Tumor cell uptake and selectivity of gadolinium(III)-phosphonium complexes: The role of delocalisation at the phosphonium centre

The synthesis of a series of bifunctional Gd(III) complexes 1–3 covalently bound to arylphosphonium cations possessing a varying degree of delocalisation at the phosphonium centre is presented. The influence of the degree of delocalisation was investigated with regards to in vitro cytotoxicity, cellular uptake of Gd, tumor-cell selectivity and intracellular localisation of Gd within human glioblastoma (T98G) and human glial (SVG p12) cells. Cellular uptake and selectivity studies for the Gd(III) complexes indicate that a reduced delocalisation at the phosphonium centre can lead to an enhanced Gd uptake into SVG p12 cells which results in a decrease in the overall tumor cell selectivity. Synchrotron X-ray fluorescence (microbeam XRF) imaging has demonstrated for the first time that uniform uptake of Gd(III) complex 2 within a population of T98G cells increased as a function of increasing Gd incubation times. The Gd maps show dispersed spots of high intensity which are consistent with mitochondrial uptake.Australian Research Council (ARC DP120100958 and ARC DP140100176

Medicolegal costs of bile duct injuries incurred during laparoscopic cholecystectomy

AbstractBackgroundWhen laparoscopic cholecystectomy (LC) is performed successfully, recovery is faster than after open cholecystectomy. However, LC results in higher incidences of biliary, bowel and vascular injury.MethodsWe performed a retrospective review of LC-related claims reported to the National Health Service Litigation Authority (NHSLA) during 2000–2005. The data were analysed from a medicolegal perspective to assess the effects of type of injury and delay in recognition on litigation costs.ResultsA total of 208 claims following laparoscopic procedures in general surgery were reported to NHSLA during 2000–2005, of which 133 (64%) were related to LC. Bile duct injury (BDI) accounted for the majority of claims (72%); bowel injury and ‘others’ accounted for 9% and 19%, respectively. Only 20% of BDIs were recognized during surgery; the majority were missed and diagnosed later. Claims related to LC resulted in payments totalling £6m, of which £4.3m was paid out for BDIs. The average cost was higher for patients who suffered a delay in diagnosis, as was the chance of a successful claim.ConclusionsBile duct injury incurred during LC remains a serious hazard for patients. The resulting complications have led to litigation that has caused a huge financial drain on the health care system. Delayed recognition appears to correlate with more costly litigation

Discovery of Novel, Dual Mechanism ERK Inhibitors by Affinity Selection Screening of an Inactive Kinase

An affinity-based mass spectrometry screening technology was used to identify novel binders to both nonphosphorylated and phosphorylated ERK2. Screening of inactive ERK2 identified a pyrrolidine analogue <b>1</b> that bound to both nonphosphorylated and phosphorylated ERK2 and inhibited ERK2 kinase activity. Chemical optimization identified compound <b>4</b> as a novel, potent, and highly selective ERK1,2 inhibitor which not only demonstrated inhibition of phosphorylation of ERK substrate p90RSK but also demonstrated inhibition of ERK1,2 phosphorylation on the activation loop. X-ray cocrystallography revealed that upon binding of compound <b>4</b> to ERK2, Tyr34 undergoes a rotation (flip) along with a shift in the poly-Gly rich loop to create a new binding pocket into which <b>4</b> can bind. This new binding mode represents a novel mechanism by which high affinity ATP-competitive compounds may achieve excellent kinase selectivity