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At least 1,009 records · Page 56Linked to original sources
PubMed1988

Observations on exsudation of fibronectin, fibrinogen and albumin in the brain after carotid infusion of hyperosmolar solutions. An immunohistochemical study in the rat indicating longlasting changes in the brain microenvironment and multifocal nerve cell injuries.

An immunohistochemical study was carried out on rat brain to determine if a transient opening of the blood-brain barrier (BBB), leading to extravasation of serum albumin, is also associated with exudation and cellular uptake of fibronectin and fibrinogen. Both of them might exert important biological effects provided that they pass the BBB and come into contact with cells of the brain parenchyma. Hyperosmolar solutions of urea or mannitol were infused in the carotid artery for 30 s to open the BBB and the animals were killed at various time intervals thereafter. Formaldehyde-fixed, paraffin-embedded material was used for immunohistochemical demonstration of extravasated proteins by an avidin-biotin peroxidase technique. Multifocal, often confluent areas of widely different sizes with signs of albumin extravasation were observed both in the grey and the white matter of the cerebral hemispheres exposed to the hyperosmolar solutions. Much less pronounced changes were observed in rats given an intracarotid saline infusion alone. Immunoreactive material indicating extravasation of fibronectin and fibrinogen was present in the infused cerebral hemispheres but albumin immunoreactivity was much more widespread. Reaction product was observed in vascular walls, presumably in extracellular spaces and in nerve cells. Immunoreactivity in the perikaryon of neurons formed different patterns in various cells. A granular type most probably represents accumulation of the proteins in lysosomal organelles after pinocytotic uptake into the neuron. The second so-called diffuse variety is presumably the result of a severe nerve cell injury with an uncontrolled leakage of proteins into the cytoplasm. Our results indicate that vascular walls, extracellular spaces, glial cells and neurons will be exposed to extravasated fibronectin and fibrinogen as well as to albumin and that antigenic sites in such compounds remain for a long period after the BBB opening. In addition, there are indications that carotid infusions of hyperosmolar solutions may cause nerve cell injuries in regions with BBB opening. These findings have obvious clinical and experimental significance.

Animals↗
PubMed1997

[Microsensor-controlled feedback bioactuators as a semi-integrated basis for biophysical cancer treatment].

Acidic microenvironmental conditions combined with large hypoxic areas are ubiquitous hallmarks of most solid tumors. They result from a poorly organized vascularization and a deviant energy metabolism. There is convincing evidence supporting the hypothesis that such physico-chemical conditions promote the microevolution of malignant cells, inhibit the cellular immune response, and favor tumor cell invasion. In agreement with published data, our cell biological analyses and computer simulations indicate that treatment schemes which restore a tumor microenvironment reflecting that one found in normal tissues might improve the efficiency of immunotherapies and classical methods for cancer treatment. We suggest that the tumor microenvironment could be effectively monitored and manipulated by means of silicon-based feedback bioactuators which are controlled by integrated microsensors. In principle, miniaturized bioactuators can be implanted directly at the sites of inoperable tumors and metastases where they function as a "pH clamp" and thereby can reconstitute normal physicochemical conditions. Drug application could be precisely controlled by an integrated microprocessor. Our paper summarizes the current state of development of microsensor-based feedback bioactuators and outlines possible applications in biophysical cancer treatment.

Automation↗
PubMed2001

Tumor physiology and drug resistance.

Clinical resistance is usually assumed to be due to the initial presence or selection of drug-resistant cells in tumors. While important, it is suggested in this review that genetically-determined causes of cellular resistance represent but one cause (and possibly not the major cause) of effective clinical resistance of solid tumors. Factors that depend on tumor physiology, and on the microenvironment and three-dimensional structure of solid tumors, may have a profound influence on their sensitivity to anti-cancer drugs. Particular emphasis is placed on the limited penetration of some drugs from tumor blood vessels and on the repopulation of tumor cells between courses of chemotherapy as causes of clinical resistance. Both of these mechanisms are amenable to modulation to improve therapeutic index. Failure to recognize that clinical drug resistance cannot be explained entirely by mechanisms operative at the level of the single cell may lead to disappointing results in clinical trials such as, for example, clinical failure of the strategy of reversal of multidrug resistance.

Animals↗
PubMed1997

Fibronectin upregulates in vitro generation of dendritic Langerhans cells from human cord blood CD34+ progenitors.

Several studies have demonstrated that dendritic cells can be generated in vitro from CD34+ hematopoietic progenitor cells. In vivo, dendritic cells are found in many tissues and reside in direct proximity to extracellular matrix proteins. Because extracellular matrix proteins affect differentiation and location of cells in tissues, this study was designed to investigate potential effects of extracellular matrix proteins on differentiation of dendritic cells. Dendritic cells were generated from CD34+ human cord blood cells in the presence of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha for 6 d and subsequently cultured for an additional 6-d period on tissue culture plates coated with various extracellular matrix proteins. Among the extracellular matrix proteins tested, exposure to fibronectin stimulated dendritic cell/Langerhans cell differentiation as indicated by the 50% increase of the number of cells expressing the Birbeck granule-associated marker Lag and displaying numerous Birbeck granules. Adhesion on fibronectin was shown to be specifically mediated by the integrin alpha5beta1. Because laminin and collagen were unable to cause similar changes in Langerhans cell development, these results suggest that fibronectin may cause changes affecting cellular differentiation of progenitors. Hematopoietic progenitors may exhibit maturational regulated differences in response to both matrix molecules and cytokines. The influence of combined signals emanating from a supportive microenvironment, specific integrins, and particular cytokines in the differentiation of Langerhans cells is discussed.

Antigens, CD1↗
PubMed2004

Hypoxia regulation of the cell cycle in malignant melanoma: putative role for the cyclin-dependent kinase inhibitor p27.

BACKGROUND: Intratumor hypoxia has been shown to promote more aggressive and metastatic cancer phenotypes that are associated with treatment resistance and poor prognosis. Cellular proliferation and its control are known to be important components of tumor progression. Hypoxia induces cell-cycle arrest in cultured cell lines, possibly via up-regulation of the cyclin-dependent kinase inhibitor p27. The effect of hypoxia on cell-cycle regulation in excised human tumors has not been investigated. METHODS: We performed immunohistochemistry for p27 and Ki-67 on 10 formalin-fixed paraffin-embedded metastatic melanomas, selected on the basis of histological evidence of zonal/geographic necrosis, adjacent to areas with viable perivascular tumor cells. RESULTS: In the majority of cases, there was a significant increase in p27 staining in cells adjacent to necrotic areas compared to perivascular zones. An inverse staining pattern between Ki-67 and p27 was identified in these tumors. Tumors with no zonal increase in p27 staining demonstrated a diffuse pattern of staining for Ki-67 within tumor nests. CONCLUSIONS: While increased cellular proliferation is a characteristic of cancer, subsets of human melanomas may retain the ability to regulate their rate of proliferation in response to changes in the tumor microenvironment. The hypoxia-mediated cell-cycle arrest (decreased Ki-67) in these tumors may be mediated by p27 up-regulation.

Cell Cycle↗
PubMed1990

The effect of hypoxia on capillary endothelial cell function: modulation of barrier and coagulant function.

As the cells forming the luminal vascular surface, endothelium is exposed to alterations in the vascular microenvironment, such as hypoxaemia. In this report we demonstrate that hypoxia, with pO2 as low as 12-14 mmHg, was not toxic to endothelium, but reversibly modulated central cellular functions essential for maintenance of homeostasis: permeability of monolayers to solutes increased in a dose-dependent manner, and cell surface coagulant properties were shifted to promote activation of coagulation. The anticoagulant cofactor thrombomodulin was suppressed and an apparently novel activator of factor X, distinct from the classical extrinsic and intrinsic systems, was induced. The hypoxia-induced factor X activator was cell surface-associated, had properties of a cysteine protease, had Mr corresponding to approximately 100 kDa, based on sodium dodecyl sulphate-polyacrylamide electrophoresis (SDS-PAGE), and isoelectric point (pI) approximately 5.0. These findings indicate that hypoxia dynamically modulates endothelial function providing insights into the contribution of microvascular endothelial dysfunction in the pathogenesis of vascular lesions.

Animals↗
PubMed2002

Presence of host ICAM-1 in laboratory and clinical strains of human immunodeficiency virus type 1 increases virus infectivity and CD4(+)-T-cell depletion in human lymphoid tissue, a major site of replication in vivo.

Human immunodeficiency virus type 1 (HIV-1) incorporates several host proteins. Earlier studies have indicated that such foreign constituents can modulate the virus life cycle, although the potential roles that these proteins might play in the viral pathology in vivo remain unclear. In an attempt to shed light on this issue, we first exposed explants of human lymphoid tissue to isogenic viruses except for the presence or absence of host-derived ICAM-1. Incorporation of ICAM-1 alone increased HIV-1 infectivity for human tonsillar tissue cultured ex vivo. This observation was made for viruses bearing distinct coreceptor utilization profiles. Conversion of LFA-1 to a high-affinity-high-avidity state for ICAM-1 further augmented the susceptibility of human tonsillar histocultures to infection by ICAM-1-bearing virions. A more massive depletion of CD4(+) T lymphocytes was seen with X4 ICAM-1/POS viruses than with isogenic ICAM-1/NEG virions. Exposure of X4 and R5 primary isolates of HIV-1 to a blocking anti-ICAM-1 antibody resulted in a decrease of virus infection. Finally, X4 and R5 virions derived from a natural human lymphoid tissue microenvironment incorporated high levels of ICAM-1. Altogether, these results indicate that the incorporation of host ICAM-1 can significantly modulate the biology of HIV-1 in a cellular milieu recognized as the major site of replication in vivo and suggest that host proteins found in HIV-1 particles may participate in the pathogenesis of this disease.

CD4-Positive T-Lymphocytes↗
PubMed1985

Structure-function relationships in pancreatic islets: support for intraislet modulation of insulin secretion.

Pancreatic islet B cell function was studied in vitro using three structurally different preparations of islet tissues: isolated, intact islets, dispersed islet cells attached singly to microcarrier beads, and reaggregated islet cells. Mechanisms of intercellular communication are eliminated with single cell preparations, whereas in aggregates cell to cell communications are reestablished and a defined microenvironment restored. Perifusion studies measured nonstimulated and glucose- and arginine-stimulated insulin release from the three islet tissues. Insulin secretion rates were expressed as a function of cellular DNA content, permitting direct comparison between tissues. During perifusion with low (2.8 or 5.5 mM) glucose concentrations, secretion rates of single islet cells were up to 6-fold greater (P less than 0.001) than those of intact islets. Perifusion of islet cells with 2.8 mM glucose and 100 or 500 pg glucagon/ml had no effect whereas GH-release-inhibiting factor (330 and 1000 pg/ml) decreased nonstimulated insulin secretion rates by 15% (P less than 0.05). After reaggregation, basal insulin secretion rates were restored toward those of intact islets. Glucose (5.5-30 mM) and L-arginine (5-20 mM) elicited first phase insulin responses from single islet cells that were not significantly different from those observed with intact islets; in contrast, second phase responses of single islets to glucose were approximately 50% those seen with intact islets, and their second phase responses to arginine were absent. Single islet cell first and second phase insulin responses to 5.5 mM glucose were enhanced 2.2-fold (P less than 0.01) and 2.8-fold (P less than 0.05), respectively, in the presence of exogenous glucagon, resulting in secretory profiles characteristic of intact islets. Reaggregation of single islet cells was associated with markedly increased first and second phase insulin responses to both glucose and arginine stimulation. These data show that disruption of the islet microanatomy results in alteration of insulin secretory responses and that these effects can be reversed, in part by exogenous glucagon and GH-release-inhibiting factor, and by reaggregation. Although different mechanisms appear important for nonstimulated, first and second phase insulin release, the findings support a role for both direct intercellular communication and hormonal secretion by islet A and D cells in the modulation of B cell function.

Animals↗
PubMed2005

Mechanisms and markers of carcinogenesis and neoplastic progression.

Neoplastic transformation evolves over a period of time involving the progression of the cellular immunophenotype (IP) from normal to hyperplastic to dysplastic, and finally, to fully malignant IPs. Superimposed on these changes is the interaction of the initiated cell with its microenvironment, whereby the neoplastically transformed cells, through the regulation or dysregulation of cytoskeletal, integrin, protease and adhesion molecules, develop a novel manner of relation with their surrounding microenvironment. Studies of the neuroendocrine-immune network revealed that the hormonal and cytokine milieu plays an important role impacting the growth and dedifferentiation capabilities of neoplastic cells. This is further affected by the tumour cells themselves determining the constitution of this hormonal microenvironment, allowing the most aggressive and invasive of neoplastically transformed cell clones to promote their own growth and dissemination. The elucidation of the steps of the progression of cancer from premalignant to metastatic and invasive forms is of utmost importance in the differential diagnosis of neoplasms and in the establishment of more efficacious therapeutic regimens. These regimens will certainly begin to take on a more individualised form. The functional characterisation of various human malignancies as to the neoplastically transformed cells' IP, the bases of their interaction with tissue stromal elements, and the molecules involved in the humoral microenvironment of the particular stage of tumour will certainly allow for the better diagnosis, staging, prognostication and treatment of cancers in the future. This paper reviews carcinogenesis from nutritional, genetic and molecular, and humoral aspects, and discusses the importance of tumour markers in the diagnosis and therapeutic management of human cancer.

Animals↗
PubMed2004

The morphological analysis of the haematopoietic microenvironment of the bone marrow at foetuses from preterm pregnancies.

The aim of the study was morphological assessment of the haematopoietic microenvironment of the bone marrow in foetuses from preterm pregnancies. For the morphological assessment the bone marrow was taken from sternum during an autopsy examination. After standard preparation, cellular elements of individual developmental lines were identified with the application of immunohistochemical methods. Evaluation of the bone marrow stroma elements was performed on the basis of configuration of the vascular sinuses, connective tissue elements, mutual topographic relations and integrin occurrence. The assessment of the argentophilic fibres was carried out with impregnation with silver according to the Gomori method. The configuration of the vascular sinuses was defined with morphometric evaluation with MicroImage-Olympus Kit. Identification of the 'young vascular forms' was performed with immunohistochemical methods with the use of endothelial cell antibodies and factor VIII. The presence of integrin was discovered in individual megakaryocytes, endothelial cells of sinus vessels and singular cells forming a stroma. However, no differences were found in the quantity of argentophilic fibres. The study revealed that ontogenetic development of haematopoietic tissue not only consists in alterations connected with the maturing process and cellular differentiation, but in topographic changes as well.

Bone Marrow↗
PubMed1988

Hierarchical organization of hematopoietic microenvironments: role of proteoglycans.

The orderly process of hematopoietic cell differentiation depends on the organization of specific microenvironments which function by assembling progenitor cells and appropriate concentrations of necessary growth factors. We propose that this organization involves a spectrum of microenvironmental complexity concomitant with changing cellular requirements, that it is achieved by the extracellular matrix produced by marrow stromal cells, and that its specificity is conferred by the heterogeneity intrinsic in the conformation of proteoglycans and their constituent glycosaminoglycans.

Animals↗
PubMed1977

Immunological capacity of the chicken embryo. II. Humoral immune responses in embryos and young chickens bursectomized and sham-bursectomized at 52--64 h of incubation.

White Rock embryos surgically "bursectomized" at 52--64 h of incubation, and shambursectomized embryos were injected with 10(6) guinea-pig red blood cells on day 12 of incubation, and tested for plaque-forming cells and serum haemagglutinins 3, 5, 7, 10, 15 and 19 days after immunization, i.e. as 15- to 19-day-old embryos and 1- to 10-day-old chickens. The number of natural plaque-forming cells detected by direct or indirect techniques was small in nonimmunized shambursectomized and bursectomized embryos, but increased in very young chickens. The injection of guinea-pig red blood cells induced a significant increase in the number of direct and indirect plaque-forming cells in the spleen of bursectomized and sham-bursectomized embryos and chickens. Agglutination of papain-treated guinea-pig red blood cells and indirect anti-chicken globulin (Coombs) test revealed the presence of natural agglutinins for guinea-pig and for sheep erythrocytes in non-immunized sham-and bursectomized embryos. A small number of sera from nonimmunized bursectomized and sham-bursectomized embryos contained IgM. The immunization with guinea-pig red blood cells increased the antibody production in both bursectomized and sham-bursectomized embryos and chickens. Sham-bursectomized embryos responded better to antigenic stimulation than bursectomized embryos. The injection of guinea-pig red blood produced an enlargement of the spleen only in bursectomized embryos and chickens. The first plasma cells appeared in nonimmunized sham-and bursectomized 6-day-old chickens. The number of plasma cells increased in chickens immunized as embryos. Cytomorphological analysis of the thymus, bone marrow and liver did not reveal apparent differences between bursectomized, sham-bursectomized embryos and very young chickens. It has been postulated that the chicken embryo has an antibody-producing system composed of the bursal and the nonbursal (or accessory "bursal") microenvironment, the latter being bursa-independent. The final microenvironmental network for the formation of Bu lymphocytes is the result of coordinated activities of a variety of intrinsic cellular and humoral factors.

Animals↗
PubMed1995

Fluconazole therapy in a rhesus monkey (Macaca mulatta) with epidural Trichosporon beigelii in a cephalic recording cylinder.

An adult female rhesus monkey with a cephalic recording cylinder surgically implanted over a craniotomy site developed cloudy cylinder fluid and a white gelatinous plaque on the epidural capsule surface. Results of baseline hematologic, serum biochemical, and cerebrospinal fluid analysis and simian retrovirus panel were unremarkable. Aerobic culture of the cylinder fluid yielded a pure culture of Trichosporon beigelii. This organism is a ubiquitous saprophytic fungus that is a potential pathogen, especially in the immunocompromised host. Factors that could have contributed to the infection included a microenvironment in the cylinder that was favorable to fungal growth, and presence of a dural pseudocapsule of collagen and granulation tissue in the implant which could have inhibited cellular defense mechanisms. An intravenous formulation of fluconazole was selected for direct application into the recording cylinder on the basis of safety and efficacy. Fluconazole is a highly water-soluble, metabolically stable bis-triazole antifungal with excellent cerebrospinal fluid penetration and low toxicity. A 4-week course of treatment eliminated Trichosporon organisms from the cylinder. Change to oral administration of fluconazole was made at that time to allow use of cephalic cylinder antibiotics that are incompatible with fluconazole. Further treatment with fluconazole was continued orally for 3 more months to prevent fungal recrudescence. Culture of cylinder fluid was performed periodically for 6 months after resolution, and results remained negative for T. beigelii. This case is believed to be the first reported T. beigelii infection in a non-human primate. Fluconazole was effective in eliminating the infection from the cylinder and preventing its recurrence.

Animals↗
PubMedDate not supplied

[The role of glycosaminoglycans and proteoglycans in hemopoiesis and the physiological functions of the blood cells].

Literature review as well as own data on the role of glycosaminoglycans and proteoglycans of leukocytes, platelets and hemopoietic microenvironment are presented. These compounds are involved in the storage of lysosomal enzymes, cationic antibacterial polypeptides and other granular constituents of blood cells, take part in mediating of cellular interactions, occurring in hematopoiesis, phagocytosis, immunity and other processes. Due to the capacity to react with many substances, including enzymes, cell growth factors, cytokines, receptors, changing their conformation and biological activity glycosaminoglycans and proteoglycans can take part in regulation of cell adhesion, migration, proliferation differentiation and special functions of various types of hematopoietic and lymphoid cells.

Animals↗
PubMed2004

Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm.

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.

Animals↗
PubMed1995

Human non-small cell lung cancer cells express a type 2 cytokine pattern.

In addition to infiltrating inflammatory cells, tumors also produce cytokines and growth factors that may alter tumor growth, tumor immunogenicity, and the host immune response. To characterize the expression profile of human non-small cell lung cancer (NSCLC)-derived cytokines, the mRNA expression of type 1 and type 2 cytokines in five human NSCLC lines was analyzed by reverse transcriptase-PCR. Expression of interleukin 5 (IL-5) and IL-10 was demonstrated in all tumor lines evaluated, whereas IL-4 was present in three of five lines and IL-13 was present in two of five lines. In contrast, none of the tumor lines expressed IL-2 and IFN-gamma. Type 2 cytokine protein production by NSCLC lines was confirmed by immunoprecipitation and cytokine specific ELISA. Tumor-derived IL-10 secretion was significantly augmented by exogenous recombinant cytokines including IL-4 and tumor necrosis factor-alpha. To evaluate whether fresh NSCLC nodules also express a type 2 cytokine pattern, the content of type 1 and type 2 cytokines in tissue homogenates from 13 fresh NSCLC nodules and normal lung surgical specimens was assessed. Human NSCLC nodules contain significantly more type 2 cytokines than does normal lung tissue when corrected for total protein concentration. To identify the cellular source of type 2 cytokine production in tumor nodules, immunohistology was performed on sections from 5 lung squamous cell carcinomas and 5 adenocarcinomas. All of the specimens revealed positive staining for type 2 cytokines within tumor cells. In summary, we report that human NSCLC cells produce type 2 cytokines both in situ and in vitro, which may play an active immunoregulatory role in the lung cancer microenvironment.

Base Sequence↗
PubMed1980

Spleen hemolytic plaque-forming cell response and generation of cytotoxic cells in genetically obese (C57Bl/6J ob/ob) mice.

Cell-mediated immune responses were evaluated in genetically obese (C57Bl/6J ob/ob) mice and lean controls. The thymus and spleen weighed less and contained fewer mononuclear cells in obese animals compared with controls. The total number of direct and indirect plaque-forming cells in the spleen of obese mice immunized intraperitoneally with sheep red blood cells was reduced, however, when the results were expressed as plaques/10(6) mononuclear cells, the proportion of antibody-producing cells was higher in the obese. Ob/ob mice immunized in vivo with allogeneic EL-4 lymphoma cells showed markedly diminished capacity to generate cytotoxic cells, whereas such response after in vitro immunization was comparable in the two groups of animals. These observations suggest that altered cell-mediated immune response in obese animals is the result of a deleterious microenvironment.

Animals↗
PubMed2003

Control of NKT cell differentiation by tissue-specific microenvironments.

CD1d-restricted Valpha14 NKT cells play an important role in both Th1- and Th2-type immune responses. To determine whether NKT cells develop two functionally distinct subsets that provoke different types of responses, we examined the phenotypes and cellular functions of NK1.1(+) and DX5(+) T cells. We found that both NK1.1(+) and DX5(+) T cells are CD1d-restricted Valpha14 T cells with identical Ag specificities, phenotypes, tissue locations, and functions. Similar to the NK1.1 marker, the DX5 marker (CD49b) is expressed on mature NKT cells in both NK1.1 allele-positive and allele-negative strains. However, when NK1.1(+) and DX5(+) NKT cells isolated from different tissues were compared, we found that thymic and splenic NKT cells differed not only in their cytokine profiles, but also in their phenotype and requirements for costimulatory signals. Thymic NKT cells displayed the phenotype of activated T cells and could be fully activated by TCR ligation. In contrast, splenic NKT cells displayed the phenotype of memory T cells and required a costimulatory signal for activation. Furthermore, the function and phenotype of thymic and splenic NKT cells were modulated by APCs from various tissues that expressed different levels of costimulatory molecules. Modulation of NKT cell function and differentiation may be mediated by synergic effects of costimulatory molecules on the surface of APCs. The results of the present study suggest that the costimulatory signals of tissue-specific APCs are key factors for NKT cell differentiation, and these signals cannot be replaced by anti-CD28 or anti-CD40 ligand Abs.

Animals↗