Pathway profiling of a novel SRC inhibitor,AZD0424, in combination with MEK inhibitors for cancer treatment

A more comprehensive understanding of how cells respond to drug intervention, the likely immediate signalling responses and how resistance may develop within different microenvironments will help inform treatment regimes. The nonreceptor tyrosine kinase SRC regulates many cellular signalling processes, and pharmacological inhibition has long been a target of cancer drug discovery projects. Here, we describe the in vitro and in vivo characterisation of the small‐molecule SRC inhibitor AZD0424. We show that AZD0424 potently inhibits the phosphorylation of tyrosine‐419 of SRC (IC50 ~ 100 nm) in many cancer cell lines; however, inhibition of cell viability, via a G1 cell cycle arrest, was observed only in a subset of cancer cell lines in the low (on target) micromolar range. We profiled the changes in intracellular pathway signalling in cancer cells following exposure to AZD0424 and other targeted therapies using reverse‐phase protein array (RPPA) analysis. We demonstrate that SRC is activated in response to treatment of KRAS‐mutant colorectal cell lines with MEK inhibitors (trametinib or AZD6244) and that AZD0424 abrogates this. Cell lines treated with trametinib or AZD6244 in combination with AZD0424 had reduced EGFR, FAK and SRC compensatory activation, and cell viability was synergistically inhibited. In vivo, trametinib treatment of mice‐bearing HCT116 tumours increased phosphorylation of SRC on Tyr419, and, when combined with AZD0424, inhibition of tumour growth was greater than with trametinib alone. We also demonstrate that drug‐induced resistance to trametinib is not re‐sensitised by AZD0424 treatment in vitro, likely as a result of multiple compensatory signalling mechanisms; however, inhibition of SRC remains an effective way to block invasion of trametinib‐resistant tumour cells. These data imply that SRC inhibition may offer a useful addition to MEK inhibitor combination strategies.     

Nonpurging bulimia: A distinct subtype of bulimia nervosa

Bulimics whose primary method of purgation was self-induced vomiting (purgers) were compared to bulimics who did not purge (nonpurgers), using standardized diagnostic instruments. Differences in eating patterns, demographic characteristics, past and present DSM-III-R diagnoses, mood and personality traits were found. Purgers were younger, more likely to be single, and binged more frequently than nonpurgers. More purgers had Major Depression, Panic Disorder, or past Anorexia Nervosa than did nonpurgers. Purgers scored higher on the narcissistic, masochistic (self-defeating), and borderline scales of the Personality Disorders Examination. In contrast, nonpurgers were more likely to be overweight and have history of substance abuse than purgers. These findings support the view that nonpurging bulimics constitute a distinct clinical group, and suggest that differences between purging and nonpurging bulimics may reflect differences in core pathology.     

Plasma endothelin response to acute hypoglycaemia in adults with Type 1 diabetes.

AIMS: To determine whether acute insulin-induced hypoglycaemia provokes a detectable alteration in peripheral plasma endothelin (ET) concentrations in humans with Type 1 diabetes. METHODS: Serial plasma concentrations of ET were measured in 20 patients with Type 1 diabetes during controlled hypoglycaemia induced by intravenous infusion of soluble insulin. RESULTS: A significant increase was observed in plasma ET concentrations, from 3.80 +/- 0.31 pg/ml at baseline to 6.72 +/- 1.47 pg/ml at 60 min after the onset of the hypoglycaemic reaction (P < 0.05). CONCLUSIONS: Acute insulin-induced hypoglycaemia induces a rise in plasma endothelin concentrations in people with Type 1 diabetes. This finding is consistent with a putative role for ET in the mediation of hypoglycaemia-induced vasoconstriction, and the possible precipitation of macrovascular or microvascular events.     

An unusual cause of severe hypoglycaemia in type 1 diabetes mellitus. Antepartum pituitary failure: a case report and literature review.

We describe an unusual cause of severe hypoglycaemia, secondary to hypopituitarism as a result of antepartum pituitary failure, in a pregnant patient with type 1 diabetes mellitus (T1DM). Antepartum pituitary failure is a very rare condition, which has been reported only in a very small number of pregnant patients with diabetes and presents with an acute onset headache and a sub-arachnoid haemorrhage-like picture. It is a potentially fatal condition to the mother and the child if not recognised and treated. Our case report highlights the importance of thinking about hypopituitarism, as a cause of recurrent hypoglycaemia in pregnant patients with T1DM as missing the diagnosis could be fatal to the mother and child.     

Project 2000. Perceptions of the philosophy and practice of nursing: preparation for practice

As part of a comprehensive study of perceptions of the philosophy and practice of nursing Project 2000 students and newly qualified diplomates were asked to reflect on their Project 2000 course as a preparation for professional practice. Data were collected from both students and diplomates through self-completion questionnaires and a small number of interviews with diplomates in two study centres, one in the north and the other in the south of England. Nurse managers and G grade practitioners were invited in focus group interviews to discuss the Project 2000 preparation and assess the diplomates 'fitness for purpose'. Findings suggest that the majority of students and diplomates acknowledged that the course had prepared them well. They acknowledged the importance of the inter-personal skills component of the course, together with the life sciences input. The diplomates particularly valued the theoretical aspect of the course, being well versed in research and keen to continue their learning. Perceived limitations of the course were the management preparation and course organization. Practical skill deficits were perceived as initial skills deficits only. Managers and practitioners were keen to employ the diplomates, whilst acknowledging their need for support and preceptorship. Three important issues for nursing and nurse education are discussed, including the balance of the Project 2000 course, preceptorship and support, and preparation for a role in the community.