback from external reviewers and the PGCC. The PGCC approved the final practice guideline report. CONCLUSIONS: For adult patients with a clinical and radiographic diagnosis of brain metastases (single or multiple) we conclude that, • Surgical excision should be considered for patients with good performance status, minimal or no evidence of extracranial disease, and a surgically accessible single brain metastasis. • Postoperative whole brain radiotherapy (WBRT) should be considered to reduce the risk of tumour recurrence for patients who have undergone resection of a single brain metastasis. • Radiosurgery boost with WBRT may improve survival in select patients with unresectable single brain metastases. • The whole brain should be irradiated for multiple brain metastases. Standard dose-fractionation schedules are 3000 cGy in 10 fractions or 2000 cGy in 5 fractions. • Radiosensitizers are not recommended outside research studies. • In select patients, radiosurgery may be considered as boost therapy with WBRT to improve local tumour control. Radiosurgery boost may improve survival in select patients. • Chemotherapy as primary therapy or chemotherapy with WBRT remains experimental. • Supportive care is an option but there is a lack of Level 1 evidence as to which subsets of patients should be managed with supportive care alone. Qualifying statements addressing factors to consider when applying these recommendations are provided in the full report. The rigorous development, external review and approval process has resulted in a practice guideline that is strongly endorsed by Ontario practitioners