Tumorigenicity of ten karyotypically distinct cell types present in the human melanoma cell line MeWo-A

The earliest passage of the human melanoma cell line, MeWo-A, consists of ten cell types that can be distinguished on the basis of chromosome markers. Two of these cell types have chromosomes with long homogeneously staining regions (HSR) containing sequences derived from the short arm of a chromosome #15. In one cell type the HSR is found on a chromosome #15 and in the other it is on a der(15;10)-HSR chromosome. Four other cell types were identifiable by morphologic differences of the short arm of chromosome #13, whereas, the four remaining cell types were identifiable by the presence of prominent satellites on other chromosomes. This study was directed at assessing the relative tumorigenic properties of the different cell types by injecting different numbers of cells intraperitoneally, subcutaneously, or intravenously into Balb/c nude mice. The primary tumors and nodules that developed in the peritoneal cavity and lungs were explanted into tissue culture. One hundred metaphase chromosome spreads from each established cell line were analyzed cytogenetically to detect changes in proportions of the different cell types. The cell type containing the der(15;10)-HSR chromosome was present in only 20% of the cells injected, but increased in proportion to between 28% and 98% after growth in nude mice. Although the degree of selection of the der(15;10)-HSR-containing cell type was influenced by the number of cells injected, the consistent selection of these cells strongly suggests that this cell type has a growth advantage. Because the 15-HSR-containing cell type rarely increased in proportion, it is likely that the HSR by itself can not confer the enhanced tumorigenic phenotype but requires the expression of other sequences present on other MeWo chromosomes to provide the selective growth advantage to the cells in which it is found.     

Longitudinal assessment of family support among homeless mentally ill participants in a supported housing program

Although strengthening the family relations of individuals with severe mental illness has been identified as an important objective for community-based case management programs, little is known about the impact of such programs on patterns of family relations over time. This study assesses longitudinally the family support of a large sample of homeless mentally ill individuals participating in a supported housing program. The program randomly assigned participants to one of four experimental conditions created by varying the level of access to independent housing and the intensity of case management services provided. Substantial improvements were found during the 3-year follow-up period for frequency of family interaction, perceived availability, and satisfaction with family. Regression analyses were used to model factors correlated with change. Improvement in support was not associated with housing or case management conditions. Increased levels of family support were associated with housing status and mental health status. Clients in stable independent and community housing showed greater improvement than a group of clients living in an unstable housing environment. Substantial gains in family relations also occurred among a subgroup who did not achieve housing stability, but received family housing assistance during follow-up. The lack of relationship between the experimental intervention and change in support is discussed. © 1998 John Wiley & Sons, Inc.     

N‐acetyl transferase 2 genotypes,meat intake and breast cancer risk

Heterocyclic amines (HAs) are carcinogens produced by high‐temperature cooking of meat and animal protein; metabolism of HA is influenced by polymorphisms in the N‐ acetyltransferase‐2 (NAT‐2) gene. Data from a variety of sources suggest that HA may play a role in human carcinogenesis. We examined the associations between meat intake and cooking method, acetylator genotype and breast cancer risk in a sub‐cohort of 32,826 women in the Nurses' Health Study who gave a blood sample in 1989–1990. Women who were diagnosed with breast cancer (n = 466) after blood draw and prior to June 1, 1994, were matched to 466 controls. Overall, rapid acetylators were not at increased risk of breast cancer compared with slow acetylators (multivariate OR = 1.1, 95% CI 0.8–1.5), and there were no associations between meat intake or cooking method of meat and breast cancer risk. Rapid acetylators with the highest red meat intake (one or more servings per day) were not at increased risk of breast cancer compared with slow acetylators with the lowest red meat intake (OR = 1.1, 95% CI 0.7–1.8). Frequent intake of charred meat among rapid acetylators (one or more times per week) was not associated with increased risk (OR = 1.2, 95% CI 0.6–2.3) compared with slow acetylators who ate charred meat less than once per month. We observed no significant associations for rapid acetylators who frequently consumed beef, pork or lamb cooked with high‐temperature cooking methods, such as barbecuing (OR = 0.9, 95% CI 0.4–1.9) or roasting (OR = 0.9, 95% CI 0.5–1.6). Our data suggest that HAs may not be a major cause of breast cancer, although we cannot exclude misclassification of HA intake as the reason for the lack of association. We observed no evidence of differential susceptibility to these exposures by NAT2 genotype. Int. J. Cancer 80:13–17, 1999. © 1999 Wiley‐Liss, Inc.     

Disassembly of microtubules by intense terahertz pulses

The biological effects of terahertz (THz) radiation have been observed across multiple levels of biological organization, however the sub-cellular mechanisms underlying the phenotypic changes remain to be elucidated. Filamentous protein complexes such as microtubules are essential cytoskeletal structures that regulate diverse biological functions, and these may be an important target for THz interactions underlying THz-induced effects observed at the cellular or tissue level. Here, we show disassembly of microtubules within minutes of exposure to extended trains of intense, picosecond-duration THz pulses. Further, the rate of disassembly depends on THz intensity and spectral content. As inhibition of microtubule dynamics is a mechanism of clinically-utilized anti-cancer agents, disruption of microtubule networks may indicate a potential therapeutic mechanism of intense THz pulses.     

Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation.

Zn(2+) is found in glutamatergic nerve terminals throughout the mammalian forebrain and has diverse extracellular and intracellular actions. The anatomical location and possible synaptic signaling role for this cation have led to the hypothesis that Zn(2+) is released from presynaptic boutons, traverses the synaptic cleft, and enters postsynaptic neurons. However, these events have not been directly observed or characterized. Here we show, using microfluorescence imaging in rat hippocampal slices, that brief trains of electrical stimulation of mossy fibers caused immediate release of Zn(2+) from synaptic terminals into the extracellular microenvironment. Release was induced across a broad range of stimulus intensities and frequencies, including those likely to induce long-term potentiation. The amount of Zn(2+) release was dependent on stimulation frequency (1-200 Hz) and intensity. Release of Zn(2+) required sodium-dependent action potentials and was dependent on extracellular Ca(2+). Once released, Zn(2+) crosses the synaptic cleft and enters postsynaptic neurons, producing increases in intracellular Zn(2+) concentration. These results indicate that, like a neurotransmitter, Zn(2+) is stored in synaptic vesicles and is released into the synaptic cleft. However, unlike conventional transmitters, it also enters postsynaptic neurons, where it may have manifold physiological functions as an intracellular second messenger.     

Hormonal alterations in experimental diabetes: Role of a primary disturbance in calcium homeostasis

Summary Chronic diabetes mellitus in the rat is attended by a reduced bone turnover and growth arrest, decreased circulating immunoreactive parathyroid hormone (iPTH), and hypercorticosteronism. Since chronic insulin deficiency in the rat is associated with intestinal hyperabsorption of calcium and a positive calcium balance that may account for the decreased iPTH, as well as other hormonal alterations observed in these animals, we studied the effect of long-term (5 week) dietary calcium restriction (0.1% Ca, 0.8% P) in control and streptozotocin-induced diabetic rats. Chronic diabetic rats reared on a normal calcium (1.2% Ca) diet had increased serum calcium and phosphate (Pi) concentrations and were markedly hypercalciuric and phosphaturic compared with controls. Serum corticosterone was increased and iPTH markedly decreased in the diabetic animals. Dietary Ca restriction (0.1% Ca) decreased urinary calcium excretion and resulted in a comparable phosphaturic response in both control and diabetic rats. Moreover, although Ca restriction in diabetic animals had no appreciable effect on serum insulin, serum glucose, or urinary glucose excretion, it was associated with a marked increase in circulating iPTH; this resulted in serum concentrations comparable with that observed in control animals reared on the low Ca diet. These results support the hypothesis that the decreased circulating iPTH observed in chronic diabetic rats results predominantly from their intestinal hyperabsorption of Ca. In contrast to control animals, diabetic rats reared on a low Ca diet failed to maintain their serum Ca despite the marked increase in serum iPTH and striking decrease in calciuria, thus underscoring the reliance of these animals on intestinal hyperabsorption of Ca to maintain Ca balance under conditions of adequate Ca intake. Serum corticosterone was insignificantly altered by dietary Ca restriction in control rats; hypercorticosteronism, characteristically observed in diabetic rats, was normalized by Ca restriction. We conclude that a primary disturbance in Ca homeostasis may contribute, in part, to hormonal alterations observed in chronic experimental diabetes.     

Granulocyte Fc-IgG and C3b receptor expression in the primary myelodysplastic syndromes (MDS): relationship with dysgranulopoiesis and evidence for heterogeneity of morphological subgroups.

The expression of Fc-IgG and C3b membrane receptors by granulocytes and their precursors was examined in 78 patients with primary myeloid dysplasia (MDS). The marrows were categorized into five morphological groups, broadly corresponding to those described by the FAB group, and further graded into mild and severe according to the severity of dysgranulopoiesis. Fractionated bone marrow and peripheral blood granulocyte receptors were assessed by rosette formation with optimally sensitized ox erythrocytes and the results compared with those found in 17 normal marrows and with those previously reported in megaloblastic anaemia. Fc-IgG and C3b receptor expression was generally increased in maturing granulocytes in all MDS diagnostic groups but premature expression was particularly marked in chronic myelomonocytic leukaemia and refractory cytopenia. Receptor patterns showed a better correlation with the severity of dysgranulopoiesis than with the morphological types. It is suggested that, as in megaloblastic anaemia, changes in membrane receptor expression reflect nuclear-cytoplasmic asynchrony. The results further indicate considerable immunological heterogeneity of granulocytes within individual MDS categories.     

Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) causes vascular shutdown in preclinical models. Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies were performed in the phase I trials to examine changes related to blood flow and permeability in tumor and muscle. PATIENTS AND METHODS: Sixteen patients treated with DMXAA from 500 to 4,900 mg/m(2) had DCE-MRI examinations before and after treatment. The maximum gradient, the maximum enhancement, and the area under the signal-intensity-time curve (AUC) over the first 90 seconds were calculated for each pixel in regions of interest (ROIs) in muscle and tumor, and the median value for each ROI was obtained. Changes after treatment were compared with 95% limits of agreement for an individual and for groups using data from our reproducibility study. RESULTS: Nine of 16 patients had significant reductions in AUC 24 hours after the first dose of DMXAA, and eight of 11 patients had reductions of up to 66% in AUC 24 hours after the last dose. Mean reductions in gradient, enhancement, and AUC were 25%, 18%, and 31%, respectively, 24 hours after the last dose, significantly greater than the 95% limits of change for a group of 11 patients. Enhancement and AUC in muscle 24 hours after the first dose were significantly reduced, but no significant changes were seen 24 hours after the last dose. CONCLUSION: DMXAA significantly reduces DCE-MRI parameters related to tumor blood flow, over a wide dose range, consistent with the reported tumor vascular targeting activity. Further clinical evaluation of DMXAA is warranted.