Antineuroblastoma activity of desferoxamine in human cell lines

That ferritin, an iron storage protein, can be produced by neuroblastoma cells raises the possibility that iron may have some role in promoting tumor cell growth. To explore this possibility, we studied the effects of desferoxamine, a compound which chelates iron, on viability of CHP 126 and CHP 100, two human neuroblastoma cell lines. Cells (5 X 10(4)) were incubated with graded amounts of desferoxamine or ferrioxamine, an iron-saturated analogue of desferoxamine. Within 5 days of exposure to 60 microM desferoxamine, approximately 90% of cells from each of these cell lines were dead. This effect was dose dependent, was not seen with ferrioxamine, and could be prevented by coincubation with greater than stoichiometric amounts of ferric citrate. As determined by binding of OK-T9, desferoxamine also resulted in increased expression of receptors for transferrin, an iron transport protein. Desferoxamine had only minimal effects on viability of several non-neuroblastoma cell lines. These results suggest that iron is required for growth of neuroblastoma and that desferoxamine has potent, specific, antineuroblastoma activity in vitro.     

Global transcriptional profiling demonstrates the combination of type I and type II interferon enhances antiviral and immune responses at clinically relevant doses.

A role for type II interferon (IFN-gamma) in resolving viral infection is suggested by the correlation of hepatitis C virus (HCV) clearance with enhancement of IFN-gamma-producing activated T cells in the resolution of acute HCV infection. Using vesicular stomatitis virus (VSV), a synergistic direct antiviral effect was documented using IFN-gamma1b and a potent, consensus type I IFN (IFN alfacon-1). Global expression profiling following EC50 exposure to IFN alfacon-1, IFN-gamma1b, or a cocktail of the two allowed the antiviral state to be correlated with induction of a subset of IFN-stimulated genes (ISGs). Genes identified through this analysis corresponded to classic antiviral components, ISGs more recently associated with direct antiviral functions, as well as expressed sequence tags (ESTs) and hypothetical proteins. The magnitude of these antiviral EC50-correlated expression events in human hepatoma (Huh7) cells exposed to clinically relevant doses of IFN alfacon-1, IFN-gamma1b, or a cocktail of the two was also probed because the standard of care for patients with chronic hepatitis C is type I IFN-containing regimens. Relative to type I IFNs used alone, the addition of type II IFN caused enhanced expression not only of many of the genes correlated with the direct antiviral state but also of genes involved in (1) antigen presentation to cytotoxic T lymphocytes (CTLs), (2) macrophage, natural killer (NK), and T helper 1 (Th1) cell recruitment and activation, (3) complement system function, (4) apoptosis, and (5) ISGs with unknown functions. As many of these processes are correlated clinically with resolution of chronic HCV infection, the combined use of these IFNs could display a beneficial effect on viral clearance in patients infected with HCV and other viruses through enhancement of one of these processes or of the direct antiviral state.     

氯仿重结晶棉酚的质量研究

报道了氯仿重结晶的棉酚的化学性质,样品在不同温度下干燥恒重后,经熔点、薄层层析、紫外光谱、红外光谱、X-射线衍射、热重量分析、元素(C,H,Cl)分析及棉酚合量测定等一系列的分析,确证了在60℃以下棉酚与氯仿成溶剂化物(solvate)。随着干燥温度的升高或在室温长时间的贮存,此现象逐渐消失,100℃真空干燥恒重后成为纯棉酚。     

Lack of significant activity of 2'-deoxycoformycin alone or in combination with adenine arabinoside in relapsed childhood acute lymphoblastic leukemia. A randomized phase II trial from the Childrens Cancer Study Group.

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.     

Mechanism of antineuroblastoma activity of deferoxamine in vitro

Deferoxamine previously has been shown to have potent activity in vitro against human neuroblastoma cells, activity that results from its ability to chelate iron. To further understand the mechanism of deferoxamine-induced cytotoxicity, we looked at its effects on cell cycling and on DNA, RNA, and protein synthesis by CHP 126, a cell line that is derived from tumor tissue of a patient with a neuroblastoma and that is known to be drug sensitive. After 24 hours of exposure to 60 mumol/L deferoxamine, there was a 35% increase in the percent of cells in the nonproliferating and prereplicative phases of the cell cycle and a corresponding decrease in the percent of cells in the DNA synthesis, postreplicative, and mitotic phases of the cell cycle, results that are consistent with a block of cell cycle progression at the early DNA synthesis phase. The inhibitory effects of deferoxamine on DNA synthesis were confirmed by demonstration of a 60% decrease in thymidine incorporation into DNA in short-term cultures of CHP 126. Effects on RNA and protein synthesis were minimal. Equivalent effects on growth were seen by using several chelators that interact with different iron pools, suggesting that both intracellular and extracellular iron are required for growth of neuroblastoma cells.     

Alprazolam as an adjunct to propranolol in anxious outpatients with stable angina pectoris

A double-blind crossover comparison is reported of the effects of alprazolam and placebo on anxiety and angina in 27 ambulatory outpatients with angina pectoris stabilized on propranolol. Alprazolam was shown to be a safe treatment when combined with propranolol in these patients. Patients receiving alprazolam with propranolol reported more improvement on their targeted symptoms than did patients receiving placebo with propranolol. The side effect most often reported was moderate drowsiness or sedation; no unusual side effects emerged. There was no evidence that alprazolam compromised the patients' response to propranolol.     

Human fibroblast tissue factor is inhibited by lipoprotein-associated coagulation inhibitor and placental anticoagulant protein but not by apolipoprotein A-II

Studies of proteins that inhibit tissue factor activity have generally been conducted using either an extracted tissue homogenate ("thromboplastin") or tissue factor protein reconstituted into phospholipid vesicles rather than with tissue factor expressed in cell membranes (its physiological environment). In the present study, a human fibroblast cell strain was used to evaluate the effects of lipoprotein associated coagulation inhibitor (LACI), placental anticoagulant protein (PAP), and apolipoprotein A-II (apo A-II) on human tissue factor in cell membranes. LACI was tested from 7.8 to 500 pmol/L on fibroblasts cultured at cell densities ranging from 3,500 to 9,925 cells/well, and caused a progressive inhibition of tissue factor activity. PAP was tested from 3.9 nmol/L to 1 mumol/L at cell densities ranging from 4,500 to 15,400 cells/well and caused up to 83% inhibition of tissue factor activity. Inhibition by these proteins appeared to be influenced by cell density as well as whether the cells were intact or disrupted. Apo A-II, up to 1 mumol/L, did not inhibit the tissue factor activity of intact or disrupted fibroblasts at any cell density examined even though it did inhibit the activity of tissue factor in phospholipid vesicles. Of these inhibitors of tissue factor-dependent activation of factor X, LACI was the most effective in suppressing the generation of factor Xa activity. The effects obtained with apo A-II are clearly dependent on the nature of the tissue factor preparation with which it is tested. The disparity between the inhibitory effect of apo A-II on the activity of tissue factor reconstituted into lipid vesicles and the absence of effect on the activity of tissue factor remaining in cell membranes serves to reemphasize the necessity of reexamining results obtained with model systems using as nearly physiological reagents as possible.     

Psychotherapy for depression: current and future directions in research, theory, practice and public policy

This article is based on a symposium held at the 1998 Annual Meeting of Society for Psychotherapy Research (Snow Bird, Utah). Recognized experts addressed current and future directions in psychotherapy for depression from the perspectives of process and outcome research, basic research, theoretical models, clinical practice and training, and public policy. The specific issues discussed at the symposium included the strengths and limitations of major forms of psychotherapy; the therapeutic factors common and unique to different approaches; the future viability of current theories of depression; the role of treatment manuals in clinical practice and training; the development of new interventions based on basic research; and the priorities that should guide federal funding.