Immunologic purging of marrow assessed by polymerase chain reaction.
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Biomedical subjects
Publications and source records attributed to A J Murgo.
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The P2T purinergic receptor for ADP has previously been found only in platelets. We investigated the effect of ADP on the concentration of intracellular free calcium ([Ca++]i) in fura-2-loaded K562 leukemia cells, a cell line with the potential for megakaryocytic differentiation. ADP causes a rapid and transient increase in [Ca++]i, which peaks within 5 to 10 sec. The EC50 for this response is 0.4 microM. A major portion of the increased calcium is due to mobilization of intracellular stores because the response to ADP is only partially reduced in the absence of extracellular calcium. Exposure to ADP desensitizes K562 cells to additional administrations of this nucleotide. Pretreatment of K562 cells with the protein kinase C activator phorbol 12-myristate 13-acetate completely blocks the response to ADP. This effect of phorbol 12-myristate 13-acetate is prevented by the protein kinase C inhibitor staurosporine, but staurosporine does not affect the progression of desensitization after repeated ADP exposures. ATP does not increase [Ca++]i in K562 cells, but antagonizes the response to ADP. We propose that the P2T receptor for ADP in K562 cells is an early marker for megakaryocytic differentiation. Furthermore, this immortalized nucleated cell line may be a useful model to decipher the signal transduction pathways involved in the ADP response.
During the last decade, the process by which the FDA regulates investigational new drugs has become a renewed focus of national attention. The ability of the FDA to maintain a balance between accelerating the availability of new drugs and ensuring that patients do not receive unsafe or ineffective treatments has been particularly challenged by the AIDS crisis. In response to this crisis, the FDA has revised its regulations and created various formal mechanisms for expediting the development and accessibility of promising new therapies to treat AIDS and other serious illnesses. Regulatory requirements have been reduced and consultation with the FDA to discuss the planning and design of clinical research is encouraged.
Stress, distress and a variety of psychiatric illnesses, notably the affective disorders, are increasingly reported to be associated with immunosuppression. The concept that psychic distress may predispose to medical illness is centuries old but has only recently attracted the attention of the scientific community at large. Interdisciplinary collaboration has established psychoneuroimmunology, or neuroimmunomodulation, as a new field of investigation with the goal of rigorous scientific research into the elusive mind-body connection. This has resulted in the rapid accumulation of information which falls across the boundary lines of psychiatry, immunology, neurosciences and endocrinology. Here David Khansari, Anthony Murgo and Robert Faith review the effects of stress on the endocrine and central nervous systems and the interactions between these systems and the immune response after exposure to stress signals.
The present study was undertaken to determine the effect of the opioid receptor antagonist, naloxone, on the growth of B16 melanoma, a murine tumor known to possess opioid receptors. Naloxone inhibited the growth of B16 melanoma in vitro when monolayer cultures were continuously exposed to concentrations of greater than or equal to 0.25 mg/ml. Tumor cell proliferation as measured by [3H]thymidine ([3H]Tdr) incorporation is reduced by a continuous 48-h treatment with greater than or equal to 0.025 mg/ml but slightly enhanced by a 6-h treatment. The administration of naloxone to mice caused a transient inhibition of subcutaneous local tumor growth at doses of 0.1, 1 and 10 mg/kg daily. At a dose of 10 mg/kg daily, naloxone caused a slight reduction in the number of pulmonary metastases following the intravenous inoculation of tumor cells. The mechanism by which naloxone inhibits tumor growth in vivo is not clear, but factors other than direct cytotoxicity may also be involved. The results further support the role of the endogenous opioid system in the modulation of tumor growth.
A better understanding of cellular immunology and advances in recombinant DNA technology have led to a new dimension in the immunological treatment of cancer in which the potential for success is greatly increased. The number of biological agents with the ability to enhance the host's anti-tumor defense mechanisms has markedly increased during the last decade. The development of clinical trials with these biological response modifiers is an area of intense research. As a result of these investigations, a variety of malignancies now can be treated successfully by immunological approaches.
Studies were performed to investigate the effects of the endogenous opioid peptide methionine enkephalin on experimental metastasis of the murine B-16 melanoma and on murine splenic natural killer cell activity. Methionine enkephalin was shown to significantly inhibit tumor metastasis and significantly enhance splenic natural killer cell activity. These results indicate that the endogenous opioids can modulate the immune response and tumor defense and that methionine-enkephalin may prove to be a beneficial adjunct to the therapy of neoplastic disease.
An increased incidence of thromboembolic events has been described in women receiving chemotherapy for breast cancer. The etiology of this enhanced thrombotic state has not been defined. We performed serial coagulation studies in 15 women during 1 monthly cycle of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer; seven adjuvant and eight metastatic. Plasma protein C levels were measured by anticoagulant, amidolytic, and antigenic techniques. Antigen levels of both total and free plasma protein S were quantitated by immunoelectrophoresis. Plasma levels of protein C, an important vitamin K-dependent inhibitor of blood coagulation and a profibrinolytic agent, and protein S, a cofactor for protein C, decreased 1 and 2 weeks after initiation of chemotherapy compared with pretreatment values. Plasma levels of factor VII and fibrinogen also decreased. The changes in protein C and protein S may contribute to the enhanced thrombotic tendency described in this setting. Possible mechanisms for the decreases in plasma protein C, protein S, factor VII, and fibrinogen are discussed.
Host resistance to disease is dependent upon a number of factors. Recent evidence indicates that natural killer (NK) cells play an important role in resistance to both neoplastic and virally induced disease. Treatment of C57Bl/6 mice with methionine-enkephalin (1, 3, 10, or 30 mg/kg body weight) results in significant increases in NK activity of splenic lymphocytes 20 hours after injection of the enkephalin. Enkephalin treatment also enhances host resistance. The short-term survival of A/J female mice after HSV-2 infection was significantly increased by daily subcutaneous injections (3 mg/kg body weight) of methionine-enkephalin. Similarly, daily doses of 50 micrograms of methionine-enkephalin for 7 to 14 days inhibit the local subcutaneous tumor growth of B15 melanoma in C57Bl/6 mice.
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A 19-year-old man with acute lymphoblastic leukemia (ALL) presented with 82,000 WBC/microL, 57% eosinophils, and cardiorespiratory symptoms. Lymphoblast infiltration of the meninges and testes developed without eosinophil infiltration at these sites and peripheral blood and marrow lymphoblast counts progressively increased, while blood eosinophilia disappeared. The patient's bone marrow cells had a clonal cytogenetic abnormality--t(5;14), (q?,q32)--which disappeared during remission and reappeared during disease relapse. Including this case, three patients with ALL and hypereosinophilia have had cytogenetic studies with G-banding. All three had 14q + chromosomal abnormalities and two had a similar translocation t(5,14), (q?,q32). Survival of the 26 ALL patients with hypereosinophilia reported since 1973 was similar to that of 52 age- and sex-matched historical-control patients without hypereosinophilia treated during the same time interval.
The value of serum lactate dehydrogenase (LDH) levels and bone scan results in predicting marrow involvement in small-cell carcinoma of the lung (SCCL) was studied. Records of 79 patients with SCCL who had undergone 92 bone marrow examinations were reviewed. None of 25 patients with marrow involvement had a normal LDH and a negative bone scan, compared with 23 of 59 in the uninvolved group. We conclude that patients with SCCL with both negative bone scans and normal LDH values have a less than 5% chance of marrow involvement.
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To initiate investigations into the effects of enkephalins on immune function in cancer patients, the effect of methionine-enkephalin and leucine-enkephalin on natural killer (NK) cell activity in isolated peripheral blood lymphocytes from cancer patients was investigated. Incubation of lymphocytes with either enkephalin resulted in significant increases in NK cell activity. At effector:target cell ratios of 100:1, 33:1 and 11:1 leucine-enkephalin significantly (p less than 0.05) enhanced NK activity at dilutions of 10(-6), 10(-8), 10(-10), and 10(-14) mg/ml. Similar results were obtained with methionine-enkephalin with the exception that the 10(-6) dilution gave insignificant changes at both the 33:1 and 11:1 cell ratios. The results indicate a difference in dose response to both enkephalins between lymphocytes from cancer patients and normal volunteers.
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The authors report a case of renal failure and microangiopathic hemolytic anemia associated with the administration of mitomycin C in a 62-year-old man. Examination of the renal biopsy specimen revealed glomerular sclerosis and necrosis with interstitial fibrosis on light microscopy. Electron microscopic findings revealed deposits of fibrin within the glomeruli and interstitial tissue and separation of glomerular epithelial cells from the underlying lamina densa. Following plasma exchange, the hemolytic process improved, but renal failure persisted.
Methionine-enkephalin (Met-Enk) and ZnCl2 in combination enhances active T cell rosette formation of human peripheral blood lymphocytes to a greater degree than either of the agents used separately. Enhancement of rosette formation by Met-Enk plus ZnCl2 was not inhibited by the opiate receptor antagonist naloxone but was completely blocked by the zinc chelator 1,10-phenanthroline. The results suggest a relationship between zinc and Met-Enk and that zinc may be a modulator of enkephalin binding and function in the immune system as well as the nervous system.