Purging of acute myeloid leukemic cells by ether lipids and hyperthermia

Ether lipids (EL) and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemic cells. In this study, the combined effects of EL (ET-18-OCH3, ET-16-NHCOCH3, or BM 41.440) and hyperthermia on the growth of hematopoietic progenitors, myeloid leukemic cell lines, and leukemic cells obtained from patients with acute myeloid leukemia (AML) were examined to determine if this combination resulted in a greater selective killing of leukemic cells than that achieved by either EL or heat alone. When the cells were treated simultaneously with EL (50 micrograms/mL) and hyperthermia (42 degrees C) for one hour, the killing of leukemic cell line cells was enhanced considerably. Among the three EL, however, the combination of ET-18-OCH3 and heat seemed to be the most cytotoxic to leukemic cell line cells with no effect on the growth of hematopoietic progenitors. An increase in the duration of treatment with ET-18-OCH3 to four hours with heat added during the last hour resulted in a further reduction of leukemic cell line cells while sparing 50% of hematopoietic progenitors after cryopreservation. The combined treatment with ET-18-OCH3 and heat also inhibited the growth of leukemic progenitors obtained from AML patients by 97% to 100%. These data indicate that the combined treatment with EL and hyperthermia might offer an efficient means to eliminate myeloid leukemic cells in vitro.     

Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia

Elevated numbers of primitive Philadelphia chromosome-positive (Ph+) progenitors, including long-term culture-initiating cells (LTC-IC) as well as colony-forming cells (CFC), have been previously described in the blood of patients with chronic myeloid leukemia (CML) in chronic phase with high white blood cell counts. In the present study, which focused primarily on an analysis of circulating progenitors present in such patients at diagnosis, we discovered the frequent and occasionally exclusive presence of circulating normal (Ph-) LTC-IC, often at levels above those seen for LTC-IC in the blood of normal individuals. The presence of detectable numbers of circulating Ph- LTC-IC was independent of the fact that the same peripheral blood samples also contained elevated numbers of predominantly or exclusively Ph+ CFC. Interestingly, both the Ph+ and Ph- LTC-IC in these samples were CD34+CD71- and variably CD38- and Thy-1+, as previously documented for LTC-IC in normal marrow. Thus, neither CD38 nor Thy-1 expression was useful for discriminating between Ph+ and Ph- LTC-IC in mixed populations. Nevertheless, an association of these phenotypes with LTC- IC function did allow highly enriched (> 5% pure) suspensions of either Ph+ or Ph- LTC-IC to be obtained from selected samples of CML blood in which the initial LTC-IC population was either predominantly Ph+ or Ph- , respectively. These findings suggest that the mechanisms causing mobilization of leukemic stem cells in untreated CML patients may affect their normal counterparts. They also indicate a possible new source of autologous cells for the support of intensive therapy of CML patients. Finally, they provide a method for obtaining the most highly purified populations of Ph+ LTC-IC described to date. This method should be useful for further analyses of the molecular activities of these very primitive neoplastic cells.     

Human Mate Selection and Addiction: a Conceptual Critique

The authors review past work on modeling human mate selection, and suggest, using illustrations from existing literature on the impact of alcoholism on relationship formation and dissolution and reproduction, that the challenges of adequately characterizing human mate selection have not yet been overcome. Some paths forwards are suggested.     

Functional Redundancy of SWI/SNF Catalytic Subunits in Maintaining Vascular Endothelial Cells in the Adult Heart

Rationale: Mating type switching/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complexes utilize either BRG1 or BRM as a catalytic subunit to alter nucleosome position and regulate gene expression. BRG1 is required for vascular endothelial cell (VEC) development and embryonic survival, whereas BRM is dispensable. Objective: To circumvent embryonic lethality and study Brg1 function in adult tissues, we used conditional gene targeting. To evaluate possible Brg1-Brm redundancy, we analyzed Brg1 mutant mice on wild-type and Brm-deficient backgrounds. Methods and Results: The inducible Mx1-Cre driver was used to mutate Brg1 in adult mice. These conditional-null mutants exhibited a tissue-specific phenotype and unanticipated functional compensation between Brg1 and Brm. Brg1 single mutants were healthy and had a normal lifespan, whereas Brg1/Brm double mutants exhibited cardiovascular defects and died within 1 month. BRG1 and BRM were required for the viability of VECs but not other cell types where both genes were also knocked out. The VEC phenotype was most evident in the heart, particularly in the microvasculature of the outer myocardium, and was recapitulated in primary cells ex vivo. VEC death resulted in vascular leakage, cardiac hemorrhage, secondary death of cardiomyocytes due to ischemia, and ventricular dissections. Conclusions: BRG1-catalyzed SWI/SNF complexes are particularly important in cardiovascular tissues. However, in contrast to embryonic development, in which Brm does not compensate, Brg1 is required in adult VECs only when Brm is also mutated. These results demonstrate for the first time that Brm functionally compensates for Brg1 in vivo and that there are significant changes in the relative importance of BRG1- and BRM-catalyzed SWI/SNF complexes during the development of an essential cell lineage.     

Carotid intima-media thickness among human immunodeficiency virus-infected patients without coronary calcium

Subjects infected with human immunodeficiency virus (HIV) have increased risk for atherosclerosis. Carotid artery intima-media thickness (IMT) assessed using ultrasound and coronary artery calcium (CAC) detected using computed tomography predict cardiovascular risk in the general population; however, their usefulness and comparability in patients with HIV are less well defined. The purpose of this study was to compare IMT and CAC in the detection of atherosclerosis in subjects with HIV. CAC and IMT were measured in 253 HIV-infected and 58 uninfected adults. Associations among HIV-related factors, traditional risk factors, and CAC and IMT were evaluated. The distribution of IMT among subjects with and without CAC was compared. Among the patients with HIV, 37% had detectable CAC compared to 28% of controls (p = 0.19); 16% of the patients with HIV had CAC >100 compared to 5% of controls (p = 0.03). With either detectable or undetectable CAC, HIV-infected subjects had higher IMT compared to controls (1.02 ± 0.34 vs 0.78 ± 0.12 mm, p <0.0001), even after adjustment for traditional risk factors. Among those with undetectable CAC, 34% of patients with HIV had markedly increased IMT (≥1 mm) compared to no controls (p <0.0001). HIV-related factors were associated with IMT but not with CAC. In conclusion, patients with HIV and controls had similar rates of detectable CAC, while absolute CAC scores were modestly higher in the HIV group. Conversely, carotid IMT detected advanced subclinical atherosclerosis in patients with HIV even in the absence of CAC. Thus, with HIV, IMT is associated with disease-related factors and may be a more sensitive indicator of subclinical atherosclerosis than CAC.     

Neural activation for actual and imagined movement following unilateral hand transplantation: a case study

ABSTRACT

Transplantation of a donor hand has been successful as a surgical treatment following amputation, but little is known regarding the brain mechanisms contributing to the recovery of motor function. We report functional magnetic resonance imaging (fMRI) findings for neural activation related to actual and imagined movement, for a 54-year-old male patient, who had received a donor hand transplant 50 years following amputation. Two assessments, conducted 3 months and 6 months post-operatively, demonstrate engagement of motor-control related brain regions for the transplanted hand, during both actual and imagined movement of the fingers. The intact hand exhibited a more intense and focused pattern of activation for actual movement relative to imagined movement, whereas activation for the transplanted hand was more widely distributed and did not clearly differentiate actual and imagined movement. However, the spatial overlap of actual-movement and imagined-movement voxels, for the transplanted hand, did increase over time to a level comparable to that of the intact hand. At these relatively early post-operative assessments, brain regions outside of the canonical motor-control networks appear to be supporting movement of the transplanted hand.