Martin J. Cline

Transcription of c-onc genes c-rasKi and c-fms during mouse development.

We investigated the expression of cellular sequences c-rasKi and c-fms, which are homologous to the oncogenes of Kirsten rat sarcoma virus and the McDonough strain of feline sarcoma virus, during murine development and in a variety of mouse tissues. The c-rasKi gene was found to be transcribed into two mRNA species of approximately 2.0 and 4.4 kilobases, whereas a single c-fms-related transcript of approximately 3.7 kilobases was identified. The c-rasKi gene appeared to be expressed ubiquitously, since similar levels of transcripts were observed in embryos, fetuses, extraembryonal structures, and a variety of postnatal tissues. In contrast, significant expression of c-fms was found to be confined to the placenta and extraembryonal membranes (i.e., combined yolk sac and amnion). The concentration of c-fms transcripts in the placenta increased approximately 15-fold (relative to day-7 to day-9 conceptuses) during development before reaching a plateau at day 14 to 15 of gestation. The time course of cfms expression in the extraembryonal membranes appeared to parallel the stage-specific pattern observed in the placenta. The level of c-fms transcripts in the extraembryonal tissues reached a level which was approximately 20- to 50-fold greater than that in the fetus. These findings suggest that the c-fms gene product may play a role in differentiation of extraembryonal structures or in transport processes occurring in these tissues. Our results indicate that the c-onc genes analyzed in the present study exert essentially different functions during mouse development.

Leukocyte candidacidal activity and resistance to systemic candidiasis in patients with cancer

The ability of leukocytes from subjects with various neoplasms to ingest and kill the opportunistic pathogen Candida albicans was tested. Although their ability to ingest C. albicans was unimpaired, neutrophils from patients with advanced Hodgkins disease and acute leukemia and from patients receiving chemotherapy for metastatic cancer frequently manifested impaired candidacidal activity. In some instances, functionally deficient neutrophils were found to have low levels of myeloperoxidase and lysozyme activity, possibly reflecting a generalized decrease in the lysosomal enzyme content of these cells. Previous studies have suggested that neutrophils play a prominent role in normal resistance to systemic C. albicans infection. Leukopenia, impaired leukocyte mobilization, and intrinsically deficient neutrophil candidacidal activity may combine to place certain cancer patients at high risk of developing systemic candidiasis.

Plasma kinins and cortisol: a possible explanation of the anti-inflammatory action of cortisol.

Kinins are naturally occurring vasoactive polypeptides thought to be mediators of acute inflammatory responses. Kinins are released from a plasma protein substrate by glass-activated plasma enzymes (kallikreins) or by isolated intact granulocytes. Cortisol in concentrations of 2.5 x 10-6 to 2.5 x 10-5M prevented the release of active kinin from substrate by granulocytes or contact with glass. Deoxycorticosterone, progesterone, and etiocholanolone in comparable concentrations were significantly less effective in preventing kinin release. Plasma obtained from patients receiving prednisone released no kinin after activation by glass and less kinin than control plasma when exposed to granulocytes. Cortisol also partially inhibited the release of kinin by purified urinary kallikrein. Certain adrenocorticosteroids may exert their anti-inflammatory effect by inhibiting the release of plasma kinins. Steroids may act in part by preventing interaction between the activated kallikrein and its substrate.

The interaction of leukocytes and the kinin system.

Abstract Kinin-generating and kinin-destroying (kininase) activities were demonstrable in normal and neoplastic granulocytes and eosinophils but not in lymphocytes. At physiologic pH, both activities were present mainly in the soluble fraction of the cells. At pH 5·5, granulocyte kininase activity was also found in the granule fraction. Kinin generation by granulocytes required factor XII (Hageman factor) in the substrate and was inhibited by low oxygen tension, dinitrophenol, potassium cyanide, and colchicine. Synthetic bradykinin had no demonstrable effect on the stability of leukocyte granules. An expanded model of the interaction of granulocytes and kinins in inflammatory reactions which integrates these observations is presented. From the available information, it seems reasonable to propose that glucocorticoids may inhibit kinin release by granulocytes, plasma, and tissue kallikreins and that colchicine may inhibit at least generation of kinins by granulocytes.

Oncogenes: Implications for the Diagnosis and Treatment of Cancer

Cellular oncogenes comprise a small family of genes, highly conserved throughout vertebrate evolution, that code for proteins with diverse functions including DNA binding, protein kinase, and cellular growth factor activities. Cellular oncogenes are important in certain aspects of the proliferation and differentiation of normal cells. Under some circumstances these genes may also induce malignant transformation of normal cells. Various mechanisms may underlie their involvement in carcinogenesis. Incorporation of all, or part of, cellular oncogenes into RNA tumor viruses, mutations in gene structure, or translocation of cellular oncogenes from one chromosome to another may all be associated with the induction of malignant change in cells. In some of these situations altered oncogene products are made. Knowledge about the biology of oncogenes may lead to improved techniques for cancer detection and perhaps new approaches to cancer treatment.

Synthesis of macroglobulins in vitro.

THE increased concentration of macroglobulin (IgM) in the sera of patients with macroglobulmaemia is usually ascribed to excessive production of the protein by neoplastic cells of the lymphocytic series. This inference is based on, two observations: the association of increased concentrations of IgM and abnormal “lymphocytoid” or “plasmacytoid” cells, and the staining of these cells by fluorescein-labelled antibody to IgM (ref. 1). Recently, a patient (J. P.) with γ-macroglobulinaemia and circulating lymphosarcoma cells (leucolymphosarcoma) offered a rare opportunity to examine directly the capacity of these cells to synthesize IgM. For comparison, the synthesis of IgM by leucocytes of a normal subject and of patients with various haematological diseases was also investigated. In additional experiments, the synthesis of ribonucleic acid (RNA) by the lymphosarcoma cells and certain other leucocytes was investigated.