A deletion and point mutation study of the human papillomavirus type 16 major capsid gene

Recombinant human papillomavirus (HPV) virus-like particles (VLPs) made from the major capsid protein L1 are promising vaccine candidates for use as vaccines against genital and other HPV infections, and particularly against HPV-16. However, HPV-16 genotype variants have different binding affinities for neutralising mouse Mabs raised against HPV-16 L1 VLPs. This paper analyses, using a panel of well-characterised Mabs, the effects on the antigenicity of various C- and N-terminal deletants of HPV-16 L1 made in insect cells via recombinant baculovirus, of an A → T mutation at residue 266 (A266T), and of a C → G mutation at conserved position 428 (C428G). The effects of these changes on assembly of the variant L1s were studied by electron microscopy. Binding of Mab H16:E70 to A266T was reduced by almost half in comparison to wild type L1. Retention of the C-terminal region 428-483 was critical for the binding of conformation-specific Mabs (H16:V5, H16:E70, H16:U4 and H16:9A) whereas deletion of the nuclear localisation signal (NLS) or the C428G mutation or an N-terminal deletion (residues 2-9) did not affect the antigenicity. The N-terminal deletion resulted in a mixed population of 30 and 55 nm VLPs, which differs from the same construct expressed in Escherichia coli, whereas pentamer aggregates resulted from deletion of the 428-465 region or the C428G mutation. The results have implications both for considering use of single-genotype HPV vaccines, and for design of novel second-generation vaccines. © 2006 Elsevier B.V. All rights reserved.

Therapeutic immunisation of rabbits with cottontail rabbit papillomavirus (CRPV) virus-like particles (VLP) induces regression of established papillomas

There is overwhelming evidence that persistent infection with high-risk human papillomaviruses (HR-HPV) is the main risk factor for invasive cancer of the cervix. Due to this global public health burden, two prophylactic HPV L1 virus-like particles (VLP) vaccines have been developed. While these vaccines have demonstrated excellent type-specific prevention of infection by the homologous vaccine types (high and low risk HPV types), no data have been reported on the therapeutic effects in people already infected with the low-risk HPV type. In this study we explored whether regression of CRPV-induced papillomas could be achieved following immunisation of out-bred New Zealand White rabbits with CRPV VLPs. Rabbits immunised with CRPV VLPs had papillomas that were significantly smaller compared to the negative control rabbit group (P ≤ 0.05). This data demonstrates the therapeutic potential of PV VLPs in a well-understood animal model with potential important implications for human therapeutic vaccination for low-risk HPVs. © 2008 Govan et al; licensee BioMed Central Ltd.

Minimum important difference between patients with rheumatoid arthritis : the patient's perspective

OBJECTIVE: To determine the point at which differences in clinical assessment scores on physical ability, pain and overall condition are sufficiently large to correspond to a subjective perception of a meaningful difference from the perspective of the patient. METHODS: Forty patients with a diagnosis of rheumatoid arthritis participated in an evening of clinical assessment and one-on-one conversations with each other regarding their arthritic condition. The assessments included tender and swollen joint counts, clinician and patient global assessments, participant assessment of pain and the Health Assessment Questionnaire (HAQ) on physical ability. After each conversation, participants rated themselves relative to their conversational partner on physical ability, pain and overall condition. These subjective comparative ratings were compared to the differences of the individual clinical assessments. RESULTS: In total there were 120 conversations. Generally participants judged themselves as less disabled than others. They rated themselves as "somewhat better" than their conversation partner when they had a (mean) 7% better score on the HAQ, 6% less pain, and 9% better global assessment. In contrast, they rated themselves as "somewhat worse" when they had a (mean) 16% worse score on the HAQ, 16% more pain, and 29% worse global assessment. CONCLUSIONS: Patients view clinically important differences in an asymmetric manner. These results can provide guidance in interpreting results and planning clinical trials.

Contribution to single-point closure Reynolds-stress modelling of inhomogeneous flow

This paper is concerned with recent advances in the development of near wall-normal-free Reynolds-stress models, whose single point closure formulation, based on the inhomogeneity direction concept, is completely independent of the distance from the wall, and of the normal to the wall direction. In the present approach the direction of the inhomogeneity unit vector is decoupled from the coefficient functions of the inhomogeneous terms. A study of the relative influence of the particular closures used for the rapid redistribution terms and for the turbulent diffusion is undertaken, through comparison with measurements, and with a baseline Reynolds-stress model (RSM) using geometric wall normals. It is shown that wall-normal-free rsms can be reformulated as a projection on a tensorial basis that includes the inhomogeneity direction unit vector, suggesting that the theory of the redistribution tensor closure should be revised by taking into account inhomogeneity effects in the tensorial integrity basis used for its representation.

Getting the point : the role of gesture in managing intersubjectivity in a design activity

This paper illustrates the complexity of pointing as it is employed in a design workshop. Using the method of interaction analysis, we argue that pointing is not merely employed to index, locate, or fix reference to an object. It also constitutes a practice for reestablishing intersubjectivity and solving interactional trouble such as misunderstandings or disagreements by virtue of enlisting something as part of the participants’ shared experience. We use this analysis to discuss implications for how such practices might be supported with computer mediation, arguing for a “bricolage” approach to systems development that emphasizes the provision of resources for users to collaboratively negotiate the accomplishment of intersubjectivity ra- ther than systems that try to support pointing as a specific gestural action.

Joint Ventures Law in Australia (3rd ed.)

Following on from the 2nd edition published in 2005, this new edition updates its predecessor and adds considerable new material as a result of changes in the law generally and commercial approaches to financing joint ventures in particular. Of special note, Financing of Joint Ventures has been completely re-written with considerable additions to take account of the new legislative regimes such as the Personal Property Securities. The impact of climate change legislation has been covered, specifically carbon pricing with additional material on structuring generally and particularly in relation to large joint ventures with governments through Public Private Partnerships. A new Chapter has been added called Resources Joint Ventures and undertakes a thorough analysis of a typical resources joint venture and is heavily cross referenced into the chapter on Default which has also been updated. In addition, International Joint Ventures now includes additional material on structuring and dispute resolution and Joint Ventures and the Competition and Consumer Act has been substantially re-written to take account of 2009 legislative amendments on cartel conduct, and the impact of changes wrought by the Competition and Consumer Act 2010. All other chapters and material has been updated to accommodate other legislative changes and new case law over the seven years since the last edition.

Common law obligations of good faith in non-fiduciary joint ventures

This chapter is devoted to the issue of non-fiduciary common law obligations of good faith, as they may arise in the performance and enforcement of joint ventures. In recent times a rush of commercial contractual claims involving good faith has signified the need for a separate chapter examining this issue. Although most of these decisions have arisen in commercial contexts other than joint ventures, the decisions, nevertheless, warrant careful consideration to the extent that they cast light on the likely contours of the common law good faith obligation as it may apply in the joint venture context.

Joint ventures and the Competition and Consumer Act

The purpose of this chapter is to analyse the way in which joint venture agreements can fall within the competition provisions of the Competition and Consumer Act 2010, and the circumstances in which authorisation may be available for joint venture collaborations.

Intellectual Property and Joint Ventures

Following upon the success of the 2nd edition published in 2005, this new edition not only updates its predecessor but also adds considerable new material in consequences of changes in the law generally and commercial approaches to financing joint ventures in particular. Of special note are the following: Financing of Joint Ventures has been completely re-written with considerable additions to take account of the new legislative regimes such as the Personal Property Securities, the impact of climate change legislation, specifically carbon pricing with additional material on structuring generally and particularly in relation to large joint ventures with governments through Public Private Partnerships. A new Chapter called Resources Joint Ventures undertakes a thorough analysis of a typical resources joint venture and is heavily cross referenced into the chapter on Default which has also been updated. International Joint Ventures now includes additional material on structuring and dispute resolution. Joint Ventures and the Competition and Consumer Act has been substantially re-written to take account of 2009 legislative amendments on cartel conduct, and the impact of changes wrought by the Competition and Consumer Act 2010. All other chapters and material has been updated to accommodate other legislative changes and new case law over the seven years since the last edition.

Lifting the joint venture veil : liability of related entities for misleading conduct of agents engaged by joint venture partners

At common law, a corporation may be liable vicariously for the conduct of its appointed agents, employees or directors. This generally requires the agent or employee to be acting in the course of his or her agency or employment and, in the case of representations, to have actual or implied authority to make the representations. The circumstances in which a corporation may be liable for the conduct of its agents, employees or directors is broadened under the Australian Consumer Law (ACL) to where one of these parties engages in conduct “on behalf of” the corporation. As the decision in Bennett v Elysium Noosa Pty Ltd (in liq) demonstrates, this may extend to liability for the misleading conduct of a salesperson for the joint venture to parties who are not formal members of the joint venture, but where the joint venture activities are within the course of the entity’s “business, affairs or activities”.

Assignment of lease between lessees as joint tenants-is lessor’s consent required?

The decision of Lockrey v Historic Houses Trust of New South Wales [2012] NSWSC 654 raises an interesting issue about the necessity of seeking the consent of the lessor where there is an assignment of a lease between joint tenants who already hold the lease when one joint tenant sells the business operated on the leased premises to the other joint tenant. A secondary issue raised by the proceedings concerns whether the lessor’s consent was unreasonably withheld under the processes under Retail Leases Act 1994 (NSW) (“the Act”) upon the grounds of lack of provision of information as to the remaining lessee’s financial standing.

Adaptive radiotherapy for virally mediated head and neck cancer : predicting which patients may benefit most

Background: Recent clinical studies have demonstrated an emerging subgroup of head and neck cancers that are virally mediated. This disease appears to be a distinct clinical entity with patients presenting younger and with more advanced nodal disease, having lower tobacco and alcohol exposure and highly radiosensitive tumours. This means they are living longer, often with the debilitating functional side effects of treatment. The primary objective of this study was to determine how virally mediated nasopharyngeal and oropharyngeal cancers respond to radiation therapy treatment. The aim was to determine risk categories and corresponding adaptive treatment management strategies to proactively manage these patients. Method/Results: 121 patients with virally mediated, node positive nasopharyngeal or oropharyngeal cancer who received radiotherapy treatment with curative intent between 2005 and 2010 were studied. Relevant patient demographics including age, gender, diagnosis, TNM stage, pre-treatment nodal size and dose delivered was recorded. Each patient’s treatment plan was reviewed to determine if another computed tomography (re-CT) scan was performed and at what time point (dose/fraction) this occurred. The justification for this re-CT was determined using four categories: tumour and/or nodal regression, weight loss, both or other. Patients who underwent a re-CT were further investigated to determine whether a new plan was calculated. If a re-plan was performed, the dosimetric effect was quantified by comparing dose volume histograms of planning target volumes and critical structures from the actual treatment delivered and the original treatment plan. Preliminary results demonstrated that 25/121 (20.7%) patients required a re-CT and that these re-CTs were performed between fractions 20 to 25 of treatment. The justification for these re-CTs consisted of a combination of tumour and/or nodal regression and weight loss. 16/25 (13.2%) patients had a replan calculated. 9 (7.4%) of these replans were implemented clinically due to the resultant dosimetric effect calculated. The data collected from this assessment was statistically analysed to identify the major determining factors for patients to undergo a re-CT and/or replan. Specific factors identified included nodal size and timing of the required intervention (i.e. how when a plan is to be adapted). This data was used to generate specific risk profiles that will form the basis of a biologically guided adaptive treatment management strategy for virally mediated head and neck cancer. Conclusion: Preliminary data indicates that virally mediated head and neck cancers respond significantly during radiation treatment (tumour and/or nodal regression and weight loss). Implications of this response are the potential underdosing or overdosing of tumour and/or surrounding critical structures. This could lead to sub-optimal patient outcomes and compromised quality of life. Consequently, the development of adaptive treatment strategies that improve organ sparing for this patient group is important to ensure delivery of the prescribed dose to the tumour volume whilst minimizing the dose received to surrounding critical structures. This could reduce side effects and improve overall patient quality of life. The risk profiles and associated adaptive treatment approaches developed in this study will be tested prospectively in the clinical setting in Phase 2 of this investigation.