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Differential Responsiveness (differential + responsiveness)

Distribution by Scientific Domains

Medical Sciences	57%
Life Sciences	42%

Selected Abstracts

Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone, melatonin

JOURNAL OF PINEAL RESEARCH, Issue 4 2000
Prahlad T. Ram
The estrogen receptor (ER)-positive MCF-7 human breast cancer cell line has been used extensively for the study of estrogen-responsive human breast cancer. However, various levels of estrogen responsiveness have been described in different stocks of MCF-7 cells. Because we have previously shown that the pineal hormone, melatonin, inhibits proliferation of MCF-7 cells and can modulate ER expression and transactivation, we investigated if various stocks of MCF-7 cells exhibit a differential responsiveness to the anti-proliferative effects of melatonin and the possible mechanisms involved. The MCF-7 stocks (M, O, H) were examined for: (1) mitogenic response to estradiol; (2) steady-state ER mRNA levels; (3) expression of the mt1 melatonin membrane receptor; (4) growth inhibition by melatonin; and (5) melatonin's modulation of expression of the ER and the estrogen-regulated genes, PgR, TGF, and pS2. For all of these parameters, there was a stock-specific response which showed: MCF-7M>MCF-7O>MCF-7 H. These results demonstrate that there are significant differences in the responsiveness of various stocks of MCF-7 breast cancer cells to the growth-inhibitory effects of melatonin which can be correlated with both the level of ER mRNA expression and the degree of estrogen-responsiveness. These findings suggest that not only may these differences have some impact on the cells' estrogen-response pathway, but also that the primary growth-inhibitory effects of melatonin are transduced through the membrane-associated G-protein coupled mt1 melatonin receptor. [source]

Differential responsiveness of human hepatoma cells versus normal hepatocytes to TRAIL in combination with either histone deacetylase inhibitors or conventional cytostatics

CANCER SCIENCE, Issue 8 2008
Johanna Dzieran
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising candidate for the treatment of cancer because it elicits cell death in many tumor cells while sparing most normal cells. Liver cancer, however, is largely resistant to TRAIL and, thus, requires sensitization for TRAIL-mediated cytotoxicity. Sensitization may be achieved by cotreatment with chemotherapeutic agents. In this study, we comparatively investigated the treatment efficacy of TRAIL in combination with histone deacetylase inhibitors (HDI) versus TRAIL in combination with conventional cytostatics in the hepatocellular carcinoma cell line HepG2 and in the childhood hepatoblastoma cell line Huh6. We found that TRAIL resistance could be overcome by cotreatment with the HDI vorinostat, sodium butyrate and MS-275, but not by cotreatment with the cytostatics carboplatin and etoposide. However, TRAIL combination treatment bears the risk of sensitizing otherwise TRAIL-resistant normal cells. We thus explored a potential cytotoxic effect of combined HDI/TRAIL treatment in normal hepatocytes: TRAIL in conjunction with HDI did not impose any cytotoxicity on the non-malignant cells. In searching for the determinants of HDI-mediated TRAIL sensitization in hepatoma cells, we observed that HDI treatment did not increase cell-surface expression of proapoptotic TRAIL receptors. Instead, HDI treatment enhanced TRAIL-induced cleavage of Bid. In conclusion, our data suggest that HDI are potent sensitizers to TRAIL in hepatoma cells and that the combination of HDI and TRAIL is selectively active in hepatoma cells without affecting normal hepatocytes, indicating that the combination of HDI and TRAIL may be an effective approach for the treatment of advanced liver cancer. (Cancer Sci 2008; 99: 1685,1692) [source]

Brain Imaging in Migraine Research

HEADACHE, Issue 9 2010
David Borsook MD
Understanding the pathophysiology and pharmacology of migraine has been driven by astute clinical observations, elegant experimental medicine studies, and importantly by studying highly effective anti-migraine agents in the laboratory and the clinic. Significant progress has been made in the use of functional brain imaging to compliment observational studies of migraine phenotypes by highlighting pathways within the brain that may be involved in predisposition to migraine, modulating migraine pain or that could be sensitive to pharmacological or behavioral therapeutic intervention (Fig. 1). In drug discovery, molecular imaging approaches compliment functional neuroimaging by visualizing migraine drug targets within the brain. Molecular imaging enables the selection and evaluation of drug candidates by confirming that they engage their targets sufficiently at well tolerated doses to test our therapeutic hypotheses. Figure 1.,. Imaging and defining the migraine brain disease state: from anatomy to chemical entities (targets) to functional systems (function and pathways) (from Borsook et al31 with permission, Nature Publishing Group). Migraine is a progressive disorder. Developing our knowledge of where drugs act in the brain and of how the brain is altered in both episodic migraine (interictal state and ictal state) and chronic migraine are important steps to understanding why there is such differential responsiveness to therapeutics among migraine patients and to improving how they are evaluated and treated. [source]

PTH-dependent adenylyl cyclase activation in SaOS-2 cells: Passage dependent effects on G protein interactions

JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2002
Hong Gao
Parathyroid hormone (PTH) sensitive adenylyl cyclase activity (ACA) in SaOS-2 cells varies as a function of cell passage. In early passage (EP) cells (<,6), ACA in response to PTH and forskolin (FOR) was relatively low and equivalent, whereas in late passage (LP) cells (>,22), PTH exceeded FOR dependent ACA. Potential biochemical mechanisms for this passage dependent change in ACA were considered. In EP, prolonged exposure to pertussis toxin (PT) markedly enhanced ACA activity in response to PTH, Isoproterenol and Gpp(NH)p, whereas ACA in response to FOR was decreased. In contrast, the identical treatment of LP with PT diminished all ACA in response to PTH, Gpp(NH)p, and FOR. The dose dependent effects of PT on subsequent [32P]ADP-ribosylation of its substrates, GTPase activity, as well as FOR-dependent ACA, were equivalent in EP and LP. The relative amounts of G,i and G,s proteins, as determined both by Western blot, PT and cholera toxin (CT) dependent [32P]ADP-ribosylation, were quantitatively similar in EP and LP. Western blot levels of G,s and G,i proteins were not influenced by prior exposure to PT. Both PT and CT dependent [32P]ADP-ribosylation were dose-dependently decreased following exposure to PT. However, the PT-dependent decline in CT-dependent [32P]ADP-ribosylation occurred with enhanced sensitivity in LP. The protein synthesis inhibitor cycloheximide partially reversed the PT associated decrease in FOR dependent ACA in EP. In contrast, cycloheximide completely reversed the PT associated decrease in FOR and as well as PTH dependent ACA in LP. G,s activity, revealed by cyc, reconstitution, was not altered either by cell passage or exposure to PT. The results suggest that the coupling between the components of the complex may be pivotally important in the differential responsiveness of early and late passage SaOS-2 cells to PTH. J. Cell. Physiol. 193: 10,18, 2002. © 2002 Wiley-Liss, Inc. [source]

Responsiveness to staff support: evaluating the impact of individual characteristics on the effectiveness of active support training using a conditional probability approach

JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 8 2002
C. Smith
Abstract Background Active support training was fully conducted in 38 community houses accommodating 106 adults with intellectual disabilities (ID; group 1), but not in a further 36 accommodating 82 adults with ID (group 2). The aims of the present study were to analyse whether staff became more effective in supporting resident activity after the implementation of active support, and whether there was evidence of differential responsiveness by people with differing status in relation to adaptive behaviour, psychiatric diagnosis, challenging behaviour or autism. Methods Observations of staff:resident interaction and resident engagement in activity were taken before and after active support training. Changes in Yule's Q statistics, indicating the likelihood that resident engagement in activity followed staff giving residents verbal instruction or non-verbal assistance, were compared for the two groups. In addition, changes in similar statistics were compared for residents within group 1: (1) with Adaptive Behaviour Scale (ABS) scores above and below 180; and (2) with and without severe challenging behaviour, the triad of social impairments and mental illness. Results Yule's Q for engagement given non-verbal assistance significantly increased post-training among group 1, but not among group 2. Similar significant increases were found among group 1 residents with ABS scores below 180 without challenging behaviour, with and without the triad of social impairments, and without mental illness, but not with an ABS score above 180, with challenging behaviour and with mental illness. Conclusion The present analysis reinforces previous studies on the effectiveness of active support training for adults with more severe ID (i.e. with ABS scores below 180). Active support was as effective for people with the triad of social impairments as for those without it. However, the effectiveness of support offered to people with challenging behaviour or mental illness did not significantly increase. [source]

Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone, melatonin

N -methyl-d-aspartate Receptor Responses Are Differentially Modulated by Noncompetitive Receptor Antagonists and Ethanol in Inbred Long-Sleep and Short-Sleep Mice: Behavior and Electrophysiology

ALCOHOLISM, Issue 12 2000
Taleen Hanania
Background: Short-sleep (SS) mice exhibit higher locomotor activity than do long-sleep (LS) mice when injected with low doses of ethanol or the noncompetitive N -methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine). SS mice also have higher densities of brain NMDARs. However, two strains of LS X SS recombinant inbred (RI) mice also show differential activation to ethanol and MK-801, but have similar numbers of NMDARs. Here we used inbred LS (ILS) and SS (ISS) mice to investigate further the relationship between NMDARs and sensitivity to the stimulant effects of low doses of ethanol. Methods: Open field activity and spontaneous alternations were measured after saline or drug injection. [3H]MK-801 binding parameters were determined in hippocampus, cortex, striatum, and nucleus accumbens. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of hippocampal slices. Results: Systemic injection of either ethanol or MK-801 increased locomotor activity to a greater extent in ISS mice than in ILS mice. The competitive NMDAR antagonist 2-carboxypiperazin-4-yl-propyl-1,1phosphonic acid (±CPP) depressed activity of ILS, but not ISS, mice. No strain differences were observed in spontaneous alternations or in the number or affinity of NMDARs in the brain regions examined. Likewise, the magnitudes of hippocampal NMDAR-mediated fEPSPs were similar in ILS and ISS mice and were inhibited to the same extent by a competitive NMDAR antagonist. However, both ethanol and the NMDAR NR2B receptor antagonist ifenprodil inhibited the late component of hippocampal NMDAR fEPSPs to a greater extent in ISS, than in ILS, mice. Conclusions: Differential ethanol- and MK-801-induced behavioral activation in ILS and ISS mice was not associated with differences in NMDAR number. Nonetheless, pharmacological differences in hippocampal NMDAR responsiveness suggest that ISS mice express NMDARs that have a greater sensitivity to noncompetitive, but not competitive, NMDAR antagonists. These differences, which may reflect differences in NMDAR subunit composition, could underlie the differential responsiveness to low doses of ethanol in ILS and ISS mice. [source]