A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice.

LKB1 has been identified as a component of the major upstream kinase of AMP-activated protein kinase (AMPK) in skeletal muscle. To investigate the roles of LKB1 in skeletal muscle, we used muscle-specific LKB1 knockout (MLKB1KO) mice that exhibit low expression of LKB1 in heart and skeletal muscle, but not in other tissues. The importance of LKB1 in muscle physiology was demonstrated by the observation that electrical stimulation of the muscle in situ increased AMPK phosphorylation and activity in the wild-type (WT) but not in the muscle-specific LKB1KO mice. Likewise, phosphorylation of acetyl-CoA carboxylase (ACC) was markedly attenuated in the KO mice. The LKB1KO mice had difficulty running on the treadmill and exhibited marked reduction in distance run in voluntary running wheels over a 3-wk period (5.9 +/- 0.9 km/day for WT vs. 1.7 +/- 0.7 km/day for MLKB1KO mice). The MLKB1KO mice anesthetized at rest exhibited significantly decreased phospho-AMPK and phospho-ACC compared with WT mice. KO mice exhibited lower levels of mitochondrial protein expression in the red and white regions of the quadriceps. These observations, along with previous observations from other laboratories, clearly demonstrate that LKB1 is the major upstream kinase in skeletal muscle and that it is essential for maintaining mitochondrial marker proteins in skeletal muscle. These data provide evidence for a critical role of LKB1 in muscle physiology, one of which is maintaining basal levels of mitochondrial oxidative enzymes. Capacity for voluntary running is compromised with muscle and heart LKB1 deficiency.

Gender and the behavioral manifestations of neuropathic pain.

A model of peripheral nerve injury was used to study gender differences in the development and progression of chronic constriction injury (CCI)-induced hyperalgesia and allodynia in male and female Fischer 344 FBNF1 hybrid rats. Rats were randomly assigned to one of the following treatment groups: (1) gonadally intact unligated males (male); (2) gonadally intact ligated males (male (CCI)); (3) castrated ligated males (male (CAS/CCI)); (4) gonadally intact unligated females (female); (5) gonadally intact ligated females (female (CCI)); and (6) ovariectomized ligated females (female (OVX/CCI)). A plantar analgesia meter and calibrated von Frey pressure filaments were used as the analgesiometric assays. In the absence of nerve injury, gonadally intact males responded significantly faster than females to a thermal nociceptive stimulus. The onset of the behavioral manifestations of unilateral ligation of the sciatic nerve did not differ as a function of sex or hormonal status (e.g., gonadally intact and gonadectomized male and female rats developed thermal hyperalgesia within 14 days post-CCI). Paw withdrawal latency (PWL) values of gonadally intact males returned to baseline control values after postligation day 14, whereas gonadally intact females, ovariectomized females and castrated males continued to elicit robust thermal hyperalgesic symptoms throughout the 35-day duration of the experiment. Allodynic responses to peripheral nerve injury were less variable across genders. These data suggest that the mechanisms underlying chronic nociceptive processing differ as a function of gender and gonadal hormone status.

Lag phase quantification for solid gastric emptying studies.

UNLABELLED: This study compared the different calculation methods of the solid gastric emptying lag phase and evaluated the effect of the temporal sampling interval on the calculated value using the modified power exponential (MPE) method. METHODS: Twenty normal control subjects and 42 patients had anterior and posterior image acquisition on a multihead gamma camera, one frame per minute x 90. ROIs were selected for the stomach, gastric antrum and small bowel. Time-activity curves (TACs) were generated for anterior, posterior and geometric mean data. The lag phase was calculated using various methods such as transition point, starting index, first appearance of bowel activity (FABA), MPE and antral peak filling time. To determine the importance of the temporal sampling rate on the calculation of the lag phase by the MPE, intervals between 1 and 20 min were analyzed. RESULTS: The transition point, starting index and FABA correlated extremely high (r = > or = 0.92) in normal control subjects and patients. Normal lag phase values were mean 22-24 +/- 10 min for transition point, starting index and FABA compared with 47 +/- 18 min for the MPE method (p < 0.0001). The MPE correlated poorly with the other method (r = 0.74). Antral peak filling time correlated poorly (r = 0.47) with transition point, starting index and FABA, but somewhat better with the MPE (r = 0.70). Comparing 15-min versus 1-min sampling intervals using the MPE, 35% of subjects had values that differed by > or = 7.5 min and 10% had values differing by > or = 15 min. CONCLUSION: The lag phase calculated by the MPE correlated poorly with other methods, and its accuracy was limited by the rate of the temporal sampling. The transition point, starting index and FABA all highly correlated with each other; the latter is a particularly reliable physiological indicator and is easily quantified using a small-bowel TAC.

Diagnosis of intracranial lymphoma in patients with AIDS: value of 201TI single-photon emission computed tomography.

OBJECTIVE: Although the prevalence of intracranial lymphoma is high among patients with AIDS, current imaging techniques are not reliable for differentiating this tumor from other common nonneoplastic lesions, such as those seen in toxoplasmosis. The purpose of this study was to prospectively investigate the use of 201Tl single-photon emission computed tomography (SPECT) in identifying intracranial lymphoma in patients with AIDS. SUBJECTS AND METHODS: Thirteen patients with AIDS and intracranial masses underwent 201Tl imaging with a three-headed SPECT camera. Sic of the 13 were subsequently proved to have lymphoma. Studies were interpreted prospectively as showing tumor if uptake of 201Tl was increased in the region where the lesion was seen on MR images. A lesion-to-nonlesion uptake ratio (counts/pixel) was calculated retrospectively. RESULTS: The SPECT images of six patients were interpreted prospectively as showing no lymphoma. Uptake ratios in these six patients were 0.77-1.95 (mean, 1.45). In each, tumor was excluded as a final diagnosis (four had toxoplasmosis, one had progressive multifocal leukoencephalopathy, and one had venous angioma). Among the seven patients with SPECT images interpreted as showing lymphoma, six were later proved to have lymphoma (uptake ratio: mean, 3.65; range, 2.95-4.30; p < .005). The SPECT findings in the seventh patient were classified as false-positive for tumor on the basis of the prospective interpretation of the images; three concurrent infections were found at autopsy. The uptake ratio in this patient was low (1.81), suggesting that quantification might have diagnostic usefulness for improving accuracy. CONCLUSION: This preliminary study indicates that 201Tl SPECT might be a useful, noninvasive method for differentiating intracranial lymphoma from nonneoplastic lesions in patients with AIDS.

Diurnal rhythmicity and Air Force flight accidents due to pilot error.

In order to evaluate the possible role of an endogenous rhythmic factor in Air Force flight accidents a retrospective study was carried out. The study included all Air Force (aircraft) flying accidents which have been attributed to pilot's error and which occurred, in peace time missions, over a period of 12 years (1968-1980). The frequency of hourly accidents was computed separately, for each year, for each month, for each day of the week, and for each calendar day. Identical computations were carried out for the frequency of hourly flights. When the hourly ratios of these two parameters were computed, by dividing the value of one parameter to the other at each hour, a rhythmic (rather than constant) diurnal pattern was obtained. The pattern was defined as the "Hourly Accident Coefficient (HAC)". The HAC values ranged from 1.58 to 0.68 (pooled data for all surveyed aircrafts) and from 4.12 to 0.74 (data for fighter planes). The pattern, which exhibited a diurnal rhythm, was independent of the frequency of flights and appeared to be related to the sleep-wake cycle of the pilots, especially to the time of waking from the night sleep. The results are used as a directive for a progressive study aimed at evaluating the practical implications of the presented observations.