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501.
Oza V Ashwell S Almeida L Brassil P Breed J Deng C Gero T Grondine M Horn C Ioannidis S Liu D Lyne P Newcombe N Pass M Read J Ready S Rowsell S Su M Toader D Vasbinder M Yu D Yu Y Xue Y Zabludoff S Janetka J 《Journal of medicinal chemistry》2012,55(11):5130-5142
Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models. 相似文献
502.
We have examined the cyto- and chemoarchitecture of the trigeminal nuclei of two monotremes using Nissl staining, enzyme reactivity for cytochrome oxidase, immunoreactivity for calcium binding proteins and non-phosphorylated neurofilament (SMI-32 antibody) and lectin histochemistry (Griffonia simplicifolia isolectin B4). The principal trigeminal nucleus and the oralis and interpolaris spinal trigeminal nuclei were substantially larger in the platypus than in either the echidna or rat, but the caudalis subnucleus was similar in size in both monotremes and the rat. The numerical density of Nissl stained neurons was higher in the principal, oralis and interpolaris nuclei of the platypus relative to the echidna, but similar to that in the rat. Neuropil immunoreactivity for parvalbumin was particularly intense in the principal trigeminal, oralis and interpolaris subnuclei of the platypus, but the numerical density of parvalbumin immunoreactive neurons was not particularly high in these nuclei of the platypus. Neuropil immunoreactivity for calbindin and calretinin was relatively weak in both monotremes, although calretinin immunoreactive somata made up a large proportion of neurons in the principal, oralis and interpolaris subnuclei of the echidna. Distribution of calretinin immunoreactivity and Griffonia simplicifolia B4 isolectin reactivity suggested that the caudalis subnucleus of the echidna does not have a clearly defined gelatinosus region. Our findings indicate that the trigeminal nuclei of the echidna do not appear to be highly specialized, but that the principal, oralis and interpolaris subnuclei of the platypus trigeminal complex are highly differentiated, presumably for processing of tactile and electrosensory information from the bill. 相似文献
503.
IMAGING LUNG AERATION AND LUNG LIQUID CLEARANCE AT BIRTH USING PHASE CONTRAST X-RAY IMAGING 总被引:1,自引:1,他引:0
Stuart B Hooper Marcus J Kitchen Melissa LL Siew Robert A Lewis reas Fouras Arjan B te Pas Karen KW Siu Naoto Yagi Kentaro Uesugi Megan J Wallace 《Clinical and experimental pharmacology & physiology》2009,36(1):117-125
- 1 The transition to extra‐uterine life at birth is critically dependent on airway liquid clearance to allow the entry of air and the onset of gaseous ventilation. We have used phase contrast X‐ray imaging to identify factors that regulate lung aeration at birth in spontaneously breathing term and mechanically ventilated preterm rabbit pups.
- 2 Phase contrast X‐ray imaging exploits the difference in refractive index between air and water to enhance image contrast, enabling the smallest air‐filled structures of the lung (alveoli; < 100 µm) to be resolved. Using this technique, the lungs become visible as they aerate, allowing the air–liquid interface to be observed as it moves distally during lung aeration.
- 3 Spontaneously breathing term rabbit pups rapidly aerate their lungs, with most fully recruiting their functional residual capacity (FRC) within the first few breaths. The increase in FRC occurs mainly during individual breaths, demonstrating that airway liquid clearance and lung aeration is closely associated with inspiration. We suggest that transpulmonary pressures generated by inspiration provide a hydrostatic pressure gradient for the movement of water out of the airways and into the surrounding lung tissue after birth.
- 4 In mechanically ventilated preterm pups, lung aeration is closely associated with lung inflation and a positive end‐expiratory pressure is required to generate and maintain FRC after birth.
- 5 In summary, phase contrast X‐ray imaging can image the air‐filled lung with high temporal and spatial resolution and is ideal for identifying factors that regulate lung aeration at birth in both spontaneously breathing term and mechanically ventilated preterm neonates.
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