Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo?

Purpose: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application.

Experimental Design: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using “mismatch” following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition.

Results: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect.

Conclusion: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit.

Quantifying Alcohol-Related Mortality: Should Alcohol-Related Contributory Causes of Death be Included?

Aims: The aim of the study was to assess whether alcohol-related mortality data in the UK should be extended to include contributory as well as underlying cause of death. Methods: A total of 101,320 deaths registered in Northern Ireland between 2001 and 2007 were analysed to determine the quantity and characteristics of those with an underlying or contributory alcohol-related cause of death. Results: Alcohol was found to be an underlying cause of death in 1690 cases (1.7% of deaths) and a contributory cause in a further 1105 cases. Analyses show that the addition of alcohol-related contributory causes of deaths would increase the male-female ratio, result in steeper socio-economic gradients and amplify the apparent rate of increase of alcohol-related deaths. The significant contribution of alcohol to external causes of death, such as accidents and suicide, is also more evident. Conclusions: Using only underlying cause of death undoubtedly underestimates the burden of alcohol-related harm and may provide an inaccurate picture of those most likely to suffer from an alcohol-related death, especially among younger men.

Professional Negligence, Solicitors: Recent Case Law, 2014

In preparation for this talk I have reviewed cases of interest in the High Courts and Courts of Appeal of England and Wales and Northern Ireland from the past two years or so on professional negligence and liability and principally relating to solicitors.

There are six topics of interest: the general duty of care demanded of solicitors in the carrying out of their professional obligations; whether there is a specific duty on a solicitor to warn or advise a client of any implied risk in, say, a commercial transaction; what is the scope of the duty on a solicitor to explain the content of or clauses in a legal document; a recent case of interest applying the White v Jones principle to a disappointed beneficiary seeking to make a claim against a solicitor who negligently prepared a will; the practical, limitation issue of how to pinpoint in a professional negligence claim when the damage was first sustained by the claimant; and finally some case law here and in England and Wales on the (costs) implications for solicitors relating to any failure to adhere to case management protocols or related court directions.

Avoiding Negligence and Profusion: The failure of the Joint-Stock form in the Anglo-Indian Tea Trade, 1840-1870

In the 19th century, firms operating in the Anglo-Indian tea trade were organised using a variety ownership forms including the partnership, joint-stock and a combination of the two known as the Managing agency. Faced with both an increasing need for fixed capital and high agency costs caused by the distance between owners and managers, the firms adapted and increasingly adopted the hybrid managing agency model to overcome these problems. Using new data from Calcutta and Bengal Commercial Registers and detailed case studies of the Assam Company and Gillanders, Arbuthnot and Co, this paper demonstrates that British entrepreneurs did not see the choice of ownership as a dichotomy or firm boundaries as fixed, but instead innovatively drew on the strengths of different forms of ownership to compete and grow successfully.

The vulnerable subject of negligence law

The approach taken by English courts to the duty of care question in negligence has been subject to harsh criticism in recent years. This article examines this fundamental issue in tort law, drawing upon Canadian and Australian jurisprudence by way of comparison. From this analysis, the concept of vulnerability is developed as a productive means of understanding the duty of care. Vulnerability is of increasing interest in legal and political theory and it is of particular relevance to the law of negligence. In addition to aiding doctrinal coherence, vulnerability – with its focus on relationships and care – has the potential to broaden the way in which the subject of tort law is conceived because it challenges dominant assumptions about autonomy as being prior to the relationships on which it is dependent.

Non-contributory pensions: Bolivia and Antigua in an international context

Includes bibliography

The Chilean system of contributory pensions as locus of rivalry and of a new social compact

This study assesses the contributory pension system in Chile and offers some recommendations for reform, from the viewpoint of social rights that generate expectations of satisfaction. The primary objective of any pension system is to provide income security to the elderly, and contributory pensions must reflect the savings achieved throughout working life in order to guarantee that, for similar levels of effort, similar and proportionate protection will be obtained.