Inhibiting the RAS oncogenic protein has largely been through targeting the switch regions that interact with signalling effector proteins. Here, we report designed ankyrin repeat proteins (DARPins) macromolecules that specifically inhibit the KRAS isoform by binding to an allosteric site encompassing the region around KRAS-specific residue histidine 95 at the helix α3/loop 7/helix α4 interface. We show that these DARPins specifically inhibit KRAS/effector interactions and the dependent downstream signalling pathways in cancer cells. Binding by the DARPins at that region influences KRAS/effector interactions in different ways, including KRAS nucleotide exchange and inhibiting KRAS dimerization at the plasma membrane. These results highlight the importance of targeting the α3/loop 7/α4 interface, a previously untargeted site in RAS, for specifically inhibiting KRAS function.

There was insufficient evidence that glycerine gel dressings, breast shells with lanolin, lanolin alone, or the all-purpose nipple ointment significantly improved maternal perceptions of nipple pain. The results from these four trials of good methodological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin.The quality of the evidence for this review did not lead to robust conclusions regarding the objectives assessed. We included only four trials, incorporating 656 women, in the review and all four trials compared varying interventions, participants, study outcome measures, and standards of usual care. The methodological quality of the included studies was good but the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly because single studies with few participants contributed data for analysis.

PurposeModern neuraxial labour analgesia reflects a shift in obstetrical anesthesia thinking – away from a simple focus on pain relief towards a focus on the overall quality of analgesia. However, advances in the methods used to measure outcomes have not kept pace with clinical progress, and these approaches must evolve to facilitate meaningful assessment of the advances provided towards the quality of analgesia. Developing a tool to measure the quality of neuraxial labour analgesia that research has achieved is best guided by women’s perspectives. As the initial step in developing an instrument to quantitatively measure quality neuraxial labour analgesia, this qualitative descriptive study explored childbearing women’s experiences and perspectives regarding this subject.MethodsTwenty-eight postpartum women, all delivering with neuraxial labour analgesia, were recruited from three hospitals in the greater Toronto area. Twenty-five women described a priori plans to use neuraxial labour analgesia, or they described themselves as having been open to the idea. Women’s experiences and perspectives of neuraxial labour analgesia were explored in focus groups and in-depth interviews ≤72 hr following childbirth.ResultsFour major themes emerged: 1)The Enormity of Labour Pain; 2) Fear and Anxiety Related to Epidural Pain Relief; 3) What Women Value about Epidural Pain Relief; and 4) The Relative Value of Achieving Epidural Pain Relief vs Avoidance of Epidural Drug Side Effects. Participants broadly described quality neuraxial labour analgesia as pain relief without side effects. Responses affirmed the importance of traditionally measured outcomes as attributes of quality neuraxial labour analgesia, e.g., pain relief and side effects, as well as the overall importance of pain control during labour and delivery. For research to capture the experience of quality neuraxial labour analgesia, findings suggest that this outcome involves physical, cognitive, and emotional dimensions that must be measured. The findings further suggest an important relationship between each of these dimensions and perceptions of control.ConclusionsWomen’s perspectives must be incorporated into the assessment of quality neuraxial labour analgesia in order for research to measure this outcome in a meaningful manner. Study findings have important implications for scale development, interpretation of existing research, and antenatal education.