Identification of 6-Anilino Imidazo[4,5-c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers.

The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.

Research midwives: look at the evidence!

Evidence based practice underpins modern healthcare and includes the use of research knowledge, consideration of an individual's circumstances and their personal preferences. Maternal and child health care interventions aim to prevent disease and disability and promote health and wellbeing. Before interventions are brought into practice the benefits and risks should be adequately evaluated to ensure clinicians and those receiving the interventions fully understand the potential effects. A multidisciplinary team approach to the development of research initiatives is advantageous. The team should include clinicians, researchers and service users working together to answer important clinical questions. It is our view that clinical research midwives are pivotal to the success of maternal and child health improvement initiatives. For example they can help reduce the gap between clinical practice and research by making research understandable to clinicians and applicable to practice by working in partnership with academics.

Alternative positions for the baby at birth before clamping the umbilical cord.

BACKGROUND: The third stage of labour is from birth of the baby until delivery of the placenta. Clamping the umbilical cord is one component of active management of the third stage. Deferring cord clamping allows blood flow between the baby and the placenta to continue; net transfer to the baby is called placental transfusion. If the cord is clamped immediately placental transfusion is restricted. Gravity is one of several factors that may influence the volume and duration of placental transfusion at both vaginal and caesarean births. Hence raising or lowering the baby whilst the cord is intact may influence placental transfusion, which in turn may affect outcome for the baby and the woman. OBJECTIVES: To compare the effects of alternative positions for the baby between birth and cord clamping on outcome for the baby, outcome for the mother and on use of health service resources. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010). SELECTION CRITERIA: Randomised trials comparing alternative positions for the baby at vaginal and caesarean birth, before clamping of the umbilical cord. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and quality. When necessary, we contacted study authors for additional information. MAIN RESULTS: Thirty-seven studies (7559 mother-infant pairs) were excluded: 33 (7296) because they did not compare alternative positions for the baby before clamping the umbilical cord and four (263) due to quasi-random allocation. No studies met the inclusion criteria. One additional trial is ongoing. AUTHORS' CONCLUSIONS: No randomised trials have assessed the influence of gravity on placental transfusion. Large, well-designed randomised trials are needed to assess whether gravity influences placental transfusion at vaginal and caesarean births and, if so, whether this affects short-term and long-term outcome for the baby and for the mother.

Care during the third stage of labour: a postal survey of UK midwives and obstetricians.

BACKGROUND: There are two approaches to care during the third stage of labour: Active management includes three components: administration of a prophylactic uterotonic drug, cord clamping and controlled cord traction. For physiological care, intervention occurs only if there is clinical need. Evidence to guide care during the third stage is limited and there is variation in recommendations which may contribute to differences in practice. This paper describes current UK practice during the third stage of labour. METHODS: A postal survey of 2230 fellows and members of the Royal College of Obstetricians and Gynaecologists (RCOG) and 2400 members of the Royal College of Midwives was undertaken. Respondents were asked about care during the third stage of labour, for vaginal and caesarean births and their views on the need for more evidence to guide care in the third stage. The data were analysed in Excel and presented as descriptive statistics. RESULTS: 1189 (53%) fellows and members of the RCOG and 1702 (71%) midwives responded, of whom 926 (78%) and 1297 (76%) respectively had conducted or supervised births in the last year. 93% (863/926) of obstetricians and 73% (942/1297) of midwives report 'always or usually' using active management. 66% (611/926) of obstetricians and 33% (430/1297) of midwives give the uterotonic drug with delivery of the anterior shoulder; this was intramuscular Syntometrine(R) for 79% (728/926) and 86% (1118/1293) respectively. For term births, 74% (682/926) of obstetricians and 41% (526/1297) of midwives clamp the cord within 20 seconds, as do 57% (523/926) and 55% (707/1297) for preterm births. Controlled cord traction was used by 94% of both obstetricians and midwives. For caesarean births, intravenous oxytocin was the uterotonic used by 90% (837/926) of obstetricians; 79% (726/926) clamp the cord within 20 seconds for term births as do 63% (576/926) for preterm births.Physiological management was used 'always or usually' by 2% (21/926) of obstetricians and 9% (121/1297) of midwives. 81% (747/926) of obstetricians and 89% (1151/1297) of midwives thought more evidence from randomised trials was needed; the most popular question was when is best to clamp the cord. CONCLUSIONS: Active management of the third stage of labour is widely used by both obstetricians and midwives in the UK. Syntometrine(R) is usually used for vaginal births and oxytocin for caesarean births; when this is given and when the cord is clamped varies.