Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

Design and optimization of potent and orally bioavailable tetrahydronaphthalene Raf inhibitors.

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

Exploring dual professional identities, the role of the nurse tutor in higher education in the UK: role complexity and tensions.

AIMS: This paper presents a discussion on the role of the nurse, teachers in mainstream education and nurse educators, reviewing theories of professional identity and how these theories have had an impact on practice. BACKGROUND: The professional identity of both the teacher and nurse aspect of the nurse educator role is reviewed using historical perspectives to define the role of a nurse from doctor's handmaiden to autonomous practitioner, and determine society's idea of a teacher. DATA SOURCES: The literature reviewed for this paper has been drawn from the Cumulated Index Nursing And Allied Heath Literature, Educational Resources Information Centre, Professional Development Collection and Education-line. The period of literature publications taken up for review was 1960-2009 to gain a historical view and the main phrases used were Nurse Education and Educators, Nurse Roles, Professionalism and Professional Development. DISCUSSION: Issues of role complexity were considered, highlighting tensions, supposed or actual and ethical obligation in healthcare education. The apparent need to gain professional status is discussed. IMPLICATIONS FOR NURSING: Tensions and complexities in the nurse educator's role combine, causing problems in their practice. Opinions are that nurse educators are expert nurses and teachers. Published authors believe that there is a need for the nurse educator to maintain specialist knowledge in nursing practice, yet there is little discussion relating to specializing in teaching practice. CONCLUSIONS: Combining the roles of nurse and teacher removes each concrete identity. A role crisis occurs when nurse educators may be unable to prove their professional ability in nursing or establish their professional position as a teacher.

Discovery and optimization of pyrazoline compounds as B-Raf inhibitors.

The discovery of novel pyrazoline derivatives as B-Raf (V600E) inhibitors is described in this report. Chemical modification of the pyrazoline scaffold led to the development of SAR and identified potent and selective inhibitors of B-Raf (V600E). Determination of the pharmacokinetic properties of selected inhibitors is also reported.

Qualitative health needs assessment of a former mining community.

This paper reports on a health needs assessment that set out to elicit the perceived and expressed health and wellbeing needs of the residents of a former mining village in Kent. Data was principally collected from residents, professionals and stakeholders through focus groups and interviews. Open days enabled key themes to emerge and provided verification of the research findings. A wide range of services and improvements that would have an impact on wellbeing were identified, requiring a multi-agency approach to delivery, but primary health care services were regarded as the priority. The outcome of the study has been a commitment from the primary care trust to provide a part-time nurse practitioner/prescriber in the village and to employ a community centre manager to support health promotion activities and thereby address the concerns raised by the residents and stakeholders.

Narcolepsy in children: a single-center clinical experience.

Although the initial manifestations of narcolepsy in children may differ from those with adult onset, hypersomnia remains the most common presenting sign. This study aimed to (1) describe the clinical and polysomnographic features, and treatment outcomes, of a group of children with narcolepsy, and (2) describe other sleep disorders to be considered in the differential diagnosis of hypersomnia and which may coexist with narcolepsy. A retrospective review of 125 children referred in 1 year for hypersomnia revealed 20 patients (16%) with narcolepsy. Of these, only 15% exhibited cataplexy, 10% experienced hallucinations, and none manifested sleep paralysis. Eighty-five percent of children with narcolepsy had sleep-disordered breathing on polysomnography. Body mass indices of these children were higher than for healthy, age-matched controls subjects. Other polysomnography findings included periodic limb movements of sleep (25%) and parasomnias (5%). The multiple sleep latency test revealed a mean sleep latency of 6.14 minutes, with sleep-onset rapid eye movement periods (median, 2/5 naps). Treatment with modafinil and sodium oxybate provided optimal control of daytime sleepiness. Physicians should routinely screen for hypersomnia in children by obtaining a detailed history and, in appropriate situations, ordering polysomnographic testing to rule out narcolepsy and other causes of hypersomnia.

Association between inadequate sleep and insulin resistance in obese children.

OBJECTIVE: To analyze the relationships between sleep duration, obstructive sleep apnea syndrome (OSAS), and markers of insulin resistance in obese children. STUDY DESIGN: Forty obese children were evaluated for sleep-related complaints. Each child underwent a polysomnogram, an oral glucose tolerance test (OGTT), and fasting lipid panel tests. Indices of insulin resistance (HOMA-IR and WBISI) and insulin secretion (IGI) were calculated based on the results of the OGTT. Markers of insulin resistance were compared among groups categorized according to polysomnogram results. RESULTS: Subjects with shorter sleep duration had higher fasting insulin, peak insulin, and HOMA-IR levels and lower WBISI levels, findings suggestive of insulin resistance. In contrast, differences in body mass index z scores were not observed. Subjects with OSAS (32 of 40 children) had higher triglyceride levels and HOMA-IR values than those without OSAS, but did not differ in sleep duration. Multiple linear regression analysis revealed that HOMA-IR was significantly correlated with age, sleep duration, and percentage of rapid-eye-movement sleep. CONCLUSIONS: Insulin resistance in obese children is associated with short sleep duration and OSAS.

Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.

This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.