Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Richard Nixon, Reputation, and Watergate

This examines Richard Nixon's campaign for post-Watergate redemption and his enduring failure to escape the negative effect of watergate on his historical reputatio

The ortho-plastic approach to soft tissue management in trauma.

Fractures with associated soft tissue injuries, or those termed 'open,' are not uncommon. There has been much discussion regarding there management, with the guidance from the combined British Orthopaedic Association and British Association and Aesthetic Surgeons teams widely accepted as the gold level of therapy. We aim to discuss the current evidence about the initial management of this group of injuries, taking a journey from arrival in the accident and emergency department through to the point of definitive closure. Other modes of therapy are also reviewed