Shining a light on cell signaling in leukemia through proteomics: relevance for the clinic

Introduction: Although cure rates for acute leukemia have steadily improved over the past decades, leukemia remains a deadly disease. Enhanced risk stratification and new therapies are needed to improve outcome. Extensive genetic analyses have identified many mutations that contribute to the development of leukemia. However, most mutations occur infrequently and most gene alterations have been difficult to target. Most patients have more than one driver mutation in combination with secondary mutations, that result in a leukemic transformation via the alteration of proteins. The proteomics of acute leukemia could more directly identify proteins to facilitate risk stratification, predict chemoresistance and aid selection of therapy.

Areas covered: This review discusses aberrantly expressed proteins identified by mass spectrometry and reverse phase protein arrays and their relationship to survival. In addition, we will discuss proteins in the context of functionally related protein groups.

Expert commentary: Proteomics is a powerful tool to analyze protein abundance and functional alterations simultaneously for large numbers of patients. In the forthcoming years, validation of tools to quickly assess protein levels to enable routine rapid profiling of proteins with differential abundance and functional activation may be used as adjuncts to aid in therapy selection and to provide additional prognostic insights.     

Isolation of a bunyamwera group arbovirus from a naturally infected caribou

A Bunyamwera group arbovirus was isolated from the blood and from the brain of a female caribou parasitized with meningeal worms. The virus passed through a 0.45 micron filter; was ether sensitive; possessed no hemagglutination properties; could be propagated in suckling mice, 6-day old chick embryos, and BHK-21 tissue culture; and produced plaques in chick embryo fibroblast tissue culture. Neither complement-fixation or neutralization tests were sensitive enough to determine the serotype of the virus.     

Behavioral effects of changing group membership among captive lowland gorillas

Group membership was modified among 4 gorilla groups at Zoo Atlanta in an attempt to increase compatibility and sexual behavior. The modifications ultimately moved 7 adult females among the groups. The moves were made by individually introducing the new group members to the old members, resulting in 18 total introductions. Several individual and social behaviors differed in the two conditions. The most obvious change was a temporary increase in aggressive display behaviors, as well as an increase in contact and social examination, in the postmovement condition. Additionally, the individual behaviors of travelling and eating increased after the introductions, while resting decreased. Other self-maintenance behaviors did not change. Finally, there was an increase in time mothers and offspring spent closer to one another following the moves. Previous research and anecdotal evidence suggest that gorillas respond to changes in group membership with aggression; these data support and extend those data to different age/sex groups, postmovement trends in behavior, and other aspects of gorilla behavior. © 1996 Wiley-Liss, Inc.     

First-in-Man Open Clinical Trial of a Combined rdESAT-6 and rCFP-10 Tuberculosis Specific Skin Test Reagent

Background

Tuberculin is still the only available skin test reagent for the diagnosis of mycobacterial infection. The product has a remarkable sensitivity, but poor specificity. Previous studies, including two human phase I clinical trials, have indicated that rdESAT-6 has a potential as an improved skin test reagent. Animal studies have shown that the sensitivity may be increased by inclusion of the genetically related CFP-10 antigen in the preparation without loosing specificity.

Methodology

In this study a Lactococcus fermented, recombinant skin test reagent consisting of a 1∶1 wt/wt of rdESAT-6 and CFP-10 was manufactured according to GMP standards and tested for the first time in 42 healthy adult volunteers. The two doses of 0.01 µg or 0.1 µg were injected intradermally by the Mantoux technique with 6 or 12 weeks interval. No serious adverse events and only mild adverse reactions were reported. The reagent elicited a positive skin test reaction after the first injection in one participant, who most likely was latently infected with M. tuberculosis as indicated by an appreciable IFN γ response just below the Quantiferon® cut-off level at the screening visit. None of the remaining participants in the four groups had any skin test reactions and sensitisation by the reagent could therefore be excluded.

Conclusion

The investigational skin test reagent rdESAT-6 and CFP-10 appeared safe and non-sensitising in this first-in-man clinical trial in human volunteers and can now be tested in larger clinical trials involving individuals with latent M. tuberculosis infection or active TB disease.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00793702","term_id":"NCT00793702"}}NCT00793702     

Seed dormancy release and germination characteristics of <i>Corispermum lehmannianum</i> Bunge,an endemic species in the Gurbantunggut desert of China

Seed dormancy release and germination of Corispermum lehmannianum Bunge were tested using various treatments: temperature, cold stratification, gibberelins (GA3), dry storage and sand burial. Results showed that temperature and light did not affect the germination of fresh seeds, cold stratification and GA3 could improve seed germination, whereas dry storage and sand burial did not. The germination percentage was highest at 35/20 °C after the cold stratification and GA3 treatments. Corispermum lehmannianum seeds were classified as non-deep, Type-2, physiological dormancy (PD), whose seed dormancy could be released by cold stratification and GA3.     

New insights into the respiration and metabolic physiology of Lystrosaurus

Laaß, M., Hampe, O., Schudack, M., Hoff, C., Kardjilov, N. and Hilger A. (2010). New insights into the respiration and metabolic physiology of Lystrosaurus. —Acta Zoologica (Stockholm) 92 : 363–371. The first examination by neutron tomography of a skull of Lystrosaurus declivis (Therapsida, Anomodontia) from the Lower Triassic of South Africa showed complexly constructed cartilaginous maxilloturbinals in the nasal cavity. They were situated directly in the respiratory air flow and fill out most of the ventral part of the nasal chamber. Because maxilloturbinals in extant mammals and birds serve as a countercurrent exchange system for thermoregulation and humidification, their presence in the anomodont Lystrosaurus suggests strongly that Lystrosaurus was already endothermic. The endothermic metabolism allowed Lystrosaurus to tolerate high ambient temperature fluctuations. The complexly constructed maxilloturbinals could have reduced respiratory water loss because of higher ventilation rates in drought conditions in the Karoo basin.     

A conserved histidine in human DNLZ/HEP is required for stimulation of HSPA9 ATPase activity

The DNL-type zinc-finger protein DNLZ regulates the activity and solubility of the human mitochondrial chaperone HSPA9. To identify DNLZ residues that are critical for chaperone regulation, we carried out an alanine mutagenesis scan of charged residues in a W115I mutant of human DNLZ and assessed the effect of each mutation on interactions with HSPA9. All mutants analyzed promote the solubility of HSPA9 upon expression in Escherichia coli. However, binding studies examining the effect of DNLZ mutants on chaperone tryptophan fluorescence identified three mutations (R81A, H107A, and D111A) that decrease DNLZ binding affinity for nucleotide-free chaperone. In addition, ATPase measurements revealed that DNLZ–R81A and DNLZ–D111A both stimulate the catalytic activity HSPA9, whereas DNLZ–H107A does not elicit an increase in activity even when present at a concentration that is 10-fold higher than the level required for half-maximal stimulation by DNLZ. These findings implicate a conserved histidine as critical for DNLZ regulation of mitochondrial HSPA9 catalytic activity.     

Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings

Impaired metabolism in peripheral skeletal muscles potentially contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). We used (31)P-magnetic resonance spectroscopy ((31)P-MRS) to examine the energy cost and skeletal muscle energetics in six patients with COPD during dynamic plantar flexion exercise compared with six well-matched healthy control subjects. Patients with COPD displayed a higher energy cost of muscle contraction compared with the controls (control: 6.1 ± 3.1% of rest·min(-1)·W(-1), COPD: 13.6 ± 8.3% of rest·min(-1)·W(-1), P = 0.01). Although, the initial phosphocreatine resynthesis rate was also significantly attenuated in patients with COPD compared with controls (control: 74 ± 17% of rest/min, COPD: 52 ± 13% of rest/min, P = 0.04), when scaled to power output, oxidative ATP synthesis was similar between groups (6.5 ± 2.3% of rest·min(-1)·W(-1) in control and 7.8 ± 3.9% of rest·min(-1)·W(-1) in COPD, P = 0.52). Therefore, our results reveal, for the first time that in a small subset of patients with COPD a higher ATP cost of muscle contraction may substantially contribute to the lower mechanical efficiency previously reported in this population. In addition, it appears that some patients with COPD have preserved mitochondrial function and normal energy supply in lower limb skeletal muscle.