Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan

An in vitro model of acquired melphalan resistance was developed by serial incubation of an MCF-7 human breast cancer cell line in increasing concentrations of melphalan. The resulting derivative cell line, Me1R MCF-7, was 30-fold resistant to melphalan. Uptake studies demonstrated decreased initial melphalan accumulation in Me1R MCF-7 cells. Inverse-reciprocal plots of initial melphalan uptake revealed a 4-fold decrease in the apparent Vmax of Me1R MCF-7 compared with WT MCF-7 (516 amol cell-1 min-1 vs 2110 amol cell-1 min-1 respectively) as well as a decrease in the apparent Kt (36 microM vs 70 microM respectively). Two amino acid transporters have previously been identified as melphalan transporters: system L, which is sodium-independent and inhibited by 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH), and system ASC which is sodium dependent and unaffected by BCH. At low concentrations of melphalan (3-30 microM), 1mM BCH competition eliminated the differences between the two cell lines, thus implicating an alteration of the system L transporter in the transport defect in the resistant cells. Me1R MCF-7 cells were also evaluated for glutathione-mediated detoxification mechanisms associated with melphalan resistance. There was no difference between Me1R MCF-7 and WT MCF-7 in glutathione content, glutathione-S-transferase activity and expression of pi class glutathione S-transferase RNA. In addition, buthionine sulfoximine did not reverse melphalan resistance in Me1R MCF-7 cells. Therefore, Me1R MCF-7 cells provide an in vitro model of transport-mediated melphalan resistance in human breast cancer cells.     

Brain-derived neurotrophic factor rapidly enhances phosphorylation of the postsynaptic N-methyl-D-aspartate receptor subunit 1

Although neurotrophins have traditionally been regarded as neuronal survival factors, recent work has suggested a role for these factors in synaptic plasticity. In particular, brain-derived neurotrophic factor (BDNF) rapidly enhances synaptic transmission in hippocampal neurons through trkB receptor stimulation and postsynaptic phosphorylation mechanisms. Activation of trkB also modulates hippocampal long-term potentiation, in which postsynaptic N-methyl-D-aspartate glutamate receptors play a key role. However, the final common pathway through which BDNF increases postsynaptic responsiveness is unknown. We now report that BDNF, within 5 min of exposure, elicits a dose-dependent increase in phosphorylation of the N-methyl-D-aspartate receptor subunit 1. This acute effect occurred in hippocampal synaptoneurosomes, which contain pre- and postsynaptic elements, and in isolated hippocampal postsynaptic densities. Nerve growth factor, in contrast, caused no enhancement of phosphorylation. These results suggest a potential mechanism for trophin-induced potentiation of synaptic transmission.     

Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia

Virus-specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. In individuals who control viremia in the absence of antiviral therapy, polyclonal, persistent, and vigorous HIV-1-specific CD4+ T cell proliferative responses were present, resulting in the elaboration of interferon-gamma and antiviral beta chemokines. In persons with chronic infection, HIV-1-specific proliferative responses to p24 were inversely related to viral load. Strong HIV-1-specific proliferative responses were also detected following treatment of acutely infected persons with potent antiviral therapy. The HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.     

Older adult controlled drinkers and abstainers

Little is known about the lifetime course of alcohol problems, especially during late adulthood. Many individuals with a history of alcohol problems achieve remission of their symptoms through abstinence or controlled drinking. This study examined 135 older adults with a prior history of alcohol diagnoses who were symptom free for at least the past year. Two groups were identified based on their alcohol consumption within the past year: abstinent individuals (n = 92) and controlled drinkers (n = 43). The groups did not differ in age, racial composition, education, income, or years since their last alcohol-related symptom, but they did differ in gender composition, indices of alcoholism severity, history of formal and informal treatment, as well as lifetime alcohol consumption patterns. Abstinent individuals had more severe alcohol problems, consumed higher amounts of alcohol on drinking days, had more years of heavy alcohol consumption, and were more likely to have attended alcohol treatment and Alcoholics Anonymous (AA). The controlled drinkers had a longer history of moderate social drinking, and their current consumption habits appeared to be similar to symptom-free older adult drinkers. The results suggest that gender, alcoholism severity, history of formal and informal treatment, and past consumption patterns are associated with whether older adults with histories of alcoholism attain successful outcomes through abstinence or controlled drinking.     

Blindness limitations in optical coherence domain reflectometry

The theoretical and measured limitations on dynamic range near strong reflections in optical coherence domain reflectometry are examined. A model and data are presented that show that such blindness limitations can be caused by broad spectral tails from the superluminescent diodes typically used in such measurements.<>     

Effects of two low-fat diets, high and low in polyunsaturated fatty acids, on plasma lipid peroxides and serum vitamin E levels in free-living hypercholesterolaemic men

Diet enriched with polyunsaturated fat may increase the susceptibility of LDL to oxidation. Therefore the effects of two low-fat diets on plasma lipid peroxides in free-living mildly hypercholesterolaemic men (n = 37) were investigated in a randomized single-blind 28-week study. Composition of the diets were (1) American Heart Association (AHA) type 32/10:8:8 (indicating percentages of energy from total fat/saturated fat:monoenes:polyenes in actual diet); (2) low-fat 30/12:8:3. The subjects kept 3-day dietary records five times during the study to estimate the intake of nutrients. Plasma lipid peroxides were measured photometrically as the thiobarbituric-acid reactive substances (TBARS). Levels of serum vitamin E during the study were also determined. Mean change (+/- SD) in serum low density lipoprotein (LDL) cholesterol was similar in both groups (-0.32 +/- 0.76 vs -0.32 +/- 0.87 mmol/l) (AHA type vs low-fat). Level of TBARS decreased (P < 0.05) during the AHA type diet (-8.4 +/- 37.1%) (mean +/- SD) and increased (P = 0.228) during the low-fat diet (+8.7 +/- 27.0%) from 0 to 6 months. The mean intake of total active tocopherols was greater (14.7 +/- 3.7 mg) during the AHA type diet compared to the low-fat diet (7.8 +/- 2.1 mg). Serum vitamin E to LDL cholesterol ratio increased from 8.9 +/- 2.9 to 9.6 +/- 2.4 nmol/mmol (0 vs 6 months) (P = 0.07) during the AHA type diet and from 8.6 +/- 2.6 to 9.3 +/- 2.4 nmol/mmol (P = 0.159) during the low-fat diet.(ABSTRACT TRUNCATED AT 250 WORDS)