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461.
Rothenberg ML; Mickley LA; Cole DE; Balis FM; Tsuruo T; Poplack DG; Fojo AT 《Blood》1989,74(4):1388-1395
Increased expression of the multidrug resistance gene (mdr-1/P-170) and the dihydrofolate reductase (DHFR) gene have been implicated in the development of in vitro drug resistance. Overexpression, with or without gene amplification, is seen in the development of drug resistance in culture and it has been postulated that genetic modulation of mdr-1/P-170 and DHFR may also be involved in the development of clinical drug resistance. We screened lymphoblasts from 28 patients with acute lymphoblastic leukemia (ALL) for evidence of overexpression of mdr-1/P-170 using RNAse protection, RNA in situ hybridization and immunohistochemistry. Overexpression of mdr-1/P-170 without gene amplification was detected in samples from four patients (three after multiple relapses, one at presentation). Overexpression of mdr-1/P-170 was heterogeneous within the population of malignant lymphoblasts as demonstrated by RNA in situ hybridization, immunohistochemistry, and drug uptake using daunomycin autofluorescence analysis. There was no evidence of overexpression of DHFR in any of the eight patient samples tested by RNAse protection nor was there any evidence of gene amplification in 11 patient samples on Southern blot analysis. From these observations it appears that overexpression without gene amplification of mdr-1/P-170 may be one mechanism of clinical drug resistance in ALL. 相似文献
462.
The role of neutrophil membrane glycoprotein GP-150 in neutrophil adherence to endothelium in vitro 总被引:46,自引:0,他引:46
Harlan JM; Killen PD; Senecal FM; Schwartz BR; Yee EK; Taylor RF; Beatty PG; Price TH; Ochs HD 《Blood》1985,66(1):167-178
We have previously described two patients with a congenital defect in neutrophil function characterized by an inability to form pus. The patients' neutrophils lack a membrane glycoprotein of mol wt 150,000 daltons (GP-150) on analysis by SDS-PAGE. This glycoprotein is part of a membrane antigen complex recognized by the murine monoclonal antibody (MoAb) 60.3. Addition of MoAb 60.3 to normal neutrophils produces defects in chemotaxis and phagocytosis in vitro similar to those observed in the patients. Since neutrophil adherence to vascular endothelium is prerequisite to neutrophil emigration in vivo, we examined the interaction of the patients' neutrophils and normal neutrophils treated with MoAb 60.3 with cultured endothelium. Adherence was determined as the percentage of 51Cr-labeled purified peripheral blood neutrophils which remained adherent to plastic wells or endothelial monolayers after a 45-minute incubation at 37 degrees C. The percentage of neutrophils from patient 1 remaining adherent to uncoated, fibronectin-coated, or laminin-coated plastic was similar to that observed in normal neutrophils (55% to 84% adherence with normal neutrophils v 73% to 78% adherence with the patient's neutrophils and 63% to 82% adherence with MoAb 60.3-treated normal neutrophils). The adherence of the neutrophils from patient 1 and MoAb 60.3-treated normal neutrophils to human or bovine endothelium in serum-free medium was also not significantly different from that observed in normal neutrophils (less than 10% adherence with normal, MoAb 60.3-treated, and patient neutrophils). In medium containing 10% autologous or heterologous human plasma, however, the adherence of neutrophils from patient 1 or MoAb 60.3-treated normal neutrophils to endothelial monolayers was significantly reduced (35% +/- 7% of normal neutrophils in seven experiments). Although phorbol myristate acetate (PMA) (10 ng/mL) and calcium ionophore A23187 (10(-5) mol/L) markedly increased the adherence of normal neutrophils to endothelial monolayers in serum- free medium (40% to 85% adherence), neither agent increased the adherence of the neutrophils from patient 1 or normal neutrophils treated with MoAb 60.3 (less than 5% adherence). The adherence of PMA- activated neutrophils from patient 2 to endothelial monolayers was also markedly decreased when compared with that of normal neutrophils. Postsecretory cell-free supernatants from PMA-activated normal neutrophils failed to augment adherence of neutrophils from patient 1 (less than 5% adherence).(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
463.
464.
We have previously observed that ionizing radiation induces tyrosine phosphorylation in human B-lymphocyte precursors by stimulation of unidentified tyrosine kinases and this phosphorylation is substantially augmented by vanadate. Ionizing radiation generates reactive oxygen intermediates (ROI). Because H2O2 is a potent ROI generator that readily crosses the plasma membrane, we used H2O2 to examine the effects of ROI on signal transduction. We now provide evidence that the tyrosine kinase inhibitor herbimycin A and the free radical scavenger N- acetyl-cysteine inhibit both radiation-induced and H2O2-induced activation of NF-kappa B, indicating that activation triggered by ROI is dependent on tyrosine kinase activity. H2O2 was found to stimulate Ins-1,4,5-P3 production in a tyrosine kinase-dependent manner and to induce calcium signals that were greatly augmented by vanadate. The synergistic induction of tyrosine phosphorylation by H2O2 plus vanadate included physiologically relevant proteins such as PLC gamma 1. Although treatment of cells with H2O2 alone did not affect the activity of src family kinases, treatment with H2O2 plus vanadate led to activation of the p56lck and p59fyn tyrosine kinases. The combined inhibition of phosphatases and activation of kinases provides a potent mechanism for the synergistic effects of H2O2 plus vanadate. Induction of tyrosine phosphorylation by ROI may thus lead to many of the pleiotropic effects of ROI in lymphoid cells, including downstream activation of PLC gamma 1 and NF-kappa B. 相似文献
465.
466.
Long-term treatment of lupus nephritis with cyclosporin A 总被引:9,自引:0,他引:9
Tam LS; Li EK; Leung CB; Wong KC; Lai FM; Wang A; Szeto CC; Lui SF 《QJM : monthly journal of the Association of Physicians》1998,91(8):573-580
We evaluated the efficacy and safety of long-term treatment with
cyclosporin A (CSA) in type IV lupus nephritis. Seventeen patients with
biopsy-proven WHO type IV lupus nephritis were enrolled in a prospective,
open study. Twelve of the 17 completed 48 months of treatment with CSA and
prednisolone. Three patients required the addition of azathioprine, at 12,
38 and 47 months, respectively, for cutaneous disease flare with refractory
rashes. One patient was lost to follow-up at 40 months. The mean +/- SD
duration of treatment was 43.2 +/- 10.1 months (range 15.7-48 months). A
significant reduction of proteinuria and a significant rise in serum
albumin were noted 1 month after initiation of treatment. Improvement was
maintained throughout the study except for three patients who relapsed with
recurrence of nephrotic syndrome. There were no significant changes in
serum creatinine level or creatinine clearances throughout the study.
Repeat renal biopsy at 12 months following treatment with CSA showed
histological improvement, with WHO type II changes in all 17 patients
accompanying significant reduction in activity indices. Patients with
baseline haemoglobin (Hgb) levels < 12 g/dl showed significant
improvement. Serum C3 and C4 levels were not changed significantly.
Corticosteroid-sparing effects were noted. Side-effects included
hypertension, gum hypertrophy and mild hirsuitism, but were not serious.
Combination therapy using CSA and prednisone is effective and safe for
long-term treatment in lupus patients with WHO type IV nephritis.
相似文献
467.
Regulatory mechanisms in cell-mediated immune responses. VI. Interaction of H-2 and non-H-2 genes in elaboration of mixed leukocyte reaction suppressor factor
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Previous studies have shown that alloantigen-activated spleen T cells produce a soluble factor which suppresses mixed lymphocyte reaction proliferative responses, and that the interaction between suppressor and responder cells is controlled by genes of the H-2 complex. However a defect in the expression of suppressor activity was identified in the mouse strain C57BL/6J. Factor prepared from alloactivated B6 spleen cells failed to suppress MLR responses of syngeneic or H-2 compatible responder cells. Unimpaired suppressor factor production by other H-2 (b) strains and failure of suppressor factor production by a B6 congenic strain, B6.C-H-2(d) isolated the defective gene to the non-H-2 portion of the genome. In addition, the defect appeared to be related specifically to inability to produce an active factor, while the capacity to respond to suppressor molecules was unimpaired. The genetic character of the non-H-2 gene action was identified in F1 hybrid studies. Initially F(1) hybrids of the nondefective histoincompatible strains were studied. Suppressor factor from F1 cells suppressed the responses of both parental strains, and parental factors each suppressed the response of F(1) cells. Adsorption of F(1) factor with Con A-activated thymocytes of either parental strain removed suppressor activity specific for that strain, leaving activity against the other parental strain intact. The data support cedominant expression and production of distinct, parental H-2 haplotype-specific suppressor molecules by F(1) suppressor cells. An F(1) hybrid of the defective B6 strain with nondefective BALB/c produced suppressor factor which was also capable of suppressing both parental strains. Production of a suppressive B6-reactive factor by F(1) cells was verified by adsorption studies. Thus it appears that non-H-2 genes of the BALB/c parent acted in a genetically dominant fashion to provide the function required for expression of B6 suppressor molecules. We conclude that multiple genes control the expression of alloactivated suppressor cell activity, with at least one gene mapped to the I-C subregion of the murine major histocompatibility complex and one or more genes mapped to the non-H-2 gene complement. 相似文献
468.
469.
Effect of dialysate calcium concentrations on intradialytic blood pressure course in cardiac-compromised patients 总被引:1,自引:0,他引:1
FM van der Sande EC Cheriex WH van Kuijk KM Leunissen 《American journal of kidney diseases》1998,32(1):125-131
To prevent hypercalcemia in the treatment of secondary hyperparathyroidism, low calcium (L-Ca) dialysate is advocated. However, changes in ionized calcium (i-Ca) levels have a pivotal role in myocardial contraction and could influence blood pressure stability during dialysis. Recently, our group found in patients with normal cardiac function a significant decrease in blood pressure (decrease in systolic blood pressure [DSBP]: -13 mm Hg and decrease in mean arterial pressure [DMAP]: -7 mm Hg) during dialysis with L-Ca dialysate compared with high calcium (H-Ca) dialysate, and this was mainly related to a decreased left ventricular contractility with use of L-Ca dialysate. On the basis of these data, it could be expected that changes in i-Ca levels during dialysis are of more clinical importance in cardiac-compromised patients (CCpts), New York Heart Association classifications III and IV. In this study, the effects of L-Ca dialysate (1.25 mmol/L) and H-Ca dialysate (1.75 mmol/L) on arterial blood pressure parameters (systolic [SBP], diastolic [DBP], and mean arterial blood pressure [MAP]), heart rate, stroke distance (SDist), and minute distance (MDist) during 3 hours of a standardized ultrafiltration/hemodialysis (UF+HD) in nine CCpts was investigated. i-Ca levels increased significantly with H-Ca dialysate UF+HD, whereas there was no change with L-Ca dialysate. SBP, DBP, and MAP decreased statistically and clinically significantly during UF+HD with L-Ca dialysate and were significantly lower with the use of L-Ca dialysate compared with H-Ca dialysate. SDist and MDist decreased significantly with L-Ca dialysate, whereas there were no changes in SDist and MDist with H-Ca dialysate. The predialysis and postdialysis index of systemic vascular resistance (SVRI) was similar between L-Ca dialysate and H-Ca dialysate use. Between the two groups, there were no significant differences in changes in SVRI. From this study, we can conclude that changes in i-Ca levels are a very important determinant of the blood pressure response during UF+HD in CCpts, and this response is mediated by changes in myocardial contractility. 相似文献
470.