Biomedical subjects
Publications and source records attributed to E Jonasch.
Vaccination therapy for human malignancies is an ever-evolving technology. Great strides are being made in our understanding of the various components of the immune system and how best to manipulate these components.
UNLABELLED: For the past 40 years, various forms of interferon (IFN) have been evaluated as therapy in a number of malignant and non-malignant diseases. With the advent of gene cloning, large quantities of pure IFN became available for clinical study. This paper reviews the biology, pharmacology, and clinical applications of IFN formulations most commonly used in oncology. It then reviews the most common side effects seen in patients treated with IFN, and makes recommendations for the management of IFN-induced toxicity. The major oncological indications for IFN include melanoma, renal cell carcinoma, AIDS-related Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, and chronic myelogenous leukemia. Unfortunately, IFN therapy is associated with significant toxicity, which can be divided into constitutional, neuropsychiatric, hematologic, and hepatic effects. These toxicities have a major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient. Careful attention to all aspects of patient care can result in improved tolerability of this difficult but promising therapy. CONCLUSION: a better understanding of IFN biology, indications, side effect profiles, and toxicity management will aid in optimizing its use in the treatment of patients with cancer.
The antibiotic radicicol suppresses transformation in a variety of transformed cells. The antineoplastic effects of the drug have been attributed to the degradation of Raf and the inactivation of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreading, suppresses anchorage-independent cell growth, and increases the expression of the high-molecular weight tropomyosin isoform TM-2 in cells stably expressing a constitutively active form of MEK-1 as well as in ras-transformed cells. Furthermore, the reverting effects of the drug are achieved at concentrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90(RSK). In contrast, low concentrations of radicicol significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription. The lack of correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletion or disruption of proximal signaling events in the mitogen-activated protein kinase pathway are not the predominant mechanisms by which the drug suppresses the transformed phenotype. Our observation that low concentrations of radicicol block transcriptional activities mediated by AP-1 and SRF suggests that interference with signaling upstream of these transcription factors may contribute to the reverting effects of the drug.
BACKGROUND: The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. METHODS: The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. RESULTS: The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. CONCLUSIONS: Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients.
Transformation is accompanied by the down-regulation of the high molecular weight isoforms of non-muscle tropomyosin. Several lines of evidence suggest that tropomyosin down-regulation may be essential for ras-induced tumorigenicity. It is unclear which of the many signaling pathways downstream of Ras are involved in tropomyosin down-regulation. Here we demonstrate that Raf activation induces tropomyosin down-regulation comparable to that induced by Ras. Expression of the effector-domain mutant Ras-G12V,Y40C, which is unable to bind Raf, induced only modest down-modulation of tropomyosin. Treatment with the MEK-specific inhibitor PD98059 had little effect on tropomyosin levels in ras- or raf-transformed cells. In contrast, a mutant form of MEK-1, MEK-1-S218A,S222A, restored tropomyosin levels in ras-transformed NIH3T3 cells almost to the levels observed in non-transformed cells. MEK-1-S218A,S222A does not inhibit MEK phosphorylation and is a poor inhibitor of ERK phosphorylation. These data suggest that this mutant form of MEK-1 interferes with a yet uncharacterized pathway controlled by Raf. We conclude that the ras-induced down-modulation of tropomyosin is predominantly Raf-mediated, but MEK-independent, and that a novel pathway exists downstream of Raf which may play an important role in regulation of the cytoskeleton.
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During a period of 11 years 2672 traumatic subluxations of the radial head have been treated. This accident are mostly be found from 1--4 years of patients, especially in 61.4% in women. The reposition was in all the cases conservative.
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Only part of the tibial condylar fractures may be treated in a conservative way, because they are always in connection with the knee joint. By means of an exact classification of fractures into different types the indication for conservative treatment is determined. The way how conservative treatment has to be performed is described.
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