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PubMed1978

Synergistic effect of tumor virus transformation and tumor promoter treatment on the production of plasminogen activator by chick embryo fibroblasts.

Cultures of Rous sarcoma virus-transformed chick embryo fibroblasts (RSVCEF) produce 50-fold more of the protease plasminogen activator (PA), than do normal chick embryo fibroblasts. Treatment of RSVCEF cultures with the tumor promoter phorbol myristate acetate (PMA) further enhances (8- to 12-fold) the level of PA activity. Increased levels of PA activity in RSVCEF are observed as early as 1 to 2 hr after PMA treatment. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrates that the PA produced by PMA-treated cultures has a molecular weight identical to that of the PA produced by untreated cultures. PA induction by PMA cannot be accomplished in cell-free extracts, but requires protein synthesis in intact cells. Under serum-free conditions, PMA-treated RSVCEF secrete high levels of PA for 4 to 6 days and undergo pronounced morphological alterations. Modified culture conditions and the use of PMA to induce PA has allowed for the accumulation of large amounts of RSVCEF culture fluid and the subsequent purification of the enzyme. The sensitivity of transformed CEF to PMA and the generation of enhanced proteolytic activity in the cellular microenvironment may provide a model system to examine the role of both PA in malignant transformation and PMA in tumor promotion.

Avian Sarcoma Viruses↗
PubMed1989

Zinc and diet for tinnitus.

Management of cellular microenvironment by dietary alteration provides a complex, highly sophisticated, physiologic and biochemical approach to tinnitus.

Humans↗
PubMed1987

Activation of immature cortical thymocytes through the T11 sheep erythrocyte binding protein.

Two major pathways, the T cell receptor and the T11 alternate pathway, allow for T cell activation. In the human thymus, the T cell antigen receptor complex is reduced or absent on immature thymocytes, whereas the T11 glycoprotein is present at high cell surface density on all thymocytes. To determine whether activation through the T11 pathway induces similar or different changes in mature and immature thymocytes, we fractionated thymocytes according to their surface expression of the T3-T cell receptor (T3/Ti) complex. We report that two populations, one with high and one with low T3/Ti expression, can be activated through the T11 pathway to undergo nuclear activation and express IL 2 receptors. Moreover, in the absence of accessory cells, only the most mature population, expressing high T3 density, could be induced to proliferate, whereas the subset representing immature cortical thymocytes required accessory cells for proliferation. These findings suggest that the cellular microenvironment may have a critical role in regulating the activation of immature cortical thymocytes and that this cell population may not represent "nonfunctional" dead end cells, but rather a valid intermediate in human thymic differentiation.

Antigens, Differentiation, T-Lymphocyte↗
PubMedDate not supplied

The macrophage as a production site for hematopoietic regulator molecules: sensing and responding to normal and pathophysiological signals.

Several functional capacities of the macrophage enable it to act as an "administrator" cell for normal and pathophysiological hemopoietic regulation. Its capacity of sensing and responding to physiso-chemical, cellular and humoral signals indicates that it can regulate myelomonocytopoiesis and erythropoiesis. This occurs by modulating colony stimulating factor and erythropoietin production in response to lactoferrin and oxygen tension respectively. Detection of erythropoietin gene expression in macrophages, both in vitro and in vivo, implies that the macrophage is an "active" member of the hemopoietic cellular microenvironment. Since a subpopulation of macrophages is responsible for this function, a model is proposed in which other hemopoietic regulator molecules may be produced by distinct subpopulations of macrophages under steady-state conditions.

Animals↗
PubMed1988

Erythropoietin gene expression in vitro and in vivo detected by in situ hybridization.

Macrophages derived from unstimulated and unseparated mouse bone marrow cells have been shown to release erythropoietin into the extracellular fluid. Additional proof that macrophages can produce the hormone would be a demonstration that the gene is expressed and the mature protein released. In situ hybridization using a 1.2 kb biotinylated erythropoietin DNA probe demonstrates that both cultured macrophages and those present in normal mouse bone marrow express the gene. These results are discussed in terms of the role played by the macrophage in the hemopoietic cellular microenvironment and indicate that a subpopulation is responsible for this function and that cell interactions play an important role in hemopoietic differentiation.

Animals↗
PubMed1986

Immunodeficiency and cancer: mechanisms involved.

This is a short overview concerning possible relationships between immunodeficiency and cancerogenesis/leukemogenesis. Following introductory remarks on concomitant and sinecomitant antitumor immunity, various factors/mechanisms that could influence tumor-host-interactions are discussed, in particular properties of neoplastic cell lines, the microenvironment, cellular components of nonspecific resistance, and specific, i.e. antigen-directed, cell-mediated and humoral immune responses against cancer cells. The increased incidence of malignant neoplastic processes in patients with inherited or acquired immunodeficiency raises the question if a lack of antitumoral defense or ineffective antiviral immunity is more important. Available data indicate that once a cancer has reached a certain size, the chances for the host to reject it solely with the help of its immune apparatus are minimal. The possibility remains that immune reactions may be more efficacious against small numbers of immunogenic tumor cells, i.e. in the very earliest phase of a neoplastic process and when the cancer begins to metastasize.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats.

Human breast cancer xenografts in T-cell-deficient rnu/rnu rats permit the detailed and systematic study of blood flow, oxygen supply, and characterization of the cellular microenvironment of human tumors in vivo. Using an epigastric pouching technique, it is possible to obtain a tissue-isolated preparation which makes direct studies of blood flow and oxygen supply in human tumors feasible. So far, medullary and squamous cell carcinomas of the breast from patients have been investigated under well-defined systemic conditions. At comparable tumor sizes, the average blood flow rate through human breast cancer xenografts is higher in medullary than in squamous cell carcinomas (0.17 versus 0.10 ml X g-1 X min-1). Blood flow per unit tumor mass significantly decreases with increasing wet weight. No significant differences are obvious when comparing the flow values of pre- and postmenopausal tumors or of cancer tissues with different hormone receptor capacities. On the average, the oxygen consumption rates of human breast cancer xenografts are 10.4 in medullary and 7.7 microliter O2 X g-1 X min-1 in squamous cell carcinomas. With increasing tumor mass, the O2 consumption rate per unit weight significantly decreases. This decrease parallels the respective decline of tumor blood flow, implying that the O2 consumption rate of the cancer cells in vivo is mostly limited by the nutritive blood flow, i.e., by the O2 availability to the tumors. Due to a restricted blood supply, the O2 utilization of human breast cancer xenografts is high. Tissue oxygenation in microareas of human breast cancers xenotransplanted s.c. into nude rats is mostly inadequate. As a consequence, tissue hypoxia and anoxia are common findings even in very early growth stages. Due to marked intra- and intertumor variabilities in blood flow, heterogeneities in the tissue oxygenation are characteristic features of human breast cancer xenografts. From the results obtained it is concluded that human breast cancers growing as xenografts in rnu/rnu rats may be useful tools for cancer research, especially for investigations of blood flow, tissue oxygenation, and substrate turnover.

Animals↗
PubMedDate not supplied

[Changes in the positive P.A.S. reaction of the cytoplasm of giant cells. Role of etiologic factors and the giant cell reaction].

The search for alpha-amylase resistant, P.A.S. positive cytoplasm has been carried out in 206 giant cell lesions with or without specific inflammatory features and with neogenetic and degenerative plasmodia. It allowed to distinguish: --P.A.S. positivity in inflammatory cells of any nature, however with quantitative variations linked to etiologic factors (pathogen agent and disposition), to site, to the age of the plasmodia, and particularly, with negativation of the reaction in ancient lesions;--negativity of the neogenetic and degenerative plasmodia, save the giant cell articular lesions. Cells containing glycogen particularly (muscular tumors, renal or placental) are easily identified thanks to enzymatic digestion tests. Variations observed in the inflammatory cells seem to be the reflect of an active metabolism bringing about resorption phenomena but probably also immunization processes acting at the level of the cellular microenvironment.

Cytoplasm↗
PubMed1983

The distribution of stellate cell descending axons in the rat cerebellum: a Golgi and a combined Golgi-electron microscopical study.

Axonal descending branches of stellate cells in the molecular layer of the cerebellar cortex of the rat were studied by means of Golgi and combined Golgi-ultrastructural methods. Special attention was paid to those branches from more superficially located cell bodies. With the Golgi method, it was observed that the number of axons from stellate cells forming pericellular baskets and 'pinceaux' increases as their cell bodies come to lie deeper in the layer. With the combined Golgi-ultrastructural method, it was verified that the synaptic contacts established by these axons are identical to those of axons from basket cells, either contacting Purkinje cell bodies or lying around the axon initial segments, where they establish septate-like junctions. This overlapping of axonal territories between stellate and basket cells is in accordance with the hypothesis that these interneurons, although situated at different levels of the cerebellar molecular layer, may be genetically identical cells. Their diversity of form would depend on the cellular microenvironment present at the time of differentiation.

Animals↗
PubMed1983

Regulation of the immune response in experimental models of autoimmune disorders: resistance of (NZB X NZW)F1 mice to tolerance induction in vivo.

Studies were carried out to test whether tolerance to alloantigens and to heterologous proteins could be induced in (NZB X NZW)F1 (B/W) female mice, compared with females of various other mouse strains, including BALB/c, C3H/eb, C57Bl/Ka and (BALB/c X C57Bl/6)F1. Untreated BALB/c and B/W mice were resistant to tolerance induction by deaggregated BSA, while all other strains were susceptible, as indicated by their lack of response to antigen challenge. Tolerance induction to BSA was further potentiated in all mouse strains including BALB/c with the exception of B/W, following prior conditioning of the mice with total lymphoid irradiation (TLI). Similarly, specific and permanent tolerance to H-2 incompatible alloantigens was successfully induced in TLI conditioned BALB/c, C3H/eb, (BALB/c X C57Bl/6)F1 injected with bone marrow cells, however, B/W mice were resistant. Stable chimeras could be established in TLI treated B/W mice only across a semi-allogeneic combination (BALB/c--greater than B/W). No graft vs host disease (GVHD) was observed in any of the chimeras including B/W mice. We conclude that B/W mice are resistant to tolerance induction to heterologous proteins and alloantigens, even after TLI conditioning. We postulate that this phenomenon is a function of both the intrinsic properties of the haemopoietic stem cells, including their differentiated progeny, as well as characteristics of their cellular microenvironment.

Animals↗
PubMed1982

Action of deoxycoformycin on human T cell colonies in vitro.

The potent adenosine deaminase inhibitor, deoxycoformycin (dCF), is currently under evaluation in the treatment of lymphoid malignancy. We show that dCF inhibits the growth in soft agar of T cell colonies from PHA stimulated human peripheral blood lymphocytes. In contrast to previous attempts to develop an in vitro model for analysis of the drug's action, concentrations lower than 10(-9)M are effective, and no 'priming' by pharmacological concentrations of adenosine is required. Maximum inhibition is obtained when dCF is present over the first 4 hr of cellular exposure to PHA. T cells already proliferating in response to PHA are less sensitive to dCF, implying that S-phase events are not primary targets of the drug's action. Colony inhibition does not appear to be due to alteration in the production of, or sensitivity to, soluble T cell growth factors. In suspension cultures, dCF at concentrations up to 10(-5)M fails to inhibit early PHA-induced volume changes, or later mitosis, in peripheral blood lymphocytes. The results show that there is a critical dCF sensitive step early in PHA stimulation. It involves those T cells capable of forming colonies and may be conditioned by the cellular microenvironment.

Adult↗
PubMed1982

Isolation of quiescent cells from multicellular tumor spheroids using centrifugal elutriation.

A quiescent (nonproliferating) subpopulation was identified by flow cytometric analysis using two-step acridine orange staining in the EMT6/Rochester, N. Y. subline multicellular tumor spheroid, an in vitro culture system which provides a cellular microenvironment which mimics that of many of in vivo tumors. To isolate a viable quiescent cell subpopulation, centrifugal elutriation which allows for cell separation mainly on the basis of size was used. This technique provided single cells of relatively homogeneous cell volume which varied over a wide range (approximately 100 to 5000 cu microgram). Though the relatively small cell volume fractions were the most enriched (82%) in quiescent cells, such cells were also observed in significant numbers (congruent to 20%) even in the largest cell fractions. The cell clonogenicity of the various elutriation constant in fractions was also assessed and shown to be lowest (plating efficiency congruent to 20%) in the small spheroid cells but relatively constant in fractions containing intermediate and large cells (plating efficiency congruent to 50%). Continuous [3H]thymidine labeling indicated a slower rate of accumulation of labeled cells in the small spheroid cells, which may result from the transition of proliferating spheroid cells to the quiescent compartment during the course of labeling. These finding indicate the utility of centrifugal elutriation for quiescent cell characterization in in vitro tumor systems.

Animals↗
PubMed1981

[Patterns in the lesions of different sections of the hemopoietic system in leukemia].

Morphological examinations of the hemopoietic system in 43 patients died of different forms of leukemias revealed irregular involvement into the leukemic processes of its different parts. Differences in the spread of leukemic lesions in the spleen, lymph nodes, tonsils and other lymphoid formations in lympho- and myeloleukemias were demonstrated. They are discussed from the point of view of the concept on metastatic involvement of different parts of the hemopoietic system in leukemias and on the importance in the development of these lesions of the cellular microenvironment. Also, the importance of atrophic changes of the thymus and other lymphoid structures as manifestations of immunological insufficiency which is one of the most significant conditions for the development of leukemia is discussed.

Adult↗
PubMed1994

Cell surface syndecan-1 on distinct cell types differs in fine structure and ligand binding of its heparan sulfate chains.

Heparan sulfate (HS) can bind a large variety of biological effectors, including extracellular matrix components, growth factors, chemokines, degradative enzymes, and protease inhibitors. Where studied, HS is known to be structurally heterogeneous and to vary in sulfation pattern between cells and tissues. Because heparan sulfate can represent several distinct proteoglycans, we asked whether the structural variation in the heparan sulfate chains of a single species of cell surface proteoglycan is a reproducible, differentiated characteristic and whether the variation can result in distinct biological functions. We studied the molecular structure and binding affinity for type I collagen and fibroblast growth factor-2 of syndecan-1 purified from the surfaces of NMuMG normal murine mammary gland epithelia, NIH/3T3 fibroblasts, and BALB/3T3 endothelioid cells. Syndecan-1 from these cell types varied in molecular mass largely due to variation in the length of the HS chains. Although the highly sulfated and N-acetylated domains in these HS chains were organized similarly, the number of highly sulfated domains differed. The disaccharide compositions were also similar except for reproducible and consistent differences in the amount of hexuronic acid-N-sulfated-6-O-sulfated glucosamine and 2-O-sulfated hexuronic acid-N-sulfated glucosamine. These differences were confirmed by oligosaccharide mapping, which showed cell type-specific variations in the composition of the highly sulfated domains. These structural variations correlated with cell type-specific differences in the affinity of syndecan-1 and its isolated HS chains for type I collagen. However, no differences in affinity for fibroblast growth factor-2 were detected. The results indicate that the size, fine structure, and ligand affinity of the HS chains on a single proteoglycan species differ in a consistent and reproducible manner between cell types. Thus, the variation in structure and binding ability of HS on syndecan-1 is a differentiated characteristic of the cell type that can enable cells to respond distinctly to the HS-binding effectors in the cellular microenvironment.

3T3 Cells↗
PubMed1993

[The treatment of biological material by Falck's method and its modifications using a device of original design].

Automation of the process of detecting adrenergic nerve structures helped obtain reliable positive results even in cases with low mediator concentration in body tissues. We have elaborated a new method of subsequent staining and microphotographing of biological specimens which permit registration of specific features of adrenergic nerve terminals histologic architecture and their cellular microenvironment.

Adrenergic Fibers↗
PubMed1993

Brain self-organization dynamics.

During early phases of brain development gene expression and postranslational modifications of gene expression are controlled by biochemical signals which are produced in a cellular microenvironment. Later in brain development there is a difference from the development of other organs because electrical signals are added to biochemical messengers as a further signaling in the self-organizing between genes and their respective environments. It must be considered that these electrical signals are capable in influencing gene expression and postranslational modifications. Electrical signals are transported by neuronal processes over distances and with highly topological selectively. This enlarges the range and complexity of the "environment" available to self-organization process. The "environment" relevant to brain self-organization includes all domains with which the evolving brain is capable to interact and from which it receives messages. The same electrical signals which convey messages are used by the brain as information carriers for computational process. The key concept in theories and modeling is that of refference. Cyclical process of emergent goal seeking, refference and sensory feedback constitute the basis for a subject consciousness. This cycle suggest further "inference" that the physiological basis of cause and effect lies in the mechanism of reafference. This tract results in the replacement of sensory stimuli by self-organization activity patterns that are contingent on past experience, present motivational state and expectancy of the future.

Amygdala↗
PubMed1995

Eicosanoids in rheumatoid arthritis.

Eicosanoids are potent mediators in the cellular microenvironment. Eicosanoids have different effects depending on tissue or organ, the polyunsaturated fatty acid content of the diet of the individual, and the net effect of local microenvironmental factors--as eicosanoids, cytokines, and hormones modulate each others' effects through a complex, multilevel network of interactions. In general, eicosanoids have significant net proinflammatory effects. In RA, the net proinflammatory effects of the prostanoids is underscored by the effectiveness of the cyclooxygenase antagonists (NSAIDs), and recent data indicate a proinflammatory effect of the leukotrienes. Changes in the dietary polyunsaturated fatty acid composition to increased intake of marine n-3 fatty acids and/or dihomogamma-linolenic acid may favorably modulate eicosanoid synthesis towards less inflammatory or antiinflammatory eicosanoids and may ameliorate disease activity in RA. Recent advances in the biochemistry and molecular biology of the eicosanoid receptors and the synthetic pathways of eicosanoids will provide opportunities for advances in the therapeutics for RA, including selective cyclooxygenase (PGHS-2) antagonists, selective eicosanoid receptor antagonists and agonists, and selective inhibitors of PGH2 isomerases and enzymes of the 5-lipoxygenase pathway.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Immunocytochemical observation of multidrug resistance (MDR) p170 glycoprotein expression in human osteosarcoma cells. The clinical significance of MDR protein overexpression.

Resistance to several cytotoxic agents (MultiDrug Resistance MDR), including anthracyclines, vinca alkaloids and epipodophylline derivatives can occur in human osteosarcoma (OS) cells, detected by the overexpression of a 170 kD glycoprotein (p170), as a result of increased expression of the MDR gene (mdr1). The p170 glycoprotein in normal cells is a membrane transport system protein and its quantitative increase results in increased drug efflux and decreased intracellular drug concentration. Normal renal epithelial cells express p170 as a function of their secretory duties therefore this human tissue was used as a positive tissue control in our immunocytochemical study. This partially retrospective immunocytochemical study was carried out on routine, 10% neutral formalin fixed, decalcified, paraffin embedded, tissue sections of 43 OSs, treated between 1981 and 1993 at the Orthopaedic Hospital of Los Angeles. The immunoperoxidase antigen detection protocol, submitted by Hsu et al (1981) was employed. The search for p170 was carried out with three newly developed monoclonal antibodies (MoABs) (JSB-I, C-219 and C-494, from Signet Laboratories, Dedham, MA 02026). The initial expression of MDR was not detectable in seven OSs. 36/43 OSs expressed p170 on/in their cells. Heterogenous cellular microenvironment and various grades of differentiation features were also determined in the examined OSs. In 17/43 OS cases presence of intensive staining (probably overexpression) of p170 protein was registered. The 43 OSs exhibited different staining patterns with each MoAB. MoAB JSB-I reacted with a transmembranic antigen epitope. The long incubation time with C-219 resulted in heterogeneous cytoplasmic staining. MoAB C-494 also produced an intensive staining mainly localized on the cell membrane of the OS cells. These statistically significant immunocytochemical results suggest a direct correlation between the quantitative presence of p170 glycoprotein in human OS cells and the efficacy of the employed chemotherapy. Future observations employing the in situ hybridization technique will allow the quantitative measurement of the primary or secondary presence of MDR glycoprotein in human OS cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗