Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia.

PURPOSE: Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206. Experimental Methods: We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA). RESULTS: In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%-17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%-45%) and limited inhibition of downstream targets. CONCLUSIONS: Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored.

The subthalamic region is activated during valence-related emotional processing in patients with Parkinson's disease.

Visual stimuli are judged for their emotional significance based on two fundamental dimensions, valence and arousal, and may lead to changes in neural and body functions like attention, affect, memory and heart rate. Alterations in behaviour and mood have been encountered in patients with Parkinson's disease (PD) undergoing functional neurosurgery, suggesting that electrical high-frequency stimulation of the subthalamic nucleus (STN) may interfere with emotional information processing. Here, we use the opportunity to directly record neuronal activity from the STN macroelectrodes in patients with PD during presentation of emotionally laden and neutral pictures taken from the International Affective Picture System (IAPS) to further elucidate the role of the STN in emotional processing. We found a significant event-related desynchronization of STN alpha activity with pleasant stimuli that correlated with the individual valence rating of the pictures. Our findings suggest involvement of the human STN in valence-related emotional information processing that can potentially be altered during high-frequency stimulation of the STN in PD leading to behavioural complications.

Effect of dietary supplementation with conjugated linoleic acid on markers of calcium and bone metabolism in healthy adult men.

INTRODUCTION: Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism in experimental animals and cells in culture, but there are limited human data available. OBJECTIVE: To investigate the effect of CLA supplementation on biomarkers of calcium and bone metabolism in healthy adult males. DESIGN: The study consisted of a double-blind, placebo-controlled trial in which 60 healthy adult males (aged 39-64 y) were randomly assigned to receive daily either 3.0 g CLA isomer blend (50:50% cis-9,trans-11:trans-10,cis-12 isomers) or a palm/bean oil blend (placebo) for 8 weeks. Urine and blood samples were collected at weeks 0 and 8 and were analysed for biomarkers of calcium and bone metabolism. RESULTS: Supplementation with CLA or placebo for 8 weeks had no significant effects on markers of bone formation (serum osteocalcin and bone-specific alkaline phosphatase) or bone resorption (serum C-telopeptide-related fraction of type 1 collagen degradation products, urinary N-telopeptide-related fraction of type 1 collagen degradation products, urinary pyridinoline and deoxypyridinoline), or on serum or urinary calcium levels. Baseline levels of these biochemical parameters were similar in both groups of subjects. While the placebo had no effect, CLA supplementation resulted in a three-fold increase (P<0.00001) in cis-9,trans-11 CLA isomer in total plasma lipids. CONCLUSION: Under the conditions tested in this double-blind, placebo-controlled trial in adult men, a CLA supplement of mixed isomers did not affect markers of calcium or bone metabolism. Further investigation of the effects of CLA on calcium and bone metabolism in other gender- and age-groups is warranted.

Chemoradiation therapy is effective for the palliative treatment of malignant dysphagia.

Between 1993 and 2001, 106 patients with esophageal cancer were reviewed at a multidisciplinary clinic and treated with palliative intent by chemoradiation therapy. This study assesses the palliative benefit on dysphagia and documents the toxicity of this treatment. The study population comprised 72 men and 34 women with a median age of 69 years. Patients were treated with a median radiation dose of 35 Gy in 15 fractions with a concurrent single course of 5 FU-based chemotherapy. Dysphagia was measured at the beginning and completion of treatment and at monthly intervals until death, using a modified DeMeester (4-point) score. Treatment was well tolerated, with only 5% of patients failing to complete therapy. The treatment-related mortality was 6%. The median survival for the study population was 7 months. The median baseline score at presentation was 2 (difficulty with soft food). Following treatment, 49% of patients were assessed as having a dysphagia score of 0 (no dysphagia). Seventy-eight per cent had an improvement of at least one grade in their dysphagia score after treatment. Only 14% of patients showed no improvement with treatment. Fifty-one per cent maintained improved swallowing until the time of last follow-up or death. This single-institution study shows that chemoradiation therapy administered for the palliation of malignant dysphagia is well tolerated and produces a sustainable normalization in swallowing for almost half of all patients.

The effect of magnesium supplementation on biochemical markers of bone metabolism or blood pressure in healthy young adult females.

OBJECTIVES: To investigate the effects of increasing Mg intakes, above the usual dietary intake, on blood pressure and on biomarkers of bone metabolism in healthy young adult females. DESIGN: A double-blind, placebo-controlled, randomised crossover Mg intervention trial. SETTING: The study was conducted in the Department of Nutrition, University College, Cork, Ireland. SUBJECTS: Twenty-six healthy (normotensive) adult females aged 20-28 y were recruited from University College, Cork. INTERVENTION: Subjects were randomly assigned to their self-selected diets (approximately 11 mmol Mg/d) or their self-selected diet with a 10 mmol/d Mg supplement as Mg(OH)2 (approximately 22 mmol Mg/d) for 28 d followed by cross-over to the alternative diet for a further 28 d. During each dietary period urines (last 3 d) and blood (morning of 27 d) were collected and blood pressure was measured on the morning of 28 d. RESULTS: Increasing Mg intake from the usual level (11 mmol/d) to 22 mmol/d for 28d increased urinary excretion of Mg by 36% and erythrocyte Mg content by 5% but had no effect on serum Mg, Ca, PTH, osteocalcin or bone-specific alkaline phosphatase (biomarkers of bone formation), urinary pyridinium crosslinks of collagen (biomarkers of bone resorption), or on blood pressure. CONCLUSION: Increasing the mean Mg intake in healthy young adult females above the usual dietary intake, which is currently above the US EAR (estimated average requirement), but below the US RDA for Mg, does not affect blood pressure or the rate of bone turnover.

Attenuating the hypertensive response to laryngoscopy and endotracheal intubation using awake fibreoptic intubation.

Blood pressure and pulse rate measurements were recorded in 35 patients undergoing endotracheal intubation during general anaesthesia (Group A), and 35 patients who had an awake fibreoptic intubation under local anaesthesia (Group B). The mean arterial pressure in Group A rose by a mean of 35 mmHg immediately after intubation, compared with a mean fall of 9 mmHg in Group B. The mean pulse rate in Group A rose by 24 beats per minute (b.p.m.) immediately after intubation, compared with a rise of 3 b.p.m. in Group B. Both these differences were statistically significant (P less than 0.0001 and P less than 0.001 respectively, Mann Whitney U test). Postoperative discomfort was assessed 24 h later by means of linear analogue scales. There was a statistically higher mean score in relation to nose discomfort in Group B (P less than 0.002). Awake fibreoptic intubation successfully reduces the pressor response to endotracheal intubation in normotensive adults. It is suitable for use in those patients who are at risk from the pressor response.

Insensible water loss in newborn infants.

In this review we have described, in some detail, the physical processes involved in water loss from both the skin and lungs. Although at first glance these physical processes may seem complex and confusing, once the basic concepts are grasped, the effect of the many variables in both the babies and their environment on IWL can be seen more clearly. Measurement of IWL, or its components, TEWL and RWL, is difficult in newborn infants. Some of the difficulties arise because of the nature of the subject being studied, and because of inaccuracy in the measuring apparatus. The difficulties in the subjects include lack of cooperation, and the presence of severe illness, both of which may limit the representativeness of any sample of babies that is eventually studied successfully. The size of the subjects studied means that small amounts of water are given off in any fixed period of time. Consequently, the accuracy of the measuring instruments has to be high. As we have discussed, each of the methods used to estimate IWL, TEWL, or RWL has limitations and potential inaccuracies. Despite the difficulties in obtaining estimates of IWL in newborn infants, there have been many studies over the years that have provided clinically useful data. More recently, improved survival of VLBW infants has lead to an awareness that IWL is substantially increased in these tiny babies. The best way to manage the problems of water and heat balance associated with increased IWL in VLBW infants remains to be determined.